Platelet-Rich Plasma/Chitosan/Chondroitin sulfate immunomodulatory hydrogel Co-Networks for diabetic wound Repair: Functions and molecular mechanisms

Diabetic wound healing encounters numerous challenges including bacterial infection, macrophage dysfunction, excessive inflammation, and oxidative stress, causing delays in the overlapping processes of inflammation, proliferation, and remodeling and thus imposing a high burden on patients. Platelet-rich plasma (PRP) has demonstrated significant potential for diabetic wound treatment by promoting granulation tissue formation, collagen deposition, re-epithelialization, and angiogenesis. However, the underlying molecular and cellular mechanisms remain unclear. Here, immunomodulatory hydrogel co-networks based on PRP, with strong hemostatic, antibacterial, and free radical scavenging effects, are developed for diabetic wound treatment. In vitro and in vivo, the hydrogels can reduce endothelial cell apoptosis and promote tube formation by regulating the oxidative stress microenvironment. For anti-inflammatory and tissue repair, the hydrogels can facilitate the M2 macrophage polarization by inhibiting phosphorylation of p-IκBα and p-P65 in the NF-κB signaling pathway. Through increasing the expression of key angiogenic factors (HIF-1α, VEGF, and FGF2), the hydrogels can significantly promote angiogenesis and the formation of endothelial cell tubular structures. These findings offer new insight into the synergistic regulatory contributions of the PRP-based therapy throughout multiple stages of healing, thereby establishing a biomolecular and cellular foundation for advanced diabetic wound management.