Plastic Surgery Research Council

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Fat Grafting Reverses Radiation-induced Skin Fibrosis And Groin Contracture
Mimi R. Borrelli, MD, Ronak A. Patel, Jan Sokol, Dre Irizarry, Dung Nguyen, MD, Arash Momeni, MD, Michael T. Longaker, MD, MA, Derrick C. Wan.
Stanford, Palo Alto, CA, USA.

PURPOSE: Radiotherapy (RT) is an effective adjunctive treatment of cancer; it can reduce tumor size and decrease local cancer recurrence. A significant adverse effect of RT, however, is the fibrosis incurred in the soft tissue surrounding the tumor. RT activates a number of fibrotic pathways which cause continued and substantial dermal induration with increasing time since exposure. Radiation-induced soft tissue fibrosis can alter cosmesis and result in functional impairments, such as impaired swallowing and limb contracture. Fat grafting is a minimally-invasive surgical technique gaining popularity for its ability prevent or reverse the radiation-induced soft tissue fibrosis. We developed a mouse model of radiation-induced hind limb contracture and explored the effects of fat-grafting in this context.METHODS: We used Prrx1Cre;R26mTmG mice, in whom a fibrogenic subpopulation of fibroblasts in ventral skin (PRRX-1+) are labelled by embryonic expression Cre, to explore the effects of radiation subpopulations of fibrogenic fibroblasts. The hind limbs of PRRX-1 mice were irradiated with 30 Gy fractionated in 5 Gy doses every two days for a total of 12 days. Significant limb contracture developed during the one-month recovery period. At this point, the mice were sacrificed, and hind limbs were processed for histology. Next, the hind limbs of CD-1 nude mice were irradiated with the same regimen, to explore the therapeutic effects of fat graft grafting. At five-weeks post irradiation, 200ul of human lipoaspirate fat or lipoaspirate enriched with adipose-derived stromal cells (ASCs, 10,000 cells/200ul) was injected into the subcutaneous space of the irradiated hind limbs (Fig. 1A). Control mice were injected with saline or received sham surgery with no injection. Limb extensibility was measured every two weeks for a total of 12-weeks, at which point mice were sacrificed for hind limb skin mechanical strength testing (MST) and histologic analysis.RESULTS: Normal 0 false false false EN-AU X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Calibri",sans-serif; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;} Hind limb irradiation significantly reduced limb extensibility compared to the non-irradiated side, with the greatest benefit of fat grafting was observed in the mice who received fat supplemented with SVFs, and little or no benefit seen in mice who received saline or sham treatment (Fig. 1B). These functional differences were associated with in a significant increase in the fibrogenic Prrx1+ fibroblast subpopulation (Fig. 1C). Fat grafting progressively improved limb extension, reduced skin stiffness, and reversed the fibrotic histological changes in the skin (Fig. 1D). CONCLUSION: Our mouse model of radiation-induced hind limb contracture enables a detailed dissection of the interaction between grafted fat and radiation-induced soft tissue contracture. We show that fat grafting can reverse the fibrotic changes seen in irradiated skin and can improve the extensibility of contracted limbs post irradiation.
irradiated skin and can improve the extensibility of contracted limbs post irradiation.


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