Tissue-Protective Mechanisms of Bioactive Phytochemicals in Flap Surgery

Abstract

Despite careful preoperative planning, surgical flaps are prone to ischemic tissue damage and ischemia-reperfusion injury. The resulting wound breakdown and flap necrosis increase both treatment costs and patient morbidity. Hence, there is a need for strategies to promote flap survival and prevent ischemia-induced tissue damage. Phytochemicals, defined as non-essential, bioactive, and plant-derived molecules, are attractive candidates for perioperative treatment as they have little to no side effects and are well tolerated by most patients. Furthermore, they have been shown to exert beneficial combinations of pro-angiogenic, anti-inflammatory, anti-oxidant, and anti-apoptotic effects. This review provides an overview of bioactive phytochemicals that have been used to increase flap survival in preclinical animal models and discusses the underlying molecular and cellular mechanisms.

Keywords: flap; herbal medicine; ischemia–reperfusion injury; necrosis; nutraceuticals; phytochemicals.

FIGURE 1

Beneficial effects of phytochemicals on ischemic flap injury. These include pro-angiogenic, anti-inflammatory, anti-oxidant, and anti-apoptotic mechanisms, which are mediated by the up- or downregulation of various signaling molecules. P-Akt = phosphorylated protein kinase B; BAX = B-cell lymphoma 2-associated X protein; BCL-2 = B-cell lymphoma 2; CASP-3 = caspase-3; CAT = catalase; CDH-5 = cadherin-5; COX-2 = cyclooxygenase-2; CYC = cytochrome C; eNOS = endothelial nitric oxidase synthase; GSH = glutathione; GSH-Px = glutathione peroxidase; HIF-1α = hypoxia-inducible factor-1α; HO-1 = hemeoxygenase-1; ICAM-1 = intercellular adhesion molecule-1; IL-1β/IL-6 = interleukin-1β/interleukin-6; iNOS = inducible nitric oxide synthase; IκB = nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor; LC3 = microtubule-associated proteins 1A/1B light chain 3B; MMP-2/MMP-9 = matrix metalloproteinase-2/matrix metalloproteinase-9; MPO = myeloperoxidase; NF-κB = nuclear factor kappa-light-chain-enhancer of activated B cells; NO = nitric oxide; Nrf-2 = nuclear factor erythroid 2-related factor-2; SOD = superoxide dismutase; TLR-4 = toll-like receptor-4; TNF-α = tumor necrosis factor-α; VEGF = vascular endothelial growth factor.

FIGURE 2

Schematic of the three most frequently used animal flap models. (A) The superficial inferior epigastric artery flap enables the transient interruption of the blood flow into the flap with a clap. (B) The random pattern “McFarlane” flap is designed on the dorsum of the animal. In the majority of studies, the flap base is located caudally and both sacral arteries (SAs) are ligated to ensure distal flap necrosis. (C) The more recently established multi-territory dorsal perforator flap includes the supply area of the thoracodorsal (TDA), intercostal (ICA), and deep circumflex iliac artery (DCIA). By raising the flap on the vascular axis of the DCIA, this model simulates the physiology of perforator flaps.