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Objective vascular assessment is frequently required before microvascular reconstruction involving the lower extremities. The purpose of this study was to evaluate the reliability of magnetic resonance angiography (MRA) for preoperative assessment before free flap surgery. Five patients underwent preoperative MRA: one before fibula harvest for oromandibular reconstruction, and four before muscle free flap reconstruction of the lower extremity. In all patients, the tibioperoneal trunk, anterior tibial, posterior tibial, and peroneal arteries were well visualized to the ankle, including pathological occlusions. The radiographic findings were demonstrated at surgery and were confirmed to be accurate. These findings facilitated and guided the surgical procedure. This study strongly suggests the accuracy and surgical relevance of MRA before free flap surgery. MRA is desirable over angiography because of its noninvasive nature. It may also be better than ultrasonography because the latter is highly dependent on the technician (particularly in identifying the peroneal artery). MRA may likely replace angiography as the objective procedure of choice before microvascular surgery.

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Composite free tissue reconstruction for floor-of-mouth defects are thought of as single-stage procedures. However, postoperative wound complications often require additional soft-tissue coverage to salvage the initial reconstruction. Nasolabial flaps interpolated into the oral cavity offer an expedient solution to soft-tissue deficits encountered during complicated floor-of-mouth reconstructions. The records of 39 patients undergoing free tissue reconstruction, from July 1995 to December 1999 at Shands Hospital and the Gainesville VA Medical Center, for floor-of-mouth defects were reviewed. Six patients developed postoperative wound complications that compromised the initial reconstruction. In all patients, inferiorly based nasolabial flaps were used to provide additional soft-tissue coverage and wound closure. Radiation therapy and facial artery ligation did not affect the outcome. Complete wound healing and salvage of the initial reconstruction was achieved in all 6 patients.

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We report a patient with a highly unusual and previously unreported complication with the use of the pectoralis major muscle to treat the infected median sternotomy. The diagnosis of painful myospasm was made by a combination of physical findings and exclusion of other conditions such as recurrent infection. Treatment by pectoral denervation was relatively simple and highly successful. Patients with chest-wall pain after sternal wound reconstruction should have myospasm entertained as a possible cause.

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Melanotic neuroectodermal tumor of infancy is a rare pigmented neoplasm occurring in infants before 1 year of age. It is a rapidly growing tumor that most frequently affects the craniofacial skeleton. Although melanotic neuroectodermal tumor of infancy is benign in the vast majority of cases, inadequate excision, occasional multicentricity, and a small malignant potential result in a fairly high recurrence rate. On the basis of data obtained from the literature and our clinical experience, we advocate an aggressive surgical approach consisting of complete surgical excision when vital structures are not involved. Histopathologic confirmation of complete excision is mandatory to minimize the risk of recurrence and provide the patient with curative treatment and minimal morbidity.

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In response to cutaneous injury, expression of collagenase-1 is induced in keratinocytes via alpha2beta1 contact with native type I collagen, and enzyme activity is essential for cell migration over this substratum. However, the cellular mechanism(s) mediating integrin signaling remain poorly understood. We demonstrate here that treatment of keratinocytes cultured on type I collagen with epidermal growth factor receptor (EGFR) blocking antibodies or a specific receptor antagonist inhibited cell migration across type I collagen and the matrix-directed stimulation of collagenase-1 production. Additionally, stimulation of collagenase-1 expression by hepatocyte growth factor, transforming growth factor-beta1, and interferon-gamma was blocked by EGFR inhibitors, suggesting a required EGFR autocrine signaling step for enzyme expression. Collagenase-1 mRNA was not detectable in keratinocytes isolated immediately from normal skin, but increased progressively following 2 h of contact with collagen. In contrast, EGFR mRNA was expressed at high steady-state levels in keratinocytes isolated immediately from intact skin but was absent following 2 h cell contact with collagen, suggesting down-regulation following receptor activation. Indeed, tyrosine phosphorylation of the EGFR was evident as early as 10 min following cell contact with collagen. Treatment of keratinocytes cultured on collagen with EGFR antagonist or heparin-binding (HB)-EGF neutralizing antibodies dramatically inhibited the sustained expression (6-24 h) of collagenase-1 mRNA, whereas initial induction by collagen alone (2 h) was unaffected. Finally, expression of collagenase-1 in ex vivo wounded skin and re-epithelialization of partial thickness porcine burn wounds was blocked following treatment with EGFR inhibitors. These results demonstrate that keratinocyte contact with type I collagen is sufficient to induce collagenase-1 expression, whereas sustained enzyme production requires autocrine EGFR activation by HB-EGF as an obligatory intermediate step, thereby maintaining collagenase-1-dependent migration during the re-epithelialization of epidermal wounds.

