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Deferoxamine Mitigates Radiation-Induced Hypovascularity and Improves Tissue Elasticity in a Rat Irradiated TRAM Flap Model
Alexander F. Mericli, M.D., Anusuya Das, Ph.D., Ryan Best, Ph.D., Pamela Rodeheaver, B.S., George Rodeheaver, Ph.D., Kant Y. Lin, M.D..
University of Virginia, Charlottesville, VA, USA.
Purpose: The beneficial effects of radiation therapy for the treatment of breast cancer are indisputable, however irradiation also results in permanent damage to the microvasculature, leading to dermal damage and inelastic tissue. Clinically, therapeutic radiation after autologous breast reconstruction is associated with an elevated complication rate and distortion of the soft tissue. Deferoxamine (DFX) is an FDA-approved iron-chelating medication that has also been shown to increase angiogenesis. We hypothesize that the application of DFX will result in increased vascularity and improved tissue elasticity in a rat irradiated TRAM flap model.
Methods: Fifteen Sprague-Dawley rats were randomized to three groups: control, XRT, and XRT+DFX. All rats underwent a right pedicled TRAM flap. After recovering from surgery, the flaps in the XRT and XRT+DFX groups were radiated with 35 Gy in a single dose. Four weeks after radiation, rats in the XRT+DFX group were treated with DFX injected subcutaneously into the flap every other day for ten days. Rats were euthanized and perfused; flaps were imaged with micro computed-tomographic angiography (mCTA). Vascular radiomorphometrics were calculated and statistical comparison was conducted. Flap creep and stress relaxation was assessed using an Instron tensiometer. H&E, picrosirius red, and Verhoeff Van Gieson stains were performed.
Results: Radiated flaps demonstrated gross stigmata of cutaneous radiation injury within four weeks: transient erythema followed by alopecia, and a shiny/waxy appearance. Histologically, the epidermis in the XRT flaps was thicker than in the XRT+DFX and control flaps - a finding well described in irradiated skin (control = 42 µm; XRT = 79 µm; XRT+DFX = 34 µm; p<.001). Using picrosirius red staining, the scar index was calculated: the greatest scar index was associated with the XRT flaps, followed by the XRT+DFX and control flaps (2.4 vs 1.8 vs 1.8 ; p=.01). mCTA demonstrated increased vascularity in the XRT+DFX flaps compared to XRT alone (Figure 1). Similarly, histologic analysis revealed an increased number of blood vessels per high-powered field (vHPF) in the XRT+DFX flaps (control=2 vHPF; XRT=1.25 vHPF; XRT+DFX=2.4 vHPF; p=.04). The creep curve was indicative of increased elasticity in the XRT+DFX flaps compared to XRT flaps. (Figure 2). Additionally, the Verhoeff Van Gieson stain for elastin indicated a greater elastin content in the dermis of the XRT+DFX flaps compared to XRT flaps.
Conclusions: Flaps in the XRT group were quantifiably different than the control (thicker epidermis, greater scar index, less vasculature). The subcutaneous administration of DFX is associated with increased vascularity after radiation, as measured by mCTA and histologic analysis. Additionally, radiated flaps that received DFX demonstrated a lower scar index, greater elasticity and higher elastin content. DFX appears to mitigate radiation-induced hypovascularity and improve tissue elasticity in a rat model of soft tissue reconstruction.
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