Faculty Bibliography

Chronic hyperglycemia impairs intracellular redox homeostasis and contributes to impaired diabetic tissue regeneration. The Keap1/Nrf2 pathway is a critical regulator of the endogenous antioxidant response system and its dysfunction has been implicated in numerous pathologies. Here, we characterize the effect of chronic hyperglycemia on Nrf2 signaling within a diabetic cutaneous regeneration model. We characterized the effects of chronic hyperglycemia on the Keap1/Nrf2 pathway within models of diabetic cutaneous wound regeneration. We assessed reactive oxygen species (ROS) production and antioxidant gene expression following alterations in the Nrf2 suppressor, Keap1, and the subsequent changes in Nrf2 signaling. We also developed a topical siRNA-based therapy to restore redox homeostasis within diabetic wounds. Western blot demonstrated that chronic hyperglycemia-associated oxidative stress inhibits nuclear translocation of Nrf2 and impairs activation of antioxidant genes, thus contributing to ROS accumulation. Keap1 inhibition increased Nrf2 nuclear translocation, increased antioxidant gene expression, and reduced ROS production to normoglycemic levels, both in vitro and in vivo. Topical siKeap1 therapy resulted in improved regenerative capacity of diabetic wounds and accelerated closure. We report that chronic hyperglycemia weakens the endogenous antioxidant response and the consequences of this defect are manifested by intracellular redox dysregulation, which can be restored by Keap1 inhibition. Targeted siRNA-based therapy represents a novel, efficacious strategy to reestablish redox homeostasis and accelerate diabetic cutaneous tissue regeneration.

Unilateral breast reconstruction poses a special set of challenges to the reconstructive breast surgeon compared to bilateral reconstructions. No studies to date provide an objective comparison between autologous and implant based reconstructions in matching the contralateral breast. This study compares the quantitative postoperative results between unilateral implant and autologous flap reconstructions in matching the native breast in shape, size, and projection using three-dimensional (3D) imaging. Sixty-four patients who underwent unilateral mastectomy with tissue expander (TE)-implant (n = 34) or autologous microvascular free transverse rectus abdominus myocutaneous (TRAM; n = 18) or deep inferior epigastric artery perforator (DIEP; n = 12) flap (n = 30) reconstruction from 2007 to 2010 were analyzed. Key patient demographics and risk factors were collected. Using 3D scans of patients obtained during pre and postoperative visits including over 1 year follow-ups for both groups, 3D models were constructed and analyzed for total breast volume, anterior-posterior projection from the chest wall, and 3D comparison. No significant differences in mean age, body mass index, or total number of reconstructive surgeries were observed between the two groups (TE-implant: 52.2 +/- 10, 23.9 +/- 3.7, 3 +/- 0.9; autologous: 50.7 +/- 9.4, 25.4 +/- 3.9, 2.9 +/- 1.3; p > 0.05). The total volume difference between the reconstructed and contralateral breasts in the TE-implant group was insignificant: 27.1 +/- 22.2 cc, similar to the autologous group: 29.5 +/- 24.7 cc, as was the variance of breast volume from the mean. In both groups, the reconstructed breast had a larger volume. A-P projections were similar between the contralateral and the reconstructed breasts in the TE-implant group: 72.5 +/- 3.21 mm versus 71.7 +/- 3.5 mm (p > 0.05). The autologous reconstructed breast had statistically insignificant but less A-P projection compared to the contralateral breast (81.9 +/- 16.1 mm versus 61.5 +/- 9.5 mm; p > 0.05). Variance of A-P projection from the mean was additionally insignificant between the contralateral and reconstructed breasts. Both groups produced similar asymmetry scores based on global 3D comparison (TE-implant: 2.24 +/- 0.3 mm; autologous: 1.96 +/- 0.2 mm; p > 0.05). Lastly, when the autologous group was further subdivided into TRAM and DIEP cohorts, no significant differences in breast volume, A-P projection or symmetry existed. Using 3D imaging, we demonstrate that both TE-implant and autologous reconstruction can achieve symmetrical surgical results with the same number of operations. This study demonstrates that breast symmetry, while an important consideration in the breast reconstruction algorithm, should not be the sole consideration in a patient' decision to proceed with autologous versus TE-implant reconstruction.