Dynamic Self‐Clickable Decellularized Matrix Hydrogels for Regulating Vascularity and Enhancing Muscle Regeneration

ABSTRACT Decellularized matrix (dECM) derived from small intestine submucosa (SIS) has been increasingly used in tissue engineering and regenerative medicine. While dECM provides cell‐adhesive and protease‐labile sequences to support cell‐matrix interactions, its crosslinking into hydrogels has been largely limited to temperature‐induced gelation, which offers limited tunability. To address this challenge, we previously reported the synthesis of bovine decellularized SIS‐norbornene (dSIS‐NB) for crosslinking into cytocompatible thiol‐norbornene hydrogels with pro‐angiogenic and pro‐vasculogenic properties. In this study, we conducted proteomic profiling to analyze the protein compositions of bovine dSIS and dSIS‐NB. In addition to various collagens, we discovered that bovine dSIS contained significant amounts of fibrillin‐I, a glycoprotein stabilized by intra‐ and inter‐molecular disulfide bonds. We leveraged these disulfide bonds to fabricate ‘self‐clickable’ dSIS‐NB thiol‐norbornene hydrogels without the need for additional thiol‐bearing crosslinker (e.g., 4‐arm poly(ethylene glycol)‐thiol). Furthermore, we exploited thiol‐disulfide exchange in self‐clickable dSIS‐NB hydrogels to enable light‐induced spatiotemporal tuning of hydrogel stiffness and labeling of bioactive ligands. Finally, the dynamic and self‐clickable dSIS‐NB hydrogels were used as an in vitro cell culture model to study local vascular compression and as an injectable, cell‐laden matrix to treat volumetric muscle loss.