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Treatment of large and/or invasive head and neck cancers results in defects that are complex, such that immediate free tissue transfer provides the best functional outcomes. Consequently, delayed use of free flaps in such patients is seldom seen in today's practice. The purpose of this study was to analyze a recent experience of such delayed microsurgical procedures to evaluate their efficacy and outcomes. Between November 1995 and May 1997, 13 patients underwent free flap reconstruction of residual or secondary defects following initial head and neck cancer ablation. Preoperative status was categorized as open wounds in 8 patients, oral incontinence in 9 patients, poor speech in 5 patients, and difficulty swallowing in 7 patients. Microvascular reconstruction was performed for the mandible and floor of the mouth/chin in 7 patients, cervical esophagus in 2 patients, sinus cavity in 2 patients, and one patient each underwent microvascular reconstruction of the orbit and cranial base. The free flaps utilized were fibular osteocutaneous (N = 6), radial forearm fasciocutaneous (N = 2), rectus abdominis (N = 2), jejunum (N = 1), radial forearm osteocutaneous (N = 1), and serratus (N = 1). There were no flap failures and the overall complication rate was 62%. Functional outcomes were best for the static conditions of open wound and oral incontinence, each demonstrating a 75% and 78% substantial improvement respectively. Conversely, functional improvement in dynamic functions such as poor speech and difficulty swallowing fared less well. Only 60% of patients with poor speech and 14% with difficulty swallowing showed significant improvement despite aggressive speech and swallowing therapy. These data show that the functional outcomes of free flap reconstruction of delayed head and neck cancer complications are inferior to those expected with immediate reconstruction using free tissue transfer. Nevertheless, reconstruction can be very useful with a high likelihood of flap survival and patient improvement.

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The purpose of this study was to provide molecular and mechanistic evaluation of an ischemic wound model in rats to determine if it is a valid model for human chronic wounds. Compared to acute wounds, human chronic wounds contain markedly elevated levels of proinflammatory cytokines and matrix metalloproteinases, while matrix metalloproteinase inhibitors and growth factor activity are diminished. Accordingly, tissue from ischemic and normal rat wounds were analyzed for cytokine, proteases and growth factor levels. Dorsal full thickness punch wounds were created in rats using a reproducible template. The ischemic wound group (n = 10) had six uniformly placed wounds within a bipedicled dorsal flap. The control group (n = 10) had the same wounds created without elevation of a flap. On postwound days 3, 6 and 13 wounds were excised and analyzed. Protein levels for tumor necrosis factor-alpha were determined with a rat-specific enzyme-linked immunosorbent assay, while mRNA was determined by RNase protection assay. Matrix metalloproteinases and serine protease detection was done using gelatin and casein zymography, respectively. Significant delay in healing was achieved in the ischemic group: 50% healing for control wounds was at 7 days and 11 days for ischemic wounds (p < 0.001). No significant differences between wound groups were found for interleukin-1beta, and mRNA for tumor necrosis factor-alpha and interleukin-1beta. However, at day 13 ischemic wounds contained significantly more tumor necrosis factor-alpha than controls and normal skin (586 +/- 106 pg/biopsy vs. 79 +/- 7 pg/biopsy vs. 52 +/- 2 pg/biopsy; p < 0. 001). Zymography showed substantially greater quantities of matrix metalloproteinase-2, matrix metalloproteinase-9, and serine proteases in ischemic wounds. This model of delayed healing in rats shares many of the key biochemical, molecular and mechanistic characteristics found in human chronic wounds, namely elevated tumor necrosis factor-alpha and protease levels. As such, this model will likely prove to be useful in chronic wound research, particularly in developing novel therapeutics.

