Although it is known that systemic diseases such as diabetes result in impaired wound healing, the mechanism for this impairment is not understood. Because fibroblasts are essential for wound repair, we compared the in vitro behavior of fibroblasts cultured from diabetic, leptin receptor-deficient (db/db) mice with wild-type fibroblasts from mice of the same genetic background in processes important during tissue repair. Adult diabetic mouse fibroblast migration exhibited a 75% reduction in migration compared to normal fibroblasts (P < 0.001) and was not significantly stimulated by hypoxia (1% O(2)), whereas wild-type fibroblast migration was up-regulated nearly twofold in hypoxic conditions (P < 0.05). Diabetic fibroblasts produced twice the amount of pro-matrix metalloproteinase-9 as normal fibroblasts, as measured by both gelatin zymography and enzyme-linked immunosorbent assay (P < 0.05). Adult diabetic fibroblasts exhibited a sevenfold impairment in vascular endothelial growth factor (VEGF) production (4.5 +/- 1.3 pg/ml versus 34.8 +/- 3.3 pg/ml, P < 0.001) compared to wild-type fibroblasts. Moreover, wild-type fibroblast production of VEGF increased threefold in response to hypoxia, whereas diabetic fibroblast production of VEGF was not up-regulated in hypoxic conditions (P < 0.001). To address the question whether these differences resulted from chronic hyperglycemia or absence of the leptin receptor, fibroblasts were harvested from newborn db/db mice before the onset of diabetes (4 to 5 weeks old). These fibroblasts showed no impairments in VEGF production under basal or hypoxic conditions, confirming that the results from db/db fibroblasts in mature mice resulted from the diabetic state and were not because of alterations in the leptin-leptin receptor axis. Markers of cellular viability including proliferation and senescence were not significantly different between diabetic and wild-type fibroblasts. We conclude that, in vitro, diabetic fibroblasts show selective impairments in discrete cellular processes critical for tissue repair including cellular migration, VEGF production, and the response to hypoxia. The VEGF abnormalities developed concurrently with the onset of hyperglycemia and were not seen in normoglycemic, leptin receptor-deficient db/db mice. These observations support a role for fibroblast dysfunction in the impaired wound healing observed in human diabetics, and also suggest a mechanism for the poor clinical outcomes that occur after ischemic injury in diabetic patients.

The hedgehog family of morphogens (sonic [Shh], Indian, and desert hedgehog) are central regulators of embryologic growth and tissue patterning. Although recent work implicates Shh in postnatal tissue repair and development, conclusive evidence is lacking. Here, we demonstrated the importance of Shh in wound repair, by examining the effects of cyclopamine, a specific inhibitor of the Shh signaling cascade, on tissue repair. Using a murine-splinted excisional wound model, which attenuates wound contraction in this loose-skinned rodent, we established that, by all measures (wound closure, epithelialization, granulation formation, vascularity, and proliferation), wound healing was profoundly impaired when Shh signaling was disrupted. Because embryonic disruption of Shh is associated with distinct phenotypic defects, our findings invite investigation of the potential role of Shh signaling under postnatal conditions associated with disregulated wound healing.

This model of cutaneous radiation injury delivers reproducible localized effects, mimicking the injury pattern seen in human subjects. This technique can be used to study radiation-induced injury to evaluate preventative and therapeutic strategies for these clinical issues.

Fibroblasts represent a highly mechanoresponsive cell type known to play key roles in normal and pathologic processes such as wound healing, joint contracture, and hypertrophic scarring. In this study, we used a novel fibroblast-populated collagen lattice (FPCL) isometric tension model, allowing us to apply graded biaxial loads to dermal fibroblasts in a 3-dimensional matrix. Cell morphology demonstrated dose-dependent transition from round cells lacking stress fibers in nonloaded lattices to a broad, elongated morphology with prominent actin stress fibers in 800-mg-loaded lattices. Using quantitative real-time RT-PCR, a dose dependent induction of both collagen-1 and collagen-3 mRNA up to 2.8- and 3-fold, respectively, as well as a 2.5-fold induction of MMP-1 (collagenase) over unloaded FPCLs was observed. Quantitative expression of the proapoptotic gene Bax was down-regulated over 4-fold in mechanically strained FPCLs. These results suggest that mechanical strain up-regulates matrix remodeling genes and down-regulates normal cellular apoptosis, resulting in more cells, each of which produces more matrix. This "double burden" may underlie the pathophysiology of hypertrophic scars and other fibrotic processes in vivo.

The inflammatory response to ionizing radiation (IR) includes a proangiogenic effect that could be counterproductive in cancer but can be exploited for treating impaired wound healing. We demonstrate for the first time that IR stimulates hypoxia-inducible factor-1␣ (

The ability to affect gene expression via topical therapy has profound therapeutic implications for conditions characterized by open wounds including cutaneous neoplasms, thermal injury, skin disorders and dysfunctional wound healing. Specifically targeting local gene expression avoids systemic toxicity and simplifies treatment. We have developed a new method of topical matrix-based short interfering RNA application to precisely and effectively silence local gene expression in nondelimited wounds.

Background: The purpose of this study was to evaluate breast tissue expanders with magnetic ports for safety in patients undergoing abdominal/pelvic magnetic resonance angiography before autologous breast reconstruction. Methods: Magnetic resonance angiography of the abdomen and pelvis at 1.5 T was performed in 71 patients in prone position with tissue expanders with magnetic ports labeled “MR Unsafe” from July of 2012 to May of 2014. Patients were monitored during magnetic resonance angiography for tissue expander–related symptoms, and the chest wall tissue adjacent to the tissue expander was examined for injury at the time of tissue expander removal for breast reconstruction. Retrospective review of these patients’ clinical records was performed. T2-weighted fast spin echo, steady-state free precession and gadolinium-enhanced spoiled gradient echo sequences were assessed for image artifacts. Results: No patient had tissue expander or magnetic port migration during the magnetic resonance examination and none reported pain during scanning. On tissue expander removal (71 patients, 112 implants), the surgeons reported no evidence of tissue damage, and there were no operative complications at those sites of breast reconstruction. Conclusion: Magnetic resonance angiography of the abdomen and pelvis in patients with certain breast tissue expanders containing magnetic ports can be performed safely at 1.5 T for pre–autologous flap breast reconstruction perforator vessel mapping. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

The evolution of techniques in plastic surgery and orthopedic surgery over the past few decades has enabled a great level of success in limb salvage. Limb salvage can now be achieved when faced with trauma, tumor, sepsis, or vascular disease. In fact, "What can be salvaged?" is now a less common debate among clinicians than "What should be salvaged?" Often discussions among surgeons from various subspecialties, including orthopedics, plastics, trauma, and vascular surgery, are characterized by how each of them can perform their respective part of the salvage operation, be it bony fixation, revascularization, or soft-tissue coverage, but none of them is certain whether it should be attempted. What is needed in these clinical situations is an interdisciplinary team approach led by individual or groups of clinicians who are familiar not only with their own subspecialized skills but also with those of their colleagues and the outcomes associated with integrated efforts at limb salvage. The concept of orthoplastic surgery is based on such an idea, where the combined skills and techniques of the orthopedic surgeon and reconstructive microsurgeon are used in concert to direct efforts toward limb salvage or decide against it when it is not indicated. This article presents a review of the roles of the two subspecialties and how an orthoplastic team can function with the current techniques to improve outcomes in limb salvage surgery.