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Anatomy and physiology of the cornea

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Duke University

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REVIEW/UPDATE

Anatomy and physiology of the cornea

Derek W. DelMonte, MD, Terry Kim, MD

The importance of the cornea to the ocular structure and visual system is often overlooked
because of the corneas unassuming transparent nature. The cornea lacks the neurobiological
sophistication of the retina and the dynamic movement of the lens; yet, without its clarity, the
eye would not be able to perform its necessary functions. The complexity of structure and function
necessary to maintain such elegant simplicity is the wonder that draws us to one of the most
important components of our visual system.
Financial Disclosure: Neither author has a financial or proprietary interest in any material or
method mentioned.
J Cataract Refract Surg 2011; 37:588598 Q 2011 ASCRS and ESCRS

Editors Note: In this issue, we begin a series of review articles that will provide a framework for understanding what
we do and do not know about corneal biomechanics and
methods to evaluate this important topic. The article in
this issue provides a basic understanding of corneal anatomy and physiology. Subsequent articles, which will be
published during 2011, will review the status of the corneal
endothelium after refractive surgery and provide an introduction to our understanding of corneal biomechanics and
the means by which we measure corneal biomechanical
properties, including topography, tomography, and wavefront analysis.
The cornea is a transparent avascular connective tissue that acts as the primary infectious and structural
barrier of the eye. Together with the overlying tear
film, it also provides a proper anterior refractive surface for the eye. Its clarity is the result of many factors
including the structural anatomy and physiology of its
cellular components. In this article, we describe the
intricate and delicate balance of cellular components
and factors that create the most important refractive
component of our ocular system.

Submitted: June 29, 2010.

Final revision submitted: October 27, 2010.
Accepted: October 29, 2010.
From the Department of Ophthalmology, Duke University Eye Center,
Duke University Medical Center, Durham, North Carolina, USA.
Corresponding author: Terry Kim, MD, Duke University School of
Medicine, Cornea and External Disease Service, Refractive Surgery
Service, Duke University Eye Center, 2351 Erwin Road, Duke
University Eye Center, DUMC 3802, Durham, North Carolina
27710-3802, USA. E-mail: terry.kim@duke.edu.

588

Q 2011 ASCRS and ESCRS

Published by Elsevier Inc.

ANATOMY OF THE CORNEA

In the average adult, the horizontal diameter of the
cornea is 11.5 to 12.0 mm1 and about 1.0 mm larger
than the vertical diameter. It is approximately
0.5 mm thick at the center and gradually increases in
thickness toward the periphery. The shape of the cornea is prolatedflatter in the periphery and steeper
centrallydwhich creates an aspheric optical system.
Corneal shape and curvature are governed by the
intrinsic biomechanical structure and extrinsic environment. Anterior corneal stromal rigidity appears to
be particularly important in maintaining the corneal
curvature.2 Organizational differences in the collagen
bundles of the anterior stroma may contribute to
a tighter cohesive strength in this area and may also
explain why the anterior curvature resists change to
stromal hydration much more than the posterior
stroma, which tends to more easily develop folds.
Stromal hydration also appears to affect the corneas
response to strain and shear forces.3
The human cornea consists of 5 recognized layers, 3
cellular (epithelium, stroma, endothelium) and 2 interface (Bowman membrane, Descemet membrane)
(Figure 1).
Epithelium
The epithelial surface of the cornea creates the first
barrier to the outside environment and is an integral
part of the tear filmcornea interface that is critical to
the refractive power of the eye. It is a stratified, nonkeratinizing squamous layer characterized by extreme
uniformity from limbus to limbus.
Embryologically, the corneal epithelium is derived
from surface ectoderm between 5 and 6 weeks of gestation. It is composed of nonkeratinized, stratified
0886-3350/$ - see front matter
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Figure 1. Light micrograph of normal endothelium (original magnification 100). Note the single-cell endothelial layer with a Descemet
membrane of uniform thickness (epithelial surface at top of figure).
Reprinted with permission of Ophthalmology.4 Copyright 2008
Elsevier.

