the corneal stroma during contact lens wear

www.elsevier.com/locate/clae

Contact Lens & Anterior Eye 28 (2005) 3–12

The corneal stroma during contact lens wear

Isabelle Jalbert*, Fiona Stapleton

The Vision Cooperative Research Centre, School of Optometry and Vision Science, The University of New South Wales,

Sydney, NSW 2052, Australia

Abstract

Recent technological advances have lead to novel descriptions of the microanatomy of the corneal stroma. In the first section of this review,

these findings and the role they play in the maintenance of vital properties such as corneal transparency, mechanical strength, homeostasis,

wound-healing response and metabolism are described. In the second part, contact lens induced stromal alterations such as acidosis, oedema,

striae, thinning and opacities are reviewed as well as the more recently described phenomenon of microdot deposits and keratocyte loss with

an emphasis on how lens wearing stromal effects can be minimised.

# 2004 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

Keywords: Corneal stroma; Keratocyte; Proteoglycan; Contact lens wear; Hypoxia; Hypercapnia

1. Introduction

Approximately one hundred million people wear contact

lenses worldwide and this number is rapidly increasing. The

stroma is almost single-handedly responsible for the

transparency, strength and healing properties of the cornea.

Any detrimental effects contact lenses may have on the

corneal stroma are therefore highly significant in terms of

public health; yet, this is an area of research that has

traditionally attracted limited interest. The purpose of this

review is therefore to describe the corneal stroma and its

properties (transparency, mechanical strength, homeostasis,

wound-healing response and metabolism) before summar-

ising how these can be altered by contact lens wear.

2. Gross anatomy

The stroma or substantia propria, sandwiched between

the epithelium and Bowman’s layer anteriorly and the

corneal endothelium and its supporting Descemet’s mem-

brane posteriorly, is about 500 mm thick and constitutes up

to 90% of the total corneal thickness [1]. A ground substance

or extracellular matrix and a small population of cells

* Corresponding author. Tel.: +61 2 9385 7868; fax: +61 2 9385 7401.

E-mail address: [email protected] (I. Jalbert).

1367-0484/$ – see front matter # 2004 British Contact Lens Association. Publi

doi:10.1016/j.clae.2004.09.003

consisting primarily of specialised corneal fibroblasts called

keratocytes are scattered between regularly arranged

lamellae of collagen bundles (primarily type I collagen).

Blood vessels are absent. Nerve axons and their associated

Schwann cells are occasionally observed in the anterior and

middle stroma. There are on average 233 lamellae in the

central human stroma [2] and up to 500 in the stromal

periphery [3]. Lamellae are denser, narrower (0.5–30 mm),

thinner (0.2–1.2 mm) [4] and more intertwined [5] in the

anterior third stroma (Fig. 1A, top) while in the posterior two

thirds (Fig. 1A, bottom) the lamellae are wider (100–

200 mm) [4], parallel, orthogonally (medial–lateral and

inferior–superior axes) [6] aligned and can be up to 4 mm

thick [2,4,5,7]. Yet, branching and interlacing of the larger

posterior stromal lamellae remains a relatively frequent

occurrence [8]. Lamellae typically are thought to run from

limbus to limbus [1], however, obliquely orientated anterior

lamellae may insert directly into Bowman’s membrane [3].

Whilst only 17% of the entire (anterior and posterior

combined) lamellae are preferentially aligned in the corneal

centre, this appears to increase as one moves to the periphery

[9] until the very peripheral stroma, where lamellae take a

circular course [3,6,9].

Numbering approximately 2.4 million in the adult [10],

keratocytes by far outnumber any other cellular elements

occasionally observed in the human stroma such as

lymphocytes, macrophages and polymorphonuclear leuko-

shed by Elsevier Ltd. All rights reserved.

