Intelligent drug delivery-wound healing integrated hydrogel dressing for Type 2 Diabetes Mellitus wounds with wound microenvironment modulation

Diabetic wounds are a major complication for diabetic patients, with the high sugar and high ROS microenvironment leading to slow healing and a high risk of infection. To tackle these issues effectively, there is a critical need for advanced wound care solutions that can dynamically respond to the fluctuating conditions within the wound bed. In this study, we developed an intelligent, responsive hydrogel dressing designed to modulate the wound microenvironment to promote diabetic wound healing. This hydrogel is capable of responsively releasing the blood glucose-regulating drug (sitagliptin (Sit)) and, in accordance with the inflammatory condition, it dispenses the anti-inflammatory drug nimesulide (Nim) on demand. Consequently, it ameliorates the diabetic wound microenvironment, greatly accelerating wound healing. This hydrogel is composed of carboxymethyl chitosan (CMC), oxidized hyaluronic acid methacrylate (OHM), 1-butyl-3-vinylimidazolium bromide (IL), Sit, and methoxy poly(ethylene glycol)-thioketal-poly(ε-caprolactone)@Nim (GKL@Nim (GN)) micelles that release anti-inflammatory drugs in response to ROS, forming a Schiff base/double bond dual network intelligent hydrogel. The hydrogel demonstrates good performance in responsive drug release, in vitro inflammatory modulation, ionic conductivity, swelling, biodegradability, and self-healing capabilities. In the full-thickness skin defect wound healing assay using a Type 2 Diabetes Mellitus (T2DM) mouse model, the hydrogel group exhibited remarkable therapeutic effects, achieving an 80.2 % wound closure ratio on day 7, markedly superior to the Tegaderm™ film group (24.2 %). By day 14, wound closure in the hydrogel group reached 96.3 %. Histological assessments verified that hydrogel significantly enhanced angiogenesis and collagen deposition. Immunohistochemical analyses confirmed the hydrogel's efficacy in substantially decreasing IL-6 levels (25.7 %) and augmenting CD31 expression (315.3 %). Collectively, this intelligent hydrogel dressing holds immense promise for the treatment of diabetic wounds.