Clinical Applications of Nitric Oxide in Diabetic Wound Healing

A diabetic wound is a long-term diabetes complication increasing the risk of mortality and amputation-related disability and decreasing the quality of life. Due to incorrect and incomplete use of standard therapies, complementary therapeutic strategies, including elevation of wound nitric oxide (NO) level by using NO donors, precursors, and inducers, have received attention in in vitro studies, animal experiments, and clinical trials. Here, we aimed to review the potential clinical applications of NO in accelerating wound healing in diabetes. Exogenous NO in the gaseous form or as acidified nitrite-containing ointments, NO-containing sprays, and NO-containing hydrogels has been applied in wound healing. Although limited clinical trials have been conducted to assess the efficiency of NO in accelerating diabetic wound healing, 56-100% effectiveness was reported for NO-based treatments compared to standard care. The known physiological functions of NO in wound healing include increasing the local blood flow, inducing angiogenesis, collagen synthesis, re-epithelization, wound closure, and anti-inflammatory effects via enforcing immune responses, and promoting potent broad-spectrum antibacterial effects. Considering the limited existing evidence, clinical trials with predefined effect sizes, i.e., wound area reduction, wound healing rate, and length of hospital stay, are required to confirm the efficiency of NO-based therapies compared to standard treatment.