I. Jalbert, F. Stapleton / Contact Lens & Anterior Eye 28 (2005) 3–124

Fig. 1. Gross and microscopic anatomy of the human stroma. (A) Cross-sectional section of anterior (top) and posterior (bottom) cornea stained with

haematoxylin and eosin. Inset: full section. BZ: Bowman’s layer; DM: Descemet’s membrane; En: endothelium; K: keratocytes (from [3]). (B) Schematic

representation of the human keratocyte network. The thin flattened cells connect with each other through their long thin processes that extent within and

sometimes between lamellae (from [1]). (C) Microscopic anatomy. Mid-stromal lamellae cross each other at large angles (magnification �32,500). Inset:

regularly spaced parallel collagen fibrils constitute each lamellae (magnification �90,000) (from [3]).

cytes [1] and account for approximately 2.4% of stromal

volume [11]. Keratocytes are responsible for the synthesis

and maintenance of collagen fibrils and extracellular matrix

[12]. They are unevenly distributed through the stroma with

their density increasing from the posterior to the anterior

[13,14] and possibly increasing [13] or decreasing [15] from

the central to the peripheral stroma. In cross-section,

keratocytes appear as flattened, thin cells (0.5–0.7 mm) [16]

lodged mostly between and occasionally inside stromal

lamellae [1,16]. In frontal section, keratocyte nuclei range in

size from 7 to 13 mm and have numerous long thin branching

processes (0.05–0.90 mm) appearing to form a circular

‘‘corkscrew’’ like network within and between stromal

lamellae (Fig. 1B) [16].

The ground substance consists of water, non-fibril

forming collagens, proteoglycans, glycoproteins, other

soluble proteins and inorganic salts. A number of major

proteoglycans have been identified in the stroma of vertebrae

namely the three keratan sulfate proteoglycans keratocan

[17], lumican [18] and mimecan [19] and the chondroitin/

dermatan sulfate proteoglycan decorin [20]. A differential

distribution of proteoglycans is noted with a decreasing ratio

of dermatan sulfate proteoglycan to keratan sulfate

proteoglycan from the anterior to the posterior stroma

[21]. Amorphous material, sometimes large amounts of it, is

found between collagen fibres and between distal branches

of keratocytes [1,16].

3. Microscopic anatomy

Stromal lamellae comprise a collection of narrow

(23 nm), uniform, parallel and regularly spaced (20 nm)

collagen fibrils (Fig. 1C) [22]. Mean fibril diameter varies

little from the centre to the periphery, however, fibril spacing

across the central stroma measures 5–7% lower than in the

peripheral stroma [23]. Negatively stained collagen fibrils

exhibit cross-striations or banding at a periodicity or D-

period of 64 nm [24]. This occurs because collagen

molecules in the triple-helical fibrillar structures are packed

in a staggered arrangement so that parallel molecules are

displaced by a quarter of their length with respect to their

neighbours [25].

Based on their innocuous appearance in cross-sections

and the extremely slow turnover time of stromal collagen

[26,27], it has been generally accepted that keratocytes are

largely inactive cells with a slow turnover [28]. This

inactivity was recently challenged by the observation of

large numbers of organelles such as mitochondriae, rough

endoplasmic reticulum, Golgi fields, centrioles and vesicles

in frontal sections of keratocytes [16]. Two different aspects

of keratocytes are noted ultrastructurally, one of which has a

lighter cytoplasm and a nucleus containing considerably

more peripheral heterochromatin than the other type [16].

Numerous fenestrations (80–160 nm), spine-like protrusions

and smaller omega-shaped structures (40–60 nm) are

I. Jalbert, F. Stapleton / Contact Lens & Anterior Eye 28 (2005) 3–12 5

observed along the plasma membrane and at the surface of

keratocytes [16]. In some instances, collagen fibres appear to

connect with keratocytes at the sites of the fenestrations

[16]. Such fenestrations may facilitate the transport of

nutrients and metabolites in the avascular stroma. Gap

junctions are frequently observed between keratocytes

[16,29] while tight junctions are rarely seen [1].

There are topographical differences in the ultrastructural

aspect of keratocytes as those located in the anterior stroma

contain up to three times more mitochondria, have more

pronounced fenestrations and more frequently display the

aspect characterised by lighter cytoplasm and more

abundant peripheral nuclear heterochromatin [16]. These

findings may be a simple reflection of the higher oxygen

(O2) availability at the anterior than at the posterior corneal

surface [12] producing a more metabolically active anterior

stroma. Interestingly, the presence of difference types or

populations of keratocytes may provide a basis for the

regional differences in the production of proteoglycans by

these keratocytes as described in the previous section.

