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Kim et al. Plast Aesthet Res 2018;5:31 I http://dx.doi.org/10.20517/2347-9264.2018.26 Page 5 of 8

Plenty of in vivo studies investigated the role of ASCs in either normal or pathological wound healing in
more detail. In normal wound healing, where ASCs were transferred into wounds by local injection, seeded
on scaffolds (fibrin, collagen, acellular dermal matrix, etc.), as cell sheets or even systemically, the vast major-
[21]
ity suggests a beneficial ASC effect on wound healing . However, due to the limited clinical relevance of
ASC treatment in physiologically healing wounds and considering the increase of patients with wounds not
responding to conventional treatment paradigms, animal models focusing on pathological wound healing
attract more attention.

As type 2 diabetes is undoubtedly the greatest trigger for delayed wound repair, it also covers the largest
[32]
body of evidence. Maharlooei et al. for instance locally injected excisional wounds in diabetic rats with
ASCs and found wound healing rates almost comparable to those of normal rats. Similar observations were
made in many other diabetic mice and rat models that saw ASC-induced keratinocyte and fibroblast regen-
[33]
eration as well as improved wound vascularization. Among these, the study of Nambu et al. specifically
used ASCs isolated from diabetic mice whereas all other authors used ASCs from either healthy human
patients or healthy animals. Importantly, the authors found that even ASCs from diabetic mice significantly
accelerated healing of excisional wounds. In the same way, ASCs appear to promote wound healing under
[34]
ischemia. Steinberg et al. reported enhanced wound granulation in rabbit ears under ischemic conditions
(wounding after ligating two of three main arteries of the ear) upon ASC treatment and comparable obser-
vations were made in other animal models. Chronic wounds are frequently found in irradiated area and thus
are subject to intense investigation. ASCs administered directly into the irradiated wound, intramuscularly
e.g., into the irradiated limbs or even intravenously led to markedly increased cutaneous wound repair in
rats and mice, respectively [35-37] .

Taken together, existing experimental data mostly support the positive effect of ASCs on cutaneous wound
repair while there is no consensus on the exact protocol of ASC transfer to the wound side.

CLINICAL APPLICATION OF ASCS IN CUTANEOUS WOUND REPAIR
For cutaneous wound repair in the clinical setting, ASCs may be transplanted to the wound by different
ways: fat grafts, fat grafts enriched by cell fractions/SVF/ASCs or pure ASCs via stem cell therapy. While fat
grafts and enriched fat grafts surely contain ASCs to a certain extent, only the transplantation of purely in
vitro expanded and characterized ASCs as mostly done in animal studies permits to draw definite conclu-
sions of the genuine ASC effect on cutaneous wound repair. However, only few clinical studies follow exact
ASC isolation protocols due to regulatory issues and use SVF/cell fraction enriched fat grafts instead in
different critical wounds (diabetic foot ulcers, radiation injury, peripheral artery disease (PAD), venous leg
ulcers and burn scars).

[38]
In 2010, Akita et al. reported healing of radiation wounds without adverse effects by applying ASCs seeded
on an artificial dermis (Terudermis®). At a closer look, however, ASCs were isolated by Celution® rather than
[39]
according to precise ASC isolation protocols with an unclear number of patients. Bura et al. performed
a phase 1 study on the effect of in vitro expanded ASCs on ulcers due to critical limb ischemia. The authors
found increased oxygen pressure in the affected limbs, improved ulcer healing with no adverse effects. Al-
though the authors used proper ASC isolation protocols, the small number of merely seven patients with
[40]
no control group did not allow a statistical evaluation of the results. In 2015, Liu et al. summarized exist-
ing data on mesenchymal stem cells including ASCs on PAD in a total of 527 patients divided in 13 clinical
studies. Stem cells were applied intramuscularly, intravenously or intraarterially. Although no difference
in the all-cause mortality was found, a significant improvement of ulcer healing, amputation rate and the
[41]
ankle-brachial-index were observed. In a review of the feasibility of ASCs in venous leg ulcers, Zollino et al.
concluded that ASCs induce new well-vascularized tissue formation at the transplanted site with only mi-
[42]
nor complications. Conde-Green et al. reviewed twelve studies that addressed the clinical application fat