physiology of cornea

1. PHYSIOLOGY OF
CORNEA
PRESENTED BY: SHREEJI
SHRESTHA

2. History
Cornea = Kerato
Kerato in greek = Horn/shield like
Ancient believe cornea derived from
same material as horn.

3. Functions of cornea
Refractive surface of eye (43D)
Protects intraocular contents
Absorbs topically applied drugs
Wound repair after anterior segment
injury

4. Biochemical composition of cornea
Metabolism of cornea
Corneal transparency
Drug Permeability
Corneal wound healing
Corneal and contact lens

5. Biochemical composition: Epithelium
10% of total wet weight
1. Water : 70% of wet weight
2. Protein synthesis: 5 times higher then stroma
3. Lipids: phospholipid and cholesterol
4. Enzyme: glycolysis, Krebs cycle, Na-k ATPase
5. Glycogen, glutathione, ascorbic acid
6. Acetycholine: cation transport
7. Electrolyte: K=142mEq/L, Na=75, Cl=30

6. Stroma:90% of total thickness
1. Water (78%)
2. Cells: Keratinocyte
3. Collagen : Type 1,V,VI,XII,XIV
4. Soluble proteins: albumin, immunoglobulin, glycoprotein
5. Proteoglycans (GAG): keratan sulphate, chondroitin sulphate,
Chondroitin( hydrophilic)
6. Enzyme
7. Matrix metalloproteinases
8. Proteinase inhibitor
9. Electrolyte

8. COLLAGEN:
▪ embedded in hydrated matrix of proteoglycans
▪ High glycine, proline and hydroxyproline
▪ Mature collagen – helix composed of 2 alpha chains and 1 beta
chain
▪ Dissolved by proteolytic enzyme: collagenase (corneal ulcer)
▪ In Acid burn: Collagen gelatin (burn being less serious)
GAG: imbibe water, maintain hydration and transparency
mucopolysaccharidosis: increase GAG
MMP: secreted by inflammatory cells:- maintain framework
eg:)MMP-1 (collagenase) MMP-2 (gelatinase A = normal cornea)

9. Predescemet’s and Descemets membrane:
High hydroxyproline, glycine
no GAG
Insoluble (except in burn)
Resistant to enzymatic action
Endothelium:
Single layered
Enzyme

10. Metabolism of cornea
OXYGEN
Closure of the eyelids during sleep- reduces the amount of
oxygen - metabolism changes from aerobic to anaerobic
during sleep.
rigid lens(PMMA):less gas permeability interfere with O2
uptake intracellular edema, decrease glycogen, increase
lactic acid.
Mean total corneal oxygen consumption – 9.5ml O2/cm²/hr
Air

11. Glucose
Aqueous humor - main source
Tear film and perilimbal capillaries- negligible
min requirement:- 50-60 mg/cm2/hr
Additional glucose: break down of glycogen in
epithelium at 25 mg/cm2/hr
Amino acids-
Aqueous humour by passive diffusion

12. Metabolic pathway in cornea
Diffusion
NADP
NADPH
Biosynthesis of lipid DNA

13. Corneal transparency: 1.corneal
epithelium and tear film

14. 2.Arrangement of stromal lamellae
a) Maurice theory( 1957: crystalline lattice theory)
As fibrils are regularly arranged in lattice with
diameter (275-300 A) and separated by less than
wavelength of light 4000 to 7000 A
light scattered by individual fibers is cancelled by
destructive interference with light scattered by
neighboring fibers

15. b) Goldman and benedek (1967)
Lattice arrangement is not a necessary condition
for stromal transparency
Refractive elements in tissues whose dimensions
are <200nm compared with wavelength of light
(500nm) should not scatter as much light as
predicted by Crystalline lattice theory
limitations: fail to explain rapid clouding of cornea
with increase in IOP

16. 3.corneal vascularization
Avascular except for small loops invading the
periphery for about 1mm.
Defense mechanism against noxious agents.
Facilitates nutrition, transport of systemic
antibiotics and drugs.

