The Cornea

Cornea
Unit 3
Biochemical composition including protein and enzymes and
electrolyte, specialty of protein arrangement, dehydration,
Regulation of dehydration, transparency and refractive power.
Abnormalities and Changes in contact lens wearer.

Cornea
Two primary physiological function
1. To act as a powerful refracting lens of fixed focus that transmits light in
an orderly fashion for proper image formation
2. To protect the intraocular contents

• Water - 70%
• Protein synthesis in epithelium is five times higher than the stroma and about 2
times higher than the endothelium and Descemet’s membrane
• Lipids – 5.4% of dry weight
• Enzymes necessary for metabolism
• Acetylcholine and cholinesterase are also present in high levels in epithelium
• Electrolytes (Na+, K+, Cl-): epithelium contains high concentration of K+ and
low concentration of Na+ and Cl- as compared to the stroma
Epithelium
• Collagen fibrils embedded in hydrated matrix of proteoglycans,
essentially constitute the corneal stroma -70%
• Type 1, Type 5 (10-20%), Type 6 (15.1%),
• The diameter of corneal collagen fibrils is 35 nm and spacing
between them is 55nm
• soluble proteins (Ig G, A, M)
• Proteoglycans: Keratin sulphate, chondroitin sulphate and
chondroitin
• Enzymes
• Matrix metalloproteinases (MMP-1, MMP-2, MMP-3)
• Electrolytes
Stroma
Cornea

• Biochemical composition of cornea is heterogenous owing to differences in cellularity and morphology of
its different layers namely epithelium, Bowman's membrane, stroma, pre Descemet's membrane and
endothelium
• Under normal conditions, biochemically cornea consists of approximately 80% water and 20% solids
(19.8% organic matter and 0.2% inorganic salts)
• However, hydration of cornea is quite variable, since exposure of the cornea in the living animals allows
sufficient evaporation to reduce corneal hydration
BIOCHEMICAL COMPOSITION OF CORNEA

Epithelium
Corneal epithelium constitutes 10% of the total wet weight of the cornea. Its essential biochemical
components are as follows:
• Water represents 70% of the wet weight
• Protein synthesis in epithelium is five times higher than the stroma and about 2 times higher than the
endothelium and Descemet’s membrane
• Lipids (phospholipids and cholesterol) are mainly present in the cell membranes and constitute about
5.4% of the dry weight of the epithelium. Enzymes necessary for glycolysis, Krebs cycle and Na, K activated
ATPase are present in high levels in the epithelium.

• The epithelium contains ATP (2000 mmol/kg wet weight), glycogen (10 mg/g), glutathione (75 to 180
mg/g) and ascorbic acid (47 to 94 mg/ 100 g)
• Acetylcholine (ACh) and cholinesterases are also present in high levels in epithelium. Perhaps these play a
role in cation transport as well as in trophic nerve function.
• Electrolytes. Epithelium contains high concentration of K+ (142 mEq/l.O) and low concentration of Na (75
mEq/1H,O) and Cl (30 mEq/l H2O) as compared to the stroma

STROMA
Stroma constitutes main bulk (90% of total thickness) of the cornea. It contains 75 to 80% water (wet weight).
Remaining solids (20 to 25%) include mainly extracellular collagen, other soluble proteins,
mucopolysaccharides (chondroitin, keratan sulphate, and dermatan sulphate) and salts

STROMA
Differences in the biochemical composition of anterior and posterior stroma:
• Anterior stroma has less water (3.04 gm H2O dry wt)as compaired to posterior stroma (3.85 gm H2O dry
wt). This is due to atmospheric drying and increased amount of dermatan sulphate which has less water
sorptive capacity.
• Less glucose, 3.89 um/gm H,O in anterior stroma as compared to posterior stroma (4.93 um/gm H2O)
• More dermatan sulphate and less keratan sulphate in anterior stroma.

STROMA: Collagen
• Collagen fibrils (lamellae), embedded in hydrated matrix of proteoglycans, essentially constitute the
corneal stroma
• These present the typical 64-66 nm periodicity of the collagen
• Collagen constitutes approximately 70% of dry weight of human cornea. Type I collagen is the
predominant type, although collagen types III, V (10-20%), VI (15.1%), VII, XII and XIV have also been found
in normal adult cornea.
• The diameter of corneal collagen fibrils (35 nm) and spacing between these fibrils (55 nm) is remarkably
constant.

STROMA: Collagen
• There appears to be an inverse correlation between the number of carbohydrate units and the fibril
diameter of collagen
• The corneal collagen, like the collagen from other structures such as skin and tendons, has a high glycine,
proline and hydroxyproline content
• The mature collagen is a helix composed of two alpha chains (molecular weight 80,000) and one beta
chain (molecular weight 160000)
• The corneal collagen is dissolved by proteolytic enzymes such as collagenase, which has important
implication in corneal ulceration. In boiling water or acids, the corneal collagen is converted into gelatin,
which accounts for the acid corneal burns being less serious than the alkali burns.

