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RenuvaŽ Restores Volume And Promotes Regeneration Of Irradiated Soft Tissue
Mimi R. Borrelli, MBBS, MSU, Sandeep Adem, MS, Nestor M. Diaz Deleon, Tavish Spargo, PA, Dung Nguyen, MD, Rahim Nazerali, MD, Arash Momeni, MD, Derrick C. Wan, MD.
Stanford, menlo park, CA, USA.

PURPOSE: Radiation therapy (RT) remains a cornerstone of modern cancer management, but radiation-induced soft tissue atrophy and fibrosis severely limit subsequent surgical reconstructions. Recent reports have shown fat grafting to successfully restore volume and promote soft tissue regeneration at irradiated sites. Similar to autologous fat, decellularized adipose tissue extracellular matrices (DAMs) such as RenuvaŽ have been developed to address contour deformities. Here, we explored the volume retention of RenuvaŽ within irradiated tissue and whether RenuvaŽ can also promote a regenerative response to radiation-induced soft tissue injury. METHODS: Adult Crl:Nu-Foxn1nu mice (n=6) were treated with 30 Gy external beam radiation to the scalp, followed by a one-month recovery period to allow for the chronic effects of radiation damage in the skin develop. Mice were then injected with 200μl of: 1) 100% fat; 2) 50:50 RenuvaŽ:fat; or 3) 100% RenuvaŽ (Fig. 1A&B). Allografts were injected into the calvarial region of recipient mice, and graft retention was monitored radiographically over 8 weeks. Mice were then harvested, skin was tested for mechanical strength, and both skin and explanted grafts were prepared for histological assessment. Fibroblast subpopulations within the irradiated skin were also evaluated by flow cytometry. RESULTS: Radiographic volume retention was similar in mice grafted with 100% fat and 50:50 RenuvaŽ:fat, with a tendency towards greater retention in the 50:50 group at 8 weeks (Fig. 1C). Renuva alone was associated with tissue necrosis and minimal retention. The irradiated skin overlying the grafts showed decreased stiffness in mice grafted with 50:50 RenuvaŽ:fat compared to 100% fat grafts (Fig. 1D). Histologic analysis of explanted grafts demonstrated an abundance of adipocytes and fibrous connective tissue formation throughout the scaffold. However, the RenuvaŽ:fat explants showed greater cellularity, with fewer adipocytes. The skin appeared histologically similar in terms of thickness and collagen deposition (Fig. 1E). At a cellular level, there were more CD26+ papillary fibroblasts and adipocyte precursors (***p=0.0001), and less pro-fibrotic reticular fibroblasts in the skin overlying the 50:50 RenuvaŽ:fat grafts (****p<0.0001) (Fig. 1F). CONCLUSION: These data suggest that the DAM RenuvaŽ, when injected together with fat, can retain volume and improve irradiated skin biomechanical properties. This may occur through expansion of more regenerative fibroblast subpopulations. Together, these data highlight the potential for DAM to serve as a potential filler for soft tissue reconstruction in irradiated and atrophic sites.


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