17. Pathogenesis of corneal vascularization
1. Chemical theory
Presence of VSF & VEGF or destruction of VIF
2. Mechanical theory
blood vessel cannot invade cornea- compact nature
3. Combined theory
Stimulates new vessel
growth
Prevents vascular
invasion
Loosening
Corneal edema
Neovascularization

18. 4. Corneal hydration
Normal cornea - relative dehydration - corneal
transparency
water - 80%
kept constant by:
Draw water in cornea
Swelling pressure of storma, IOP
Prevent flow of water
Epithelium
Draw water out of cornea
Pumping action of endothelium

19. a) Stromal swelling pressure
Anti parallel GAG duplex(tertirary structure) produce
long range electrostatic repulsive force - swelling
pressure
amount of force cornea must create to counter
balance corneal edema
has Cohesive and high
tensile stiffness - resist.
expansion - SP = 55mmhg

20. Conversely, GAG - form double folded helix in
aqueous solution
attracts and bind Na cations
osmotic effect
Diffusion and absorption of water
Hence, CCT (540 ) is maintained due to balance
between
Fixed negatively charged
GAG induced swelling
pressure
through anions repulsive
force
Cationic attractive force
imbibing more water

21. Repulsion anionic charges on GAG - expands tissue -
drawing fluid into cornea by negative pressure -
imbibition pressure ( -40mmhg)
Semipermeable - Epithelium and Endothelium - barrier to
excessive flow of water and diffusion of electrolyte into
storma
Epithelium offer twice resistance to water
Hence, loss of barrier Function and increase in IOP -
corneal edema
IP = IOP -SP

22. During sleep, diurnal variation in hydration occurs -
Increase in CCT due to reduced oxygen level and loss of
evaporation by lid closure
on awakening, CCT revert back to normal in 1-2 hours
If cornea is hydrated > 5% - scattering of light - loses its
transparency
Conc of GAG is more in posterior stroma, hence anterior
stroma swells mildly
posterior stroma - swells three times it normal thickness

24. c) hydration by active pump mechanism
located in the endothelial cell’s basolateral cell membrane
transport ions, sodium (Na+) and bicarbonate (HCO3−), out
of the stroma into the aqueous humor
osmotic gradient and
water is thus osmotically drawn from the stroma into the
aqueous humor.
osmotic gradient can be maintained only if the endothelial
barrier is intact.
major endothelial pump: Na-K ATPase
average pump site density of 4.4 trillion sites/ mm2

25. c) hydration by active pump mechanism
Na k ATPase pump failure:- stromal edema, subepithelial
fibrosis, epithelial bullae ( Fuchs endothelial dystrophy)
oubain

26. d) evaporation of water from tear film
inc its osmolarity - drawing water from cornea -
trasparency
e) IOP - IOP > SP = epithelial edema
other factors:- 5) Epithelium non keratinized
6) Non-myelinated nerve fibers

27. Drug permeability across cornea
Volume of normal adult tear flim is 7-9microL and Max cul
de sac can maintain - 25 - 30 microL
Volume of 1 drop = 40 microL
most of drug runs out of eye and remainder is diluted to
approx 25%
both volume and Conc of drug are reduced
after topical administration 10% drug enter stroma by
Corneal penetration
50-90% goes to systemic circulation by conjunctival
vasculature

28. Topical drugs also reach the vitreous cavity - via the
conjunctival–scleral–choroid–RPE–retina
The advantages of topical delivery are .
convenience
non-invasiveness,
its avoidance of first-pass metabolism in the liver
its ability to locally target cornea and anterior segment
tissues with high drug concentrations.
The main disadvantages are
its high dynamic drug clearance rates and its static

29. lipid and water solubility
epithelium and endothelium are lipophilic- crossed
by lipid-soluble drug.
storma - hydrophilic
hence, drug should be amphipathic
Some preservative e.g. Benzalkonium chloride -
impair integrity of epithelium and increase
penetration

30. Molecular size, weight, concentration
all lipid soluble cross epithelium irrespective of size
whereas water soluble molecule < 4 A only filter
through pores
Weight - < 500 can pass
Drug with large molecular size if used in high
concentration - small amount can cross
eg. Pilocarpine, atropine depend upon concentration

