The Biomechanical Effects of Deferoxamine on Irradiated Soft Tissue

Radiation therapy is an invaluable and necessary tool in the treatment of breast cancer, having been shown to improve both local disease control and overall survival.1–3 However, the ability of external beam radiation to eradicate and control breast cancer comes at a cost to the surrounding soft tissue, which can lead to complications including infection, implant exposure, capsular contracture, a poor cosmetic result, revision surgery and reconstructive failure.4 In the United States, 80% of all breast reconstruction procedures are implant-based.5 Unfortunately, the complication rate of implant-based breast reconstruction in the setting of radiation therapy is nearly 50%.4,6 To date, no therapy has been developed to reduce the negative effects of radiation on the surrounding soft tissue which remains a barrier to progress in the field. The long-term goal of our laboratory is to find novel approaches with a high translational potential that can mitigate the deleterious effects of radiation on the breast soft tissue envelope. Deferoxamine (DFX) is an FDA-approved iron-chelating agent that has been shown to increase angiogenesis and tissue elasticity in preclinical irradiated models of autologous and tissue expander breast reconstruction.7,8 Previous studies have used ex vivo approaches to measure the effects of DFX on irradiated soft-tissue, which only consider the elastic component of the tissue while ignoring the viscous properties that also contribute to soft tissue biomechanics. Furthermore, because ex vivo biomechanical measurements are taken postmortem, tissue degradation and ischemia alter the mechanical properties.9 In addition, the viscous tissue component may extravasate from the edges of isolated tissue explants. These elements make it difficult to extrapolate the effects that DFX may have on irradiated soft tissues. Thus, the biomechanical effects of DFX on irradiated soft issue at the tissue and functional component levels have yet to be fully evaluated. In order to quantify these mechanical changes, this preclinical pilot study will use a custom-fabricated robotic device to acquire real time tissue load-displacement data to determine the effects of DFX on irradiated tissue viscoelastic properties in vivo using quasilinear mathematical modeling. This study also proposes to use atomic force microscopy to study the biomechanical effects of DFX on elasticity at the collagen fibril level. Our central hypothesis is that DFX will improve tissue viscoelastic properties by increasing dermal collagen elasticity and organization at the fibril level in irradiated soft tissue. Collectively, the results of this study will allow researchers and clinicians to draw more accurate conclusions about the effects of DFX on irradiated and expanded soft tissue which could have profound implications on mitigating the high number of complications associated with radiation therapy and implant-based breast reconstruction. Aim 1: To determine the biomechanical effects of DFX on viscoelastic properties at the tissue level in an irradiated animal model of tissue expander breast reconstruction using quasilinear viscoelastic mathematical modeling Rationale: DFX has been shown to increase angiogenesis and tissue elasticity in other irradiated animal models.10,11 Quasilinear viscoelastic modeling is the current standard for predicting soft tissue deformation in biological specimens.12,13 To achieve this aim, we will use a custom-fabricated stress-relaxation device to determine biomechanical properties at the tissue level in-vivo. Quasilinear viscoelastic mathematical modeling will be used to calculate the tissue viscoelastic response. Hypothesis: Irradiated animals that have been treated with DFX will show an improvement in tissue viscoelastic response when compared to negative vehicle controls. Aim 2: To determine the effect of DFX on dermal collagen fibril elasticity using atomic force microscopy Rationale: Radiation therapy causes small vessel fibrosis leading to dermal damage and decreased tissue elasticity. DFX has been shown to increase dermal vascularization and collagen organization using atomic force microscopy (AFM), but supporting mechanical data are lacking. To accomplish this aim, we will use AFM in order to quantify dermal collagen fibril elasticity. Hypothesis: Irradiated animals that have been treated with DFX will exhibit both an increased dermal collagen fibril elastic response and confirm recent findings of improved dermal collagen fibril organization on AFM when compared to negative vehicle controls. The proposed study will provide greater insight into the biomechanical effects of DFX on irradiated soft tissue, knowledge that is currently lacking yet promises to yield novel insight into the translational potential of this FDA-approved drug. I am well-prepared to undertake this research, but require mentorship in three critical areas: soft-tissue biomechanics, biostatistics, and basic science breast reconstruction research. My mentorship team includes experts in each of these areas and has the breadth of expertise to help me obtain these critical multidisciplinary skills. This pilot data will be used for an F32 proposal to the National Cancer Institute.