Conformational Transition‐Driven Self‐Folding Hydrogel Based on Silk Fibroin and Gelatin for Tissue Engineering Applications

Abstract Self‐folding is a rapidly evolving method for converting flat objects into three‐dimensional (3D) structures. However, because there are few materials with suitable properties, the application of self‐folding in tissue engineering has been hindered greatly. Herein, a novel self‐folding hydrogel using conformational transition mechanism is developed by employing photocrosslinkable silk fibroin and gelatin composite hydrogel. It is hypothesized that differences in the amount of beta‐sheet ( β ‐sheet) formation between the upper and lower layers will supply additional folding stress and drive the self‐folding behavior of a bilayer patch, which can improve the mechanical properties and long‐term stability of the self‐folded structure. In this study, the impact of various proportions of β ‐sheets in composite hydrogels on their swelling, mechanics, and internal microstructures are investigated. Subsequently, the folding process parameters are optimized, and diffusion through the folded tubular structure is studied with a perfusion test. Finally, it is proven that the self‐folding hydrogel system is cytocompatible and can be utilized to build a 3D coculture system of “endothelial cells–smooth muscle cells”. These findings suggest that the self‐folding hydrogel can be a promising candidate for applications in blood vessel tissue engineering and regenerative medicine.