Anatomy , Physiology and

biochemistry of cornea
Presenter-Yordanos (R1)

Moderator- Dr Yared
Outline
 Embryogenesis

 Surface Anatomy

 Histology and physiology

 Biochemistry

 Innervations

 Congenital anomaly

 referance
OVERVIEW
 Cornea is clear, transparent, avascular and
highly innervated

 Covers anterior one six of total circumference

of the globe

 Protect intraocular content and contribute

2/3 of refractive power of eye
Embryology
 After lens vesicle formation ( at 4-5 wk)
surface ectoderm cell cover the defect left by
lens vesicles invagination and form two cell
layerd primitive epithelium.
 This primitive epithelium produce collagen
fibrils and GAG which occupy the space
between epithelium and lens (primary
acellular stroma).

 At 5th week a first wave of neural crest

derived mesenchyme migrate from margin of
optic cup rim along posterior surface of
primary stroma forming two cell layered
endothelium
 . At 7 week 2nd wave of mesenchyme invades
anteriorly and posteriorly to endothelium.
and the anterior one differentiate into
keratocytes in the stroma.
 At 8th week endothelium become monolayer
and start to produce descement’s membrane
 sometime between the eyelids fuses (8week)
and open (26 week), the epithelium stratify to
four layers thick

 By 3 months of gestation corneal nerve start

to invade stroma and penetrate Bowman’s
layer to reach epithelium

 Late 4th month acellular Boweman’s layer

form
 5 month of gestation tight junction ( zona
occuledent) on epithelial cell

 5-7 month cornea become transparent

 7 month resembles adult except the size

Post natal aging
 Epithelial basement membrane growth

 Decrease keratocyte, subbasal nerve fiber,

endothelial cell density

 Increased stiffness, strength, and thoughness

of stroma
 Descemet’s membrane thickening of an
additional 6-11μm

 Degeneration of extracellular matrix.

 Negative effect of aging on cornea

 impaired corneal wound healing

 Decrease corneal sensation

 Decreased extensibility of its tissue

Surface Anatomy
When
 viewed anteriorly the cornea appear elliptical

-11-12 mm horizontal

- 9-11mm vertically

- Scleralization superiorly and inferiorly

accounts for difference

When
 viewed from Posterior, the cornea is circular

-11.7mm both horizontally and vertically

 Curvature

-Anterior cornea become flatter in periphery

giving a cornea prolate shape

- Asphericity prevents from spherical aberration

-Average radius of curvature of anterior and

posterior cornea is 7.8mm & 6.5mm respectively
- big difference in radius of curvature of sclera
(11.7mm) and cornea results in 1.5-2mm transitional
zone where the cornea meats sclera called limbus.

- Limbus is important because it contains adult stem

cell, trabecular mesh work ,is inciting site for a few
immunologic disease and site for surgical entry to
anterior segment.
 Thickness

- 0.52mm , central

- 0.65mm , peripheral

-no change in thickness with age

- abnormal tissue thinning indicate corneal

dystrophy
 Zones of the cornea
 Central zone-1-2mm fits a spherical

surface

 Para central zone- 3-4mm represents an

area of progressive flattening

 Peripheral zone-area of greatest flattening

and asphericity of the normal cornea.
Microscopic Anatomy
Epithelium
 The anterior most cell layer of the cornea

 its 50μm thick in central cornea

 Multilayered consists of :

-Apical cell squamous layer

-polygonal shaped wing cells

-Basal layer
 Apical cell - 4-5μm in thickness

- covered by microvili

- apical margin posses tight junction

- lateral and basal posses gap junction

 Wing cell – 12-15μm in diameter

- desmosal and gap junction present

 Basal cell-10μm in width and10-20μm in height

- single layer of columnar cells

- posses mitotic activity

- adhere to basements membrane by

hemidesimosome
Anchoring structures
 Hemidesmosomes

 Basal lamina – maintains organization of

epithelium
- has 3 layers; lamina lucida
lamina densa
lamina reticula

 Anchoring Fibrils and plaques

Epithelial cell proliferation
 All corneal epithelial cell turn over every 7-10
days
 Epithelial surface maintained by basal cell

mitosis

 In addition to the basal cell mitosis
centripetal movement of cells from limbal
stem cells

 Epithelial migration is in X-Y-Z direction

 Shedding and proliferation is critical in

maintaining a smooth and uniform surface
Corneal staining
Fluorescien
 Rose Bengal and lissamine Green
Boweman’s layer
 smooth ,acellular, non regenerating layer found
between epithelium and stroma