STROMA: Proteoglycans
• Proteoglycans are a family of glycosylated proteins that contain at least one glucose amino glycan chain
covalently bonded to a protein core
• Glycosaminoglycans (GAG) or the so-called acid-mucopolysaccharides represent 4 to 4.5% of the dry
weight of the cornea
• Cornea contains three major GAG fractions namely:
1. Keratan sulphate (50%)
2. Chondroitin sulphate A (25%) and
3. Chondroitin (25%), present exclusively in the cornea)

STROMA: Proteoglycans
• GAGs are present in the interfibrillar space of the corneal stroma and account for the stromal swelling
pressure' (normal-60 mm Hg), i.e. its tendency to imbibe water and thus plays an important role in the
maintenance of the corneal hydration level and transparency as they have water sorptive capacity.
• An abnormal accumulation of GAG occurs in the corneal stroma of the patients affected by the inborn
errors of GAG metabolism known as mucopolysaccharidosis.

STROMA: Soluble proteins
• These constitute 5% of wet weight of stroma (and 25% of dry weight of the tissue) and include albumin,
immunoglobulin, and glycoproteins
• The high levels of antibody proteins (immuneglobulins G, A and M), present in the cornea have
immunologic implications
• The corneal immunoglobulins are probably derived from the serum and diffuse into the centre from the
limbus

STROMA: Enzymes
• Glycolytic and Krebs cycle enzymes are present in the stromal keratocytes
• However, the enzymatic activity of the corneal stroma is very low when compared with that of the
epithelium, on weight basis
• The adenosine triphosphate (ATP) content of the stroma is also low (10 to 15 mmol/kg wet tissue).

STROMA: Matrix metalloproteinases
• Matrix metalloproteinases (MMPs) are calcium dependent zinc containing endoproteinase family of
enzymes that breakdown components of extracellular matrix. In the cornea, they help maintain the normal
framework and have a crucial role in remodelling after injury
• MMPs are secreted as proenzymes by infiltrating inflammatory cells or by cells resident in the tissue
• They are then activated by cleavage of a peptide from their N-terminal end
• All MMPs require a metal cofactor.

STROMA: Matrix metalloproteinases
The MMPs of cornea have different substrates:
• MMP-1 (collagenase-I) is active against collagen types I, II, and III.
• MMP-2 (gelatinase A) and MMP-9 (gelatinase B) are active against collagen types IV, V, and VII as well as
gelatins and fibronectin.
• MMP-3 (stromelysin I) breaks down protein glycans and fibronectin
• MMPS 7, 8, 9, 11 are other substrates
Note. Only MMP-2 has been detected in normal cornea, the other MMPs mentioned above are found in the cornea only after injury.
MMPs 1,2 and 3 are products of stromal cells, whereas MMP-9 is produced by the corneal epithelium which is most importantly involved
in the corneal inflammation.

Proteinase inhibitor of cornea
• Proteinase inhibitor of cornea are mainly synthesized by resident cells of cornea; and some are derived
from tears, aqueous humour, and limbal blood vessels
These include:
• proteinase inhibitor, antichymotrypsin, 2 macroglobulin, Plasminogen activator inhibitor 1 and 2, and
Tissue inhibitor of metalloproteinases
• Functions Proteinase inhibitors of the cornea play a key role in corneal protection by restricting damage
during corneal inflammation, ulceration and wound healing.

ENDOTHELIUM
• Owing to delicate nature of this single cell layered structure, it has not been possible to analyse its
biochemical composition without inducing artifactual changes
• However, the histochemical examination of the endothelium has shown the presence of enzymes needed
for glycolysis and Krebs cycle

• the major non-aqueous constituents of the stroma are collagen fibrils and proteoglycans
• The collagen fibrils are made of a mixture of type I and type V collagens
• These molecules are tilted by about 15 degrees to the fibril axis, and because of this, the axial periodicity
of the fibrils is reduced to 65 nm (in tendons, the periodicity is 67 nm)
• The diameter of the fibrils is remarkably uniform and varies from species to species. In humans, it is
about 31 nm
• Proteoglycans are made of a small protein core to which one or more glycosaminoglycan (GAG) chains are
attached.
Cornea

• The GAG chains are negatively charged. In corneas we can find two different types of proteoglycans:
Chondroitin sulphate/dermatan sulphate (CD/DS) and keratan sulphate (KS)
• In bovine corneas, the length of the CS/DS proteoglycans is about 70 nm, while the KS proteoglycans
are about 40 nm long
• Proteoglycan protein cores attach to the surface of the collagen fibrils with the GAG chains projecting
outwards
• The GAG chains are able to form antiparallel links with other GAG chains from adjacent fibrils, perhaps
through the mediation of positively charged ions
Cornea

