Modulators of corneal wound healing – Where do we stand?

An enhanced understanding of corneal physiology and the fibrotic molecular pathways influencing corneal clarity has facilitated innovative research aimed at countering corneal scarring. Recent initiatives have redefined the molecular factors involved in wound healing and scarring mechanisms of the human cornea. The pathogenesis of corneal scarring involves key components of the fibrotic mechanism, including transforming growth factor beta (TGFβ), bone morphogenic protein (BMP), suppressor of mothers against decapentaplegic (Smad), connective tissue growth factor (CTGF), vascular endothelial growth factor (VEGF), and smooth muscle α-actin (α-SMA).[1] Injured corneal epithelium-derived TGFβ, platelet-derived growth factor, and other modulators appear to play a pivotal role in the development of vimentin+ alpha-smooth muscle actin+ desmin+ (V+A+D+) mature myofibroblasts in the stroma. Myofibroblasts derived from bone marrow and keratocyte-derived precursor cells define the corneal reparative process. The resultant interaction between normal and defective epithelial basement membrane (EBM) regeneration determines the severity of corneal stromal scarring. Resolution of corneal fibrosis is facilitated by injury-related influences mediated through keratocyte-derived reparative processes, which enable the reorganization of the extracellular matrix via repopulating keratocytes and apoptosis of myofibroblasts.[2,3] Fibrotic factors such as TGFβ and CTGF present in corneal epithelial-derived extracellular vehicles (EVs) promote corneal scarring by facilitating epithelial cell migration and keratocyte-to-myofibroblast differentiation.[4-6] Hence, EVs secreted by mesenchymal stem cells have been studied for their potential effects on corneal scars. Studies have shown that bone-marrow derived fibrocytes can transform into myofibroblasts, which induce fibrosis and permanent corneal scarring due to their opaque cellular structure and disorganized ECM deposition. In contrast, fibroblasts typically cause transient corneal haze.[7] Clinical strategies to address corneal scarring include pharmacological treatments and ocular surgical interventions. Drugs employed in corneal scarring management include topical corticosteroids, mitomycin C, anti-vascular endothelial growth factor agents, and both topical and systemic ascorbic acid therapy. Advances in surgical interventions include custom component replacement of scarred tissue through various types of anterior and posterior lamellar keratoplasty surgeries. Additionally, corneal neovascularization is managed using anti-VEGF injections and pannus management surgeries. The management of acquired corneal scarring with drug interventions has gained significant clinical interest in recent years. Several synthetic drugs are currently under experimental evaluation for their role in inhibiting corneal scarring [Table 1].[8-19] Among these, early therapy with topical losartan—a commonly used angiotensin II receptor blocker for hypertension and heart failure — has been widely studied for its potential to reduce corneal scar formation in cases of infectious keratitis, chemical burns, or post-surface ablation. Losartan also appears to be effective in minimizing or improving corneal neovascularization. Additionally, topical sunitinib or axitinib, tyrosine kinase inhibitors, used in conjunction with losartan for corneal neovascularization, has shown some efficacy.[19]Table 1: Drugs under evaluation for the prevention of corneal scarringEmerging therapies as alternative solutions to reduce corneal fibrosis mechanisms, currently under evaluation, include direct targeting of the genes responsible for regulating fibrosis, blocking actin remodeling during the keratocyte-to-myofibroblast transformation, reducing the proinflammatory immune response that initiates TGFβ signaling, limiting the production of fibrotic extracellular matrix, and utilizing antifibrotic recombinant proteins, cultured cells, and biomaterials. Strategies in preclinical research include protein therapies such as recombinant HGF, KINERET®(anakinra, recombinant Interleukin-1 receptor antagonist (IL-1Ra)), recombinant decorin, recombinant mitsugumin (MG) 53, and recombinant BMP7), as well as gene therapy for corneal scarring related to congenital or hereditary corneal opacity conditions and corneal dystrophies.[20] Cell-based therapies, including corneal stromal stem cells, embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells, have also been explored for minimizing corneal scarring.[20] With extensive experimental research on the multiple aspects of corneal antifibrosis mechanisms that is ongoing, it still remains to be seen whether these therapies will play a credible role in clinical applications.