Our objective was to determine the effect of a semi-synthetic sodium alginate hydrogel and its combination with platelet-rich plasma (PRP) on histopathological, biochemical, clinical, and anterior segment optical coherence tomography (AS-OCT) data. Alkali chemical burn of the cornea was induced. Injured rats were randomly divided into five equal groups and topically treated with phosphate-buffered saline (sham), platelet-rich plasma (PRP), 0.5% sodium citrate, a semi-synthetic sodium alginate hydrogel, or a combination of PRP and hydrogel (combined group) three times daily. The degree of corneal opacity (CO), corneal epithelial staining (CES), percentage of corneal epithelial defects (CEDP), degree of ciliary hyperemia (CH), neovascularization size (NVS), and extent of neovascularization (NVE) were evaluated. AS-OCT was performed at nine days, and then rats were sacrificed. Histological examination and enzyme-linked immunosorbent assays were performed to detect the concentrations of IL-1β and MMP-9 in the cornea. There were no significant differences between the groups regarding CEDP, CO, CES, CH, NVS, or NVE on the first day after corneal alkali burn injury (p > 0,05). At the last examination, CO was significantly lower in the PRP group than in the sham group (p = 0,044), while the CO concentrations were similar in terms of NVS (p > 0,05). Similarly, in terms of tissue MMP-9 levels, there were no significant differences between groups (p > 0,05). However, there was a significant difference in tissue IL-1β levels between the groups (p < 0,001). In the PRP and combined groups, the level of IL-1β was significantly lower than that in the sham group (p = 0,043 and p = 0,036, respectively). There was a significant difference in epithelial necrosis between the PRP, and it was the lowest in the combined group (p = 0,003). Epithelial thickness was highest in the combined group (p = 0,002). CEDP was significantly different at the last visit between the groups (p = 0.042). The fastest epithelial closing rate was observed for the combined group (p = 0,026). There was a significant negative correlation between tissue MMP-9 levels and corneal solidity and between tissue MMP-9 levels and the corneal area according to the AS-OCT measurements (p = 0,012 and p = 0,027, respectively). When used alone, topical hydrogel application did not significantly enhance the healing of corneal wounds. However, when combined with PRP, it leads to an increased rate of epithelial closure and neovascularization. This combination did not exacerbate inflammation or corneal opacity compared to PRP alone. The anticoagulant citrate solution in the PRP tube did not prove effective. The synergistic use of PRP and hydrogel could enhance epithelial thickness and reduce epithelial necrosis. The use of new parameters for corneal wound healing assessment was facilitated through AS-OCT image processing.

The cornea is continuously exposed to injuries, ranging from minor scratches to deep traumas. An effective healing mechanism is crucial for the cornea to restore its structure and function following major and minor insults. Transforming Growth Factor-Beta (TGF-β), a versatile signaling molecule that coordinates various cell responses, has a central role in corneal wound healing. Upon corneal injury, TGF-β is rapidly released into the extracellular environment, triggering cell migration and proliferation, the differentiation of keratocytes into myofibroblasts, and the initiation of the repair process. TGF-β-mediated processes are essential for wound closure; however, excessive levels of TGF-β can lead to fibrosis and scarring, causing impaired vision. Three primary isoforms of TGF-β exist-TGF-β1, TGF-β2, and TGF-β3. Although TGF-β isoforms share many structural and functional similarities, they present distinct roles in corneal regeneration, which adds an additional layer of complexity to understand the role of TGF-β in corneal wound healing. Further, aberrant TGF-β activity has been linked to various corneal pathologies, such as scarring and Peter\'s Anomaly. Thus, understanding the molecular and cellular mechanisms by which TGF-β1-3 regulate corneal wound healing will enable the development of potential therapeutic interventions targeting the key molecule in this process. Herein, we summarize the multifaceted roles of TGF-β in corneal wound healing, dissecting its mechanisms of action and interactions with other molecules, and outline its role in corneal pathogenesis.

