The cornea

The cornea is made up of the stroma (up to 90% of its thickness) which is bounded externally by epithelium and the Bowman's membrane and internally by Descemet's membrane and the endothelium (Figure 11.2). The mean thickness of the cornea in man is just over 0.5 mm in the central region and is composed of five to six layers of cells. It becomes 50% thicker towards the periphery as the epithelium increases to eight to ten cell layers. The cells at the base are columnar, but as they are squeezed forward by new cells, they become flatter. These cells can be classified into three groups: basal cells, an intermediate zone of 2-3 layers of polygonal cells (wing shaped) and squamous cells. The permeability of the intact corneal epithelium is low until the outermost layer is damaged, suggesting that tight junctions exist between the cells in this layer. The outer layer of the surface cells possesses microvilli, which presumably help to anchor the precorneal tear film. The cells of the basal layer show extensive interdigitation of plasma membranes and are therefore relatively permeable.

Figure 11.2 The five layers of the cornea

Immediately adjacent to the epithelium is a less ordered region of the stroma or Bowman's membrane. It is not sharply differentiated from the stroma beneath it and could be described as Bowman's layer rather than a membrane.

The stroma substantia propria consists of a set of lamellae, or plates, running parallel with the surface and superimposed on each other like the leaves of a book. Between the lamellae lie the corneal corpuscles, cells that synthesize new collagen essential for the repair and maintenance of this layer.

The stroma can be considered to have a comparatively open structure that normally allows diffusion of solutes having molecular weight below 500,000 Daltons. It can act as a barrier for very lipophilic substances that pass freely through the epithelium, while it is easily penetrated by hydrophilic solutes.

Descemet's membrane is located on the interior surface of the stroma and it is secreted by the endothelium. It is made up of a different type of collagen from that in the stroma. The endothelium consists of a single layer of flattened cells 5 pm high and 20 pm wide. These cells form a regular mosaic, each with close contact with its neighbours. The endothelium is about 200 times more permeable than the epithelium and thus represents a weak barrier. The endothelium is in contact with the aqueous humor of the anterior chamber. The endothelial layer is crossed by a passive flux of water towards the stroma, which has a tendency to swell. An active pump mechanism generates a flux in the opposite direction that controls corneal tumescence.

Although the cornea covers only one-sixth of the total surface area of the eyeball, it is considered the main pathway for the permeation of drugs into the intraocular tissues.

The conjunctiva and sclera

The conjunctiva lines the posterior surface of the eyelids and covers the exterior surface of the cornea. The portion that lines the lids is called the palpebral conjunctiva; the portion covering the white of the eyeball is called the bulbar conjunctiva. The palpebral conjunctiva is vascular and the bulbar conjunctiva is transparent. The area between the lids and the globe is termed the conjunctival sac that is open at the front at the palpebral fissure and only complete when the eyes are closed.

The sclera is composed primarily of collagen and mucopolysaccharide and forms the posterior five sixths of the protective coat of the eye. Its anterior portion is visible and constitutes the white of the eye. Attached to the sclera are the extraocular muscles. Through the sclera pass the nerves and the blood vessels that penetrate into the interior of the eye. At its posterior portion, the site of attachment of the optic nerve, the sclera becomes a thin sieve like structure, the lamina cribrosa, through which the retinal fibres leave the eye to form the optic nerve. The episcleral tissue is a loose connective and elastic tissue that covers the sclera and unites it with the conjunctiva above.

The choroid and retina

The choroid is the middle pigmented vascular coat of the posterior five-sixth of the eyeball. It is continuous with the iris in the front. It lies between the retina and the sclera and prevents the passage of light rays.

The retina is the light sensitive inner lining to the eyeball. It consists of seven nervous layers and one pigmented layer.

The aqueous humor

The aqueous humor is a clear colourless fluid with a chemical composition rather similar to that of blood plasma, but with a lower protein content. Its main function is to keep the globe reasonably firm and it is secreted continuously by the ciliary body into the posterior chamber. It flows as a gentle stream through the pupil into the anterior chamber, from which it is drained by he canal of Schlemm.

The vitreous body is a jelly made up of a form of collagen, vitrosin, and the mucopolysaccharide, hyaluronic acid. Its composition is similar to that of the cornea, but the proportion of water is much greater, about 98 percent or more, compared with about 75 percent for the cornea. The vitreous body serves to keep the underlying retina pressed against the choroid.

