Cornea is a transparent avascular connective tissue composed of 5 layers consisting of epithelium, Bowman's membrane, stroma, descemet's membrane and endothelium.
Corneal epithelium, the most outer layer of cornea is a tissue having a thickness of about 50 .mu.m composed of 5 to 6 layers of cells, and occupies about one-tenth of the thickness of cornea. This corneal epithelium can be divided into three groups, a superficial cell, wing cell and basal cell from anatomical aspect. The superficial cell is a flat polygonal cell composed of 2 to 3 layers situated on the most outer surface, and has a length of about 40 .mu.m and a thickness of about 4 .mu.m. On the surface of the superficial cell, there is seen small projections, which enhance adhesion of a lacrimal layer, particularly a mucin layer thereof and enlarge the surface area for easy diffusion and active transport of a material from the lacrimal fluid.
In cytoplasm of a superficial cell, there are seen a few mitochondria and a lot of glycogen granules. The superficial cells firmly adhere to each other and form an important barrier to prevent the invasion of foreign materials including bacteria.
The wing cell is under the superficial cell, and exists in intermediate process wherein the cell pushed out from a basal cell layer is gradually flattened to become a superficial cell. The cells are adhered to each other with desmosome and mutual insertion between the cells is observed.
The basal cells form a layer, the lowest layer of corneal epithelium, and are polyhedral cells having a height of about 18 .mu.m and a width of about 10 .mu.m. A cell mitosis is active, a daughter cell resulting from mitosis becomes a wing cell, and further turns into a superficial cell is finally exfoliated from the corneal surface. It is said that the period of this cycle is about 1 to 2 weeks. In a cell membrane in the base part of the basal cell, there is an adhesion means called hemidesmosome and it adheres to a basement membrane below. Hemidesmosome, basement membrane and anchoring fibril below play an important role in adhesion of corneal epithelium. The basement membrane has a thickness of about 50 to 60 .mu.m formed by the basal cells, and composed of Type IV collagen, laminin, heparan sulfate and the like.
Corneal epithelium is sometimes lost because of various reasons. Corneal epithelial defect can be clinically classified into simple epithelial defect, recurrent epithelial defect and persistent epithelial defect.
The simple epithelial defect occurs when an epithelial cell is deleted or decomposed for example by dry eye, corneal infective disease, stem cell depletion syndrome, injury and the like.
Diseases caused by dry eye include Riley-day syndrome, Shy-Drager syndrome, Sjogren syndrome, sarcoidosis, amyloidosis, sequela of radiotherapy, lagophthalmia, avitaminosis A, Stevens-Johnson syndrome, ocular pemphigoid, marginal blepharitis, meibomitis, sequela of intraocular surgery, contact-lens affection, diabetic corneal epitheliopathy, dry eye due to VDT operation and the like.
Disorder caused by corneal infective disease includes for example viral epitheliopathy and the like.
The stem cell depletion syndrome includes Stevens-Johnson syndrome, ocular pemphigoid, thermal or chemical burn, drug toxicity of idoxuridine (IDU) and therapeutical agents for glaucoma and the like.
The recurrent epithelial defect is caused, for example, by reduction in adhesion of a epithelial cell to stroma due to recurrent corneal epithelial erosion (including injury), map-dot-fingerprint dystrophy, grill-like corneal dystrophy, Reis-Buecklers corneal dystrophy, diabetic corneal epitheliopathy and the like.
The persistent epithelial defect is caused by disorder in migration of a epithelial cell due to, for example, chemical burn, neurotrophic keratitis, corneal infective disease, toxicity of anti-viral agent and anti-microbial agent.
It has been generally believed that when such corneal disorders, particularly wound and defect occur on corneal epithelium, healing and regeneration can be achieved only by proliferation of a basal cell in corneal epithelium, however, recent influential theory is that a stem cell existing in corneal limbus prolifirates and migrates gradually towards central part of cornea and then, the cell is pushed out on the surface of cornea for regeneration of corneal epithelium Schermer A. et al., J. Cell. Biol. 103: 49 to 62 (1986)!. Limbal epithelium exists spreading for a length of about 1 mm in corneal limbal portion which is a transition part from conjunctival epithelium to corneal epithelium, and in human, forms a specific wrinkled structure called POV (Palisades of Vogt). This limbal epithelium occupies about one-forth in the area of cornea, and differs from conjunctival epithelium in that there is no goblet cell and differs from corneal epithelium also in that a subepithelial tissue contains a blood vessel and Langerhan's cell and melanocyte exist. Further, the stem cell of corneal epithelium is believed to exist therein. In fact, when such limbal epithelium regenerates on cornea, it forms epithelium having the same function as normal corneal epithelium.
According to a rabbit experiment, after corneal epithelial defect is caused, limbal epithelium quickly repeats cell migration and proliferation, and primary healing of epithelium is completed in about 4 to 5 days. After that, epithelial proliferation continues for several days, and the thickness increases gradually and the same construction as normal corneal epithelium is formed in about 2 weeks. Though, it is a feature of regenerated conjunctival epithelium that an goblet cell is recognized in regenerated epithelium, such an goblet cell is not produced in the regeneration process. Thus, regeneration in a limbal epithelium extremely resembles regeneration in corneal epithelium in surrounding parts. However, it has been revealed that regenerated limbal epithelium two weeks after healing is not the same as the regenerated corneal epithelium. For example, it is also said that there is a little difference between their intraepithelial protein patterns while an electron-microscopic observation of the regenerated limbal epithelium somewhat resembles that of conjunctiva. Further, it is reported that migration of the epithelium regenerated from limbal epithelium are suppressed by steroid, however, they are not suppressed in the case of regenerated corneal epithelium.
In this way, the regenerated limbal epithelium in early phase after wound healing seems slightly different from corneal epithelium, however, it is considered that the same cell formation function as corneal epithelium is recovered in the long term.
In either case, when wound or defect occurs in cornea, there are fears that crisis of corneal infection increases, corneal ulcer, corneal stromal opacity and the like are caused, and a serious disorder in visual function is caused. Therefore, when wound or defect occurs in corneal epithelium, it is important to repair them as fast as possible.
However, at the present time, there are only nosotropic means like equipping with a compression eye bandage or soft contact lens, application of an eye ointment and the like, against wound and defect of corneal epithelium, and consequently, it is strongly desired to positively establish the treating methods.
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USPTO Backgrounds