Figure 2. Cross-sectional view of the corneal epithelial cell layer.

Reprinted with permission of Ophthalmology.4 Copyright 2008
Elsevier.

squamous epithelium that is 4 to 6 cell layers thick

(40 mm to 50 mm).4 As mentioned earlier, the epithelium is covered with a tear film, which is optically
important in smoothing out microirregularities of the
anterior epithelial surface. The airtear film interface,
together with the underlying cornea, provides two
thirds of the total refractive power of the eye.
The corneal epithelium and overlying tear film have
a symbiotic relationship both anatomically and physiologically. The mucinous layer of the tear film, which
is in direct contact with the corneal epithelium, is produced by the conjunctival goblet cells and interacts
closely with the corneal epithelial cell glycocalyx to allow hydrophilic spreading of the tear film with each
eyelid blink. It has been suggested that the epithelium
itself may contribute to this mucinous layer, but this is
unproven.5 Loss of the glycocalyx from injury or disease results in loss of tear-film stability and subsequent
breakdown of the ocular optical system. The tear film
is the primary protector of the corneal surface from
microbial invasion, as well as from chemical, toxic,
and foreign-body damage. The tear film also supplies
immunological and growth factors that are critical for
epithelial health, proliferation, and repair.6
Corneal epithelial cells have an average lifespan of 7
to 10 days7 and routinely undergo orderly involution,
apoptosis (programmed cell death), and desquamation. This process results in complete turnover of the
corneal epithelial layer every week as deeper cells replace the desquamating superficial cells in an orderly,
apically directed fashion. The most superficial corneal
epithelial cells form a mean of 2 to 3 layers of flat polygonal cells. These cells have extensive apical microvilli and microplicae, which in turn are covered by
a fine, closely apposed, charged glycocalyceal layer.4
This layers apical membrane projections increase the

surface area of contact and adherence between the

tear films mucinous layer and the cell membrane
(Figure 2). As discussed earlier, this is critical for
a smooth and clear optical system.
These surface cells maintain tight junctional complexes between their neighbors, which prohibit tears
from entering the intercellular spaces. This can be
demonstrated clinically by observing a healthy epithelial surfaces ability to repel dyes such as fluorescein
and rose bengal. This barrier also prevents toxins
and microbes from entering deeper corneal layers.
Beneath the superficial cell layer and just anterior to
the deepest basal layer of the epithelium are the suprabasal or wing cells. This layer is 2 to 3 cells deep and
consists of cells that are less flat than the overlying superficial cells but possess similar tight lateral intercellular junctions.
The deepest cellular layer of the corneal epithelium
is the basal layer, which comprises a single cell layer of
columnar epithelium approximately 20 mm tall. Besides the stem cells and transient amplifying cells,
basal cells are the only corneal epithelial cells capable
of mitosis.8 They are the source of wing and superficial
cells and possess lateral intercellular junctions characterized by gap junctions and zonulae adherens. The
basal cells are attached to the underlying basement
membrane by a hemidesmosomal system. This strong
attachment is what prevents the epithelium from separating from the underlying corneal layers. Abnormalities in this bonding system may result clinically in
recurrent corneal erosion syndromes or nonhealing
epithelial defects. Epithelial stem cells, which serve
as an important source of new corneal epithelium,
have been localized to the limbal basal epithelium.
As the cells migrate to the central cornea, they differentiate into transient amplifying cells (cells capable of

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Figure 3. Hypothetical scheme of limbal stem cell niche. Reprinted

with permission of Cell Research.9 Copyright 2007 Macmillan Publishers Ltd.

