Prognostic significance of tissue oxygenation changes and early signaling responses in fasciocutaneous advancement flap healing

Abstract

Regional axial flaps have become mainstays of reconstructive and plastic surgery aimed at restoring function, form and integrity of various body parts after traumatic injuries, burns, tumor resection or the repair of birth defects. Such flaps remain attached to the donor site via single intact vascular pedicle, which serves as a conduit for supplying nutrients and removing waste during wound healing process. Despite advances in surgical techniques, complications associated with partial or full flap loss remains a significant clinical problem, particularly in the angiopathic population. In addition to inducing debilitating patient stress, reconstructive failures inordinately contribute to health care costs due to prolonged hospitalization, readmission and revision surgery. The knowledge about the diagnostic biomarkers that may predict the fate of a flap can greatly improve the rate and quality of ischemic flap healing, as it permits early therapeutic interventions to reduce the risk of flap loss. Twenty three 10–12 months old Sprague‐Dawley rats underwent bilateral epigastric flap reconstruction surgery. Tissue oxygen saturation was measured in vivo by optical photoacoustic imaging between 24 and 48 hours post‐surgery and 0.75×2.5cm skin biopsies as well as wound fluid (if present) were taken from the distal part of each flap. Tissue oxygenation changes, intracellular and/or wound exudate levels of matrix metalloproteinases (MMPs), various growth factors/cytokines, as well as the activation of major cell signaling pathways (JAK/STATs, c‐Src/FAK, PI3‐kinase/Akt/eNOS, PLC‐γ/PKC/H3, HO‐1/COX‐2, Ras/ERK, SAPK/JNK, MKK/p38 MAPK, Rac/PAK) including the induction of key transcription factors (Fra‐1, c‐Myc, c‐Fos, CREB1, EGR1, Sp1) and wound healing‐associated heat shock proteins (HSP27, HSP90, HSP47), have been correlated to the degree of survival of 45 superficial inferior epigastric artery (SIEA)‐based fasciocutaneous advancement flaps as assessed by planimetry analysis, Western blotting and H&E/Masson's Trichrome staining at 9th day after the surgery. Although the level of heme oxygenase‐1 (HO‐1), a cytoprotective enzyme, which inhibits leukocyte migration to inflammatory sites, and can be induced by hypoxia or various pro‐inflammatory stimuli, was uniformly increased on average by 2.77 fold in distal segments of all surviving and partially failed flaps, there was a significant correlation between the positive or negative changes in oxygen saturation percentage of middle‐to‐distal flap sections and functional flap outcomes. Impaired flap healing was significantly associated only with a loss of HSPs. Poor outcome, to a lesser extent, correlated with increased phosphorylation of p54 JNK isoform and expression of cyclooxygenase‐2 (COX‐2) as well as inducible, but not endothelial, nitric oxide synthase (NOS).Support or Funding InformationThis Research was supported by Department of Otolaryngology ‐ Head & Neck Surgery at Thomas Jefferson University