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.

RESULTS

Fourteen studies met the inclusion criteria: five endothelial, three stromal, one epithelial, and five epithelium-stroma substitutes. Endothelial models demonstrated cell viability, expression of tight junction proteins (ZO-1, Na+/K+-ATPase), and partial restoration of corneal transparency in animal and ex vivo systems. 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.