pH-responsive polydopamine-shelled 3D-printed chitosan/collagen hydrogel integrating exosomes and an enzyme/peptide cascade for diabetic wound healing

Abstract

Diabetic chronic wounds are commonly characterized by persistent inflammation, excessive oxidative stress, impaired tissue regeneration capacity, and elevated risk of bacterial infection. These characteristics severely hinder tissue repair. This study developed a multifunctional core–shell structure 3D-printed chitosan/collagen (CS/Col) hydrogel scaffold featuring a pH-degradable shell. The core is loaded with exosomes (Exo) and epidermal growth factor (EGF), while the outer layer adsorbs glucose oxidase (GOx), superoxide dismutase (SOD), and antimicrobial peptides (AMPs), coated with polydopamine (PDA) as an acid-responsive shell. The optimized CS : Col = 3 : 2 hydrogel exhibits excellent printability, mechanical properties, and structural stability after crosslinking with genipin (GEN). The PDA shell enables tiered release in acidic inflammatory environments: early release of GOx/SOD/AMP for antibacterial and antioxidant effects, followed by Exo and EGF release to promote tissue regeneration. In vitro experiments demonstrated stable bioactivity retention, broad-spectrum antibacterial activity, and significant antioxidant capacity. The scaffold effectively induced macrophage polarization from the M1 to the M2 phenotype while promoting fibroblast and keratinocyte migration and proliferation. In vivo studies-including diabetic rat skin defects, C57 infectious dermatitis, and rabbit full-thickness ear wound models-demonstrated that the G3 core–shell scaffold significantly accelerated wound closure, reduced bacterial load, and promoted ordered collagen deposition, re-epithelialization, and skin appendage regeneration. This study provides an intelligent 3D-printed hydrogel dressing capable of multi-target synergistic regulation of the wound microenvironment, offering a novel strategy with application potential for treating complex diabetic wounds.