Background:　Mesenchymal　stem　cell　(MSC)-derived　exosomes　have　been　recognized　as　new　candidates　for　the　treatment　of　ischemic　disease　or　injury　and　may　be　an　alternative　treatment　for　cell　therapy.　This　aim　of　the　study　was　to　evaluate　whether　exosomes　derived　from　adipose　mesenchymal　stem　cell　(ADSC)　can　protect　the　skin　flap　during　ischemia-reperfusion　(I/R)　injury　and　induce　neovascularization.　Methods:　To　investigate　the　effects　of　exosomes　in　the　I/R　injury　of　flap　transplantation　in　vivo,　flaps　were　subjected　to　6　h　of　ischemia　by　ligating　the　left　superficial　inferior　epigastric　vessels　(SIEA)　followed　by　blood　perfusion.　Exosomes　derived　from　normal　ADSC　(ADSC-exos)　and　exosomes　derived　from　ADSC　preconditioned　with　H2O2　(H2O2-ADSC-exos)　were　injected　into　the　flaps.　Then,　the　blood　perfusion　unit　(BPU)　of　the　flaps　was　measured　by　Laser　Doppler　Perfusion　Imaging　(LDPI)　and　microvessel　density　was　determined　by　the　endothelial　with　cell　marker　CD31　with　Immunohistochemistry　(IHC)　staining.　Inflammatory　cell　infiltration　of　the　skin　flap　and　apoptosis　were　detected　by　hematoxylin　&　eosin　staining　(H&E)　and　the　TdT-mediated　biotinylated　dUTP　nick　end-labeling　(TUNEL)　technique.　Results:　In　vivo,　exosomes　significantly　increased　flap　survival　and　capillary　density　compared　to　I/R　on　postoperative　day　5,　and　decreased　the　inflammatory　reaction　and　apoptosis　in　the　skin　flap　(P　＜　0.05).　Furthermore,　H2O2-ADSC-exos　had　better　outcomes　compared　to　normal　exosomes　(P　＜　0.05).　ADSC-exos　could　significantly　increase　human　umbilical　vein　endothelial　cell　(HUVEC)　proliferation　(P　＜　0.05),　but　no　statistic　difference　was　found　in　exosomes　derived　from　different　microenvironments　(P　＞　0.05).　HUVEC　co-cultured　with　H2O2-ADSC-exos　increased　the　migration　ratio　and　generated　more　cord-like　structures　compared　to　ADSC-exos　and　the　control　group　(P　＜　0.05).　Conclusion:　ADSC-exos　can　enhance　skin　flap　survival,　promote　neovascularization　and　alleviate　the　inflammation　reaction　and　apoptosis　in　the　skin　flap　after　I/R　injury.　The　use　of　a　specific　microenvironment　for　in　vitro　stem　cell　culture,　such　as　one　containing　a　low　concentration　of　H2O2,　will　facilitate　the　development　of　customized　exosomes　for　cell-free　therapeutic　applications　in　skin　flap　transplantation.　(C)　2018　Elsevier　Inc.　All　rights　reserved.