• In such a way, bridges are formed between adjacent collagen fibrils. These bridges are subject to
thermal motion which prevents them from assuming a fully extended conformation
• This results in forces that tend to move adjacent fibrils close to each other. At the same time the charges
on the GAG chains attract ions and water molecules by the Donnan effect
• The increased water volume between the fibrils results in forces that tend to push the fibrils apart. A
balance between attractive and repulsive forces is reached for specific inter-fibrillar distances, which
depends on the type of proteoglycans present
Cornea

• Stromal transparency is mainly a consequence of the remarkable degree of order in the arrangement of
the collagen fibrils in the lamellæ and of fibril diameter uniformity
• Light entering the cornea is scattered by each fibril. The arrangement and the diameter of the fibrils is
such that scattered light interferes constructively only in the forward direction, allowing the light
through to the retina
• The fibrils in the lamellae are directly continuous with those of the sclera, in which they are grouped
together in fibre bundles. More collagen fibres run in a temporal-nasal direction than run in the superior-
inferior direction.
• During development of the embryo, the corneal stroma is derived from the neural crest (a source of
mesenchyme in the head and neck) which has been shown to contain mesenchymal stem cells
Cornea

Collagen fibers contained in the lamellae
of the corneal stroma (predominately
type I collagen). ➤ The fibers
have their long axes run at angles to
each other in adjacent lamellae.
Cornea

Cornea: Stromal lamellae
• Stroma ensure transparency of cornea by
lamellar arrangement of collagen
bundles
• Stroma has about 200 layers of lamellae
• Lamellae are arranged regularly almost
right angle to each other
• Each lamellae consists of bundle of
collagen:
• 200-300 bundles- centrally
• 500 bundles – peripherally
• Width about 9-260 micro meter
• Thickness about 1.15-2 nm

Cornea: Stromal lamellae
• Each lamellae comprises of a band of
collagen fibrils arranged in parallel with
each other
• Fibrils are regularly placed each other
with center to center distance of 55-60nm
• There is a unique uniformity of fibril
diameter of 22 nm from anterior to
posterior
• Regularly arranged lamellae with uniform
diameter and separation of collagen fibre
makes cornea transparent

Corneal hydration
• Normal cornea maintains itself in a state of relative dehydration (80% water
content ) which is essential for corneal transparency
• It is kept constant by
1. Factors which draw water in the cornea, like -Stromal swelling pressure (SP) -
Intraocular pressure (IOP)
2. Factors which prevent flow of water in the cornea - Mechanical barrier
function of epithelium & endothelium
3. Factors which draw water out of cornea -active pumping action of
endothelium

STROMAL SWELLING PRESSURE
• SP, 60 mmHg
• Pressure exerted by glycosaminoglycans(GAGs) of the corneal stroma which act like a sponge
• Electrostatic repulsion of the anionic charges on the GAG molecule expands the tissue, sucking in the fluid
with equal but negative pressure called, imbibition pressure (IP)

STROMAL SWELLING PRESSURE
• In vitro, IP=SP In vivo, IP is reduced by values equivalent to
IOP.
i.e. IP=IOP- SP
i.e. IP=17-60= - 43mmHg.
• Negative imbibition pressure draws out water from
stroma

Barrier function of epithelium and endothelium
• Epithelium & endothelium are semipermeable in nature.
• Function as barriers to excessive flow of water and diffusion of electrolytes into the
stroma.
• Epithelium offers most resistance to flow of water

Hydration control by active pump mechanism
a) Na+ /K+ ATPase pump system:
• Endothelium is more active than &epithelium,
• Pumps are located in basolateral membrane of endothelial cell.
• Stromal transparency develops 13-20 days after birth due to greatest increase in
pump sites/cell
• Enzyme “Na+ /K+ activated ATPase” mediate pump causes extrusion of the Na+ &
water from the stroma and thus maintain corneal transparency
• Corneal hydration depend on extent to which endothelial barrier and pump function
can be reestablished.

b) Bicarbonate dependent ATPase present in endothelium are also
reported to have role in fluid /ion balance in the cornea
c) Carbonic enhydrase enzyme catalyzes the conversion of CO2 and
water into HCO3 - and H+ , thus provides important source for HCO3 -
for endothelial pump.
d) Na+ /H+ pump has also been postulated

vi) Intraocular pressure (IOP) :
• As we know ,
I P = IOP - SP, i.e. 17- 60= - 43 mmHg,
i.e. I P is a negative pressure.
• When IOP exceeds SP, i.e. when IP becomes positive , corneal oedema results
• It can occur when there is
- high IOP and normal SP, as in acute glaucoma,
- Normal IOP and low SP, as in endothelial dystrophy

The Cornea

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