A multifunctional dihydromyricetin-loaded hydrogel for the sequential modulation of diabetic wound healing and glycemic control

Abstract

Background: The management of chronic diabetic wounds remains a formidable challenge in clinical practice. Persistent hyperglycemia triggers vasculopathy, neuropathy, and immune dysfunction, critically impeding wound repair. We developed a multifunctional hydrogel (DPFI) engineered for sequential therapeutic actions, including antibacterial, anti-inflammatory, antioxidant, pro-vascularization/epithelialization, and glycemic-regulating properties, to address these complications. Methods: DPFI hydrogels were prepared by encapsulating dihydromyricetin (DMY) into aldehyde-functionalized Pluronic F127 micelles (DMY@PF127-CHO), followed by a Schiff base reaction with amine-rich polyethyleneimine (PEI), resulting in the formation of a hydrogel for controlled drug release. The antimicrobial, antioxidant, anti-inflammatory, pro-cellular proliferative, and angiogenic properties of the hydrogels were evaluated using various techniques, including structural characterization, bacterial live/dead staining, reactive oxygen species (ROS) assays, antioxidant enzyme assays, reverse transcription–polymerase chain reaction (RT–PCR), cellular immunofluorescence staining, scratch wound healing assays, and angiogenesis assays. In vivo, the effects of the hydrogel on wound healing and glycemic control were assessed in methicillin-resistant Staphylococcus aureus-infected mice with streptozotocin-induced diabetes. Results: The hydrogel exhibits exceptional injectability, bioadhesion, and self-healing properties, facilitating the controlled, sustained release of DMY, which synergistically enhances antimicrobial effects in combination with PEI. The antioxidant activity of DMY is remarkable; it effectively scavenges ROS and induces the expression of antioxidant enzymes while promoting the phenotypic switch of M1 macrophages to M2 macrophages to mitigate inflammation. Critically, DPFI also contributes to glycemic regulation, reducing hyperglycemia-associated complications and creating a microenvironment conducive to wound repair. Comprehensive in vitro and in vivo analyses corroborate the multifaceted therapeutic capabilities of DPFI, including its antibacterial activity and abilities to clear ROS, reduce inflammation, promote angiogenesis, promote epithelialization, and modulate blood glucose levels. Conclusions: DPFI represents a promising, integrative strategy for enhanced diabetic wound management, meriting further exploration for clinical application.

Keywords

Chronic diabetic wound / Multifunctional hydrogel / Dihydromyricetin (DMY) / Sequential therapeutic modulation / Glycemic control / Antioxidant and anti-inflammatory effects

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