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Cutaneous wound healing in the fetus can occur in a nonfibrotic, regenerative manner. However, other fetal tissues such as bone and stomach heal with scar formation. In light of potential ramifications for adult hollow visceral scarring (biliary and intestinal strictures), this study was undertaken to determine if tubular visceral tissue repair in the fetus is regenerative or fibrotic. Fetal rabbits underwent laparotomy on day 24 of gestation, during which a controlled intestinal enterotomy was created and suture repaired immediately using microsurgical techniques. Maternal rabbits and adult male rabbits also underwent enterotomy and repair. After 5 days all animals were sacrificed and the wounds analyzed histologically by a pathologist in a blinded fashion. All animals demonstrated a similar degree of peri-intestinal adhesion formation. Fetal and maternal wounds contained fibroblastic and smooth muscle cell proliferation, mild inflammatory infiltration, and new blood vessel formation. The male adult wounds demonstrated a more pronounced fibrovascular healing response. Immunohistochemical staining for CD31 (endothelial cell marker) was quantitated on a scale of 0 to 4+, indicating degree of neovascularization. The mean scores for the fetal and maternal groups were similar (1.70 +/- 0.68 and 1.23 +/- 1.07 respectively), but were significantly greater for male adults (2.93 +/- 0.12; p = 0.001 by analysis of variance). The results of this study indicate that hollow visceral tissue repair in the fetal rabbit intestine occurs in a similar fibrotic manner as adult healing. This provides further evidence that regenerative healing in the fetus is not ubiquitous. Differences in the degrees of fibrosis and neovascularization between adult male and pregnant female wounds deserve further investigation.

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Fetal wound healing proceeds rapidly with minimal inflammation and fibroplasia and little or no scar formation. These observations have led to the hypothesis that fetal wound healing more closely resembles regeneration rather than adult wound repair. To test this hypothesis, this study used ultrastructural analysis of fetal and adult fibroblasts and collagen to gain greater insight into differences in the healing processes. Full-thickness, primarily closed linear incisions were created dorsally on 24-day gestational age fetal rabbits (n = 9). The fetuses were killed 5 days later, and the wounds were excised and evaluated with transmission electron microscopy. Similarly, uninjured fetal skin of the same gestational age was obtained and analyzed. Adult rabbit dermal wounds were analyzed after 8 days of healing. Resting adult dermal fibroblasts had features of quiescent, inactive cells, whereas adult wound fibroblasts were highly active and filled with secretory vesicles. In contrast, both fetal normal dermal and wound fibroblasts appeared highly active and contained numerous secretory vesicles. In the adult wound, collagen fibril diameter was only 45% of the diameter of normal dermal collagen. However, fetal wound collagen fibrils were basically the same as normal dermal collagen, having a diameter that was 82% of the size of dermal collagen. These observations suggest that fetal wound fibroblasts do not require activation from an inactivated state and that fetal wound collagen deposition undergoes more rapid organization and maturation. These findings have significance in extending our understanding of the rapidity and functional superiority of fetal wound healing compared with adult wound healing.

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Wound healing in many tissue types is essentially the same as that which occurs in skin. The repair processes that occur in bone, tendon, the alimentary tract, skin grafts, and bone grafts are substantially different from cutaneous wound repair. Because surgeons frequently encounter these tissues, it is essential to understand how they heal.

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A healing wound represents a complex series of interactions between cells, soluble mediators, and extracellular matrix. Within this multifaceted environment, there are multiple regulatory points which control the ordered series of events that lead to normal tissue repair. An alteration in this physiologic network can lead to the development of a chronic wound. This article presents an update on the numerous mediators that exist within the wound environment in both acute normal healing and chronic nonhealing wounds. We also present a hypothesis which may provide a conceptual pathophysiologic mechanism with which to understand all chronic wounds.

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Free flap reconstruction in children is often undertaken with trepidation due to a variety of perceived technical difficulties and variable reports of success. The present report examines the efficacy of free tissue transfer in children, with particular attention given to the use of fasciocutaneous flaps in burn reconstruction. Over a 12-year period, 38 free flaps were done on 30 patients with an average age of 10 years (range, 16 months-17 years). Twenty-five flaps were done for burn deformities; 6 were done for chronic back wounds; 2 each were done for chronic lower extremity wounds, lower extremity traumatic defects, and a craniofacial deformity; and 1 flap was done following the resection of a large thigh vascular malformation. The vast majority of the flaps (84%) were fasciocutaneous: 13 groin, 9 scapula, 5 radial forearm, and 4 others. The mean hospital stay was 10 days and there were 11 major complications (29%). Five of 6 flaps were salvaged by reoperation following vascular thrombosis. Six flaps were unsuccessful (84% total success). Three of these flaps were aborted intraoperatively due to technical difficulties, while 3 others were lost postoperatively due to cellulitis, thrombosis, and patient-inflicted flap removal. During follow-up (range, 1-103 months), 39% of patients underwent a minor secondary revision of the flap reconstruction. This series demonstrates the efficacy of free tissue transfer in children in providing the majority of these patients with a successful, one-stage reconstruction with morbidity similar to that reported for adult patients. Moreover, the use of fasciocutaneous free flaps for pediatric burn reconstruction is shown to provide a durable and aesthetically superior treatment of these difficult problems.

