Methotrexate-Loaded solid lipid nanoparticles enhance the viability of cutaneous flaps: potential for surgical wound healing

Skin flaps are employed to cover cutaneous denuded surfaces, but ensuing flap necrosis often occurs. Previously, rats with myocardial infarction treated with lipid-core nanoparticles (LDE) loaded with methotrexate (MTX) improved myocardial irrigation and reduced necrosis. Here, the aim was to investigate the efficacy of LDE-MTX to preserve the viability of cutaneous flaps and its implications for surgical wound healing. Twenty-eight male rats were divided into 4 groups: (1) LDE, injected intraperitoneally with LDE only; (2) MTX (1 mg/Kg commercial MTX): (3) LDE-MTX (1 mg/Kg MTX associated with LDE), and controls without treatment. LDE, MTX or LDE-MTX were repeated after 2 days. Then, flap surgery (9x3cm) was performed on the dorsal region. Injections were continued every other day until day 7 when animals were euthanized. LDE-MTX treatment improved the total viable area of the flaps with a fourfold increase in blood flow and reduced inflammatory cell number (<i>p</i> &lt; 0.001), accompanied by decreased protein expression of pro-inflammatory factors. SOD-1 was higher in LDE-MTX-treated rats (<i>p</i> &lt; 0.05). In conclusion, LDE-MTX treatment achieved total viability of cutaneous flaps, with increased irrigation and diminished local inflammation. LDE-MTX may offer efficient and cost-effective prevention of cutaneous flaps and treatment for wounds from surgical procedures to be tested in future clinical studies.

皮瓣（skin flaps）常用于覆盖皮肤缺损裸露创面，但术后皮瓣坏死常为其主要并发症。既往研究表明，负载甲氨蝶呤（methotrexate, MTX）的脂核纳米颗粒（lipid-core nanoparticles, LDE）用于治疗心肌梗死大鼠模型时，可改善心肌灌注并缩小梗死面积。本研究旨在探究LDE-MTX对皮瓣存活的保护作用，及其对手术创面愈合的临床意义。
选取28只雄性大鼠，随机分为4组：(1) LDE组：仅腹腔注射脂核纳米颗粒；(2) MTX组：给予1mg/kg市售甲氨蝶呤；(3) LDE-MTX组：给予1mg/kg甲氨蝶呤与脂核纳米颗粒的复合物；以及空白对照组（不予任何干预）。于分组后2天重复给予LDE、MTX或LDE-MTX干预；随后于大鼠背部制备9cm×3cm的皮瓣模型。后续每隔1天给药一次，直至造模后第7天处死所有大鼠。
结果显示，LDE-MTX干预组的皮瓣整体存活面积显著提升，局部血流量较对照组升高4倍，炎症细胞浸润数量显著减少（*p*<0.001），同时促炎因子的蛋白表达水平亦显著降低。超氧化物歧化酶1（SOD-1）的表达水平在LDE-MTX干预组大鼠中显著升高（*p*<0.05）。
综上，LDE-MTX干预可实现皮瓣完全存活，同时提升局部灌注水平并减轻局部炎症反应。LDE-MTX或可为手术创面及皮瓣坏死提供高效且经济的防治方案，有待后续临床研究进一步验证。