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

ischemic events and reperfusion-injury. By heating tissue to a temperature of 42 °C heat shock proteins
(HSPs) are upregulated. HSP-70, HSP-72 and HSP-32 are reported to induce mechanisms which protect
musculocutaneous, fasciocutaneous and skin flaps from ischemic injury if the hyperthermic preconditioning
was conducted 6 to 24 h before flap elevation in animal studies [70-72] .

Hypothermia has protective effects caused by the downregulation of cellular metabolism as well as the
induction of HSPs. Cooling the donor area 24 h before raising of the flap has shown to increase the expression
of HSP-32 as well as significantly increase capillary perfusion and reduce skin flap necrosis in an experimental
[73]
setting .

Other ways of tissue conditioning
Pretreatment with growth factors which induce neovascularization has been investigated by some research
groups. Until now, the application of vascular endothelial growth factor (VEGF) is the most widely investigated
growth factor. The intravascular and subcutaneous application of VEGF proved to induce angiogenesis and
increase flap survival in a rat model [74,75] . There has also been a gene therapeutic approach which showed
[76]
a reduce of ischemic tissue in random skin flap models in rats by transfection with VEGF plasmids .
Other studies investigated the effects of human basic fibroblast growth factor (bFGF). Pretreatment with
subcutaneous application of bEGF at the future donor site as well as the pretreatment of the recipient site of
the flap via gene transfection showed an increase in vascularity and tissue perfusion in skin flap models in
rats [77,78] .

Other research groups have focused on the effects of extracorporeal shock wave application (ESWA) on
angiogenesis and tissue perfusion. Through ESWA, an increase in blood flow and angiogenesis as well as an
improvement in tissue metabolism could be achieved in a mouse model [79-81] . In a rat model it could even
be found that preoperative ESWA has a similar effect as surgical delay regarding microvessel density and
[82]
perfusion, being non-invasive and easily applicable . ESWA even decreases inflammatory reactions and
[83]
therefore has a protective effect against reperfusion-injury .
A further approach is the use of stem cells in tissue conditioning. In an experimental setting with Lewis rats
it could be demonstrated that the venous application of adipose derived stem cells during reperfusion after an
ischemic event could reduce necrosis in skin flaps and local application of adipose derived stem cells to the
wound bed before suturing the flap could increase tissue perfusion and skin flap survival [84,85] .

Another means for tissue preconditioning is a pharmaceutical approach. Possible drugs should counteract the
pathophysiological processes responsible for ischemia or ischemia reperfusion-injury. Of interest are drugs
which improve microcirculation as heparin, drugs which cause vasodilation like beta-mimetics, selective
calcium channel blockers and nitric oxide donors or drugs with anti-inflammatory effects like prostaglandin-
analogues or cyclooxygenase inhibitors as could be shown in different animal models [86-91] .

Tissue conditioning and wound healing
Many of the above mentioned approaches in tissue conditioning are not only promising in plastic surgery but
also seem to be an option for the improvement of wound healing, especially in wounds which are difficult
to treat due to their size or the patients comorbidities and the resulting physiological changes in the tissue.
For example there are many clinical studies investigating the positive effects of platelet rich plasma (PRP) on
wounds, as it contains a large amount of cytokines, growth factors and chemokines [92,93] . Another, yet mainly
experimental approach is the use of hypoxia to induce angiogenesis and improve wound healing. Therapeutic
aspects using hypoxia include preconditioning cells in vitro or inducing hypoxia-mediated pathways in vivo
by gene therapy or pharmaceutical agents, which eventually leads to an increase in pro-angiogenic growth