Figure 4. Bowman scarring seen after herpes simplex keratitis. Note

the abrupt termination of Bowman membrane. Reprinted with permission of Cornea.6 Copyright 2005 Elsevier.

multiple but limited cellular division) and basal cells

(Figure 3).9
The epithelial basement membrane, approximately
0.05 mm thick, comprises type IV collagen and laminin
secreted by the basal cells. If damaged, fibronectin
levels increase and the process of healing can take up
to 6 weeks. During this time, the epithelial bond to
the underlying, newly laid basement membrane tends
to be unstable and weak.

stroma, and the collagen fibrils may change direction

to run circumferentially as they approach the limbus.12
This highly organized network reduces forward light
scatter and contributes to the transparency and
mechanical strength of the cornea.
An additional feature of the stroma is that the ultrastructure within the organization of the lamella appears to vary based on the depth within the stroma.
Deeper layers are more strictly organized than superficial layers, and this difference accounts for the
greater ease of surgical dissection in a particular plane
as one approaches the posterior depths of the corneal
stroma. This variation in stromal organization also
accounts for the differences in response to corneal
edema, as mentioned previously. Descemet folds are
the result of asymmetric swelling of the posterior
stroma imposed by the structurally more rigid anterior
cornea and structural restriction imposed by the limbus.13 Stromal swelling is therefore directed posteriorly and results in relative flattening of the posterior
surface, which can push Descemet membrane into
multiple folds that become visible as striae.
Stromal collagen fibrils are composed of type I collagen in a heterodimeric complex with type V collagen
to obtain their unique and narrow diameter.14 These
complexes are surrounded by specialized proteoglycans, consisting of keratan sulfate or chondroitin
sulfate/dermatan sulfate side chains, which help regulate hydration and structural properties.
Keratocytes are the major cell type of the stroma and
are involved in maintaining the ECM environment
(Figure 5). They are able to synthesize collagen
molecules and glycosaminoglycans while also creating
matrix metalloproteases (MMPs)dall crucial in maintaining stromal homeostasis. Most of these keratocytes
reside in the anterior stroma and contain corneal

Bowman Layer
Bowman layer (or Bowman membrane) lies just anterior to the stroma and is not a true membrane but
rather the acellular condensate of the most anterior
portion of the stroma. This smooth layer is approximately 15 mm thick and helps the cornea maintain its
shape. When disrupted, it will not regenerate and
can form a scar (Figure 4).
Stroma
The corneal stroma provides the bulk of the structural framework of the cornea and comprises roughly
80% to 85% of its thickness. Embryologically, it is the
result of a second wave of neural crest migration that
occurs in the seventh week of gestation, after establishment of the primitive endothelium. The stroma differs
from other collagenous structures in its transparency,
which is the result of precise organization of the stromal fibers and extracellular matrix (ECM).10,11 The collagen fibers are arranged in parallel bundles called
fibrils, and these fibrils are packed in parallel arranged
layers or lamellae. The stroma of the human eye contains 200 to 250 distinct lamella, each layer arranged
at right angles relative to fibers in adjacent lamellae.11
The peripheral stroma is thicker than the central

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591

Figure 5. Transmission electron microscopy of the human corneal stroma. A:

Keratocyte localized between stromal lamellae. B: Higher magnification view
showing a keratocyte in relation to collagen fibers coursing in various directions.
Reprinted with permission of Cornea.6
Copyright 2005 Elsevier.

crystallins, representing 25% to 30% of soluble protein in the cells. These crystallins appear to be responsible for reducing backscatter of light from the
keratocytes and maintaining corneal transparency.15

microscopy, but Descemet membrane produced after

birth is unbanded and has an amorphous ultrastructural texture. Descemet can accumulate up to 10 mm
in thickness with age (Figure 6).

Descemet Membrane

Endothelium

Beginning in utero at the 8-week stage, endothelial

cells continuously secrete Descemet membrane. The
anterior 3 mm secreted prior to birth has a distinctive
banded appearance when viewed by electron

Figure 6. Micrograph illustrating Descemet membrane (DM) located

between the posterior aspect of the corneal stroma (S) and the underlying endothelium (EN). The anterior banded region (A) is secreted by the endothelial cells during fetal development and is
more highly organized than the posterior amorphous region (P),
which is secreted after birth. Reprinted with permission of Principles
and Practice of Ophthalmology.13 Copyright 2008 Elsevier.

