Corneal Epithelial Wound Healing

I am constantly amazed by the human eye. The processes that are involved in visual perception, the pathophysiology of ocular diseases, and the way in which our ocular structures repair themselves following injury (to name a few) are incredible.

Last week, I had a patient with a large corneal abrasion following an injury while gardening. She was in extreme pain, had significant light sensitivity and tearing, and decreased visual acuity. She was treated with antibiotics, a cyloplegic, and ocular lubrication, and I reassured her that she would notice improvement each day for the next few days, and that she'd likely be healed by the end of the week.

I saw her back in my office the next day for a follow-up, and by that time she already felt much better and the epithelial defect was significantly smaller. She was amazed by the amount of improvement that occured in just one day... And I agreed! The corneal wound healing response is truly impressive!

Let's review... Epithelial repair of the cornea involves a multifaceted series of events that can be divided into 4 overlapping phases, each with specific physiologic functions. 

Phase 1: Latent Phase

The first phase in this process is known as the latent phase, in which there is a significant increase in metabolic activity and reorganization of the cellular structure, allowing the epithelial cells to prepare for migration over the wound surface. Unwanted necrotic cells that were damaged during the injury undergo apoptosis and are quickly shed into the tear film. Fibronectin polymerizes onto the bed of the wound, providing a transient extracellular matrix over which the migrating cells can more easily move in the ensuing phase. Additionally, hemidesmosomal attachments that are normally found between the basal cells and the basement membrane are dismantled in the immediate area surrounding the wound edge, and are replaced with weaker attachments. Furthermore, intercellular adherens and gap junctions are also lost, desmosomes are remodeled, and structural proteins and actin filaments are assembled in preparation for cellular migration.

Phase 2: Migration Phase

Phase two of the epithelial healing process is referred to as the migration phase, in which cells begin to move and cover the epithelial defect. This begins with the flattening of cells at the wound edge into a monolayer, and the formation of lamellipodia and filopodia that aid in cellular movement. Focal contacts of migrating cells to the provisional extracellular matrix, and subsequent contraction of the cytoskeletal actin filaments, allow the layer of cells to slide together as a sheet, eventually fully covering the wound bed. It is important to note that throughout the latent and migration phases, there is no mitotic activity of the cells in or around the area of the epithelial defect; these initial processes are completely independent of cellular proliferation. 

Phase 3: Cellular Proliferation

After cell migration is complete, activation of cellular proliferation in the third phase is responsible for restoring the normal epithelial cell density. Immediately following closure of the defect, the newly formed epithelium consists of only one to two cellular layers. These cells are eventually replaced through accelerated division and centripetal migration of stem cells in the basal layer, originating from both the limbus and locations distant to the wound site. Newly formed daughter cells are displaced inwards toward the more centrally located cells, and upwards in the direction of the superficial layers of the cornea, eventually differentiating into wing cells, and then squamous cells, in order to restratify the corneal epithelium. Zonula occludens are the first junctions to reform, allowing for the important restoration of the epithelial barrier function. Furthermore, the basement membrane is remodeled by the epithelial cells, and intercellular gap junctions, adherens junctions, and desmosomes are finally reassembled.

Phase 4: Attachment Phase

In the concluding phase of corneal epithelial wound healing, known as the attachment phase, the firm connections of the epithelial layer to the underlying basement membrane are re-established via the resynthesis of hemidesmosomes. Although wound closure is usually accomplished within 2 to 4 days following a corneal injury, the entire epithelial healing process typically requires weeks after to be fully restored

-Dr. Dexter