Corneal re-epithelialisation is a vital process for preserving ocular surface integrity and visual acuity. When this complex process is hindered, resulting in delayed or incomplete healing, significant clinical difficulties emerge, which can lead to persistent epithelial defects, stromal scarring, and ultimately, severe vision loss. This document examines the various clinical issues linked to slow corneal re-epithelialisation and explores innovative, forward-looking therapeutic strategies, including those utilising advanced scaffold technologies, to address these complex problems. Understanding the cellular and molecular mechanisms underlying epithelialisation is essential for developing effective interventions that promote timely and complete corneal wound closure.. Physiologically, the corneal epithelium typically heals within approximately 5 days; however, during this period, the cornea is especially vulnerable to infection, and patients often experience discomfort and a reduced quality of life. Delayed healing not only extends these risks and discomforts but can also result in more serious complications, emphasising the importance of timely and effective re-epithelialisation strategies. Persistent epithelial defects, for example, can lead to chronic inflammation, ulceration, and even corneal perforation, requiring surgical intervention to preserve the globe. Furthermore, the absence of an intact epithelial barrier exposes the underlying stromal tissue to external insults, increasing the risk of irreversible structural damage and vision loss. Current clinical approaches often face challenges with persistent defects, emphasising the urgent need for novel therapies that can not only speed up healing but also restore the cornea’s intricate architecture and function. This calls for a deeper investigation into the molecular pathways controlling corneal epithelial repair and the creation of targeted interventions that can overcome the limitations of traditional treatments. One promising direction involves developing biomimetic scaffolds that can accurately guide cellular behaviour and deliver therapeutic agents to the wound site, promoting optimal tissue regeneration. These scaffolds aim to imitate the native extracellular matrix, offering a supportive microenvironment that encourages epithelial cell migration, proliferation, and differentiation, thereby speeding up the re-establishment of a functional epithelial layer. This biomimicry is essential because wound repair involves complex interactions among various cell types, their mediators, and the extracellular matrix. Successful healing depends on restoring the epithelial cover and tissue integrity. Chronic wounds, including those of the cornea, pose a significant challenge in clinical care due to their tendency for prolonged inflammation, which hampers the transition to proliferative healing phases. This extended inflammatory response can halt the healing process, preventing the coordinated cellular actions needed for effective re-epithelialisation and tissue remodelling. The persistent inflammation often creates a vicious cycle of tissue damage and delayed healing, requiring interventions that can effectively regulate the inflammatory response and foster a pro-regenerative environment. Regenerative medicine presents promising opportunities for improving corneal wound healing through strategies such as stem cell therapy, growth factor application, and biomaterial integration to stimulate regeneration and enhance the wound microenvironment. Traditional wound management, while useful, often faces limitations in completely restoring tissue function, emphasising the need for innovative solutions beyond conventional wound dressings, which may not sufficiently offer antibacterial or antioxidant effects, or adequate mechanical support. However, recent progress in bioengineered alternative agents, including advanced wound dressing materials and innovative delivery systems, is continually enhancing the wound healing process and reducing costs, making them increasingly prominent in outpatient and perioperative management of stubborn wounds. This emphasises the vital need for advanced biomaterials and therapeutic approaches that can not only address the immediate epithelial defect but also reduce chronic inflammation and foster a regenerative rather than reparative healing response. Therefore, there is an urgent need to develop competitive therapies that go beyond conventional methods such as cell therapy, gene therapy, growth factor delivery, wound dressings, and skin grafts, which often prove unsatisfactory for all wound types. Hence, innovative smart dressings that utilise nanotechnology and advanced material science are emerging as essential tools to address these limitations, providing enhanced features for targeted drug delivery, better mechanical support, and more effective infection control. These next-generation dressings are designed to foster an optimal healing environment by incorporating sensing abilities for real-time wound monitoring and active therapeutic release. For example, nanotechnology presents a promising pathway, as nanoparticles embedded within biomaterials can impart specific beneficial properties for wound dressings, improving burn treatment and speeding up delayed healing processes. In particular, the integration of nanomaterials into wound dressings can boost their antimicrobial activity, enable sustained release of growth factors, and regulate cellular responses to promote faster epithelial migration and differentiation. Furthermore, electrospun nanofibers are especially promising for chronic wound care because of their ability to prevent microbial infiltration, sustain a balanced moisture and gas exchange environment, and stimulate cell proliferation. These nanofibers can imitate the native extracellular matrix, offering a scaffold that guides cell attachment and migration, which are vital for re-epithelialisation. Beyond their structural benefits, these advanced dressings can be engineered to include bioactive molecules or smart release systems, enabling targeted therapeutic interventions directly at the wound site. This precise delivery can enhance therapeutic outcomes and minimise systemic side effects, representing a major progress over traditional broad-spectrum treatments. This integration enables dynamic responses to changes in the wound microenvironment, such as fluctuations in pH, temperature, or inflammatory markers, through the controlled release of therapeutic agents. This capability transforms traditional passive dressings into active therapeutic platforms capable of accelerating corneal re-epithelialisation. This innovative approach can significantly shorten healing times and minimise complications, offering a more effective solution for complex corneal wounds. Among the biomaterials used to produce corneal wound healing scaffolds, silk proteins stand out owing to their exceptional biocompatibility, biodegradability, non-immunogenicity, and mechanical tunability, making them ideal candidates for creating scaffolds that promote cellular adhesion and proliferation. These properties allow silk-based scaffolds to effectively mimic the native corneal extracellular matrix, providing a superior substrate for corneal epithelial cell growth and differentiation. In particular, their ability to absorb water is crucial for maintaining a hydrated environment conducive to cellular activity and nutrient exchange, which is essential for corneal health and regeneration. In ophthalmology, silk-protein-based scaffolds are being extensively investigated for various applications, including corneal regeneration, lens, and retinal pathologies due to their ability to support cell proliferation and tissue integration. Preliminary studies have demonstrated the potential of silk fibroin scaffolds to enhance corneal re-epithelialisation by providing a supportive environment for limbal stem cell expansion and differentiation, thereby accelerating wound closure and reducing scar formation. Moreover, silk fibroin’s high permeability to oxygen and water, combined with its low thrombogenicity and inflammatory response, makes it a superior choice for corneal tissue engineering compared to other biomaterials. Preclinical and clinical data have shown promising results for corneal regeneration, often exhibiting superior outcomes in terms of transparency, structural integrity, and visual acuity compared to conventional treatments.

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