The endothelial layer of the cornea maintains corneal clarity by ensuring it remains in a relatively
deturgesced state. The intact human endothelium is
a monolayer, which appears as a honeycomb-like
mosaic when viewed from the posterior side (Figure 7).
In early embryogenesis, the posterior cornea is lined
with a neural crest-derived monolayer of orderly arranged cuboidal cells.16 Over time, these cells flatten
and become tightly adherent to one another. Immediately anterior to the flattened layer is a discontinuous
homogeneous acellular layer, which in time becomes
Descemet membrane.17 At birth, the endothelial
monolayer is approximately 10 mm thick and consists
of a uniform thickness layer of cells that spans the entire posterior corneal surface and fuses with the cells of
the trabecular meshwork.17 Similarly, Descemet membrane becomes continuous and uniform, fusing
peripherally with the trabecular beams.17 The fusion
site, known as Schwalbe line, is a gonioscopic landmark that defines the end of Descemet membrane
and the start of the trabecular meshwork.
The individual cells continue to flatten over time
and stabilize at approximately 4 mm in thickness in
adulthood. Adjacent cells share extensive lateral interdigitations and possess gap and tight junctions along
their lateral borders. The lateral membranes contain
a high density of NaC, KC-ATPase pump sites.18
The basal surface of the endothelium contains numerous hemidesmosomes that promote adhesion to
Descemet membrane.
Endothelial cell density and topography continue
to change throughout life. From the second to eighth

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Figure 7. Specular photomicrograph of normal endothelium. Note

the dark well-defined cell borders, the regular hexagonal array,
and the uniform cell size. Reprinted with permission of Cornea.6
Copyright 2005 Elsevier.

Figure 8. Major corneal loading forces in the steady state. Reprinted

with permission of Ophthalmology.4 Copyright 2008 Elsevier.

decades of life, the cell density declines from 3000

to 4000 cells/mm2 to around 2600 cells/mm2, and
the percentage of hexagonal cells declines from approximately 75% to approximately 60%.19 The central
endothelial cell density decreases at an average rate of
0.6% per year in normal corneas.20
As mentioned, the stroma is maintained in a relatively deturgesced state (78% water content) by the activity of the endothelial cells.21 This dehydration is
mediated by a pumpleak process as fluid egresses
from the corneal stroma down the osmotic gradient
from a relatively hypo-osmotic stroma toward a relatively hypertonic aqueous humor. This passive bulk
fluid movement requires no energy but is fueled by
the energy-requiring processes of transporting ions
to generate the osmotic gradient. The 2 most important
ion transport systems are the membrane-bound NaC
and KC-ATPase sites and the intracellular carbonic
anhydrase pathway. Activity in both these pathways
produces a net flux of ions from the stroma to the aqueous humor. The barrier portion of the endothelium is
unique in that it is permeable to some degree, permitting the ion flux necessary to establish the osmotic
gradient (Figure 8).17
Endothelial cells have no mitotic activity in vivo;
however, humans are born with a significant reserve.
Cell density is approximately 3500 cells/mm2 at birth,
but this number decreases gradually throughout life at
approximately 0.6% per year. It has been observed that
eyes with endothelial cell counts below 500 cells/mm2
may be at risk for the development of corneal edema.
Endothelial cell morphology (size and shape) also appears to correlate with pump function. An increase in
cell size (polymegathism) and an increase in variation
of cell shape (pleomorphism) correlate to reduced ability of the endothelial cells to deturgesce the cornea.22
The number of endothelial cells decreases with age,
trauma, inflammation, and other disease processes

