Human corneal decellularization for regenerative therapy from methods to clinical applications

The corneal stroma constitutes 80-90% of corneal thickness and is essential for transparency, strength, and refraction. Irreversible stromal opacity-caused by infection, inflammation, or trauma-can lead to corneal blindness, which according to the WHO 2024 report is the fourth leading cause of blindness worldwide. Standard treatment relies on allogeneic donor tissue via penetrating or lamellar keratoplasty. However, a global donor shortage exists, and up to 35% of collected corneas are discarded due to prior refractive surgery, low endothelial counts, or seropositivity. Moreover, graft failure, immune rejection, and complications often require re-transplantation. Recent advances in biomaterials, tissue engineering, and stem cells have spurred alternative strategies, including decellularized allogeneic or xenogeneic scaffolds, hydrogels, 3D bioprinting, and regenerative biology. Nevertheless, replicating the complex extracellular matrix (ECM) and neural network of the corneal stroma remains challenging. Decellularized human corneal tissues, particularly non‑transplant‑grade donor corneas and SMILE‑derived lenticules, have emerged as promising biomaterials that preserve native ECM architecture, reduce immunogenicity, and support stromal regeneration. This narrative review is based on a systematic literature search in PubMed, Scopus, and Web of Science (January 2010 - March 2025) using terms such as "human cornea", "decellularization", "corneal stroma", "decellularized ECM", "SMILE lenticule", "tissue engineering", and "3D bioprinting". Only peer‑reviewed original articles, reviews, and clinical studies in English were included, supplemented by manual bibliography screening. This review outlines current methods for human corneal decellularization, characterization techniques, and applications in preclinical and clinical settings. It highlights the potential of recycled human corneal ECM as a viable alternative to conventional donor tissue, and discusses challenges in standardization, immunogenicity, and regulatory pathways toward clinical translation.