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-1 alpha) through ionic and hydrophobic interactions. The PP hydrogel exhibits thermosensitive sol-gel transition, sustained SDF-1 alpha 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.