 8-12μm thick

 Composed of randomly oriented collagen fibrils

 Function of bowman membrane remains

unclear, appear to have no critical function in
corneal physiology
stroma
 Fibrous tissue layer with 450 thick ( 90% of
corneal thickness)

 Composed of predominantly water( 78%

hydrated or 3.5g H2O/g)
Dry weight of corneal stroma made up of
collagen(68%), Keratocyte (10%), proteoglycan
(9%), and salts

 strength, shape, clarity of cornea largely

determined by this layer
 Collagen
 Makes up 68% of dry weight of cornea

 Mostly type I

 Also III, V, VI

 Organized into striated fibrils, these fibrils

are combined into highly ordered ,sheet
like bundles called lamellae.
 Proteoglycans
 Hydrophilic mucopolysaccharide , in
which collagn firbrils are embedded
 Polypeptide protein cores to which

GAG are covalently bonded

 Keratan sulfate
 Dermatan sulfate
 Chondroitin sulfate
 Chondroitin
 Hyaluronic acid
 Keratan sulfate followed by dermatan sulfate is
abundant stromal GAG

 Dermatan sulfate found more anteriorly than keratan

sulfate

 This GAGs bind along the collagen fibrils at regular

spaced sites

 Less prevalent GAGs found within interfibrillar spaces

without binding

 Role of GAGS is maintain interfibrillar spacing.

 Keratocytes

 occupy 3% to 5% of the total stromal volume

 Quiescent in normal cornea

 But with injury may transform to

myofibroblasts, produce extracellular matrix,
MMPs and other collagen degrading enzymes

 May take 2-3 years for cell turnover

 Transparency
 Lattice like arrangement of collagen helps

to cancel light scatter from individual

fibrils by one another

 The small, regular diameter of individual

collagen fibril and ordered arrangement
with inter fibril space is less than visible
light wave length(400-700)
Dua’s (predecement) layer
 Newly discovered layer by Dr Harminder singh Dua’s
and his group at the university of Nottingham

 Discovered as a result of the new Big bubble

technique of crating DALK, in which air was injected
to stroma to separate decement

 Dua do several experiment where he remove

decements layer and discover the big bubble
remain, this suggests the presence of other layer.
Histology

Well defined ,accellular, and strong

15 microns thick

5-8 lamellae of type I collagen

Has more type IV and type VI than stroma

Tightly packed collagen fibrils in posterior stroma

 Medical implication of this layer

 Improve outcome of corneal graft and

transplantation i.e during big bubble
technique after injecting of air in stroma,
the bubble may burst and compromised
vision. But injecting of air in dua’s layer
reduce risk of tearing
 Corneal hydrops, a buildup of fluid in
cornea that is common in keratoconus may
be due to tear of Dua’s laye

 The understanding of corneal disease like

acute hydropes, Descemetocele and pre
decemet’s dystrophies may be affected
Descement’s layer
 Found anterior to endothelium can be
thought as the basal lamina of endothelium

 Thickness varies from 3μm at birth to 8-

10μm at adulthood

 It is extracellular secretion of endothelium

 Composed of an anterior banded zone and

posterior non banded zone
 Type III,IV,V,VI collagen are present

 Clinical significance
 Significant damage to membrane needs

corneal transplant

 Damage caused by hereditary condition

known as Fuch’s dystrophy
Endothelium
 A single layer of 400,000-500,000 hexagonal cells

 Each cell has 5 μm thickness, 20μm diameter and

cover surface area of 250μmm2

 Has apical tight junction and lateral gap junction

forming incomplete barrier to diffusion of small
molecules

 Do not regenerate
 With age there is decline in number of cells
 Rapid component
 Slow component

 Endothelium maintain its continuity by

migration and expansion of surviving cells

 Endothelial cell number decrease 50% from

birth to date. Corneal decomposition wont
occur until central cell become 500 cell/mm2
 Functions
 Barrier from aqueous humor (junctional

complexes)
 Maintaining health and clarity of cornea by

pump leak mechanism

 Secret anterior located descement’s

membrane and posterior located

glycocalyx
 Endothelial barrier and pump
 Basis of barrier function is the presence of

tight junction around apical cell margin and

gap junction along lateral membrane.
 Metabolic pump of endothelium is

controlled by the Na+/K+ ATPase

 Endothelial ion and fluid transport

 Stroma has total Na+ concentration of

179mEq/L with 134.4mEq/L free and
44.6mEq/L bound to PG.

