The cornea is one of the most heavily innervated and most sensitive tissues in the body. The density of nerve endings in the cornea is thus about 300 to 400 times greater than that in the skin.^[5],[6] Most of the sensory nerves in the cornea are derived from the ciliary nerves of the ophthalmic branch of the trigeminal nerve. The long ciliary nerves provide the perilimbal nerve ring. Nerve fibers penetrate the cornea in the deep peripheral stroma radially and then course anteriorly, forming a terminal subepithelial plexus.^[7] The nerve fibers lose their myelination within a short distance of their point of entry into the cornea, penetrate Bowman's layer, and terminate at the wing cell level of the epithelium. Loss of the superficial corneal epithelium results in exposure of the nerve endings and consequent severe ocular pain.

Slit lamp microscopy allows observation of nerve fibers in the corneal stroma. The fibers are especially prominent at the corneal periphery, where their diameter is relatively large. Laser-scanning confocal biomicroscopy has revealed networks of fine nerve fibers (subepithelial nerve plexuses) in or below the basal cell layer of the corneal epithelium.^[6,8,9] The diameter of these nerve fibers increases with distance from the anterior corneal surface (Fig. 1.3).

Histochemical studies have revealed the presence of various neurotransmitters, including substance P, calcitonin gene-related peptide, neuropeptide Y, vasoactive intestinal peptide, galanin, methionine-enkephalin, catecholamines, and acetylcholine, in the cornea.^[6,10–21] The cornea thus contains peptidergic, sympathetic, and parasympathetic nerve fibers. Degeneration or dysfunction of sensory nerves (trigeminal nerve branches) in the cornea can result in delayed healing of corneal injuries and the development of neurotrophic ulcer.

The short and long posterior ciliary nerves, which are branches of the trigeminal nerve, penetrate the sclera and provide fine sensory branches to the scleral stroma. In addition, nerve fibers are also present in the episclera. These fibers include those of vasodilative and vasoconstrictive nerves and are thought to regulate blood flow and volume in the episcleral vessels for modulation of episcleral venous pressure and outflow facility.^[22] Cells in the scleral spur are also thought to contribute to the regulation of intraocular pressure. Axons of presumably parasympathetic origin are present in the scleral spur of humans. On the other hand, cholinergic innervation of scleral spur cells appears to be rare or absent.^[23]

Vascular system

The cornea is one of the few avascular tissues in the body. Although the normal cornea does not contain blood vessels, factors derived from the blood play important roles in corneal metabolism and wound healing. The anterior ciliary artery, which is derived from the ophthalmic artery, forms a vascular arcade in the limbal region that anastomoses with vessels derived from the facial branch of the external carotid artery. The cornea is thus supplied with blood components by both internal and external carotid arteries. In certain pathological conditions, new vessels enter the transparent corneal stroma from the limbus and result in a loss of corneal transparency.

In contrast to the cornea, the episclera is highly vascularized. The episcleral vasculature shows a specialized morphology characterized by the absence of capillaries, numerous arteriovenous anastomoses, and a muscle-rich venous network, which is thought to play an important role in the regulation of intraocular pressure. Such vascularization is also apparent in the loose connective tissue of Tenon's capsule. The scleral stroma contains few blood vessels with the exception of the input and output of the vessels of the choroidal circulation.

Oxygen and nutrient supply

Corneal epithelial and endothelial cells are metabolically active. Cellular activities require adenosine triphosphate (ATP) as an energy source, with catabolism of glucose by glycolysis and the citric acid cycle generating ATP under aerobic conditions. A supply of glucose and oxygen is thus essential to maintain the normal metabolic functions of the cornea.^[24–27] The cornea is supplied with glucose by diffusion from the aqueous humor. In contrast, oxygen is supplied to the cornea primarily by diffusion from tear fluid, which absorbs oxygen from the air. Direct exposure of tear fluid to the atmosphere is thus essential for oxygenation of the cornea. Disruption of the oxygen supply to the cornea, such as that resulting from the wearing of contact lenses with less gas permeability, can lead to corneal hypoxia and consequent stromal edema.^[28–31] Closure of the eyelids during sleep also reduces the amount of oxygen that reaches the cornea. Corneal metabolism therefore changes from aerobic to anaerobic (with consequent accumulation of lactate) during sleep.^[32],[33]

Tear fluid

The corneal surface is covered by tear fluid, which protects the cornea from dehydration and helps to maintain the smooth epithelial surface. The thickness and volume of the tear film are about 7 µm and 6.5 µL, respectively.^[34],[35] The tear film consists of three layers: a superficial lipid layer (≈0.1 µm), an aqueous layer (≈7 µm), and a mucinous layer (0.02–0.05 µm).^[36] More than 98% of the total volume of the tear film is water. However, tear fluid also contains many biologically important ions and molecules, including electrolytes, glucose, immunoglobulins, lactoferrin, lysozyme, albumin, and oxygen. Moreover, it contains a wide range of biologically active substances such as histamine, prostaglandins, growth factors, and cytokines (Table 1.1). The tear film thus serves not only as a lubricant and source of nutrients for the corneal epithelium but also as a source of regulatory factors required for epithelial maintenance and repair.^[37–54]

The components of the superficial lipid layer of the tear film are supplied by meibomian glands and other secretory glands of the eyelid. The aqueous layer is derived from the lacrimal gland and accessory lacrimal glands, and the mucinous layer is produced largely by goblet cells in the conjunctival epithelium. Hypolacrimation (dry eye syndrome) can thus be classified basically into three categories attributable to lipid, aqueous, or mucin deficiency.