**INTRODUCTION:** Burn injuries are a serious threat to patients and often require surgical treatment. Split-thickness skin grafting aims to achieve rapid wound closure but requires a well-vascularized wound bed. The cell-free secretome of peripheral blood mononuclear cells (PBMCs) \_ comprising all secreted factors produced over 24 hours \_ has been shown to improve wound healing and angiogenesis in previous studies. We used human PBMC secretomes in an in vivo model that resembles the clinical setting to investigate its potential to improve the quality of regenerating skin, increase angiogenesis, and reduce scar formation after burn injury and skin grafting.

**MATERIALS AND METHODS:** Human PBMC secretomes were harvested after 24 hours under standard cell culture conditions. Gamma irradiation was used to induce apoptosis and create an additional stimulus. Standardized full-thickness burn injuries were created on the back of female pigs. After 24 hours, the necrotic areas were excised and the wounds were covered with split-thickness mesh skin grafts. Wounds were treated repeatedly with either the secretome of cultured PBMCs (SecPBMC), apoptotic PBMCs (Apo-SecPBMC), or controls. Wounds were analysed and wound biopsies were taken on days 2, 5, and 10.

**RESULTS:** We found a markedly increased mean epidermal thickness in wounds treated with either SecPBMC (116.7 μm ± 34.7) or Apo-SecPBMC (133.2 μm ± 37.6) compared to the medium (78.3 μm ± 29.2) and NaCl groups (79.3 μm ± 13.7). Epidermal differentiation (expression of keratin-10) was more advanced in the treated wounds compared to controls. Apo-SecPBMC treatment induced a two-fold increase in CD31+ cells (p\<0.05 vs. all other groups), indicating more angiogenesis. The parameters of early scarring were improved in secretome-treated wounds.

**CONCLUSIONS:** These data suggest that the repeated application of PBMC secretomes significantly improves wound healing, skin quality, and scar formation in a porcine model of burn injury and skin grafting.
