Dual-responsive antibacterial hydrogels encapsulating Periodontal Ligament Stem Cells for macrophage reprogramming and diabetic wound healing

The effective repair of chronic diabetic wounds remains challenging owing to the excessive increase in Reactive Oxygen Species and chronic inflammation. Herein, we engineer an injectable, pH/ROS-dual responsive Antibacterial hydrogel (GT-PBA/EGCG/OPU/TOB-PDLSCs) for scarless diabetic wound repair by integrating periodontal ligament stem cells (PDLSCs) into an interpenetrating polymer network (IPN) hydrogel composed of phenylboric acid-modified gelatin (GT-PBA), oxidized pullulan (OPU), epigallocatechin-3-gallate (EGCG), and tobramycin (TOB). The hydrogel is prepared through dynamic Schiff base crosslinking between GT-PBA/TOB and OPU, while phenylborate ester linkages with EGCG confer ROS-responsive degradability. This design enables sustained, on-demand release of TOB and EGCG in response to pathological pH and ROS levels. The encapsulated PDLSCs maintain high viability and proliferative capacity within the hydrogel matrix. Functionally, the hydrogel effectively scavenges intracellular ROS, reprograms macrophages toward a pro-regenerative phenotype, and enhances stem cell survival under oxidative stress. In diabetic wound models, the PDLSCs-loaded hydrogel significantly accelerates wound closure, promotes angiogenesis, and modulates inflammation. Notably, it markedly reduces scar formation, downregulates profibrotic genes YAP and En1, and facilitates regenerative healing. This multifunctional platform thus represents a promising strategy for achieving scarless repair of diabetic wounds through immunomodulation, ROS scavenging, and stem cell delivery.

Cell reprogramming; Cell therapy; Diabetic scarless wound healing; Intelligent drug delivery; Multiple stimulus-responsive hydrogel.