 Aqueous humor has 142.9mEq/L unbound Na+

creating Na+ gradient and stromal water move
out to aqueous by osmosis
Corneal Metabolism
 Epithelium
 Metabolism carried out under a broad

range of temperature, average corneal

temperature is 34.8°C

 It primarily uses glucose and glycogen for

energy production
 Glucose is metabolized in corneal
epithelium mainly by anaerobic glycolysis,
35% of glucose enter HMP

Cornea consumes approximately 3.5μl

oxygen/cm2/hr, get its oxygen from the
atmosphere under open eye
 Endothelium
 Utilizes the same carbohydrate metabolism
pathways as the epithelium.
 Atmospheric oxygen is primary source of

oxygen.
 Low oxygen during contact lens use or low

environmental oxygen result anaerobic

metabolism which increase stromal lactic
acid and CO2
Wound healing
 Epithelium

 Following a traumatic injury all of corneal

cell quickly responds to restore the
integrity of the wounded area

 Epithelium responds by initiation of

migration across the basement membrane
to cover the abraded area and re establish
barrier
 Cell migration begin about 5 hours after
wounding
 During lag phase cellular reorganization

occurs, hemidesmosomes disappear from the

basal cells, biochemical processes that
prepare the cells
 Corneal nerves have trophic effect on the

epithelium.
 Chronic sympathetic nerve stimulation on

experimental animal inhabit epithelial healing

 Stroma

 Following stromal wound keratocyte in

wounded area become activated and migrate
to the site.

 Activated keratocyte are enlarged, flat and

fusiform, increased number of RER,
prominent Golgi complexes and extensive
microtuble and cortical microfilament network
 Following injury, keratocyte migrate to
wound area and begin to remodel
Endothelium
following central endothelial injury both central and
peripheral cell densities decrease while coefficient of
variation in cell size increase (polymegathisim)

Heals in three stages

1) stage one (0-3 day)
2) stage two (4-7 day)
3) stage three (8-30 day)
Corneal immunity
 Normal cornea is devoid of blood vessels,
lymphatic, and inflammatory cells
 Class II antigen-bearing langerhans cells

found in epithelium with great densities on

periphery
 Complements C3,C4, and C5 found

throughout stroma but more on periphery

 IGg, IGA found throughout stroma IGM found

only on periphery
Cornea innervations and sensitivity
 Corneal epithelium is one of the most highly
innervated structures in the body.

 Sensitivities are 300 to 600 times that of skin

 An area of 0.01mm2 may contain 100 terminal

endings.

 Corneal major nerve supply is long cilliary nerve

which origin from ophthalmic branch of trigeminal
ganglion.
 Ophthalmic nerve and its branches

 One of sensory branch of trigeminal nerve

 Enter orbit via superior orbital fissure

 Branches
1. Nasociliary
2. Frontal nerve

3. Lacrimal
 Nasociliary nerves branches
1. two long ciliary nerve

2. Infratrochlear nerve

3. External nasal nerve

4. Communicating branch of the ciliary

ganglion
 After penetrating the sclera at posterior pole,
a mixture of sensory, sympathetic and
parasympathetic nerve fiber a ring around the
optic nerve.
 Sympathetic nerve is from superior cervical

ganglion, parasympathetic from ciliary

ganglion
 Ciliary nerve fascicles travel anteriorly

towards cornea
 This nerve fibers form a series of ring
meshworks of nerve fibers at the limbus
called limbal or pericorneal plexus

 Limbal plexus nerve supply the sensory and

autonomic innervations of the limbal vessels,
trabecular meshwork and scleral spur.
Distribution and ultra structure of
corneal nerve
 Nerve bundle enter cornea at periphery in radial
fashion parallel to the corneal surface

 Lose their periniurium and myelin sheath within

1mm of the limbus and continue only by schewan
cell sheath

 Majority of stromal nerve fibers located in anterior

third of stroma however the thick nerve trunk
move from periphery to central below the anterior
third of stroma due to collagen arrangement
73
 As they course through the stroma the nerve fibers
turn abruptly 90° and proceed towards corneal surface

 After penetrating Bowman’s layer large nerve fiber branch

divides in to many small fibers which then once again
abruptly turn 90° and continues parallel to corneal surface as
epithelial leashes.

 From sub basal area thin short and beaded terminal axone
ascends between epithelial cell
76
 Cold, touch, and pain are the only sensations recorded
from cornea

 Cold sensitivity is the result of scattered population of

Krause end –bulbs from conjunctiva epithelium
intruding onto cornea

 Touch and pain are both sub served by bare nerve

endings.

 Corneal sensitivity decrease with age, following

surgical procedure
 Neurochemistry of corneal innervations
 Sensory nerves express substance p (sp)

and/or CCGRP,PACAP, neuropeptide with

structural homology of VIP
 Autonomic nerve

-sympathetic nerve – Nor epinephrine,

NPY and/or serotonin
- parasympathetic –VIP, met-enkephalin,
NPY and gallin.
79
 Corneal nerve maintain corneal health by
their trophic influence on corneal epithelium.

