Ag nanocomposite hydrogels with immune and regenerative microenvironment regulation promote scarless healing of infected wounds

Bacterial infection, complex wound microenvironment and persistent inflammation cause delayed wound healing and scar formation, thereby disrupting the normal function and appearance of skin tissue, which is one of the most problematic clinical issues. Although Ag NPs have a strong antibacterial effect, they tend to oxidize and form aggregates in aqueous solution, which reduces their antibacterial efficacy and increases their toxicity to tissues and organs. Current research on scar treatment is limited and mainly relies on growth factors and drugs to reduce inflammation and scar tissue formation. Therefore, there is a need to develop methods that effectively combine drug delivery, antimicrobial and anti-inflammatory agents to modulate the wound microenvironment, promote wound healing, and prevent skin scarring.Herein, we developed an innovative Ag nanocomposite hydrogel (Ag NCH) by incorporating Ag nanoparticles (Ag NPs) into a matrix formed by linking catechol-modified hyaluronic acid (HA-CA) with 4-arm PEG-SH. The Ag NPs serve dual functions: they act as reservoirs for releasing Ag/Ag+ at the wound site to combat bacterial infections, and they also function as cross-linkers to ensure the sustained release of basic fibroblast growth factor (bFGF). The potent antibacterial effect of the Ag NPs embedded in the hydrogel against S.aureus was validated through comprehensive in vitro and in vivo analyses. The microstructural analysis of the hydrogels and the in vitro release studies confirmed that the Ag NCH possesses smaller pore sizes and facilitates a slower, more sustained release of bFGF. When applied to acute and infected wound sites, the Ag NCH demonstrated remarkable capabilities in reshaping the immune and regenerative microenvironment. It induced a shift from M1 to M2 macrophage polarization, down-regulated the expression of pro-inflammatory factors such as IL-6 and TNF-α, and up-regulated the expression of anti-inflammatory IL-10. Furthermore, the Ag NCH played a crucial role in regulating collagen deposition and alignment, promoting the formation of mature blood vessels, and significantly enhancing tissue reconstruction and scarless wound healing processes.We think the designed Ag NCH can provide a promising therapeutic strategy for clinical applications in scarless wound healing and antibacterial therapy.