Proteoglycans appear to have precise binding sites at

periodic bands in collagen fibrils [30]. Recent evidence

suggests that in frontal sections, 54 nm long parallel

proteoglycans attach orthogonally to and interconnect

next-nearest neighbour collagen fibres and are thus

separated by 42 nm from each other [22]. In cross-sections,

proteoglycans appear more randomly orientated but form

regular ring-like structures of 45 nm where lamellar

orientation is such that collagen fibres appear as circular

structures [22]. Proteoglycans therefore form a dense and

well-organised mutually interconnecting network with

collagen fibres [22].

4. Transparency

The refractive indices of the major components of the

stroma have been proposed to be 1.470 for collagen and

1.350 for the extracellular matrix [31]. Interestingly, the

stromal refractive index has been shown to reduce from

1.380 at the anterior surface to 1.373 at the posterior surface

[32]. Such a tissue would be expected to scatter light in an

additive fashion and become opaque yet the healthy stroma

(n = 1.375 if considered homogeneous) appears perfectly

transparent and the actual total amount of light scattered is

estimated at less than 1%. In his seminal 1957 paper,

Maurice first proposed the now classic ‘‘lattice theory’’ of

corneal transparency [31]. He suggested that the regular

arrangement of collagen fibrils of a uniform diameter

smaller than the wavelength of light (500 nm) in a lattice

causes destructive interference of the light scattered by

individual collagen fibrils in all directions except that of the

incident beam [31]. Prompted by the observation that the

shark Bowman’s layer, which is composed of randomly

oriented collagen fibres, is also transparent, Goldman and

Benedek in 1967 proposed instead that the optical principle

stating that ‘‘light is scattered only when the illuminated

medium contains spatial fluctuations in the index of

refraction over dimensions comparable with the wavelength

of light’’ can be applied to stromal transparency [33].

Effectively, the stroma is not expected to scatter significantly

simply because the collagen fibril diameter is infinitely

smaller (31 nm) than the wavelength of light (500 nm). They

suggested that transparency would only become affected

when fluctuations in refractive indices reach more than half

the wavelength of light (�250 nm) [33].

As well as the structural concepts for transparency

described above, stromal cells themselves have the potential

to affect stromal clarity. A recent study by Jester et al.

suggests that the water-soluble proteins transketolase (TKT)

and aldehyde dehydrogenase (ALDH) found in the

keratocyte bodies in the unwounded cornea may be

responsible for maintaining cellular transparency [34].

The absence of these proteins in wounded opaque corneal

tissue appears to be associated with activation of the

keratocytes into myofibroblasts and fibroblasts and an

increase in light scattering [34].

Based on the detailed stromal architecture presented in

the previous sections, the following observations can be

made. The inability of regional differences in stromal

refractive indices [32], interfibrillar spacing [23] and

lamellar architecture [2,4–7] to affect stromal transparency

is more easily explained by Goldman’s theory [33].

Borcherding et al. suggested many decades ago that the

proteoglycan composition of the stroma could be respon-

sible for the maintenance of stromal structure and

transparency [35]. In fact, the specific binding sites of

stromal proteoglycans may play a role in the regulation of

spacings between collagen fibrils. Recent evidence supports

this notion as proteoglycans and therefore interfibrillar

spacing are altered in scarred rabbit stromas [36] and the

lumican-null mouse develops corneal opacification [37].

Keratocytes have been largely ignored as a potential

hindrance to stromal transparency but recent clinical

evidence suggests that they sometimes can play a major

role in the development of corneal haze [38]. The corkscrew-

like circular arrangement of keratocytes [16] described by

Muller et al. may be involved in maximising stromal

transparency as this organisation creates equal chances for

all light rays to pass one or more keratocytes and thus

minimises variation in light scattering over the entire cornea

[16]. The sometimes large amounts of amorphous material

found in proximity to keratocytes [16] suggests that they

may also participate in the maintenance of transparency by

controlling the turnover of extracellular matrix protein.

