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Effect Of Nitric Oxide Releasing Gel On Excisional Wound Healing
chikage noishiki, MD, PhD,, Nina Kosaric, PhD, Harriet Nampima Kiwanuka, Britta A. Kuehlmann, MD, PhD,, Geoffrey C. Gurtner, MD.
Stanford University, Stanford, CA, USA.

PURPOSE: Nitric Oxide (NO) plays a pivotal role as a messenger molecule that signals to cells during wound repair. The amount of NO secreted changes during the three classic stages of wound healing: inflammation, proliferation and regeneration. NO levels normally increase rapidly after skin injury in the inflammatory phase and gradually decrease as wound healing proceeds toward the proliferation and regeneration. However, although NO is known to impact proliferation, differentiation and migration of keratinocytes, the molecular mechanisms of how increased NO concentration affects wound healing and leads to re-epithelialization and wound closure is far from completely understood. Here we reveal that local continuous administration of NO-releasing gel on excisional wound healing accelerates overall wound healing despite an initial delay in wound closure.
METHODS: Murine excisional wound model was studied to investigate the effects of NO releasing gel on angiogenesis and re-epithelialization. NO gel was created by adding cellulose derivatives to sodium nitrate solution.1) Mouse model: 15-week-old C57BL/6 mice were randomized into treatment groups: Nitric Oxide or PBS control (N=5 mice per group). A full-thickness wound was excised using a sterile 6-mm punch biopsy tool on each side of the dorsal midline. An NO- releasing gel was locally applied to the wound site twice daily until wound closure on D21.2) Tissue analyses: Wounds were harvested on day 2 and 7 after wounding and upon closure. The presence of epidermis, dermal integrity, vasculature and inflammatory cells were visualized by histology and immunofluorescent techniques. RESULTS: In the murine excisional model, NO-treated wounds healed completely four days earlier than PBS-treated wounds (Wound closure Day 15.60.7 vs. Day 19.40.5). However, initially NO-treated wounds closure was slower than PBS-treated wounds. Wounds harvester from the NO treatment group exhibited a more robust dermal layer, collagen deposition, and neovascularization. Neovascularization was evaluated using CD31 immunofluorescent staining. NO treated wounds exhibited significantly higher CD31 stain compared to the PBS control group.
CONCLUSION: The molecular mechanisms by which the amount of NO impacts wound healing and restores re-epithelialization leading to wound closure has not been identified previously. Physiological NO expression usually peaks after a few days. With NO gel treatment, NO levels are elevated immediately after skin injury. We used NO-releasing gel to demonstrate that daily application of NO gel immediately after a wound injury can accelerate overall wound healing, and the inflammatory phase may be activated early and enhance healing progression with early re-epithelialization. However, NO-treated wounds closure is initially slower. The continuous local NO treatment on excisional wound healing may be vary in its the role on proliferation, differentiation and migration of keratinocytes. Therefore, this NO gel for excisional wound healing model will be valuable contribution to advance the field of wound healing.


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