31. Ionic form of drug, pH, Tonicity
capacity to exit both in ionized and non ionized form for better
penetration
Non-ionized drug penetrate through - epithelium hence fluorescein
negatively charged ion cannot penetrate intact epithelium, this
property forms basis for fluorescein dye test.
Ionized drug - stroma
pH :- vary from 4 - 10
Tonicity: -hypotonic ( <0.9 %) increase permeability
wetting agents :- increase permeability by reducing surface tension
Prodrug :- lipophilic and after absorption converted to active

32. Drug deposit in cornea
Vortex Keratopathy : whorl like corneal
epithelial deposit in antimalarial,
amiodarone
Chlorpromazine : yellow brown
deposition in endothelium and stroma
Agyrosis: grayish deposit in endothelium

33. Maintenance of epithelium ( cell migration)
by balance among cells: (XYZ hypothesis)Thoft and
Friend proposed that an equilibrium exists between
, ,
Cells originate from Limbal stem cells
differentiation of
basal cells into
superficial cells X
centripetal
movement of
epithelial cells Y
desquamation of
epithelial cells
from the corneal
surface Z

34. Mitosis and shedding
Occurs only in basal layers
daughter cells move upward from basal layer
differentiating into wing and superficial cell
Superficial cell shed continuously and turn over
complete every week.

35. Epithelium injury and healing
injury inhibits mitosis of epithelial cell
Centripetal migration of marginal cells by rearrangement of actin
fibrils in filopodial, lamellipodia, and ruffles extension of cells
Cells separate from basal lamina and travel in amoeboid manner
(fibronection, helps in migration)
mitosis is resumed epithelial thickness reestablished
cell to substrate adhesion occurs by vinculin–talin–integrin
complex & adhesion between basal cells, basal lamina and
bowman layer via hemidesmosome and anchoring type 4
collagen fibrils

36. Factors delaying corneal epithelial healing
damage to the cellular substrate (caused by herpetic or
other infectious disease, diabetes mellitus, chemical burns,
or basement membrane injuries and/or corneal
dystrophies),
ocular surface inflammation or atopic disease,
dry eyes, neurotrophic and exposure keratopathies,
conjunctival disease ( keratoconjunctivitis),
extensive damage to the limbal stem cells, and eyelid
abnormalities
Degeneration or dysfunction of sensory nerves (trigeminal
nerve branches)

37. Factors promoting corneal healing
Reduction of exposure to toxic medication, preservative
Lubricating and tapping
minimizing use soft contact lens
Surgical eyelid closure in exposure keratopathies
Amniotic membrane patch grafting
tissue adhesive
limbal stem cell transplantation

38. stromal injury
corneal epithelial injury
Apoptosis of underlying stromal keratocyte
Proteolytic enzyme released
Breakdown of stroma macromolecules (edema)
Proliferation and migration of surviving keratocyte within
24hours (fibroblast like appearance and behavior)
Synthesize collagen and GAG
Irregular arrangement of fibrils (opacity)
production of Normal corneal matrix to induce clarity

39. Endothelium injury
healing occurs by migration and of enlargement
surrounding cell
Patient with diabetes have low endothelial count

41. Indication of specular microscopy
Prior to surgery: edema if density < 700 cells/mm2
Donor cornea evaluation: suitability for penetrating
keratoplasty
To demonstrate pathology:- guttata, descemet
membrane irregularity

43. ○ Endothelial wound:
Stage Day state of healing
I 0-1 Wound present
1-2 Cells sliding ,mitosis ,
Wound decrease in size
3 Wound completely covered
II 4-6 Establishment of monolayer
III 8-30 Remodeling of monolayer

44. contact lens and cornea
Reduces direct availability of oxygen to epithelium
Shifting from aerobic to anaerobic metabolism
hence lactate level is doubled in contact lens wear
types:
hard rigid lenses, soft contact lenses, gas permeable
lenses

45. Disadvantage
Thinning and reduction of hemidesmosome,
anchoring fibrils
Excessive use : epithelial edema, punctate
epithelial erosion
Limbal redness, endothelium polymegethism

46. Reference
Adler physiology chapter 4 cornea and sclera
Cornea fundamentals, diagnosis and management;
krachmer, chapter 1 cornea and sclera
Ophthalmology, myron yanoff, cornea and ocular
surface disease
Anatomy and physiology of eye, AK khurana, chapter
2
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