5. Mechanical properties

In order to maintain good vision, the vulnerable cornea

must not only stay transparent but it must also be strong

enough to withstand the inevitable internal and external


forces that may distort or disrupt its shape. In its normal state

of equilibrium, the cornea is subjected to forces derived from

atmospheric pressure (760 mmHg or 101 kPa) and blinking

(�200 Pa) [39] at the anterior surface and to the intraocular

pressure (�20 mmHg) of the aqueous humour at the

posterior surface. It must also be resistant to impact.

Maurice classifies the mechanical properties of the cornea as

resistance to shear, tensile strength, elasticity and adhesive

strength [40]. Because of the difficulty in establishing

reliable measurement techniques for a number of these

properties, they are poorly characterised. The scant data

available to date is summarised below. Resistance to shear is

low in the rabbit as its surfaces will slide up to 1 mm apart

when rubbed between the fingers [40]. Shear resistance is

also inversely proportional to stromal hydration [40].

Tension appears evenly distributed across the human stroma

as the anterior and posterior surfaces are equally distorted

when local forces are applied through desiccation [40]. The

finding of a decreased resistance to blunt trauma following

radial keratotomy [41], a procedure where the integrity of

the lamellar structure is compromised, gives an indication of

how tension forces are normally evenly distributed across

the stromal tissue. Tensile strength and elasticity can be

studied by isolating tissue strips and clamping them between

stretching jaws. Human stroma is poorly extensible, a

pressure change of 5–20 mmHg causing only �0.25%

stretching [40]. The measurement of globe bursting pressure

also gives an indication of the tensile strength of the globe as

a whole. Its value approximates 5 kg/cm2 and is fairly

consistent across species [40]. Rupture typically occurs at

the equator where the globe is thinnest [42]. Adhesive

strength is assessed by measuring the force required to tear

apart two layers of a strip of tissue. It is the property that

allows stroma to maintain some integrity and not fall apart

when immersed in water. This is 100 g/mm in the rabbit

stroma, is remarkably uniform throughout the length of the

sample and not sensitive to tissue hydration [40]. In contrast,

regional variations have been demonstrated in humans,

stromal cohesive strength increasing from the centre to the

periphery [43] and from the posterior to the anterior stroma

[5]. In summary, the human stroma can be broadly

characterised as having the material properties of its

principal component, collagen, as it has high tensile strength

and low extensibility. It appears to resist impact by

equalising the strain over its entire surface. Regional

variations in these properties can be related to the lamellar

composition of the stroma and other detailed anatomical

characteristics. The structure of the stroma therefore makes

for very nonisotropic mechanical properties. For example,

the increased adhesive strength in the stromal periphery is

consistent with the presence of a circumferential annulus of

peripheral stromal lamellae. Similarly, the more frequent

intertwining of stromal lamellae in the anterior stroma may

underpin its higher cohesive strength. This probably

explains the ease of dissection in the posterior stroma

compared to the anterior stroma [5]. Its also been suggested

that this property of the anterior stroma also would account

for maintenance of the corneal curvature [44]. It would be

anticipated that resistance to shear would be higher in the

anterior than the posterior stroma due to the increased

lamellar interweaving but this has yet to be demonstrated. It

is the combination of fibril diameter, orientation and tissue

collagen content that ultimately determines stromal

tensile strength. It would also appear logical that tensile

strength varies according to stromal thickness. For example,

whilst not specifically measured it has been suggested that

the decreased interfibrillar space in the central stroma

compensates for the thinner stroma and maintains tissue

strength [23].

6. Stromal homeostasis and the wound-healing response

The transparency and dimensional stability of the stroma

must also be maintained and repaired should injuries occur.