The eyelids

The eyelids are movable folds of modified fleshy skin consisting of orbital and palpebral portions positioned in front of the eyeball (Figure 11.3). They have an obvious protective function and play an important role in the maintenance of the tear film and lacrimal drainage. Fibrous tarsal plates provide the framework for the lids.

Between the bulbar and the palpebral conjunctiva there are two loose, redundant portions forming recesses that project back. These recesses are called the upper and lower fornices, or conjunctival sacs. The looseness of the conjunctiva in this region makes movements of lids and eyeball possible.

Figure 11.3 Vertical section through the eyelids and conjunctiva The precorneal tear film

The maintenance of a clear, healthy cornea requires that the anterior surface of its epithelial layer be kept moist. The precorneal tear film is a very thin fluid layer continuously bathing the corneal epithelium, the conjunctiva and walls of the conjunctival cul-desac. Normal secretion of tears by the lacrimal system is necessary for:

1. nutrition of the cornea,

2. protection against bacterial infection,

3. removal of cellular debris and foreign matter

4. formation of a stable, continuous fluid film over the cornea producing a high quality optical surface.

5. lubrication for the movement of the eyelids.

Figure 11.3 Vertical section through the eyelids and conjunctiva The precorneal tear film

The maintenance of a clear, healthy cornea requires that the anterior surface of its epithelial layer be kept moist. The precorneal tear film is a very thin fluid layer continuously bathing the corneal epithelium, the conjunctiva and walls of the conjunctival cul-desac. Normal secretion of tears by the lacrimal system is necessary for:

1. nutrition of the cornea,

2. protection against bacterial infection,

3. removal of cellular debris and foreign matter

4. formation of a stable, continuous fluid film over the cornea producing a high quality optical surface.

5. lubrication for the movement of the eyelids.

Superficial Lipid Layer

8 pm

-»Aqueous Layer

Microvilli

Figure 11.4 The structure of the tear film according to Wolff,

Mucoid Layer

Microvilli

Figure 11.4 The structure of the tear film according to Wolff,

The average tear volume in a human is 7 pl, 1 pl of which is contained in the precorneal tear film, and 3 pl in each of the tear margins. Prior to blinking, the tear volume can increase to about 30 pl. The maximum amount of fluid that can be held in the conjunctival sac is only about 10 pl As the tear layer is so thin, evaporation and lipid contamination of the mucin component of the tear fluids quickly destroys its continuity. This results in dry spots that appear usually within 15 to 30 seconds after a blink, at scattered locations on the corneal surface. The blinking action of the eyelids, which usually occurs before the actual formation of dry spots, is required to re-form the tear film layer. The blink interval should therefore, be shorter than the tear break-up time.

The precorneal tear film was first thought to be a three layered structure consisting of a superficial oily layer, a middle aqueous layer, and an adsorbed mucus layer (Figure 11.4), secreted by several glands (Figure 11.5)1. Recent research suggests that the mucus fraction extends through the tear film2

Eyelash Cornea Iris Lens

Accessory lacrimal glands

3. Glands of Krause

4. Glands of Wolfring

Main lacrimal glands

1. Orbital lobe

2. Palpebral lobe

Mucin secretors

5. Goblet cells

6. Glands of Manz

7. Crypts of Henle

Oil secretors

8. Meiomian gland

9. Glands of Moll

10. Glands of Zeis

Eyelash Cornea Iris Lens

Figure 11.5 The glands secreting the components of the precorneal tear film

The superficial oily layer is approximately 0.1 pm thick and consists of wax and cholesterol esters secreted by the Meibomian glands, the glands of Zeis at the palpebral margin of each eyelid, and the glands of Moll situated at the root of each lash. This layer reduces the evaporation from the underlying aqueous phase by a factor of 10 to 20, preventing the cornea from drying.

The aqueous layer lies below the oily layer and is the largest component of the tear film (6-10 pm thick), consisting of watery lacrimal secretions provided by the numerous accessory lacrimal glands of Kraus and Wolfring, most of which are situated in the upper conjunctival fornix.

The mucoid layer is secreted by conjunctival goblet cells, the crypts of Henle, which are situated on the conjunctival surface of the upper and lower tarsus, and the glands of Manz positioned in a circular ring on the limbal conjunctiva. Mucin is involved in adhesion of the aqueous phase to the underlying cornea, and thus keeps the cornea wettable.

Physical properties of tears

The normal pH of tears varies between 7.0 and 7.4. The pH of the tear film is influenced by any dissolved substances, particularly by the bicarbonate-carbon dioxide buffer system. When the eyelids are open, the pH of the precorneal tear film increases through loss of carbon dioxide. Solutions instilled into the lower fornix with pH below 6.6 and above 9.0 are associated with irritation, reflex tears and rapid blinking.

