Smart Hydrogel Dressing Enhances the Healing of Chronic Infectious Diabetic Wounds through Dual-Barrier Drug Delivery Action

Chronic diabetic wounds struggle to heal due to drug-resistant bacterial infections, oxidative stress microenvironment, and immune dysfunction. At present, the disease has become a huge clinical challenge. Multifunctional hydrogels with antibacterial, antioxidant, and anti-inflammatory properties are becoming an emerging trend in the treatment of chronic wounds. However, matching different bioactive functions with the wound healing process to sequentially exert antibacterial, antioxidant, anti-inflammatory, and immunomodulatory functions remains a significant challenge. In this research, a hydrogel dressing with bactericidal and anti-inflammatory properties was synthesized by crafting a pH/ROS-responsive scaffold from phenylboronic acid-grafted hyaluronic acid (HA-PBA) and 4-arm-PEG-dopamine (4A-PEG-Dopa), employing dynamic borate ester bonds. This structure was then infused with the antimicrobial peptide (AMP) and ROS-sensitive micelle mPEG-TK-PLGA loaded with quercetin (QC). This dressing embodied a dual-barrier drug delivery mechanism, engineered for the prolonged and consistent liberation of QC. In the experiment, the hydrogel dissociated within the acidic microenvironment of diabetic wounds, thereby liberating the encapsulated micelles and AMP. Upon further dissociation, the micelles release QC due to the ROS-abundant microenvironment, which could relieve oxidative stress and encourage M2 polarization of macrophage via the Akt/STAT6 signaling pathway. Therefore, this smart delivery system, developed through our innovative approach, holds promise for treating chronic infectious diabetic wounds.