Before the wound-healing response can be considered,

stromal homeostasis and cellular communication in the

unwounded cornea must be characterised. As will be

evidenced below, the stroma cannot be considered in

isolation for this exercise as many of its functions are

controlled by secretory cytokines and growth factors derived

from other ocular structures [45]. In fact, stromal–epithelial

interactions are vital to corneal homeostasis. Amongst the

best characterised are those involving hepatocyte growth

factor (HGP) and keratinocyte growth factor (KGF), which

are produced by keratocytes but have their receptors

expressed in the epithelium and regulate epithelial cell

differentiation, proliferation and motility [45]. Similarly the

cytokine interleukin-1 (IL-1) is produced in large quantities

by the epithelium with high receptor levels found in

keratocytes and is involved in upregulation of HGF and KGF

by keratocytes [45]. Little is known of the possible stromal–

endothelial interactions in the posterior cornea. As

endothelial cells produce platelet-derived growth factor

(PDGF) and IL-1, it appears likely that these soluble

mediators participate in posterior stromal homeostasis in a

similar fashion.

Many events can potentially be perceived by the cornea

as an injury including trauma, infection, refractive surgery

procedures and wear of corneal prosthesis such as contact

lenses. The stromal wound-healing response involves

keratocyte activation, migration, transformation into myofi-

broblasts and fibroblasts and the production of scar tissue

[3]. This is however typically initiated or associated with an

epithelial injury. It is now well established that the earliest

stromal response that follows epithelial injury, regardless of

its type, is death of the underlying keratocytes by apoptosis

[46]. Cytokines such as IL-1, tumour necrosis factor (TNF)

and Fas ligand produced by injured epithelial cells are

possible modulators of keratocyte apoptosis [46] and may

also influence keratocyte expression of the matrix metallo-

proteinases (MMPs) involved in tissue remodelling [45].


Wilson et al. have observed an analogous apoptosis

phenomenon in the posterior stroma following endothelial

injury [47]. Keratocytes may be affected to a depth of 50% of

stromal thickness following epithelial injury but whether

this occurs through diffusion of mediators or through

keratocyte–keratocyte communications is unclear [47]. The

corkscrew-like circular arrangement of keratocytes

described by Muller et al. suggests that they form

completely closed sheets of communicating cells [16]. This

may facilitate keratocytes communicating with each other,

allowing signal transduction not only within lamellae but

also across the depth of the stroma.

The initial apoptosis is followed by increasing keratocyte

necrosis and the initiation of the classic stromal wound-

healing response (activation, migration, transformation).

Epithelial derived cytokines such as PDGF and transforming

growth factor (TGF) mediate mitosis and migration of

keratocytes. Inflammatory cells (e.g. polymorphonuclear

leucocytes, monocytes) migrate to the stroma from the

limbal vessels in response to the production of chemokines

such as monocyte chemotactic and activating factor

(MCAF) and granulocyte colony-stimulating factor (G-

CSF) by epithelial and stromal cells [47]. These inflamma-

tory cells may be responsible for scavenging invading

microorganisms or residual apoptotic bodies present in the

stroma. Vascularisation is another possible long-term

consequence [3]. Major steps of the wound-healing cascade

were summarised by Wilson et al. [48] and are reproduced in

Fig. 2.

7. Corneal metabolism

Maintenance of corneal homeostasis requires that

significant energy be available to corneal cells. The bulk

of this energy is acquired through the catabolism of glucose

[12]. Normally, most glucose is metabolised into adenosine

triphosphate (ATP) through the aerobic Krebs cycle

resulting in the production of carbon dioxide (CO2). Whilst

the bulk of the glucose and other necessary corneal nutrients

come from the aqueous humour, most of the required oxygen

is derived by diffusion from the tear film. When sufficient

oxygen is not available, anaerobic glycolysis occurs through

the Embden–Meyerhof pathway, in which glucose is broken

down to pyruvate and then to lactate. Whilst carbon dioxide

can easily diffuse though the corneal layers, lactate is unable

to cross the epithelial barrier and must therefore be slowly

eliminated by diffusion through to the posterior cornea.

Increased concentration of lactate in the stroma leads to an

acidic shift in stromal pH (stromal acidosis) and produces an

excess osmotic solute. This in turn increases imbibition

pressure resulting in stromal oedema [12].