The surface tension of tear fluid at 33°C, the surface temperature of the eye, has been measured as between 44 and 50 mN.m-1 3. The instillation of a solution containing drugs or adjuvants that lower the surface tension may disrupt the outermost lipid layer of the tear film. The lubricant and protective effect of the oily film disappears and dry spots may be formed due to tear film evaporation. The dry spots cause irritation and reflex blinking is elicited to eliminate the sensation of a foreign body in the eye. In many cases, the sensation may be delayed for 30 minutes to 1 hour following the application, dependent on the concentration and nature of the instillate.

The evaporation process influences the tonicity of human tears when the eye is open. The osmolarity after prolonged eye closure or during sleep is 293 to 288 mOsmol. After the eye is opened, the osmolarity progressively rises at a rate of 1.43 mOsm.Kg-1.h-1 to 302 to 318 mOsm.Kg-1. Due to their molecular weight and low concentrations, proteins contribute only slightly to the total osmotic pressure, but they do influence tear viscosity. The viscosity of human tears ranges from 1.3 to 5.9 mPa.s with a mean value of 2.9 mPa.s.

Lacrimal drainage system

An efficient drainage system exists to remove excess lacrimal fluid and cell debris from the precorneal area of the eye (Figure 11.6). Tears initially drain through the lacrimal puncta, which are small circular openings of the lacrimal canalculi, situated on the medial aspect of both the upper and lower lid margins. They then pass through the mucous membrane lined lacrimal passages. The superior and inferior canalculi (approximately 8 mm in length and 1 mm in diameter) unite in the region of the medial canthus to form the common canalculus. This opens into the lacrimal sac about 3 mm below its apex. At its lower end, it is continuous with the nasolacrimal duct that passes downwards to open into the inferior meatus of the nose with a valvular mechanism at its opening. The tears finally pass into the nasopharynx.

The drainage of tears is an active process involving the lacrimal pump that is dependent on the integrity of the orbicularis muscle of the eyelids. Closure of the eyelids draws the lacrimal fluid from the puncta and canalculi into the sac by a suction effect. Opening the lids forces the lacrimal fluid from the sac into the nasolacrimal duct and then

Figure 11.6 Lacrimal drainage system

into the nose through the lower end of the sac. The valvular mechanism opens during this movement.

Blood-eye barriers

Several barriers prevent material entering the ocular circulation. The vessels of the iris have thick walls that prevent leakage of materials into the aqueous humor. The epithelium in the ciliary processes is a unique membrane that prevents the passage of most molecules, including antibiotics and proteins. However, molecules may enter the posterior chamber of the eye during the active secretion process that forms aqueous humor. Topically applied fluorescein is seen to leak across the choroidal circulation, without passing into the retinal pigment layer. Injury or inflammation can damage the blood-eye barriers, since the capillary endothelial and epithelial cells separate, resulting in destruction of the intercellular barrier and leakage of material.

The external eye is readily accessible for drug administration; however, as a consequence of its function as the visual apparatus, mechanisms are strongly developed for the clearance of foreign materials from the cornea to preserve visual acuity. This presents problems in the development of formulations for ophthalmic therapy.

Systemic administration of a drug to treat ocular disease would require a high concentrations of circulating drug in the plasma to achieve therapeutic quantities in the aqueous humour, with the increased risk of side effects. Topical administration is more direct, but conventional preparations of ophthalmic drugs, such as ointments, suspensions, or solutions, are relatively inefficient as therapeutic systems. A large proportion of the topically applied drug is immediately diluted in the tear film and excess fluid spills over the lid margin and the remainder is rapidly drained into the nasolacrimal duct. A proportion of the drug is not available for therapeutic action since it binds to the surrounding extraorbital tissues. In view of these losses frequent topical administration is necessary to maintain adequate drug levels. This results in transient periods of over and under-dosing (Figure 11.7).

Figure 11.7 Sawtooth pattern of therapy following administration of ophthalmic drugs as eye drops

Figure 11.7 Sawtooth pattern of therapy following administration of ophthalmic drugs as eye drops

Three factors have to be considered when drug delivery to the eye is attempted. Firstly, how to cross the blood-eye barrier (systemic to ocular) or cornea (external to ocular) to reach the site of action; secondly, how to localise the pharmacodynamic action at the eye and minimise drug action on other tissues and finally, how to prolong the duration of drug action such that the frequency of drug administration can be reduced.

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