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In many species, open cutaneous fetal wounds do not heal in utero. Such open wounds have been shown to close only after their exclusion from amniotic fluid, thus leading to the hypothesis that amniotic fluid inhibits open wound healing. Therefore the effect of amniotic fluid exposure on the healing of open fetal skin wounds was studied. Fetuses of New Zealand White rabbits received a full-thickness circular 4 mm diameter skin punch biopsy wound. Wounds were left uncovered, covered with a latex patch, or covered with a latex patch with a central hole (doughnut). This third group provided for wound exposure to amniotic fluid while controlling for any wound splinting effect of the patch. Wounds were harvested after 5 days, the wound area was determined planimetrically, and wound edges were examined by means of light microscopy. Analysis of glycosaminoglycans in the wound extra-cellular matrix was performed on a separate group of wounds treated similarly. Uncovered wounds enlarged by an average of 60%, whereas wounds covered with the doughnut patch enlarged by an average of 24%. In contrast, the wounds in the patch-covered group decreased in size by an average of 84%. Histologically all groups contained proliferating fibroblasts and epithelial migration at the wound edge but also an absence of granulation tissue. The patch-covered wounds, which had decreased wound area, were significantly enriched in hyaluronic acid. These results suggest that the healing of the patch-covered wounds occurs without the formation of granulation tissue, presumably through a process of cellular migration and proliferation and that healing was inhibited by exposure to amniotic fluid. Hyaluronic acid has been shown to be permissive of cellular migration and to play a key role in tissue regeneration. Therefore, we speculate that direct exposure of open wounds to amniotic fluid during the late stages of fetal development in the rabbit prevents hyaluronic acid deposition, which in turn may alter wound closure.

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Scarless fetal wound healing occurs with mild fibroplasia and neovascularization, while the wound is persistently enriched with hyaluronic acid. Conversely, adult wounds are characterized by prominent fibroplasia, neovascularization, and scar formation, and hyaluronic acid is a transient component of the early adult wound matrix. Our group has reported that enzymatic degradation of fetal rabbit wound hyaluronic acid results in marked increases in fibroplasia, collagen deposition, and neovascularization. This altered, adultlike healing response is hypothesized to have resulted from the generation of biologically active hyaluronic acid degradation products. Therefore, this study analyzes the fibrovascular inductive activity of hyaluronic acid degradation products. Fetal rabbit wounds were treated with hyaluronic acid degradation products generated by methods known to produce oligosaccharides with significant angiogenic activity. Implants from wounds treated with either of the control solutions (n = 4 for each control) had identical histologic features characterized by a mild mononuclear cell infiltrate but neither infiltrating fibroblasts nor collagen. In marked contrast, implants from wounds treated with hyaluronic acid degradation products contained infiltrating fibroblasts and collagen intermixed with numerous blood vessels. Quantitation of capillary ingrowth showed a sixfold increase in the neovascular response in wounds treated with hyaluronic acid degradation products compared with either controls (p < 0.05). This study shows that hyaluronic acid degradation products stimulate neovascularization and fibroplasia in fetal wounds. These observations suggest that a balance between hyaluronic acid accumulation and degradation has significant regulatory influence in fetal tissue repair.

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The fetal response to cutaneous injury differs markedly from that of the adult, proceeding with only minimal inflammation, minimal fibroblast proliferation, and only essential collagen deposition. Although the sequence of events in adult wound healing is well defined and thought to be controlled in part by potent polypeptide cytokines, relatively sparse information exists regarding growth factor involvement in fetal wound repair. Thus, the authors sought to examine the effect of platelet-derived growth factor (PDGF), a putative adult wound healing regulator, on the cellular and extracellular matrix events at a fetal wound site. SILASTIC wound implants containing 0, 1.0, 5.0, or 10.0 ng of human PDGF were placed subcutaneously on the backs of 24-day-gestation fetal rabbits (full term, 31 days) and then harvested after either 1, 3, or 5 days in utero. The specimens underwent standard histological processing and were evaluated in a blinded fashion. Compared with controls, PDGF-treated implants had a marked increase in acute inflammation, fibroblast recruitment, and collagen and hyaluronic acid deposition; these differences appeared to be largely time- and PDGF dose-dependent. Thus, the fetal system is responsive to an adult wound healing mediator, and these data suggest that fetal repair proceeds in the absence of PDGF.

