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Background and Objectives This study aimed to investigate the protective effect of poly-deoxyribonucleotide (PDRN) against skin flap necrosis in a murine skin flap model. Materials and Method Twenty mice with rectangular skin flaps on the dorsum were ran-domly divided into the PDRN (n=10) and pentobarbital sodium (PBS) (n=10) injection groups. PDRN (8 mg/kg) was subdermally injected at 12 different points immediately after the opera-tion. After 7 days, the flap perfusions were evaluated using a laser speckle contrast imaging(LSCI) system, and specimens were collected for immunohistochemistry analysis. Results The percentage of survival area relative to the total flap area was significantly higherin the PDRN group (60.87%±7.63%) than in the PBS group (45.23%±10.72%) ( p<0.05). Themean LSCI perfusion signal of the distal part of the skin flap in the PBS group was 0.57±0.12 ,and that in the PDRN group was 0.74±0.13 ( p<0.05). The PDRN group had a significantlylower interleukin 1 beta expression than the PBS group and higher vascular endothelial growthfactor α expression than the PBS group ( p<0.05). Conclusion These findings suggest that subdermally injected PDRN is more effective inenhancing flap survival during necrosis.