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Corneal endothelium tissue engineering: An evolution of signaling molecules, cells, and scaffolds toward 3D bioprinting and cell sheets

Cornea is an avascular and transparent tissue that focuses light on retina. Cornea is supported by the corneal‐endothelial layer through regulation of hydration homeostasis. Restoring vision in patients afflicted with corneal endothelium dysfunction‐mediated blindness most often requires corneal transplantation (CT), which faces considerable constrictions due to donor limitations. An emerging alternative to CT is corneal endothelium tissue engineering (CETE), which involves utilizing scaffold‐based methods and scaffold‐free strategies. The innovative scaffold‐free method is cell sheet engineering, which typically generates cell layers surrounded by an intact extracellular matrix, exhibiting tunable release from the stimuli‐responsive surface. In some studies, scaffold‐based or scaffold‐free technologies have been reported to achieve promising outcomes. However, yet some issues exist in translating CETE from bench to clinical practice. In this review, we compare different corneal endothelium regeneration methods and elaborate on the application of multiple cell types (stem cells, corneal endothelial cells, and endothelial precursors), signaling molecules (growth factors, cytokines, chemical compounds, and small RNAs), and natural and synthetic scaffolds for CETE. Furthermore, we discuss the importance of three‐dimensional bioprinting strategies and simulation of Descemet's membrane by biomimetic topography. Finally, we dissected the recent advances, applications, and prospects of cell sheet engineering for CETE.