Recent advances in the development of nitric oxide-releasing biomaterials and their application potentials in chronic wound healing

Chronic wounds, such as pressure ulcers, vascular ulcers and diabetic foot ulcers (DFUs), often stay in a state of pathological inflammation and suffer from persistent infection, excess inflammation, and hypoxia, thus they are difficult to be healed. Nitric oxide (NO) plays a critical role in the regulation of various wound healing processes, including inflammatory response, cell proliferation, collagen formation, antimicrobial action and angiogenesis. The important role of NO in wound healing attracts intensive research focus on NO-based wound healing therapy. However, the application of NO gas therapy needs to resolve the intrinsic shortcomings of gas therapy, such as short storage and release times as well as temporal and spatial uncontrollability of the release mode. So far, various types of NO donors, including organic nitrates (RONO₂), nitrites (RONO), S-nitrosothiols (RSNOs), nitrosamines, N-diazeniumdiolates (NONOates), and metal-NO complexes, have been developed to solidify gaseous NO and they were further encapsulated in or conjugated onto a variety of biomaterial vectors to develop NO delivery systems. NO synthetic enzyme mimics to catalyze the production and release of NO from L-arginine have also been developed. This paper reviews recent advances of NO donors, biomaterial vectors, thus-formed NO delivery systems, as well as recently emerged NO synthetic enzyme mimics. Furthermore, this review also summarizes the functions of NO releasing biomaterials that would benefit chronic wound healing, including antibacterial properties and the promotion of angiogenesis, as well as the convenient combination of light/thermal induced NO release with light/thermal therapies, and the prospects for future developing trends in this area.