First, the organization and physiology of the cornea The cornea (cornea) and the sclera together constitute the outermost fibrous membrane of the eye, while the cornea is also an important refractive interstitial, which is the necessary pathway for external light to enter the inner retina for imaging. From anterior to posterior, the cornea can be divided into five layers: the epithelium, the anterior elastic layer, the stroma, the posterior elastic layer and the endothelium, with a tear film covering the epithelium. The epithelial layer is 0.05 mm thick, accounting for 5% of the entire corneal thickness, and consists of 4-6 layers of non-keratinized squamous epithelial cells. The basal layer of epithelium at the corneal limbus contains corneal limbal stem cells, which can gradually differentiate into instant expansion cells and terminally differentiated epithelial cells, which are the source of corneal epithelial proliferation and repair, and the life cycle of corneal epithelial cells is about 7 to 14 days. The tight junctions between superficial epithelial cells prevent water from tears from entering the stroma. When the corneal epithelium is extensively deficient, the thickness of the cornea increases by 200% compared to normal. Continuous secretion of basal epithelial cells forms a 50-nm-thick basement membrane beneath it consisting of type IV collagen fibers, laminin, and other proteins. The corneal stroma accounts for about 9/10 of the corneal thickness and is composed of 200-250 layers of parallel-aligned fibrils. The fibrils in the anterior stroma have extensive interlayer intertwining, while the fibrils in the posterior stroma are wide and thick, extending from one end of the corneal limbus to the opposite side, and these fibrils are mainly type I collagen but also type III and V collagen, with uniform collagen diameter and regular arrangement and sparse collagen fiber bundles. Under normal intraocular pressure, the fiber bundles can only be extended by 0.25% of their original length. The posterior elastic layer is the basement membrane of the corneal endothelium, formed by the secretion of endothelial cells, mainly type IV collagen, the thickness of which is about 3 μm at birth and increases to 10-12 μm in adulthood. the endothelial layer is composed of hexagonal cells, which are closely interlaced in a mosaic. The mechanical barrier of the corneal endothelial cell layer, as well as the unique ion pump function, is essential for maintaining the relative dehydration of the cornea. Human corneal endothelial cells cannot regenerate in vivo after birth and rely on the expansion and migration of neighboring endothelial cells to fill the spots left by aging and damaged dead cells. Damage beyond a certain limit results in a corneal endothelial cell density less than the critical functional density (500-800 cells/mm2), which causes corneal endothelial loss of compensation, leading to persistent corneal edema and loss of transparency. Corneal transparency is maintained by the regular arrangement of intact corneal epithelial cells and tear film, collagen bundles in the stroma, the absence of blood vessels in the cornea, and the “dehydrated state”. The tightly packed epithelial cells and the overlying tear film form a smooth optical interface, resulting in a nearly uniform refractive index and reduced light scattering. The regular lattice-like arrangement of collagen fibers in the stroma acts as a diffraction grating, reducing light scatter by disrupting interference. Corneal transparency is also dependent on the semi-hydrated state maintained by the parenchymal layer of the cornea, controlled primarily by the mechanical barriers of the epithelium and endothelium and by the temperature-dependent Na+-K pump of the endothelium, which pumps stromal water from the apical cytoplasm of the endothelium into the atrial fluid in an energy-consuming transport mode. Thus the endothelium maintains approximately 78% of the water content of the stroma. If the ion pump function of endothelial cells is reduced or the tight junctions between endothelium are disrupted and water enters the stroma faster than it can be pumped out, water diffuses in the stroma and disrupts the normal arrangement of collagen fibers, thus causing astigmatism and corneal clouding. In addition, the dynamics of tear evaporation and the osmotic gradient prompt the discharge of water from the superficial corneal stroma, which also plays a role in maintaining the dehydrated state of the cornea. The nutrients required for corneal metabolism are mainly derived from glucose in the atrial fluid and oxygen diffused through the tear film; in addition, the peripheral cornea receives oxygen supplied from the vascular circulation of the corneal limbus. The cornea is one of the organs with the highest density of nerve endings in the body. Sensory nerve fibers branch from the long ciliary nerve and cross the anterior elastic lamina to form the subepithelial