(ie, Fuchs endothelial dystrophy), but the remaining

cells have the capacity to stretch and take over
the space of the degenerated endothelial cells. As this
process occurs, the remaining cells grow in size (polymegathism) and lose their hexagonal shape (pleomorphism) (Figure 9).
Blood Supply of the Cornea
Although the normal human cornea is avascular, it
relies on components of the blood to remain healthy.
These components are supplied by tiny vessels at the
outermost edge of the cornea as well as components
supplied by end branches of the facial and ophthalmic
arteries via the aqueous humor and tear film.
Nerve Supply of the Cornea
The cornea is one of the most heavily innervated and
most sensitive tissues in the body. Corneal nerves and

Figure 9. Specular photomicrograph of Fuchs dystrophy. Note dark

areas that represent guttae adjacent to areas of enlarged endothelial
cells. (Spacing of grid 0.1 mm) Reprinted with permission of Ophthalmology.4 Copyright 2008 Elsevier.

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sensation are derived from the nasociliary branch of

the first (ophthalmic) division of the trigeminal nerve.
In the superficial cornea, the nerves enter the stroma
radially in thick trunks forming plexiform arrangements, which eventually perforate Bowman membrane to provide a rich plexus beneath the basal
epithelial layer.23 The cornea also contains autonomic
sympathetic nerve fibers.
CORNEAL RESPONSES TO INJURY
Epithelial Injury
When any portion of an epithelial cell is disrupted,
the entire cell is usually lost, leaving a defect in the epithelial layer. The most common form of injury to the
epithelium is mechanical, but thermal and chemical injuries are also possible. When a mechanical force creates a break in the epithelial barrier, cells at the edge
of the abrasion begin to cover the defect within minutes by a combination of cell migration and cell
spreading. This process is preceded by almost immediate preparatory cellular changes of an anatomical,
physiological, and biochemical nature, including the
creation of cell membrane extensions, disappearance
of hemidesmosome adhesions from the basal cells,
and increase in mitochondrial energy production.
This early nonmitotic wound coverage phase can
proceed at the remarkable rate of 60 to 80 mm per
hour.24 Studies have shown that the migrating sheet
of epithelial cells is attached most firmly to the underlying substrate at the leading margin, possibly suggesting that the leading cells are pulling the
epithelial sheet as it migrates.25 The ECM protein fibronectin is thought to be a key element in the mediation of cell-to-substrate adhesion and cell migration.
By 24 to 30 hours after injury, mitosis begins to restore the epithelial cell population. Only the basal cells,
transient amplifying cells, and limbal stem cells partake in this reconstitutive mitosis.8
Stromal Injury
The separation of the stroma from the other cellular
layers of the cornea by the Bowman layer and Descemet membrane is necessary for the normal homeostasis of the cornea, and the disruption of this strict
organization is associated with activation of the stromal wound-healing process. Stromal wound healing
consists of 3 stages: repair, regeneration, and remodeling.14 Similar to the wound-healing process in skin
wounds, stromal wound healing has been shown to involve a complex interplay of cytokines, growth factors,
and chemokines; however, an important distinction is
the absence of a vascular component to the healing.26
The activation and migration of stromal keratocytes
are the first responses to a stromal injury and can occur

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within hours. These cells take on a more fibroblast-like

