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Page 2 of 10                                          Krauss et al. Plast Aesthet Res 2018;5:39  I  http://dx.doi.org/10.20517/2347-9264.2018.41

               in the transplantation of solid organs, in vascularized tissue allotransplantations (VCA) such as hand or
                                                                                                   [2,3]
               face transplantations and in free flaps. In VCA for example, cold ischemia time is 6 h on average . The
               importance of ischemia reperfusion-injury in tissue transplantation is clearly illustrated by its impact on early
                                                    [4]
               graft function as well as long-term outcomes .
               Insufficient tissue perfusion plays an important role in chronic wounds as well. Tissue hypoxia is responsible
               for a lack of energy metabolism, cell proliferation, angiogenesis, cytokine release as well as enzyme activity
                                                                         [5-7]
               and therefore leading to an impairment of the tissue repair process . Common causes for tissue hypoxia
               in chronic wounds are vascular alterations, oedema and fibrosis resulting in reduced oxygen partial pressure
                    [7]
               (pO ) . An interesting discovery is that pO  in chronic wounds is 5-20 mmHg compared to 30-50 mmHg
                  2
                                                    2
                             [8]
               in control tissue . In plastic surgery, tissue perfusion is of special concern due to the field of reconstructive
               surgery, where temporary tissue ischemia in free flaps as well as reduced perfusion in pedicled flaps has to be
               accepted to be able to treat tissue defects. In skilled and experienced hands, total flap loss is reported to occur
               in 1%-7% of cases, depending on recipient site and cause of the tissue defect [9-12] . But the rate of partial flap
               necrosis is much higher, with rates of 7%-20% in free flaps and even 20%-33% in pedicled flaps [13-16] . Partial flap
               necrosis often requires further operations, thus putting a significant burden on the affected patient as well as
               the healthcare system.

               All those examples illustrate the significance of tissue blood supply and the need for methods to improve it.
                          [17]
               Or, as Gillies  once put it, “plastic surgery is the constant battle between beauty and blood supply”.
               In this unsystematic review, we want to shed some light on the effects of ischemia and IRI on the affected
               tissue and illustrate different strategies of tissue conditioning focusing on its use in flap surgery.


               Pathomechanisms of ischemia and IRI
               The persistence of insufficient tissue perfusion or total ischemia results in a loss of oxygen supply and therefore
               causes a change of cell metabolism as an adjustment to the lack of the aerobic pathway in the respiratory
               chain. This leads to an accumulation of metabolites as well as radicals and causes cell death [18,19] . Ironically,
               restauration of perfusion causes additional tissue damage due to inflammatory mechanisms caused by the
               release of oxygen compounds. Those lead to an activation of neutrophils and a consecutive adhesion between
               granulocytes and endothelial cells causing segmental vessel occlusion in postcapillary venules, transendothelial
               leukocyte migration and the release of tissue-damaging enzymes. This pathomechanism is referred to as the
               IRI [20-25] . With regard to flap surgery, flap survival is mainly depending on the integrity of the vascular pedicle
               and its “macrovascular” perfusion . IRI on the other hand affects the microcirculation of the entire flap
                                            [26]
               due to the inflammatory process and the increase in oxygen free radicals in the early stages of reperfusion .
                                                                                                        [27]
               Therefore, partial flap necrosis is often caused by an insufficient microcirculation mainly in the distal parts of
               the flap.

               Total flap necrosis on the other hand is most often caused by thrombosis of the pedicle. Timely revision of the
               anastomosis is paramount to reestablish blood flow to the flap. However, such events can lead to an increase
               IRI which in term can lead to intravascular hemoconcentration, endothelial swelling, interstitial edema
               formation as well as inflammatory processes due to the reperfusion injury. In its highest degree, IRI can lead
               to a no-reflow phenomenon which also leads to complete flap loss [28-30] .


               Tissue conditioning
               There are different means of pre- or peri- and postoperative techniques to adapt the tissue to the subsequent
               stress during and after ischemia to prevent or minimize IRI [Table 1].
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