Chronic infected diabetic wounds are complex and often lead to severe clinical outcomes
such as sepsis, gangrene, and amputation. To address these challenges, herein we developed
a novel tri-layered scaffold to provide multi-functional therapeutic support. The
bottom poly (lactic-co-glycolic acid) (PLGA) fibrous layer contains doxycycline loaded
CuBDC nanosheets for rapid antibacterial action. The porous PLGA/gelatin middle layer
offers mechanical support and gamma-tocotrienol loaded ZIF-8 nanocrystals mitigates
oxidative stress in the wound. The PLGA top sealing fibrous layer delivers insulin
and Transforming growth factor beta (TGF-beta 1) from Zeolitic Imidazolate Framework-8
(ZIF-8) nanocrystals to promote epithelialization and modulate inflammation. Comprehensive
in vitro and in vivo evaluations demonstrated that the scaffold effectively filled
deep wounds, reduced bacterial load, controlled inflammation, and accelerated the
tissue regeneration. Histopathological analyses showed enhanced epithelialization
and partial granulation tissue remodeling. Biochemical assays indicated an increase
in glutathione peroxidase (GPx) activity and a reduction in lipid peroxidation. Gene
expression analysis revealed decreased levels of the pro-inflammatory TNF-alpha and
increased levels of the anti-inflammatory IL-10, facilitating the transition to the
proliferative phase. This multi-layered composite scaffold, with its antimicrobial,
antioxidant, and anti-inflammatory activities, controlled release capabilities, presents
a promising solution the healing process of deep, infected diabetic wounds.