appearance and behavior as they become activated.27
The keratocytes within the area of injury undergo
apoptosis, peaking 4 hours after the initial insult.28
Apoptosis appears to modulate the wound-healing
response by influencing the activation of adjacent
keratocytes.
Within 1 to 2 weeks of the initial insult, myofibroblasts with contractile properties enter the injured
area and become involved in the stromal remodeling.
These cells use increased expression of MMPs, which
are a family of proteolytic enzymes responsible for
ECM remodeling, cellmatrix interaction, inflammatory cell recruitment, and cytokine activation.29 In
the cornea, MMPs are thought to be very important
in the complex reorganization of collagen in the stromal wound.14 This theory is supported by research
looking at complex laser in situ keratomileusis
wounds that has found increased levels of MMPs, particularly in areas of significant wound trauma with
interface fibrosis.30 It has been proposed that
overexpression of these MMPs, along with activated
inflammatory cytokines, may be responsible for loss
of specific type IV collagen isoforms in the epithelial
basement membrane, leading to scarring or haze.
The interaction between these cytokines, MMPs, and
other mediators, rather than the mere presence or absence of these proteins, often plays a decisive role in
regulating the complex remodeling process during
corneal wound healing.31 This process can take
months or even years to complete; the end result sometimes reduces corneal clarity long after primary
wound healing has occurred.
Endothelial Injury
Aside from full-thickness penetrating injuries, endothelial injury primarily results from rapid focal distortion of the cellular layer. This disruption is similar to
the injuries seen from excessive corneal bending in
large-incision surgeries such as extracapsular cataract
extraction and/or from endothelial trauma caused
by high fluid turbulence during cataract surgery. Clinically, these injuries are seen as snail-track lesions or
serpentine gray lines on the endothelium.
As discussed earlier, endothelial cells do not appear
to undergo mitosis in vivo, which means the damaged
cells are rapidly replaced by enlargement of the surrounding cells and their centripetal migration into
the injured region. The process of resurfacing the injured area is completed in 3 stages that can take several
weeks. The first stage is characterized by the establishment of initial coverage of the wound by migration of
adjacent endothelial cells, which forms a temporary
incomplete barrier with reduced pump sites and

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incompletely formed tight junctions. In the second

stage, the barrier (ie, tight junctions) and subsequently
the number and quality of pump sites return to normal
levels, the endothelial cells form irregular polygons,
the corneal thickness typically returns to normal, and
transparency is restored. The third stage involves remodeling of the endothelial cells to form more regular
hexagons, which can continue for several months.17
With more severe trauma, as a result of keratoconus,
and as a possible complication of incisional anterior
segment surgery, the underlying Descemet membrane
may be torn or ruptured. If this occurs, migrating endothelial cells are required to produce new Descemet
membrane. As seen with acute corneal hydrops, focal
corneal edema may be seen early, which resolves
when the break is repaired.
One must consider other stressors in endothelial injury as surface trauma is less problematic here than
with the more superficial corneal layers. The endothelium has a restricted response to stress. Mild stress
may result in changes in cell size and shape, whereas
greater stress may result in cell loss as well as irreversible alterations in the endothelial cytoskeleton.32 Sources of stress may be metabolic (from hypoxia or
hyperglycemia) or toxic (from drugs or their preservatives) or caused by alterations in pH or osmolarity. For
example, contact lenses cause a hypoxic stress of varying degrees to the endothelium.33 Over time, this may
result in alteration of the morphology, microanatomy,
and possibly the function of the endothelium.22 Hyperglycemia is another common metabolic stress that
may produce changes in the endothelium. Compared
with the corneal endothelium in age-matched controls,
the corneal endothelium in patients with type 1 and
type 2 diabetes has a lower mean cell density and
greater pleomorphism and polymegathism.34
SURGERY AND THE CORNEA
Since the first phacoemulsification surgery performed
by Kelman in the 1960s,35 intraocular surgery has advanced rapidly. With this has come the need to ensure
corneal health and clarity during the intraoperative
and postoperative course. Nothing is worse than performing surgery to improve visual potential only to
be foiled by decreased corneal clarity due to preventable corneal injury. For this reason, ophthalmic surgeons should be aware of the potential causes of
corneal injury and know how to treat the injury should
it occur.
Epithelium
Epithelial injury during intraocular surgery is not
rare but is generally mechanical and can be treated
in the same manner as any other mechanical injury