The partial pressure of oxygen (pO2) reduces from 155 to

55 mmHg on eye closure [49]. The minimum oxygen

tension required to avoid corneal oedema approximates

75 mmHg (�10%) [50]. Lid closure may therefore be

partially responsible for the physiological 4% corneal

swelling observed in humans overnight [51]. Tear osmo-

larity decreases from 0.97% during the day to 0.89% on

waking [52]. The tear hypertonicity that follows evaporation

of the tear film on eye opening may cause some corneal

dehydration and partly account for some of the diurnal

thickness variations. However, contradictory results were

obtained when experiments conducted under various

humidity levels were attempted to confirm this hypothesis

[53,54].

8. The stroma during contact lens wear

The hallmark of contact lens wear is that it often does not

deliver the oxygen and carbon dioxide transmissibility levels

needed to avoid corneal hypoxia and hypercapnia, particu-

larly during eye closure [55]. This is compounded by a

greater reliance on anaerobic glycolysis under these

conditions with the consequences described above. Primar-

ily because of these, lens wear affects the cornea in a myriad

of ways as summarised in a number of good reviews [56–

58]. From these, the short-term effects of contact lens wear

on the stroma include acidosis, oedema and striae whilst

long-term effects include thinning and opacities. The

possible short and long-term effects of lens wear on stromal

keratocytes remain controversial and will be discussed.

9. Acidosis

Bonanno’s group characterised contact lens induced

corneal acidosis in a series of elegant experiments [59].

Using a calibrated pH-sensitive fluorescent technique, they

measured normal open-eye stromal pH at 7.55 and normal

closed-eye stromal pH at 7.39. Interestingly, whilst open-eye

wear of a thick low oxygen transmissibility (Dk) soft lens

reduced pH to 7.15, anoxia (100% nitrogen (N)) very

minimally lowered pH to 7.35. Exposure to a gas mixture of

95% nitrogen and 5% carbon dioxide, however, reduced pH

to 7.16, a level very similar to that measured during low Dk

lens wear. Stromal pH reduction was strongly related to lens

transmissibility [59]. Based on Bonanno’s findings it can be

concluded that lens wear affects stromal pH through

accumulation of lactate and carbon dioxide or through a

combination of hypoxia (metabolic acidosis) and hyper-

capnia (respiratory acidosis). Measurements of tear lactate

dehydrogenase (LDH) [60], the enzyme responsible for

lactate production, permit characterisation of metabolic

acidosis but not respiratory acidosis and as such are a less

comprehensive indicator of corneal acidosis. Interestingly,

Ichijima et al. [61] demonstrated decreased (�10–30%)

stromal lactate concentrations in the presence of persistent

corneal swelling in rigid gas permeable (RGP) wearing

rabbits after seven and 30 days of extended wear,

independent of lens oxygen transmissibility. Associated


Fig. 2. Schematic diagram of the major components of the corneal wound-

healing response (from [48], p. 629).

pH levels (i.e. stromal acidosis) were unfortunately not

reported [61]. Whilst this has yet to be demonstrated to hold

true for the human cornea, it suggests either that lactate

accumulation may not account for all changes in stromal pH

or that an adaptive phenomenon may come into play during

longer term lens wear. Ichijima et al. [61] suggest a shift

from the Embden–Meyerhof to the pentose phosphate

pathway resulting in less lactate accumulation and thus less

stromal acidosis and more nicotinamide adenine dinucleo-

tide phosphate (NADPH) in its reduced form, which would

provide an alternate source of metabolic energy.

10. Oedema

As discussed previously, hypoxia and tear hypotonicity

may both contribute to oedema. Hypercapnia, however,

appears unable to alter corneal thickness on its own [62].

Whatever the mechanisms controlling diurnal variation of

corneal thickness, superposition of a lens that restricts

oxygen availability will compound the issue. The persistent

corneal swelling demonstrated by Ichijima et al. [61] in RGP

wearing rabbits in the absence of stromal lactate accumula-

tion have lead them to suggest two additional explanations

for lens induced swelling. A direct increase in lens-induced

acidosis in stromal cells may be present. Alternatively, lens

induced inhibition of corneal epithelial cytochrome P-450

arachidonate metabolism resulting in the production of 12-r-

hete, a metabolite that can work as a membrane endothelial

pump poison [63] may be occurring. According to

Edelhauser [63], this effect would be independent of lens

oxygen transmissibility and may represent the prolonged

mechanical effect of lens wear itself.

