Construction of heparin-based hydrogel incorporated with Cu5.4O ultrasmall nanozymes for wound healing and inflammation inhibition

Excessive production of inflammatory chemokines and reactive oxygen species (ROS) can cause a feedback cycle of inflammation response that has a negative effect on cutaneous wound healing. The use of wound-dressing materials that simultaneously absorb chemokines and scavenge ROS constitutes a novel ‘weeding and uprooting’ treatment strategy for inflammatory conditions. In the present study, a composite hydrogel comprising an amine-functionalized star-shaped polyethylene glycol (starPEG) and heparin for chemokine sequestration as well as Cu(5.4)O ultrasmall nanozymes for ROS scavenging (Cu(5.4)O@Hep-PEG) was developed. The material effectively adsorbs the inflammatory chemokines monocyte chemoattractant protein-1 and interleukin-8, decreasing the migratory activity of macrophages and neutrophils. Furthermore, it scavenges the ROS in wound fluids to mitigate oxidative stress, and the sustained release of Cu(5.4)O promotes angiogenesis. In acute wounds and impaired-healing wounds (diabetic wounds), Cu(5.4)O@Hep-PEG hydrogels outperform the standard-of-care product Promogram® in terms of inflammation reduction, increased epidermis regeneration, vascularization, and wound closure.