 Dysfunction of this nerve results a

degenerative condition known as
neurotrophic keratitis
81
Role of cornea
 Light refraction
 Among 57-62 D of optical power 42D or

two third of power is from cornea

 Refractive power of the eye depends on

corneal curvature
 Refractive power of anterior cornea

computed with a formula of

 Posterior corneal power

 Total corneal power is the summation of

the two 48.2 -6.2

 Since central portion of the cornea is

thinner ,it was minus lens but function as
plus lens due to aqueous humor neutralize
most of minus optical power
 Drug delivery

 trans cornea and trans conjunctiva are

major pathway for drug delivery

 Cornea is primary pathway for lipophilic

and micro molecules.

 Corneal epithelium is lipoidal in nature and

poses resistance to hydrophilic substance
 Also corneal epithelium contain tight
junction (Zonula occludens) retard Para
cellular drug permission

 Stroma is highly hydrated structure which

posses a higher barrier to lipophilic drugs
compared to epithelium

 Corneal endothelial is leaky and facilitat

passage of macromolecule
 Corneal epithelium is the main anatomic
and physiologic permeability barrier for
drugs

 Unlike trance conjuctival, Trance corneal

drug delivery decrease the chance of drug
lose via vessles
 Ultraviolet light filtration
 UV light has more potential to cause

photochemical injury

 Although cornea is more sensitive to UV

light since it has no melanin people seldom
experience sun burn

 The cornea absorbs 100% of UV-C, 90%

UV-B, 60% of UV-A.
 UV-C absorbed by corneal epithelial due to
its high ascorbic acid content

 UV-B absorbed in anterior 100μm of

cornea due to high amount trypthophan
and ascorbic acid
Congenital anomalies of cornea
 Anomalies of size and shape
 Microcornea

- refers clear cornea with normal

thickness whose diameter is less than
10mm or 9mm in newborn

- cause is unknown, may be related fetal

growth arrest of cornea at 5th month
or overgrowth of anterior tips of optic cup
- can be transmitted as autosomal dominant
or recessive.

- concomitant anomalies include congenital

cataract, anterior segment dysgenesis,
optic nerve atrophy

- patients are usually hyperopic and

increase incidence of angle closure
glaucoma.
 Megalocornea
- bilateral non progressive corneal
enlargement with x linked recessive
inheritance

- corneal diameter measure 13-16.5mm

-etiology is related to failure of the optic

cup to grow and its anterior tips to close
- other etiologies include arrested
buphthalmos and exaggerated growth of
cornea in relation of the rest of cornea

- megalocornea may be associated with

other anomalies

- Congenital glaucoma should be ruled out

 Cornea plana
- refers to flat cornea with radius of
curvature less than 43 D

- curvature that is similar with sclera

is pathognomonic

- associated with mutation of the KERA

gene which code for keratin sulfate
- cornea plana usually associated with
sclero cornea or micro cornea

- hyperopia and any other refractive

error due to variation in globe size may
be present and angle closure and open
angle glaucoma occurs
 Abnormalities of corneal structure and/clarity
 posterior embryotoxon

-prominent anteriorly displaced

shwalbes ring that can be seen in
external examination of the eye

- inherit as a dominant trait

- the eye is usually normal but can

manifest other anterior segment
anomaly
 Axenfeld-Rieger syndrome

-ocular manifestation include presence of

posterior embryotoxon with attached iris
strands, iris hypoplasia, and glaucoma

- transmission is dominant but can be sporadic

-occurs due to late arrest in development of

anterior chamber structures
Peters
anomaly
- central corneal opacity at present at
birth

-usually associated with corneal adhesion

that extend from the iris collarette to the
border of corneal opacity

-two types of peters anomaly

1) type I- mesodermal or neuroectodermal

with no lens change association
2) typeII –surface ectoderm form associated
with lens change
-histologic finding shows localized
absence of the corneal endothelium
and Descemet’s membrane
 Posterior keratoconus
-characterized by local craterlike defect
on posterior surface of cornea with
concavity towards anterior chamber

-vision could be normal or slightly reduce

- histologically, Descemet’s shows

thinning ,anterior banding, and
posterior excrescences
 sclerocornea
-non progressive, non inflammatory
scelerization of the cornea

-most common associated ocular finding

cornea plana

- usually sporadic but has also autosomal

dominant and recessive pattern
Referance
 BCSC section 2 and 8
 Adler’s physiology of eye
 Duan’s
 Internet
THANK YOU