Holden and Mertz comprehensively demonstrated an

inverse relationship between lens Dk (over a central zone)

and the level of swelling induced [64] and suggest that

overnight oedema must be limited to �8% in order to allow

the cornea to recover to normal levels soon after eye opening

[65]. Overnight swelling in unadapted subjects ranged from

10.0 to 14.4% with hydrogel lenses, from 4.4 to 16.3% with

rigid gas permeable (RGP) lenses and from 2.0 to 5.0% with

silicone elastomer lenses [66,67] while it measured 2.7%

with silicone hydrogel lenses [68]. A high variability of the

swelling and deswelling response between subjects is

consistently reported across lens and non-lens wearing

studies [50,65,66,68–70]. A possible reduction in the level

of overnight swelling occurring over weeks or months of

wear has been reported [69,70]. This apparent adaptation

may be explained by gradual thinning of the stroma (see

Section 12) [71]. Overnight swelling subsides faster in RGP

than hydrogel lens wearers [72] and this can be attributed to

the higher oxygenation brought on by the high tear exchange

rate of rigid lenses (0.15–0.29 per blink) [73] when

compared to soft lenses (0.006–0.012 per blink) [74]. As

expected, deswell rate is lowered by stromal acidosis [75]. In

summary, whilst silicone elastomer, silicone hydrogel and

some RGP lenses meet the Holden–Mertz criteria, hydrogel

lenses are unable to do so. It should be noted that lens

pressure induced shape changes might be a confounding

factor in these results.

Bergmanson’s work in primates provides the most

comprehensive source of knowledge on the ultrastructural

aspect of lens wear-induced swelling and can reasonably be

extrapolated to humans. Stromal swelling was observed

after 24 h wear of an oxygen impermeable PMMA rigid lens

in primates. This swelling was preferentially located to the

posterior stroma around keratocytes and between lamellae

but was only observed within lamellae in rare patches where

granular material would accumulate [76]. Keratocytes

themselves became more electron dense and cytoplasmic

decomposition and pyknotic nuclei were sometimes visible,

indicative of possible keratocyte death [76]. Remarkably,

48 h of closed eye wear of a low oxygen permeability soft

lens caused stromal oedema but no apparent structural

changes in the tissue [77]. There is some evidence from

studies on explanted rabbit corneas that large amounts of


corneal swelling (over 50%) can result in loss of stromal

proteoglycans [78].

11. Striae

One of the first effects of lens wear on the stroma

described was the observation of striae in the posterior

stroma. They appear as fine wispy white vertically orientated

lines in the posterior stroma under slit lamp direct

illumination. Early on, the cause of this phenomenon was

confirmed to be corneal swelling associated with hypoxia

[79]. In an anoxic environment, striae first appeared after an

average of two and a half hours when �7% swelling was

reached, increased in number and intensity with increasing

levels of oedema and were reversible upon return to normal

atmospheric conditions [79]. Folds appear as vertical black

grooves and ridges at the level of the endothelium and are

therefore best observed using specular reflection. The

relationship between the amount of oedema and the number

of striae or folds observed was further characterised by La

Hood and Grant [80]. They demonstrated that a count of 10

striae corresponds to swelling of �11% and 10 folds �15%,

respectively [80]. Striae and folds therefore can be useful

indicators of the cornea’s physiological state without the

need for thickness measurements.

12. Thinning

As discussed above, swelling appears to diminish over

time. Holden et al. attribute this to a slow chronic thinning of

the stroma over years of wear that is masked by

superimposed oedema until lens wear has been discontinued

for a number of days or weeks [71]. Apparently non-

reversible, this effect was very small with a 2% (11 mm)

thickness reduction after 5 years of extended wear. It may

therefore be too subtle to detect in daily wearers, even after

more than 10 years of wear [15]. The stromal tissue loss may

be related to loss of keratocytes [76] and matrix

proteoglycans [78] observed in association with severe

oedema.

