A Bioinstructive Injectable Hydrogel for Enhancing Intrinsic Regeneration through Cell Recruitment and Training

Abstract Tissue regeneration requires a precisely coordinated cascade of biological events—including stem cell homing, adhesion, proliferation, and differentiation—within a supportive and dynamic microenvironment. While numerous biomaterials have been designed to modulate individual regenerative processes, there is a need for a single, clinically viable platform that can synchronously modulate multiple regenerative events. Here, the study presents a strategically engineered injectable hydrogel that recapitulates this cascade by coordinating stem cell recruitment, matrix integration, and subsequent cellular development within a single localized system. The hydrogel is composed of amphiphilic, temperature‐responsive poly(organophosphazenes) (P) conjugated with polyethyleneimine (PP), enabling the co‐loading of laminin and stromal cell‐derived factor 1‐alpha (SDF‐1α) through ionic and hydrophobic interactions. The PP hydrogel exhibits thermosensitive sol–gel transition, sustained SDF‐1α release, and prolonged laminin retention. In vitro migration, adhesion, and proliferation assays confirm that the hydrogel enhanced stem cell recruitment and integration into the matrix. In a hindlimb ischemia mouse model, local hydrogel administration improves perfusion recovery and promotes robust angiogenesis. Together, these findings suggest that the hydrogel can coordinate several regenerative processes within a localized environment, supporting improved tissue repair in the studied model.