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Radiation therapy has long been known to cause irreparable damage to the skin, initially characterized by erythema and ulceration, followed by fibrosis and thickening of the dermis and subcutaneous tissue and tissue ischemia secondary to hypovascularity. With the recent repopularization of fat grafting, multiple studies have shown the improvements in skin quality as a result of fat grafting, through both better skin uniformity and softening of the dermis.1 Fat grafting into irradiated tissue has also been shown clinically to improve functional and cosmetic outcomes, yet the resulting improvements appear to be short-lived, on the spectrum of months rather than years.2 Approaches to extend the effects of fat grafting into irradiated tissue remain of significant interest to the field. In the recent elegant article published by Flacco and colleagues, their efforts to use deferoxamine to augment the retention of fat grafts showed significant improvement in the quality of the skin and volume retention following treatment.3Fat grafting to irritated skin transfers adipocytes along with preadipocytes, stromal cells, endothelial cells, and immune cells from an area of excess fat into an area of impaired wound healing. For the newly implanted fat grafts to survive, the graft site must be optimized to allow for neovascularization to occur. Flacco et al. chose to precondition the graft site with deferoxamine with injections every other day. Deferoxamine, an iron chelator, has previously been shown to up-regulate the expression of angiogenic factors, including vascular endothelial growth factor and hypoxia-inducible factor-1α, and improve the healing of chronic wounds by increasing neovascularization.4 Additional studies have shown that deferoxamine facilitates wound healing by modulating important cytokines and growth factors, including vascular endothelial growth factor, hypoxia-inducible factor-1α, stromal cell–derived factor-1α, transforming growth factor-β1, and interleukin-10.4–6 The use of deferoxamine in combination with fat grafting by Flacco and colleagues enhanced perfusion of grafted areas and improved fat graft volume retention over time in damaged tissue consistently. These findings support not only the potential role of preconditioning the recipient site with deferoxamine but also the importance of optimizing the graft site for improved graft take.Further studies to identify a feasible mechanism to deliver the deferoxamine or to optimize the graft site for improved overall grafting and long-term survival of fat grafts will be essential for clinical translation. Delivery of deferoxamine every other day through direct injection into the recipient site may be too cumbersome for clinical feasibility. Transdermal approaches to deliver deferoxamine have been shown to be efficacious in preventing and improving chronic ulcer wounds,7 and thus studies are needed to determine whether this same technique will be efficacious in modifying the three-dimensional pocket for fat grafting. The development of nanoparticles to deliver deferoxamine with controlled release may also be a feasible alternative delivery mechanism.8,9 The deferoxamine nanoparticle formation may allow for a one-time injection into the recipient site for preconditioning.With radiation therapy as an adjunct for cancer therapy, there remains a continuous need to identify treatment modalities that will improve skin quality around irradiated tissue to minimize delayed wound healing after surgery. Fat grafting to irradiated skin has been shown to improve skin integrity, decrease pain, and improve overall cosmetic appearance of the skin.10 Optimization of the fat graft harvest, processing, and delivery into recipient tissue remains a continuous area of interest. Furthermore, identifying additional molecules to further enhance the recipient site or the fat grafts will ultimately result in further improvements in the overall survival of the skin and the survival of the grafted tissue.