Construction of multilayer multifunctional hydrogel microspheres with natural macromolecules, tannic acid, and copper for enhanced diabetic wound healing

Diabetic wounds exhibit excessive local inflammation, oxidative stress, microcirculatory disorders, and an increased risk of infection, all of which contribute to delayed healing. The development of multifunctional wound dressings is therefore critical for effective diabetic wound management. This study successfully designed and fabricated multilayer multifunctional hydrogel microspheres (COQTCu) composed of methacrylated carboxymethyl chitosanc (CSMA), oxidized carboxymethyl starch (OCMS), quaternized chitin (QC), tannic acid (TA), and copper ions (Cu 2+ ). The microspheres were constructed using photopolymerization, Schiff base reactions, electrostatic interactions, hydrogen bonding, and chelation, resulting in distinct surface morphologies and sequentially reduced diameters with each additional layer. COQTCu microspheres exhibited robust mechanical strength, excellent injectability, potent antibacterial activity, high biocompatibility, and sustained Cu 2+ release. Detailed structural analyses using fluorescently labeled molecules (OCMS-DAPI, QC-FITC, and TA-Cy5) confirmed the successful assembly of the multilayer architecture. In vitro studies demonstrated that COQTCu microspheres significantly enhanced antioxidant, anti-inflammatory, and cell migration properties. Moreover, in a diabetic wound model, treatment with COQTCu accelerated wound healing, promoted angiogenesis, reduced inflammation, and improved collagen accumulation and maturation. Overall, the multilayer multifunctional COQTCu hydrogel microspheres represent a promising therapeutic strategy for diabetic wound treatment and provide valuable insights for the future design of advanced tissue repair materials.