Corneal Physiology

Glucose and oxygen metabolism

• Oxygen is obtained by diffusion through tear film when the eye is open and from the lid vasculature and aqueous when closed

• Glucose supply to epithelium from tear film and limbal blood vessels
• Glucose supply to endothelium from aqueous

• Epithelium and endothelium metabolise glucose via the three main forms of carbohydrate catabolism

• Citric acid (Kreb’s) cycle): 24 molecules of ATP in the presence of oxygen
• Glycolysis: 2 molecules of ATP in the absence of oxygen
• This anaerobic process predominates in the epithelium representing 85% of glucose use

• Pentose-phosphate pathway (although keratocytes do not possess 6-phosphogluconate dehydrogenase and so cannot use this pathway)

• Lactic acid diffuses passively into aqueous

• When lactate accumulates (eg. due to overwearing of poorly fitting contact lenses) then only a small proportion is lost in tears and more accumulates in the stroma

• Leads to corneal oedema by altering osmotic pressures

• Lactate is also transported via an H+/lactate pump so increased lactate leads to acidification of the cornea and cell shrinkage

Electrolyte transport

• Cornea is 75-80% water
• Epithelium is relatively impermeable (see above)
• Endothelium is leaky
• At aqueous interface: Na/HCO3 co-transporter and HCO3/Cl exchanger
• At stromal interface: Na/K ATPase and Na/H antiporter
• Sodium passively diffuses into epithelium from tears down concentration gradient
• Na/K ATPase in epithelium pumps sodium into stroma in exchange for potassium
• Epithelium is therefore:
• Low sodium (70 mmol/L) 
• High potassium (140 mmol/L)
• Stroma by contrast
• Potassium concentration (20 mmol/L) is seven times lower than epithelium
• But stromal sodium is more than double (170 mmol/L)
• Low chloride concentration in stroma too (110 mmol/L)
• Electroneutrality of the stroma is compensated for by the glycosaminoglycans

• Endothelium utilises sodium and bicarbonate ion pumps to maintain hydration levels by causing passive secondary movement of water (negative hydrostatic pressure)

• Tear film tonicity affects corneal hydration, eg. adding glycerin to tear film will draw water out of cornea

• During sleep the cornea thickens due to relative hypoxia: about 4-8% during an average night

Corneal transparency

• Factors necessary for corneal transparency

• Dehydration from: endothelial activity, evaporation of tears and normal intraocular pressure (raised pressure leads to hydration)

• Acellularity and avascularity
• Regular matrix structure of collagen fibrils with destructive interference
• Consistent refractive index throughout layers

Matrix of collagen fibrils

• Diameter and spacing of collagen fibrils is remarkably constant
• Collagen fibrils of small and uniform diameter are needed for transparency
• Corneal scars have wider and longer collagen fibrils 

• Anterior third of stroma: collagen fibrils are oblique, in the posterior two thirds they are parallel

• High tensile strength between fibrils due to cross-links

• Keratan sulphate is the most common corneal proteoglycan (60%) followed by dermatan sulphate (40%) and these bind to collagen fibrils, contributing to the regulation of their spacing

• Adult stroma: keratan sulphate concentrated in posterior stroma and dermatan concentrated in anterior stroma

• The keratan sulphate:dermatan sulphate ratio decreases in corneal scars (ie. loss of keratan sulphate leading to irregularly arranged fibrils).

• Maurice hypothesis: fibril spacing causes destructive interference of the light scattered by individual fibrils leading to transparency (light is therefore not scattered at all due to the difference between the refractive index of collagen and that of stromal ground matrix).

• Endothelial damage leads to the cells becoming fibroblastic

• Retrocorneal fibrous membrane (RCFM) develops between Descemet’s and endothelium leading to loss of VA

• MMPs are produced by in-coming inflammatory cells and corneal cells in response to injury:

• Only MMP-2 (gelatinase) is found in normal cornea but others are produced on injury (including MMP-1, MMP-3, MMP-9)

• MMP-1: collagenase produced by stroma
• MMP-3: a stromelysin produced by stroma
• MMP-9: a gelatinase produced by epithelium. Involved in corneal remodelling

• These are enzymes which destroy the extracellular matrix needed for maintenance and remodelling of the cornea after damage

• MMPs are pro-angiogenic