State-of-the-art advances in tissue-engineered corneal substitutes: a systematic review (2020–2025)

Background: Corneal blindness remains a major global health burden, limited by donor shortage and graft-related complications. Tissue-engineered corneal substitutes have emerged as a promising alternative, aiming to restore corneal structure and function through bioengineered constructs. Objectives: To systematically review recent advances (2020-2025) in tissue-engineered corneal substitutes, classifying them according to the corneal layer replaced and evaluating their biological, optical, and functional performance, as well as their translational potential for clinical application. Design: A systematic review. Data sources and methods: A systematic review was conducted following Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) 2020 guidelines. Searches were performed in PubMed/MEDLINE, Scopus, and Web of Science using predefined keywords related to corneal tissue engineering. Eligible studies included experimental, preclinical, or clinical studies published between January 2020 and June 2025 describing cell-based corneal substitutes. Studies focused on keratoprostheses (KPros), acellular scaffolds, or non-cellular biomaterials were excluded. Stromal models incorporated advanced biofabrication techniques such as 3D bioprinting and neuronal co-culture, achieving > 80% optical transmittance and adequate biomechanical properties. The single epithelial model achieved complete re-epithelialization in a rabbit limbal deficiency model. Multilayered epithelium-stroma substitutes, including the NANOULCOR (Tissue Engineering Group, University of Granada, Granada, Spain) construct, exhibited safety and feasibility in preclinical and early clinical studies. Conclusion: Recent progress in corneal tissue engineering has yielded increasingly functional and biocompatible substitutes that replicate native corneal architecture. However, most studies remain limited by small sample sizes, short follow-up, and reliance on animal models. Further standardized clinical trials are required for clinical translation. Trial registration: Not applicable.