A Concave Corneal Stromal Scaffold Based on Multi-Crosslinked GelMA Hydrogel for Delaying Keratoconus Progression and...

Keratoconus (KC), a progressive corneal ectasia characterized by central thinning, elevated curvature, and compromised biomechanical integrity, presents considerable therapeutic challenges. Existing clinical interventions exhibit limited efficacy in delaying disease progression or restoring native corneal structure. We report a concave corneal stromal scaffold (CCSS) featuring a unique concave structure, fabricated based on multi-crosslinked gelatin methacryloyl and β-cyclodextrin aldehyde hydrogels and specifically designed for intrastromal implantation. In vitro characterization confirmed that the optimized gelatin methacryloyl-based hydrogel possesses high optical transparency (>90%), suitable mechanical properties, and favorable cytocompatibility. Based on finite element model analysis of stress disparities between normal cornea and KC, a concave scaffold was fabricated to prevent KC progression. In vivo rabbit models of KC resulted in increased central corneal thickness in the Sc region (scaffold center), while a specially designed incremental topology in the peripheral Sp region (scaffold periphery) contributed to significant reduction in corneal curvature. The CCSS also promoted epithelial remodeling and substantially improved biomechanical properties, exhibiting notable restorative capacity. Importantly, animal studies experimentally validated finite element model predictions that the concave topology of the CCSS effectively redistributes stress, attenuating central stress concentration and reducing apical displacement. Moreover, the scaffold demonstrated sustained structural integrity over extended periods, thereby delaying KC progression and potentially diminishing the necessity for corneal transplantation. The design principles of the CCSS may inform future therapeutic strategies for stromal corneal disorders. STATEMENT OF SIGNIFICANCE: Keratoconus (KC) as a progressive corneal ectasia characterized by structural disintegration and biomechanical weakening, for which current clinical interventions often fail to halt disease progression without biomechanical mismatch. While biomaterial-based strategies offer promise, conventional flat scaffolds cannot replicate the native stress distribution of the cornea. Here, we report a concave corneal stromal scaffold (CCSS)fabricated from a multi-crosslinked GelMA hydrogel. By synergizing material reinforcement with topological design, the CCSS actively redistributes intraocular stress from the thinned apex to the peripheral stroma, a mechanism predicted by finite element modeling and validated in vivo. Our findings provide a transformative paradigm for treating stromal corneal disorders by integrating structural restoration with biomechanical normalization, potentially reducing the reliance on corneal transplantation.