plexus under the epithelium, releasing neurotransmitters including acetylcholine, catecholamines, substance P and calcitonin gene-related peptides, making the cornea 100 times more sensitive than the conjunctiva. Any deep or superficial corneal lesion (corneal foreign body, corneal abrasion, corneal inflammation) causes pain and photophobia, which can be exacerbated by eyelid movements (especially the upper lid). Therefore, most inflammation of the cornea is accompanied by photophobia, lacrimation, and blepharospasm. The exception is herpes simplex virus keratitis, which causes hyperalgesia of the cornea. The surface of the cornea is not standard spherical, but the central 1/3 of the anterior surface is called the optical zone which is close to the sphere, and the periphery is flatter, with the nasal flattening more pronounced than the temporal. The average radius of curvature of the central cornea is 7.8mm (6.7-9.4mm), and the total refractive power of the cornea is about 43.25D, accounting for 74% of the total refractive power of the normal human eye (58.60D). Therefore, changing the refractive power of the cornea through corneal refractive surgery can correct the refractive state of the eye. Second, the pathophysiology of the cornea keratoconus is one of the major blindness-causing diseases in China. Corneal diseases mainly include inflammation, trauma, congenital anomalies, degeneration, malnutrition and tumors. Infectious corneal inflammation is more common, pneumococcus is more likely to directly infect the cornea, other pathogenic bacteria need a large number of local invasion or the body resistance to decline before easy to cause disease. There is a significant difference in the distribution of immune-related cells and active factors between the peripheral and central corneas, with the peripheral or corneal limbus containing more lymphocytes and complement components than the central corneal limbus. In addition, the periphery of the cornea and the corneoscleral rim contain antigen-presenting cells, dendritic cells (which express MHC-II and costimulatory molecules and are effective in activating T cells). In the peripheral epithelium and anterior corneal stroma, a small number of lymphocytes are present. Vascular adhesion molecules and cytokines can also attract different classes of intravascular leukocytes to the corneal limbus. Therefore, the peripheral part of the cornea or the corneal limbus is clinically susceptible to immune keratopathies (e.g., nibbling corneal ulcers, vesicular keratoconjunctivitis, and limbal corneal ulcers), whereas some infectious keratopathies tend to occur in the central corneal zone. The corneal epithelium is the first barrier against pathogenic microorganisms attacking the cornea, and when the epithelium is damaged, it is highly susceptible to infectious inflammation. Damage to the epithelium can be regenerated without scarring. The anterior corneal elastic layer cannot regenerate after damage and is filled by epithelial cells or scar tissue. The corneal stroma, which plays an important role in maintaining corneal transparency and resisting intraocular pressure, is filled in by scar tissue repair after damage, causing the cornea to lose its transparency. Damage to the posterior elastic layer of the cornea can be regenerated by endothelial cell secretion at a repair rate of 10µm per month. After disruption of the barrier function of the endothelium, the posterior elastic layer at the wound margin contracts and curls toward the stroma, and within hours, adjacent endothelial cells migrate toward the wound area to rebuild an intact endothelial monolayer structure through cellular reorganization, enlargement, and migration. As the intact monolayer of endothelial cells re-covers the posterior elastic lamina, contact inhibition and stable cellular junctions are formed between cells. At this point, the volume of cells involved in trauma repair is larger than that of cells in areas not involved in repair. If the endothelial injury is severe, localized endothelial cells form a complex layer and fibrosis, causing abnormal deposits of basement membrane-like material. The cornea is an important refractive medium, and keratoconus, especially lesions located in the central cornea, severely affects vision, so keratoconus should be treated aggressively. Each layer of the cornea has different permeability to topically applied drugs, with lipid-soluble substances rapidly passing through the tightly connected epithelial layer and water-soluble substances easily passing through the stroma. Therefore, in order to improve the bioavailability of drugs for ocular use, the ideal drug should have biphasic solubility in order to penetrate the cornea and enter the eye. Although corneal transplantation is one of the most successful organ transplants, it can be subject to immune rejection when stimulated by certain antigens, especially when neovascularization occurs in the diseased cornea.