Factors Associated With Free Flap Complications After Head and Neck Reconstruction and the Molecular Basis of Fibrotic Tissue Rearrangement in Preirradiated Soft Tissue

Abstract

Several factors are associated with free flap complications in head and neck reconstruction after radiotherapy. The present study aimed to identify the correlation between irradiation and the healing of wounds after microvascular free flap transfer and to clarify the molecular mechanisms for the differences in healing between irradiated and nonirradiated patients. A retrospective study of 81 cases of microvascular free flap transfer was conducted. Tissue samples were obtained from 3 different regions of the patients (nonirradiated oral mucosa, irradiated skin, and nonirradiated skin). Expression of transforming growth factor-beta(1) was monitored by immunohistochemistry and immunoblot analysis. The levels of matrix metalloproteinase-1 and tissue inhibitor of matrix metalloproteinase-1 were investigated qualitatively and quantitatively. Multivariate analysis revealed that only preoperative irradiation was a significant predictor of free flap complications (P = .006), with a 4 times greater risk (odds ratio 4.141). It was also shown that patients with an advanced tumor stage and those who had received chemotherapy after radiotherapy were twice as likely to develop free flap complications. Transforming growth factor-beta(1) was overexpressed in free flaps for as long as 6 months after radiotherapy. It was remarkably observed in the granulation tissue in the preirradiated skin. Moreover, extracellular matrix remodeling regulated by transforming growth factor-beta(1) was detected with decreased matrix metalloproteinase-1 and increased TIMP-1 expression in the irradiated skin. The healing of surgical wounds created by microvascular free flap transfer correlated negatively with preoperative radiotherapy. Extracellular matrix remodeling was also detectable in the free flap for up to 6 months after radiotherapy completion.