The trafficking of circulating stem and progenitor cells to areas of tissue damage is poorly understood. The chemokine stromal cell-derived factor-1 (SDF-1 or CXCL12) mediates homing of stem cells to bone marrow by binding to CXCR4 on circulating cells. SDF-1 and CXCR4 are expressed in complementary patterns during embryonic organogenesis and guide primordial stem cells to sites of rapid vascular expansion. However, the regulation of SDF-1 and its physiological role in peripheral tissue repair remain incompletely understood. Here we show that SDF-1 gene expression is regulated by the transcription factor hypoxia-inducible factor-1 (HIF-1) in endothelial cells, resulting in selective in vivo expression of SDF-1 in ischemic tissue in direct proportion to reduced oxygen tension. HIF-1-induced SDF-1 expression increases the adhesion, migration and homing of circulating CXCR4-positive progenitor cells to ischemic tissue. Blockade of SDF-1 in ischemic tissue or CXCR4 on circulating cells prevents progenitor cell recruitment to sites of injury. Discrete regions of hypoxia in the bone marrow compartment also show increased SDF-1 expression and progenitor cell tropism. These data show that the recruitment of CXCR4-positive progenitor cells to regenerating tissues is mediated by hypoxic gradients via HIF-1-induced expression of SDF-1.

Diminished production of vascular endothelial growth factor (VEGF) and decreased angiogenesis are thought to contribute to impaired tissue repair in diabetic patients. We examined whether recombinant human VEGF 165 protein would reverse the impaired wound healing phenotype in genetically diabetic mice. Paired full-thickness skin wounds on the dorsum of db/db mice received 20 g of VEGF every other day for five doses to one wound and vehicle (phosphate-buffered saline) to the other. We demonstrate significantly accelerated repair in VEGF-treated wounds with an average time to resurfacing of 12 days versus 25 days in untreated mice. VEGF-treated wounds were characterized by an early leaky, malformed vasculature followed by abundant granulation tissue deposition. The VEGF-treated wounds demonstrated increased epithelialization, increased matrix deposition, and enhanced cellular proliferation, as assessed by uptake of 5-bromodeoxyuridine. Analysis of gene expression by real-time reverse transcriptase-polymerase chain reaction demonstrates a significant up-regulation of plateletderived growth factor-B and fibroblast growth factor-2 in VEGF-treated wounds, which corresponds with the increased granulation tissue in these wounds. These experiments also demonstrated an increase in the rate of repair of the contralateral phosphate-buffered salinetreated wound when compared to wounds in diabetic mice never exposed to VEGF (18 days versus 25 days), suggesting that topical VEGF had a systemic effect. We observed increased numbers of circulating VEGFR2 ؉

Background-Advanced age is known to impair neovascularization. Because endothelial progenitor cells (EPCs) participate in this process, we examined the effects of aging on EPC recruitment and vascular incorporation. Methods and Results-Murine neovascularization was examined by use of an ischemic flap model, which demonstrated aged mice (19 to 24 months) had decreased EPC mobilization (percent mobilized 1.4Ϯ0.2% versus 0.4Ϯ0.1%, PϽ0.005) that resulted in impaired gross tissue survival compared with young mice (2 to 6 months). This decrease correlated with diminished tissue perfusion (PϽ0.005) and decreased CD31 ϩ vascular density (PϽ0.005). Gendermismatched bone marrow transplantation demonstrated significantly fewer chimeric vessels in aged mice (PϽ0.05), which confirmed a deficit in bone marrow-mediated vasculogenesis. Age had no effect on total EPC number in mice or humans. Reciprocal bone marrow transplantations confirmed that impaired neovascularization resulted from defects in the response of aged tissue to hypoxia and not from intrinsic defects in EPC function. We demonstrate that aging decreased hypoxia-inducible factor 1␣ stabilization in ischemic tissues because of increased prolyl hydroxylasemediated hydroxylation (PϽ0.05) and proteasomal degradation. This resulted in a diminished hypoxia response, including decreased stromal cell-derived factor 1 (PϽ0.005) and vascular endothelial growth factor (PϽ0.0004). This effect can be reversed with the iron chelator deferoxamine, which results in hypoxia-inducible factor 1␣ stabilization and increased tissue survival. Conclusions-Aging impairs EPC trafficking to sites of ischemia through a failure of aged tissues to normally activate the hypoxia-inducible factor 1␣-mediated hypoxia response.

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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.

Background: Facial feminization surgery entails a series of surgical procedures that help the transwoman pass as their affirmed gender. Although virtual surgical planning, with intraoperative cutting guides, and custom plates have been shown to be helpful for craniomaxillofacial reconstruction, they have not yet been studied for facial feminization surgery. The authors used cadaveric analysis for morphologic typing and to demonstrate the utility of virtual surgical planning in facial feminization surgery procedures. Methods: Male cadaveric heads underwent morphologic typing analysis of the frontal brow, lateral brow, mandibular angle, and chin regions (n = 50). Subsequently, the cadavers were split into two groups: (1) virtual surgical planning intraoperative cutting guides and (2) no preoperative planning. Both groups underwent (1) anterior frontal sinus wall setback, (2) lateral supraorbital recontouring, (3) mandibular angle reduction, and (4) osseous genioplasty narrowing. Efficiency (measured as operative time), safety (determined by dural or nerve injury), and accuracy (scored with three-dimensional computed tomographic preoperative plan versus postoperative result) were compared between groups, with significance being p < 0.05. Results: For frontal brow and lateral lower face, morphologic type 3 (severe) predominated; for lateral brow and chin, type 2 (moderate) predominated. For frontal sinus wall setback, virtual surgical planning improved efficiency (19 minutes versus 44 minutes; p < 0.05), safety (100 percent versus 88 percent; p < 0.05; less intracranial entry), and accuracy (97 percent versus 79 percent; p < 0.05) compared with no preoperative planning. For mandibular angle reduction, virtual surgical planning improved safety (100 percent versus 88 percent; p < 0.05; less inferior alveolar nerve injury) and accuracy (95 percent versus 58 percent; p < 0.05). Conclusions: Preoperative planning for facial feminization surgery is helpful to determine morphologic typing. Virtual surgical planning with the use of cutting guides/custom plates improved efficiency, safety, and accuracy when performing four key craniofacial techniques for facial feminization.

Posterior cranial vault distraction offers several benefits over traditional expansion procedures.

In our experience power-assisted suction lipectomy is a safe and excellent adjunct in fasciocutaneous flap debulking and reduces the number of secondary revision procedures necessary. We recommend its use as an adjunct in debulking and contouring flaps used in extremity reconstruction.