Therapeutic Potential of Bovine Colostrum-Derived Exosomes for Ischemia-Reperfusion Injury in Skin Flaps: A Rat Model Study.

BACKGROUND:Ischemia-reperfusion (I/R) injury remains a major cause of partial skin flap necrosis following microsurgical reconstruction. This study evaluates the therapeutic potential of bovine colostrum-derived extracellular vesicles (C-EVs) as a scalable, cell-free alternative for enhancing skin flap survival. METHODS:Twenty-four Sprague-Dawley rats were randomly assigned to Sham, Control, and Exosome groups (n=8). A 3×6-cm 2 superficial inferior epigastric artery (SIEA) flap was elevated in all animals. The Control and Exosome groups were subjected to 8 hours of ischemia followed by reperfusion, while the Sham group underwent elevation alone. The Exosome group received 200 μg of C-EVs subcutaneously on Days 0 and 3, while Control and Sham groups received PBS. On Day 7, flap survival was evaluated via macroscopic analysis and laser Doppler perfusion imaging. Histological and immunohistochemical analyses were performed on tissue harvested from the standardized watershed zone to evaluate microvessel density (MVD), pro-inflammatory cytokines, and macrophage polarization. RESULTS:C-EVs significantly improved flap survival compared to the Control group (70.50±8.24 vs. 51.75±3.62 percent, p<0.05) and enhanced vascular perfusion (70.88±5.08 vs. 58.88±6.85 percent, p<0.05). Quantitative IHC analysis revealed that C-EV treatment significantly increased MVD (149.00±3.09 vs. 71.88±6.79 vessels/mm 2, p<0.01) and suppressed pro-inflammatory cytokine expression. Furthermore, C-EVs promoted M2 macrophage polarization, evidenced by a significantly lower CD86/CD206 ratio (p<0.01). CONCLUSIONS:This study provides early-stage preliminary evidence in a controlled rat model that C-EVs can mitigate I/R injury and improve skin flap survival. Given the proof-of-concept nature of these findings, further investigation in larger models is required to determine their clinical applicability.