A Time-Programmed Bilayer Wound Dressing for Dynamic Microenvironment Modulation and Full-Thickness Regeneration in Diabetic Wounds.

Abstract

Chronic diabetic wounds suffer from dysfunctional repair programs due to accumulated advanced glycation end products (AGEs) and persistent inflammation in hyperglycemic microenvironments, posing significant clinical challenges. Current dressings predominantly focus on monofunctional interventions, failing to resolve the "inflammation-repair imbalance". In this study, we propose a chronotherapeutic bilayer system designed for stage specific regulation. The lower GelMA cryogel loaded with polyphenols acts as a "cleaner", removing AGEs via hydrogen bond capture and pore entrapment and activating the PPARγ pathway to remodel the anti-inflammatory microenvironment; The upper polycaprolactone nanofibers directionally deliver PDGF-BB, enabling sustained release to activate fibroblast migration and angiogenesis. Additionally, proteomics analysis further revealed that polyphenols downregulate multiple inflammatory factors via the PPARγ/NF-κB axis, providing a clean basal microenvironment for diabetes. In a diabetic wound model, the system demonstrated a three-step healing, marked downregulation of inflammatory markers within 72 h, accelerated re-epithelialization in 7 days, and functional hair follicle regeneration in 21 days. This study highlights the potential of "Clean-Regeneration Dual Program" bilayer assembled scaffolds in modulating the wound microenvironment and promoting tissue regeneration.