13. Opacities

Multiple small greyish white stromal opacities have been

observed in long-term contact lens wearers (more than 5

years) [81–87]. The opacities are typically asymptomatic,

bilateral, more common in the central deep posterior stroma

just anterior to Descemet’s membrane but can sometimes be

observed in the anterior and/or peripheral stroma [83,85].

Stromal micro-opacities may be associated with reduced

vision [82,84,87] and redness [82], striae or folds in

Descemet’s membrane [82] and with an increased endothe-

lial permeability [86]. They are more commonly observed in

low Dk soft lens wearers [83–85]. Their appearance may

improve after discontinuation of lens wear [82,85], with the

use of topical steroids [82] or after refitting with RGP lenses

[83,84].

These deep stromal opacities were thought to be

relatively rare. Pimenides et al. report an incidence of four

out of 324 refractive surgery candidates in their case series

but do not specify how many of these candidates were

contact lens wearers [85]. Interestingly, micro-opacities that

would have been practically impossible to detect with slit

lamp biomicroscopy have been since observed using newly

available high magnification clinical confocal microscopes

[15,88–90]. Bohnke and Masters [88] report a 100%

incidence in all soft and rigid lens wearers of more than

5 years duration and a 0% incidence in non-lens wearing

matched controls. Using an objective of lower magnifica-

tion, Hollingsworth and Efron observed micro-opacities in

59% of long-term rigid lens wearing eyes [90]. The micro-

opacities are described as highly reflective, round to

polygonal and 0.3–0.6 mm in size. These occurred equally

at all stromal depths and appeared to be preferentially

associated with keratocyte nuclei. They occurred in larger

number in soft than rigid lens wearers. Micro-opacities

coalesced into slit lamp detectable larger appearances in the

most severe cases. These micro-opacities appeared irrever-

sible in the six subjects where lens wear was discontinued

for up to 1 year [88]. Bohnke and Masters suggest that

hypoxia and the associated acidosis are the most likely cause

of these appearances and that they may consist of lipofuscin.

The significance of stromal micro-opacities remains

uncertain.

14. Keratocytes

Acute transient changes such as hyper-reflective kerato-

cyte nuclei [91] and an apparent density reduction [92] have

been described and were proposed to be related to acidosis or

stromal swelling, respectively. There are indications from

human [90,93–95] and animal [96] contact lens extended

wear trials that keratocyte loss may be occurring in the

longer term but in contrast, no effects could be demonstrated

in groups of long-term daily wearers of soft and rigid contact

lenses [15,90].

15. Summary

As evidenced in this review, the stroma is much more

complex than previously thought. It consists not only of a

regular arrangement of collagen fibrils but also of an

organised network of proteoglycans and metabolically

active keratocytes that are thought to play a major role in

the maintenance of normal stromal properties such as

transparency, strength, homeostasis and the wound-healing

response.


In order to avoid an undesirable shift to an anaerobic

metabolic pathway, the cornea requires adequate levels of

oxygen to be available. In addition, diffusion of carbon

dioxide, the normal byproduct of aerobic metabolism, must

be possible. Contact lens wear typically alters this delicate

stromal balance by impairing both oxygen availability and

carbon dioxide elimination, particularly during overnight

wear. Well-characterised consequences of lens wear there-

fore include stromal acidosis, oedema and striae in the short

term and stromal thinning and opacities in the longer term.

In addition, the availability of high magnification clinical

confocal microscopes has lead to the discoveries of stromal

microdot opacities and the demonstration of keratocyte

density reduction during contact lens wear, however, the

evidence on such findings remains controversial and

requires confirmation.

It appears, based on the evidence presented in this review,

that contact lens induced stromal changes can be minimised

by optimising the oxygen and carbon dioxide transmissi-

bility of contact lenses, particularly in the long term, so that

wearing conditions mimic the non-lens wearing environ-

ment as closely as possible. Recent findings have demon-

strated the potential for any lens wear including highly

oxygen transmissible rigid and soft lenses to affect epithelial

homeostasis [97]. Because of the close interactions existing

between the stroma and epithelium, it may be postulated that

the corneal stroma may be similarly affected. Further

investigations are necessary to confirm whether this will be

true.

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