to the corneal epithelium with minimal long-term

complications.
Bowman Layer and Stroma
Corneal refractive surgery, similar to intraocular
surgery, requires close attention to corneal anatomy
and physiology. Corneal haze and progressive ectasia
are stromal complications of corneal refractive surgery
that must be considered and addressed by surgeons
who perform refractive procedures. For example,
many people have found that corneal haze, which
was a significant complication after photorefractive
keratectomy, was seen less frequently after the introduction of flap-based surgeries that spared Bowman
layer. Corneal haze appears to be related to increased
initiation of cytokine messaging cascades and increased activity of stromal keratocytes when this barrier is breached, resulting in altered stromal healing
patterns, as discussed above.36 Reports have documented irregularities in basement membrane configuration, the presence of vacuoles in and around
keratocytes, and disorganization in the lamellar structure of the corneal stroma, all related to the activated
keratocytes.13,36 The incidence of visually significant
haze has decreased with continued advances in laser
technology, such as smaller spot sizes and larger ablation zones, as well as advances in postoperative management, such as new steroid regimens and the use of
mitomycin-C.37
The increasing demand for a 20/20 uncorrected visual outcome after cataract surgery is driving more
cataract surgeons to use incisional astigmatic keratotomy to correct existing astigmatism at the time of phacoemulsification. Although these treatments are not
new to the world of refractive surgery, they are having
a resurgence outside the traditional use by subspecialty trained refractive surgeons. These procedures
rely on the biomechanical structure of the cornea, making it imperative that surgeons know the effects of incision length, depth, and axis. Early work by Bates38
and later Lans39 identified 4 major rules governing incisional corneal outcomes: (1) deeper incisions into the
stroma provide a greater effect; (2) wound healing
and scarring of the incisions induce further effect; (3)
arcuate incisions result in flattening in the axis of the incision; and (4) radial incisions result in central flattening and peripheral corneal steepening.13 Since that
time, corneal incisional refractive surgery has been
very successful but comes with its own set of complications, including decreased corneal stability, risk for infectious keratitis, and over- or undercorrection.
Descemet Membrane and Endothelium
Descemet membrane injury and detachment is an
uncommon but serious complication of anterior

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segment surgery that has the potential to lead to significant endothelial cell loss in some cases.40 It is estimated that Descemet detachment occurs in 0.5% of
cataract surgeries; although most injuries remain small
and localized to the wound, some can extend to the
visual axis, resulting in significant morbidity.41 It
must be remembered that healing of Descemet breaks
requires endothelial cell migration and deposition of
a new basement membrane, a process that is much easier if the edges remain in close proximity. For this reason, many surgeons place air or gas bubbles in the
anterior chamber of the eye to hold the loose membrane tags against the posterior cornea as the healing
process takes place or, in larger detachments, use
a 10-0 nylon suture to reappose the detachment
mechanically.42,43
One of the most serious complications after intraocular surgery is corneal edema, which was noted
frequently during the early years of phacoemulsification surgery and is largely due to endothelial damage
at the time of surgery. In several studies, 4446 the central endothelial cell loss after phacoemulsification
ranges from 4% to 25%. Many factors likely affect the
corneal endothelium during a phacoemulsification
procedure and these can be divided into 4 groups:
(1) direct mechanical trauma to the endothelium
from the incision and inadvertent touch of the endothelium by lens fragments, instruments, or intraocular
lenses during the procedure; (2) ultrasound energy
affecting the endothelium directly or (3) via the generation of hydroxyl radicals; and (4) the biochemical and
mechanical effects of the irrigating solution (nature,
volume, turbulence).47,48
Direct trauma to the endothelium is a risk when instruments or other objects are placed in the confined
space of the anterior chamber. Care must be taken to
avoid touching the delicate endothelial cells inadvertently, as even minor trauma can result in significant
cell death. This is supported by studies reporting
that dense nuclear fragments floating in the anterior
chamber with high turbulence are a risk for endothelial trauma.49,50 For this reason, Osher51 and others
suggest a slow motion phacoemulsification technique that may minimize this trauma.
One major advance in intraocular surgery is ophthalmic viscosurgical devices (OVDs) (composed of
hydroxypropyl methylcellulose, chondroitin sulfate,
or sodium hyaluronate). These devices significantly
protect the endothelium against intraoperative
trauma.52 Different OVDs have different physical
properties (eg, rheology, shear rate, and osmotic
strength) and may provide different levels of endothelial protection from mechanical and ultrasonic insults.
The ultrasonic energy delivered to the eye during
phacoemulsification is important for removing

