Diabetic foot ulcer (DFU) is a devastating complication in diabetes patients, imposing a high risk of
amputation and economic burden on patients. Sustained
inflammation and angiogenesis hindrance are thought to be two key drivers of the pathogenesis of such
ulcers.
Nitric oxide (NO) has been proven to accelerate the healing of acute or chronic
wounds by modulating
inflammation and angiogenesis. However, the use of gas-based
therapeutics is difficult for skin
wounds. Herein, therapeutic NO gas was first prepared as stable
microbubbles, followed by incorporation into a cold Poloxamer-407 (P407)
solution. Exposed to the DFU
wound, the cold P407
solution would rapidly be transformed into a semisolid
hydrogel under body temperature and accordingly capture NO
microbubbles. The NO
microbubble-captured
hydrogel (PNO) was expected to accelerate wound healing in
diabetic feet. The NO
microbubbles had an average diameter of 0.8 ± 0.4 μm, and most of which were captured by the in situ P407
hydrogel. Moreover, the NO
microbubbles were evenly distributed inside the
hydrogel and kept for a longer time. In addition, the gelling temperature of 30% (w/v) P407
polymer (21 °C) was adjusted to 31 °C for the PNO gel, which was near the temperature of the skin surface. Rheologic studies showed that the PNO gel had mechanical strength comparable with that of the P407
hydrogel. The cold PNO
solution was conveniently sprayed or smeared on the
wound of DFU and rapidly gelled. In vivo studies showed that PNO remarkably accelerated wound healing in rats with DFU. Moreover, the sustained
inflammation at the DFU
wound was largely reversed by PNO, as reflected by the decreased levels of proinflammatory
cytokines (IL-1β, IL-6 and TNF-α) and the increased levels of anti-inflammatory
cytokines (IL-10, IL-22 and IL-13). Meanwhile, angiogenesis was significantly promoted by PNO, resulting in rich blood perfusion at the DFU
wounds. The therapeutic mechanism of PNO was highly associated with polarizing macrophages and maintaining the homeostasis of the extracellular matrix. Collectively, PNO gel may be a promising vehicle of therapeutic NO gas for DFU treatment.