Various etiologies, including diabetic keratopathy (DK), dry eye disease (DED), and neurotrophic keratopathy (NK), can disrupt corneal homeostasis, exacerbating corneal epithelial defects. Topical insulin has emerged as a promising therapy for promoting corneal wound healing and addressing underlying pathologies. This review systematically evaluates the efficacy of topical insulin across different corneal disorders. A literature review was conducted across the PubMed, Google Scholar, and Scopus research databases. The search resulted in a total of 19 articles, consisting of clinical trials, retrospective studies, and case reports. In DK, topical insulin accelerates corneal wound healing post-vitreoretinal surgery with lower concentrations showing higher outcomes when compared to conventional therapy, possibly due to improved epithelial stem cell migration. In comparison, the dry-eye disease results are inconclusive regarding patient-reported outcomes and corneal staining. For NK, topical insulin accelerates corneal wound healing and restores corneal nerve sensation. Other persistent epithelial defect (PED) etiologies that have been treated with topical insulin are infection, immune-mediated, mechanical and chemical trauma, and chronic ocular surface alterations. Although individual mechanisms for the benefits of topical insulin for each of these etiologies have not been studied, the literature demonstrates that topical insulin is efficacious for PEDs regardless of etiology. Future clinical trials need to be conducted to further evaluate optimal dosing, duration, and use of topical insulin for the restoration of the corneal surface.

Corneal melt and perforation can arise from various etiologies, including the use of toxic topical drops, particularly topical non-steroidal anti-inflammatory drugs (NSAIDs). The literature has frequently documented the association between the use of topical NSAIDs and the subsequent development of corneal ulcers. More recently, reports have emerged linking the use of oral NSAIDs and colchicine to impaired corneal wound healing and corneal perforation. This case report presents an instance of corneal melting and subsequent perforation in a medically unburdened patient who had been self-administering oral NSAIDs for one year. The evidence presented in this report suggests a plausible association between the prolonged administration of oral NSAIDs and corneal melt. Consequently, healthcare practitioners should be mindful of this potential risk when considering the prolonged use of oral NSAIDs.

The corneal epithelium is the outermost transparent barrier of the eyeball and undergoes continuous self-renewal by limbal stem cells (LSCs) during its lifetime; however, the impact of aging on LSCs remains largely unknown. Here, we showed that the healing ability of the cornea in elderly macaques (Macaca fascicularis) was significantly decreased compared to that of younger macaques. This delayed wound closure accompanied a disordered cell arrangement and corneal opacity. A novel cytokine, Secreted and Transmembrane 1 (SECTM1), was found to facilitate corneal healing and was upregulated in young macaques upon wounding. Mechanistically, SECTM1 is essential for LSC migration and proliferation, and may partially function through Cell Division Cycle Associated 7 (CDCA7). Notably, the topical application of SECTM1 to aged wounded corneas dramatically promoted re-epithelialization and improved corneal transparency in both mice and macaques. Our work suggests that aging may impair the expression of healing response factors and injury repair in non-human primate corneas, and that SECTM1 application could potentially benefit corneal wound healing in clinical treatment.

Corneal wound healing in diabetic patients is usually delayed and accompanied by excessive inflammation. However, the underlying cellular and molecular mechanisms remain poorly understood. Here, we found that somatostatin (SST), an immunosuppressive peptide produced by corneal nerve fibers, was significantly reduced in streptozotocin-induced diabetic mice. In addition, we discovered that topical administration of exogenous SST significantly improved re-epithelialization and nerve regeneration following diabetic corneal epithelial abrasion. Further analysis showed that topical SST significantly reduced the expression of injury inflammation-related genes, inhibited neutrophil infiltration, and shifted macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 in diabetic corneas\' healing. Moreover, the application of L-817,818, an agonist of the SST receptor type 5 subtype, significantly reduced the inflammatory response following epithelial injury and markedly improved the process of re-epithelialization and nerve regeneration in mice. Taken together, these data suggest that activation of the SST-SST receptor type 5 pathway significantly ameliorates diabetes-induced abnormalities in corneal wound repair in mice. Targeting this pathway may provide a novel strategy to restore impaired corneal wound closure and nerve regeneration in diabetic patients.

This study strategically incorporates epidermal growth factor (EGF) and keratinocyte growth factor (KGF) within a hyaluronic acid (HA) hydrogel to enhance corneal wound healing. The controlled release of EGF and KGF from the HA hydrogel is engineered to promote the regeneration of both the epithelial and stromal layers. Specifically, EGF plays a pivotal role in the regeneration of the epithelial layer, while KGF exhibits efficacy in the regeneration of the stromal layer. The combination of these growth factors facilitates efficient regeneration of each layer and demonstrates the capability to modulate each other\'s regenerative effects. The interplay between EGF and KGF provides an understanding of their cooperative influence on the dynamics of corneal wound healing. The results of this study contribute to the development of advanced strategies for corneal wound management and offer insights into the complex process of corneal regeneration.