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cataracts through a small incision, but it can damage

other ocular structures, particularly the delicate corneal endothelium. During early phacoemulsification
surgery, the level of corneal endothelial cell loss was
high and many patients developed corneal failure. Numerous studies found that the level of ultrasound
power used during surgery was directly proportional
to the endothelial cell loss, often attributed to direct
mechanical trauma from the sonic wave as well as
thermal injury.53,54 With the development of better
ways to protect the cornea through OVDs and
methods to modulate and decrease the phaco energy,
the rate of pseudophakic bullous keratopathy has decreased dramatically. By delivering smaller pulses or
bursts of energy in variable patterns, the phaco efficiency can be maximized while the total amount of
phaco energy, phaco time, and phaco-generated heat
within the eye is decreased, thus minimizing endothelial trauma.55
Elevated levels of oxygen-free radical species have
been identified in the eyes of patients who recently
had phacoemulsification surgery.56 These free radicals
are thought to be the result of ultrasound oscillations
that induce acoustic cavitations, leading to dissociation of water vapor.57 Several recent studies propose
that these free radicals are a significant source of endothelial damage after cataract extraction by inducing
the apoptosis cascade.58
Fluidics also play an important role in corneal health
during intraocular surgery.59 It is critical to minimize
the mechanical trauma from the turbulent flow of irrigating solutions in a confined space as well as to
maintain the delicate biochemical composition of the
anterior chamber during the procedure.
With all the ophthalmic solutions, medications, and
other agents currently used during routine phacoemulsification cataract surgery, it is important to
know the pH and osmotic tolerance range of the human corneal endothelium. Studies show that the corneal endothelium has a pH tolerance between 6.8
and 8.2, which is similar to that of the natural aqueous
humor bicarbonate buffer system.60 During cataract
surgery, the osmolality of the anterior chamber can
easily vary because of the variety of drugs and solutions used in irrigation or injection of the eye. This variation can cause the endothelial cells to become
swollen, degenerated, apoptotic, or even necrotic. If
all the essential ions are present, corneal endothelial
cells tolerate a wide range of osmolalities from 250 to
350 mOsmoles.61 Therefore, both the pH and osmolality of the intraocular solution are critical in maintaining the health of the corneal endothelium.
It is important to monitor the composition of not
only the phacoemulsification irrigating solution, but
also the many other fluids used intraocularly during

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surgery. Medications such as epinephrine, anesthetic

agents, and miotic agents are used routinely but
must be properly buffered, used in specific concentrations, and at specific temperatures to ensure endothelial health.41,62 Many preservatives in ocular
medications, such as methylparaben and benzalkonium, are toxic to the corneal endothelium.63 For this
reason, all intraocular medications should be free of
preservatives or other unnecessary additives.
Toxic anterior segment syndrome (TASS), an extreme example of endothelial toxicity, is an acute sterile anterior segment inflammation that develops after
anterior segment surgery. Findings associated with
TASS typically present within 12 to 48 hours of surgery and include diffuse limbus-to-limbus corneal
edema secondary to widespread damage to the corneal endothelium. Several large studies have not
been able to identify a single factor responsible for
this syndrome; however, problems with the cleaning
and sterilization process of surgical instruments may
be responsible.64
CONCLUSION
About the size of a postage stamp and less than half
the thickness of a United States dime, the human cornea is one of the marvels of the human body. Transparent and refractive, it offers us a clear view of the world
around us while protecting the delicate contents of the
human visual system. It is crucial that ophthalmic
surgeons appreciate the importance of this tough yet
vulnerable tissue when planning and performing intraocular and refractive corneal surgery.
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