Abstract
Chronic diabetic foot ulcers (DFUs) represent a significant clinical challenge characterized by a stalled inflammatory phase, impaired angiogenesis, and a deficiency in essential endogenous growth factors (GFs). Conventional dressings often fail due to rapid enzymatic degradation of therapeutics and lack of controlled release mechanisms. This study introduces a novel, bioinspired smart hydrogel system composed of carboxymethyl chitosan and alginate, crosslinked with ROS-cleavable bonds, designed for the on-demand release of Epidermal Growth Factor (EGF) and basic Fibroblast Growth Factor (bFGF). We hypothesized that a dual-responsive scaffold—triggered by the acidic pH and high reactive oxygen species (ROS) levels prevalent in the diabetic wound microenvironment—could provide spatiotemporal control over GF delivery. In vitro analysis demonstrated that the hydrogel exhibited high loading efficiency and released GFs in a stimuli-dependent manner, with release rates accelerating significantly at pH 5.5 and in the presence of 10 mM H2O2. In vivo evaluations using streptozotocin-induced diabetic rat models showed that the smart hydrogel treatment resulted in 94.5% wound closure by day 21, compared to only 62.1% in the control group. Histological analysis revealed enhanced re-epithelialization, organized collagen deposition, and significant neovascularization. These results suggest that the integration of stimuli-responsive biomaterials with programmed growth factor release effectively bypasses the physiological barriers of diabetic healing. This approach offers a promising paradigm for the management of non-healing chronic wounds, potentially reducing the incidence of limb amputations associated with advanced diabetic complications.