Biocatalytic nitric oxide generating hydrogels with enhanced anti-inflammatory, cell migration, and angiogenic capabilities for wound healing applications.

Although wound healing is a normal physiological process in the human body, it is often impaired by bacterial infections, ischemia, hypoxia, and excess inflammation, which can lead to chronic and non-healing wounds. Recently, injectable hydrogels with controlled nitric oxide (NO) release behaviour have become potential wound healing therapeutic agents due to their excellent biochemical, mechanical, and biological properties. Here, we proposed novel multifunctional NO-releasing hydrogels that could regulate various wound healing processes, including hemostasis, inflammation, cell proliferation and angiogenesis. By incorporating the copper nanoparticles (NPs) in the network of dual enzymatically crosslinked gelatin hydrogels (GH/Cu), NO was in situ produced via the Cu-catalyzed decomposition of endogenous RSNOs available in the blood, thus resolving the intrinsic shortcomings of NO therapies, such as the short storage and release time, as well as the burst and uncontrollable release modes. We demonstrated that the NO-releasing gelatin hydrogels enhanced the proliferation and migration of endothelial cells, while promoting the M2 (anti-inflammatory) polarization of the macrophage. Furthermore, the effects of NO release on angiogenesis were evaluated using an in vitro tube formation assay and in ovo chicken chorioallantoic membrane (CAM) assay, which revealed that GH/Cu hydrogels could significantly facilitate neovascularization, consistent with the in vivo results. Therefore, we suggested that these hydrogel systems would significantly enhance the wound healing process through the synergistic effects of the hydrogels and NO, and hence could be used as advanced wound dressing materials.