Corneal wound healing requires epithelial reorganization and stromal extracellular matrix (ECM) remodeling, with ECM proteins such as Tenascin C (TnC) regulating and maintaining corneal homeostasis. The N-terminal globular domain and C-terminal fibrinogen-related domains of TnC are separated by epidermal growth factor (EGF)-like repeats, and upto fifteen fibronectin type III domains (Tn fn). Overexpression of Tn fn 1-5 and its splice variants occurs in varied pathologies. We have previously used Tn64 (a single chain variable fragment antibody cognate to Tn fn 1-5) to establish roles of Tn fn 1-5 in fibrotic pathologies such as rheumatoid arthritis and posterior capsular opacification. Here, we show that Tn64 binds to Tn fn repeats 3-5 (which constitute the major site for binding of soluble fibronectin within TnC). Unlike other Tn fn domains, Tn fn 3-5 displays no inhibition of fibronectin matrix assembly. Rather, the Tn fn 3-5 construct is pro-fibrotic and elicits increased expression of fibronectin. We examined corneal epithelial as well as stromal wound healing through Tn64 binding to Tn fn 3-5, using a human corneal epithelial cell (HCEC) line, primary cultures of human corneal fibroblasts (HCFs), and an ex-vivo corneal organ culture model. Tn64 enhanced proliferation and adhesion of corneal epithelial cells, while inhibiting the migration of corneal fibroblasts and myofibroblasts. Tn64 appears to attenuate inflammation through downregulation of TNF-α, prevent corneal fibrosis by limiting fibronectin polymerization, and promote regeneration of corneal epithelia and stroma, suggesting that it could be developed as a therapeutic agent for effective anti-fibrotic corneal wound healing.

Corneal injury leads to impaired normal structure of the cornea. Improving the wound healing process in epithelial cells significantly contributes to ocular damage treatments. Here, we aimed to investigate the potential mechanisms of nitric oxide (NO) and its mediator, inducible nitric oxide synthase (iNOS), in the process of corneal wound healing. We established a corneal injury model of iNOS-/- mice, and treated human corneal epithelial cell lines (HCE-2) with the iNOS inhibitor L-INL, with or without NO replenishment by supplying sodium nitroferricyanide dihydrate (SNP). Our findings showed that inhibition of NO/iNOS accelerated corneal repair, enhanced uPAR (a receptor protein indicating the migration ability), and improved epithelial cell migration. Furthermore, NO/iNOS ablation activated Akt phosphorylation, reduced neutrophil marker protein MPO expression, and downregulated the transcription of inflammation cytokines CXCL-1, CXCL-2, IL-1β, IL-6, and TNF-α. However, the protective effects of NO/iNOS inhibition are significantly reduced by NO replenishment when treated with SNP. Therefore, we confirmed that inhibiting NO/iNOS improved the corneal wound healing by facilitating epithelial cell migration and reducing inflammatory reactions, which might be related to the activation of the Akt signaling pathway.

Corneal opacities are a major cause of vision loss worldwide. However, the current therapies are suboptimal to manage the corneal wound healing process. Therefore, there is an obvious need to develop new treatment strategies that are efficient in promoting wound healing in patients with severe corneal disorders. In this study, we investigated and compared the efficacy of adipose-derived mesenchymal stem cells (ADMSCs) and photobiomodulation (PBM) with polychromatic light in the NIR (600-1200 nm) alone and in combination, on corneal opacity, inflammatory response, and tissue architecture in a rat corneal opacity model created by mechanical injury. All animals were divided into four groups randomly following the injury: injury only (no treatment), ADMSCs treatment, PBM treatment and combined (ADMSCs+PBM) treatment (n = 12 eyes per group). At the 10th and 30th day following injury, corneal opacity formation, neovascularization, and corneal thickness were assessed. On the 30th day the harvested corneas were analyzed by transmission electron microscopy (TEM), histological evaluation, immunohistochemical (IHC) staining and real-time polymerase chain reaction (RT-PCR). On day 30, the corneal opacity score, neovascularization grade, and corneal thickness in all treatment groups were significantly lower in comparison with the untreated injured corneas. The TEM imaging and H&E staining together clearly revealed a significant enhancement in corneal regeneration with improved corneal microenvironment and reduced vascularization in the combined administration of PBM and ADMSCs compared to treatment of PBM and ADMSCs alone. In addition, the IHC staining, and RT-PCR analysis supported our hypothesis that combining ADMSCs therapy with PBM alleviated the inflammatory response, and significantly decreased scar formation compared to either ADMSCs or PBM alone during the corneal wound healing.