Spatial patterning of biomimetic signals in corneal regeneration

The key characteristics of the cornea, its transparency and avascularity, emerge from spatial organization of cell populations, extracellular matrix layers, biomechanical properties, and morphogenic cues. This review translates these organizing principles into contextual considerations for advancements in corneal regeneration therapies. We begin by outlining the development of the cornea, followed by how layer-specific microenvironments underpin homeostasis, and provide an outlook on current and future therapies. While full-thickness corneal transplantation remains the gold standard for global corneal blindness, definitive care is transitioning toward layer-specific procedures. These surgeries improve safety and recovery, yet remain limited by critical vulnerabilities such as donor supply scarcity and tissue rejection. Regenerative strategies are explored through full-thickness and layer-specific therapies with an ultimate goal to recapitulate native tissue by rebuilding the way it is patterned in vivo. Across the layers, successful corneal regeneration depends on reproducing where signals are presented, in what mechanical context, and with what architectural alignment. Cell-based therapies, from limbal epithelial stem cell transplantation to intrastromal keratocyte injection, require precise spatial control over the cellular microenvironment to ensure stemness, survival, and proper tissue integration. Scaffold-based therapies, by encapsulating these spatial rules into advanced fabrication platforms (such as additive manufacturing), biomaterials, and delivery schemes offers a path to long-term clarity, avascularity, and physiologic function, and exemplifies how spatial patterning drives the next generation of truly biomimetic corneal repair. Despite these advancements, achieving widespread clinical translation will require addressing key challenges, including standardizing safe cell therapies and overcoming technical limitations in the high-resolution, moderate-scale scaffold manufacturing.