Radiation-induced microenvironments – The molecular basis for free flap complications in the pre-irradiated field?

Abstract 

Background and purpose

The effect of preoperative radio- or radiochemotherapy on the survival of free flaps used for head and neck reconstruction is reported in a contradictory way. Although there is a lot of knowledge on radiation-induced wound healing disorders from animal models there are no investigations on human patients so far. Our prospective study aimed at clarifying the effect of radiotherapy on clinically apparent free flap complications and on correlating them with radiation-induced extracellular matrix (ECM) remodeling.

Materials and methods

Healing of 114 free flaps was monitored in a prospective study and correlated with different anamnestic features, such as diabetes and radio- or radiochemotherapy using multivariate regression. During the operation connective tissue biopsies were harvested from the graft beds and analyzed for Transforming Growth Factor (TGF)-β₁-expression by means of Western blotting as well as Tissue Inhibitor of Matrix-Metallo-Proteinase (TIMP)-1 and Matrix-Metallo-Proteinase (MMP)-1 by immunohistochemistry.

Results

History of radio- or radiochemotherapy was the only factor significantly predicting free flap complications. Radiochemotherapy resulted in a significant increase in TGF-β₁- and TIMP-1-expression, while MMP-1-expression was not significantly altered. Radiotherapy alone significantly increased TIMP-1-expression without detectable effects on TGF-β₁ and MMP-1.

Conclusions

Radio- and radiochemotherapy alter graft bed ECM organization prior to surgery. This alteration impacts significantly on free flap survival in the pre-irradiated field.

Keywords: Oral squamous cell carcinoma, Free flap, Failure rate, TIMP-1, MMP-1