Wound healing in the eye: Therapeutic prospects
Graphical abstract
Introduction
This review will consider two aspects of wound healing in the eye: repair and maintenance of the corneal epithelium which faces the external environment, and maintenance of the corneal stroma which provides the cornea‘s structural integrity.
To maintain a smooth optical surface, the corneal epithelium has to continuously renew itself to function as a barrier to fluctuating external surroundings and various environmental insults. After trauma the cornea typically re-epithelializes promptly, minimizing the risk of infection, opacification or perforation. In the presence of certain risk factors such as dry eye disease, diabetic keratopathy, ocular cicatrizing disorders, limbal stem cell deficiency (LSCD), chemical injury, exposure keratopathy, and neurotrophic keratopathy from prior herpetic keratitis or previous keratoplasty; epithelial defects can persist. A persistent epithelial defect (PED) is usually referred to a non-healing epithelial lesion after approximately two weeks of treatment with standard therapies to no avail [1]. They occur following exposure to toxic agents, mechanical injury or ocular surface infections and are associated with significant clinical morbidity in patients, resulting in discomfort or visual loss. The incidence of PEDs is unknown but estimated to about 200,000 per annum in the USA although significantly higher in some other parts of the world. Management of patients with PEDs can be challenging and may require an extended treatment and follow-up period. Although significant progress has been made in recent years, pharmaco-therapeutic agents that promote epithelial healing remain limited. In this article a review of current standard therapies, recently introduced alternative therapies gaining in popularity, and a look into the newest developments into ocular surface wound healing is given.
The corneal epithelium is an ectoderm derived, non-keratinized, stratified layer with a unique cytokeratin expression pattern and a reported thickness of between 48 and 53 μm [2,3]. The corneal epithelium is a barrier composed of a series of tightly networked cells seven to eight cell layers thick and attached to the basal lamina through hemidesmosomes. Cells are attached to each other with desmosomes and communicate both within and between layers via gap junctions. The epithelium serves as the eyes first line of defense against trauma. It is a fast regenerating tissue that is maintained by the integrity and functionality of a specialized stem cell population, known as limbal stem cells (LSCs). LCS are said to be located in the basal layer of the palisades of Vogt of the limbus, a narrow transition zone surrounding the cornea [4].
Regeneration of the corneal epithelial surface after an intrinsic or extrinsic insult appear to involve division, migration, and maturation of LSCs. The XYZ hypothesis proposes that the maintenance of the corneal epithelium can be represented by the formula X + Y = Z, where Z (desquamation), is the sum of X (proliferation) and Y (centripetal migration) (Fig. 1) [5,6].
The wound healing response in the cornea is a convoluted process. An intrinsic cascade involving autocrine and paracrine cytokine mediated interactions between epithelial cells, stromal keratocytes, corneal nerves, and cells of the immune system control this process. The tissue wound healing response also varies depending on the severity of the inciting injury. Upon injury, epithelial cells evoke sequential steps attempting to efficiently seal the wound and to prevent potential opportunistic infection that can result in devastation of the eye. Epithelial wound healing occurs in a phased process with specific physiological functions [7].
In the latent phase there is no movement of cells or any apparent change in cell numbers but there is reported to be an increase in metabolic activity and a reorganization of cell structures is observed [8,9]. This is accompanied by an increased synthesis of several cytoskeletal proteins with several integrins e.g. α6 and β4, located at the basal area of epithelial cells responsible for the linkage of cytoskeletal components to the underlying basement membrane [10]. In the migration phase, cells around the wound edge migrate across and cover the denuded area [11], a process which requires the synthesis of an array of actin-rich stress fibers in the cytoplasm and which can be readily blocked if topical anesthetic drugs are used [12]. This is followed by the cell proliferation stage in which epithelial cells divide and differentiate in order to restore the epithelium's original structure and complete with intercellular junctions [13]. The proliferative response appears to be compartmentalized to the limbal region with cells at the leading edge not showing an increased rate of proliferation [14]. The last phase is characterized by the establishment of cell to substrate attachments as the epithelium is stabilised and is no longer motile [15]. These phases are often overlapping and allow for the coverage of the wounded epithelium, restoration of normal cell density and reformation of cell attachments. PEDs occur when there is a failure of mechanisms which promote corneal epithelialization.
The first step in the management of any epithelial abnormality is to determine and address the underlying aetiology. Numerous pharmacological agents are currently employed to modify wound healing in patients with a PED. Patients are currently treated using a step ladder management approach utilizing a series of interventions. We will now review some of the currently available and emerging pharmaceutical agents. It is beyond the scope of this article to discuss surgical treatment options such as tarsorrhaphy, therapeutic excimer laser ablation and amniotic membrane transplantation.
Section snippets
Discontinuation of medication
The first goal when dealing with a PED is to provide the eye with an environment conducive to the innate healing ability of the ocular surface. An often overlooked cause of poor ocular healing is “medicamentosa” or toxic keratitis stemming from topical ophthalmic medication or preservatives in eye drops. Preservatives such as benzalkonium chloride (BAK) and Polyquarternium-1 are typical culprits as they are almost ubiquitously deployed in ophthalmic preparations and have consistently been shown
Growth factor derived products
Several growth factors including epidermal growth factor (EGF), keratinocyte growth factor 1 (KGF-1), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), nerve growth factor (NGF), transforming growth factor-β (TGF-β), and hepatocyte growth factor (HGF) are actively involved in corneal wound healing [53]. These low molecular weight molecules are strong mitogens of corneal epithelial cells and can enhance corneal epithelial proliferation after local administration to the eye
Wound healing in the corneal stroma and keratoconus
One of the first observable changes following injury to the corneal stroma is the death of a subpopulation of keratocytes surrounding the injury site. This initial response is thought to prevent inflammation in the rest of the cornea. Apoptosis is induced by cytokines such as interleukin-1 which is secreted from the overlying epithelium. About 6 h after injury the process of repair begins with the first event being the transition of the keratocytes around the wound edge to an activated
Conclusion
In this review, we have discussed current and emerging therapies for ocular surface wound healing. Despite the advances made in this field there remains a real need for new and improved pharmacotherapeutic agents. The healing of ocular surface wounds is a complex process involving the interaction of cells, receptors, enzyme systems, cytokines and the components of the extracellular matrix. Recent advances in understanding the processes involved in the wound healing response and the molecules
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