A Synergistic Composite Hydrogel Integrating Periplaneta americana Extract and Calamine for Refractory Diabetic Wound Healing

Background: Diabetic foot ulcers (DFUs) are difficult to heal because hyperglycemia-associated pathological exudation, excessive oxidative stress, chronic inflammation, and impaired cellular regeneration jointly maintain a nonhealing wound microenvironment. This study aimed to develop and evaluate a composite hydrogel containing Periplaneta americana (PA) extract and calamine as a Zn²⁺ source for dynamic modulation of the diabetic wound microenvironment and promotion of tissue repair. Methods: A PA composite hydrogel was prepared and assessed in vitro for reactive oxygen species (ROS)-scavenging activity and effects on fibroblast migration. Therapeutic efficacy was further evaluated in a streptozotocin (STZ)-induced diabetic full-thickness wound model in rats. Wound closure, histological remodeling, oxidative stress markers, inflammatory mediators, growth factors, angiogenesis, and AGEs-RAGE/NF-κB pathway-related changes were analyzed. Results: The composite hydrogel reduced excessive intracellular ROS and enhanced fibroblast migration in vitro compared with pathological-condition controls. In diabetic rats, topical treatment accelerated macroscopic wound closure and promoted more mature histological repair. Mechanistic analyses showed attenuation of the AGEs-RAGE/NF-κB signaling axis, accompanied by restoration of superoxide dismutase activity, reduction of malondialdehyde levels, and suppression of TNF-α-associated inflammatory responses. The improved wound microenvironment was associated with increased expression of platelet-derived growth factor and basic fibroblast growth factor, enhanced cellular proliferation, and increased neovascularization within the wound tissue. Conclusions: The PA composite hydrogel improved diabetic wound healing by concurrently alleviating oxidative and inflammatory barriers and enhancing regenerative signaling. These findings suggest that microenvironment-modulating PA composite hydrogel systems may represent a promising therapeutic strategy for refractory diabetic wounds.