Faculty Bibliography

BACKGROUND: Non-healing foot ulcers are the most common cause of non-traumatic amputation and hospitalization amongst diabetics in the developed world. Impaired wound neovascularization perpetuates a cycle of dysfunctional tissue repair and regeneration. Evidence implicates defective mobilization of marrow-derived progenitor cells (PCs) as a fundamental cause of impaired diabetic neovascularization. Currently, there are no FDA-approved therapies to address this defect. Here we report an endogenous PC strategy to improve diabetic wound neovascularization and closure through a combination therapy of AMD3100, which mobilizes marrow-derived PCs by competitively binding to the cell surface CXCR4 receptor, and PDGF-BB, which is a protein known to enhance cell growth, progenitor cell migration and angiogenesis. METHODS AND RESULTS: Wounded mice were assigned to 1 of 5 experimental arms (n = 8/arm): saline treated wild-type, saline treated diabetic, AMD3100 treated diabetic, PDGF-BB treated diabetic, and AMD3100/PDGF-BB treated diabetic. Circulating PC number and wound vascularity were analyzed for each group (n = 8/group). Cellular function was assessed in the presence of AMD3100. Using a validated preclinical model of type II diabetic wound healing, we show that AMD3100 therapy (10 mg/kg; i.p. daily) alone can rescue diabetes-specific defects in PC mobilization, but cannot restore normal wound neovascularization. Through further investigation, we demonstrate an acquired trafficking-defect within AMD3100-treated diabetic PCs that can be rescued by PDGF-BB (2 mug; topical) supplementation within the wound environment. Finally, we determine that combination therapy restores diabetic wound neovascularization and accelerates time to wound closure by 40%. CONCLUSIONS: Combination AMD3100 and PDGF-BB therapy synergistically improves BM PC mobilization and trafficking, resulting in significantly improved diabetic wound closure and neovascularization. The success of this endogenous, cell-based strategy to improve diabetic wound healing using FDA-approved therapies is inherently translatable.

BACKGROUND: The integrated model of plastic surgery education, shortly to become the standard for all 6-year programs, has set minimal but no maximal exposure to plastic surgery. The authors hypothesized that the first 3 years of integrated training will show variability among residency programs. METHODS: Rotation schedules for all 42 integrated programs were analyzed for plastic surgery versus 18 nonplastic surgery rotations for postgraduate years 1, 2, and 3 as well as cumulatively for the first 3 years. Rotations "strongly suggested" by the Residency Review Committee on Plastic Surgery and American Board of Plastic Surgery were also examined. RESULTS: Postgraduate years 1 through 3 spent a wide range of 3 to 19 months (SD +/- 4.9 months) on plastic surgery (mean, 9.1 months). General surgery also varied dramatically, with 8 to 21 months (SD +/- 4.0 months) of exposure (mean, 16.3 months). Surgical subspecialty rotations ranged substantially from 1 to 6 months (SD +/- 1.0 months). Plastic surgery exposure was greater in programs based within plastic surgery departments than within divisions (13.8 versus 8.3 months, p < 0.005). Eighteen programs (42.9 percent) had dedicated hand surgery rotations, while seven (16.7 percent) had time dedicated for research. There was also wide variability in the inclusion of 18 nonplastic surgery rotations as well as specific "strongly suggested" rotations. CONCLUSIONS: The plastic surgery experience in the first 3 years of residency training varies by a greater than 6-fold difference among integrated programs. This was also found in the 2.5-fold and 6-fold differences in general surgery and subspecialty surgery experiences. Since standardized residency training is an expectation by both accrediting bodies and the public, this variability may warrant closer attention.

BACKGROUND: Acellular dermal matrix is a commonly used adjunct in implant-based breast reconstruction. Several investigations have shown increased complications associated with its use. Therefore, the authors' institution placed strict limitations on its use and transitioned to sterile "ready-to-use" acellular dermal matrix. The purpose of this investigation was to compare the infectious complications associated with aseptic versus sterile acellular dermal matrix. METHODS: A prospective study of all patients undergoing immediate implant-based breast reconstruction at a single academic medical center between November of 2010 and October of 2012 was conducted. AlloDerm (Life Cell Corporation, Branchburg, N.J.) was used as the source of acellular dermal matrix. Breasts were divided into three cohorts: total submuscular coverage, aseptic acellular dermal matrix, and sterile, ready-to-use acellular dermal matrix. Breasts were then compared based on demographic information, cancer qualities, and complications. RESULTS: A total of 546 reconstructed breasts met inclusion criteria: 64.3 percent (n = 351) with no acellular dermal matrix, 16.5 percent (n = 90) with aseptic matrix, and 19.2 percent (n = 105) with ready-to-use matrix. When comparing reconstructions with ready-to-use versus aseptic acellular dermal matrix, patients had a decrease in overall infection (8.5 percent versus 20.0 percent; p = 0.0088), major infection (4.7 percent versus 12.2 percent; p = 0.069), and need for explantation (1.9 percent versus 6.6 percent; p = 0.1470). When comparing patients undergoing reconstruction with ready-to-use matrix to total submuscular coverage, patients had similar overall infectious complications (8.5 percent versus 5.7 percent; p = 0.3602). Diabetes mellitus, seroma, mastectomy skin flap necrosis, and aseptic acellular dermal matrix were independent predictors of infectious complications. CONCLUSIONS: Ready-to-use acellular dermal matrix in immediate implant-based breast reconstruction provides a useful adjunct. In addition, it mitigates the risks of infectious complications when compared with aseptic acellular dermal matrix. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Nonhealing bone defects are difficult to treat. As the bone morphogenic protein and transforming growth factor beta pathways have been implicated in bone healing, we hypothesized that percutaneous Smad7 silencing would enhance signaling through both pathways and improve bone formation. Critical sized parietal trephine defects were created and animals received percutaneous injection of: agarose alone or agarose containing nonsense or Smad7 small interfering RNA (siRNA). At 12 weeks, SMADs1, 2, 3, 5, 7 and 8 levels were assessed. Smad1/5/8 osteogenic target, Dlx5, and SMAD2/3 angiogenic target, plasminogen activator inhibitor-1 (Pai1), transcription levels were measured. Noncanonical signaling through TGFbeta activated kinase-1 (Tak1) and target, runt-related transcription factor 2 (Runx2) and collagen1alpha1 (Col1alpha1), transcription were also measured. Micro-computed tomography and Gomori trichome staining were used to assess healing. Percutaneous injection of Smad7 siRNA significantly knocked down Smad7 mRNA (86.3+/-2.5%) and protein levels (46.3+/-3.1%). The SMAD7 knockdown resulted in a significant increase in receptor-regulated SMADs (R-SMAD) (Smad 1/5/8 and Smad2/3) nuclear translocation. R-SMAD nuclear translocation increased Dlx5 and Pai1 transcription. Additionally, noncanonical signaling through Tak1 increased Runx2 and Col1alpha1 target transcription. Compared with animals treated with agarose alone (33.9+/-2.8% healing) and nonsense siRNA (31.5+/-11.8% healing), animals treated Smad7 siRNA had significantly great (91.2+/-3.8%) healing. Percutaneous Smad7 silencing increases signal transduction through canonical and noncanonical pathways resulting in significant bone formation. Minimally invasive gene therapies may prove effective in the treatment of nonhealing bone defects.