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Fetal wound healing is characterized by minimal inflammation, mild fibroplasia and rapid, but organized collagen deposition such that scarring is not apparent. The matrices of fetal wounds differ greatly from adult wounds in that fetal wounds are persistently enriched with hyaluronic acid (HA). It has been shown that a reduction in fetal rabbit wound HA results in an adult-like healing response with increased fibroplasia and neovascularization. These observations suggest that HA can modulate cellular activity in fetal repair. Therefore, this study was designed to define the effect of HA on fetal fibroblast function. Fibroblasts from the skin of fetal rabbits were isolated and maintained in culture medium containing either no HA (controls), 1 microgram/ml, 10 micrograms/ml or 100 micrograms/ml of HA (n = 6 for each group). Fibroblast proliferation was quantitated by DNA content in each culture, and collagen and noncollagen protein synthesis were analyzed by incorporation of [3H] proline into collagenase-digestible and collagenase-nondigestible protein, respectively. At all concentrations tested, HA significantly inhibited fetal fibroblast proliferation (p < 0.02), but stimulated collagen (p < 0.002) and noncollagen protein (p < 0.005) synthesis. These findings provide further evidence that HA affects the function of fetal fibroblasts. Moreover, this study in conjunction with previous in utero findings suggests that HA may have a regulatory influence in scarless fetal healing by affecting cellular function during the repair process.

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The rapid restoration of tissue integrity and breaking strength in healing fetal wounds is mainly a function of fetal wound collagen. In this study, the fetal and adult tissue responses to injury were characterized in terms of changes in collagen biosynthesis. Linear wounds and unwounded skin were incubated with radioactive proline, and collagen synthesis was measured as isotope incorporation into collagenase-sensitive protein. Likewise, noncollagen protein synthesis was represented by isotope incorporation into collagenase-resistant protein. Adult wounds demonstrated a preferential stimulation of collagen as compared with noncollagen protein synthesis after wounding. In contrast, both collagen and noncollagen protein synthesis were significantly elevated in the fetus during the first 5 days postwounding. Despite marked increases in fetal wound collagen synthesis above both unwounded fetal skin and adult wound levels, fetal wounds exhibited no evidence of excessive collagen deposition or scar formation after wounding. These findings suggest that the fetal response to tissue injury is a function of the distinctive qualities of fetal fibroblasts associated with the extracellular wound matrix and may involve rapid collagen turnover and degradation.

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Fetal wound healing is a remarkable process that is fundamentally different than postnatal healing. Healing of primarily closed, linear wounds occurs rapidly and without scarring. In late gestational age fetal sheep, a transition to adult-like healing occurs as evidenced by minimal scar formation. Acute inflammation is not involved, fibroblast recruitment and proliferation is minimal, the matrix of the wounds is enriched with HA and collagen deposition is highly organized so that scarring is minimal or nonexistent. Open wounds in several species do not contract, an observation that may be because of an inhibitor of contraction in amniotic fluid. The underlying mechanisms that regulate fetal wound repair are currently not well understood. An altered supply or activity of growth factors may be instrumental. Fibroblasts may preferentially produce HA secondary to a factor present within the fetal system, and HA may influence cellular and matrix events within the wound. As greater knowledge of the biologic factors of scarless healing in the fetus is gained, applications to abnormal adult healing may be developed. As the age of fetal surgery is approaching, it is essential to understand the injury response in these new patients.

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Fetal tissue repair occurs without acute inflammation, prominent fibroplasia, or marked neovascularization. The fetal wound extracellular matrix is rich in hyaluronic acid (HA), while collagen is deposited in an organized normal dermal pattern. In various biologic systems, including regeneration and development, the controlled accumulation and subsequent degradation of hyaluronic acid is associated with distinct cellular and matrix events. Therefore, it is hypothesized that the abundance of hyaluronic acid in fetal wounds may influence cellular and/or matrix events such that tissue repair is highly organized and adult-like scarring does not occur. To test this hypothesis, the hyaluronic acid content of fetal rabbit wounds was reduced by specific degradation with Streptomyces hyaluronidase. Control wounds were treated with either enzyme buffer (n = 12) or denatured enzyme solution (n = 8) and exhibited a normal fetal healing response with scattered peripheral fibroblasts, a matrix of hyaluronic acid, and no infiltrating collagen. In marked contrast, the hyaluronidase-treated wounds (n = 14) demonstrated increased fibroblast infiltration, collagen deposition, and capillary formation. A significant reduction in the hyaluronic acid content of the hyaluronidase-treated wounds was confirmed biochemically. Since the degradation of hyaluronic acid resulted in an altered healing response, this study demonstrates that hyaluronic acid affects the cellular and matrix events in fetal healing and may be partially responsible for the unique qualities of this regenerative repair process.

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