Faculty Bibliography

Diabetes is characterized by several poorly understood phenomena including dysfunctional wound healing and impaired vasculogenesis. p53, a master cell cycle regulator, is upregulated in diabetic wounds and has recently been shown to play a regulatory roles in vasculogenic pathways. We have previously described a novel method to topically silence target genes in a wound bed with small interfering (si)RNA. We hypothesized that silencing p53 results in improved diabetic wound healing and augmentation of vasculogenic mediators. Paired 4-mm stented wounds were created on diabetic db/db mice. Topically applied p53 siRNA, evenly distributed in an agarose matrix, was applied to wounds at postwound day 1 and 7 (matrix alone and nonsense siRNA served as controls). Animals were sacrificed at postwound days 10 and 24. Wound time to closure was photometrically assessed, and wounds were harvested for histology, immunohistochemistry, and immunofluorescence. Vasculogenic cytokine expression was evaluated via Western blot, reverse transcription-polymerase chain reaction, and enzyme-linked immunosorbent assay. The ANOVA/t-test was used to determine significance (p</= 0.05). Local p53 silencing resulted in faster wound healing with wound closure at 18+/-1.3 d in the treated group vs. 28+/-1.0 d in controls. The treated group demonstrated improved wound architecture at each time point while demonstrating near-complete local p53 knockdown. Moreover, treated wounds showed a 1.92-fold increase in CD31 endothelial cell staining over controls. Western blot analysis confirmed near-complete p53 knockdown in treated wounds. At day 10, VEGF secretion (enzyme-linked immunosorbent assay) was significantly increased in treated wounds (109.3+/-13.9 pg/mL) vs. controls (33.0+/-3.8 pg/mL) while reverse transcription-polymerase chain reaction demonstrated a 1.86-fold increase in SDF-1 expression in treated wounds vs. controls. This profile was reversed after the treated wounds healed and before closure of controls (day 24). Augmented vasculogenic cytokine profile and endothelial cell markers are associated with improved diabetic wound healing in topical gene therapy with p53 siRNA

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-1alpha (HIF-1alpha) up-regulation in endothelial cells (ECs), a HIF-1alpha-independent up-regulation of stromal cell-derived factor-1 (SDF-1), as well as endothelial migration, all of which are essential for angiogenesis. 5 Gray IR-induced EC HIF-1alpha and SDF-1 expression was greater when combined with hypoxia suggesting an additive effect. While small interfering RNA silencing of HIF-1alpha mRNA and abolition of HIF-1alpha protein induction down-regulated SDF-1 induction by hypoxia alone, it had little effect on SDF-1 induction by IR, demonstrating an independent pathway. SDF-1-mediated EC migration in hypoxic and/or radiation-treated media showed IR induced strong SDF-1-dependent migration of ECs, augmented by hypoxia. IR activates a novel pathway stimulating EC migration directly through the expression of SDF-1 independent of HIF-1alpha induction. These observations might be exploited for stimulation of wound healing or controlling tumor angiogenesis

Medicinal leeches are used to control venous congestion. Aeromonas in the leech gut are essential for digestion of blood. This case report describes a patient who had Aeromonas bacteremia develop after leeching. He had an injury to his hand that required replantation of his thumb. Following the surgery, leech therapy was started with ampicillin-sulbactam prophylaxis. Sepsis developed. Blood cultures were positive for Aeromonas that were resistant to ampicillin-sulbactam. The antibiotic was changed to ciprofloxacin on the basis of the sensitivity profile of the organisms. Cultures from the leech bathwater confirmed it as the source of the Aeromonas. Clinicians who use leech therapy must be aware that leeches can harbor Aeromonas species resistant to accepted prophylactic antibiotics and that sepsis may occur

Large, traumatic wounds around the proximal third of the lower extremity may have disrupted local vasculature, potentially obviating local pedicled options. However, free-tissue transfer to this area is technically challenging given the resulting paucity of recipient options and the depth of principal blood vessels. We present an anatomic and radiographic study of the proximally based peroneal vascular bundle as a recipient option in the proximal leg. Optimal approach was prone, through an incision over the fibula with dissection between lateral and posterior compartments. Magnetic resonance angiography demonstrated consistent vascular anatomy between patients. A proximally based peroneal vascular bundle protected by a cuff of flexor hallucis longus was used as a recipient vessel in free flap reconstruction of an open knee wound. The bundle itself does not require coverage by virtue of its own local muscle cuff. Caveats for its use include the need for adequate leg inflow and foot outflow.

Pathologic resections involving the maxilla/hemimaxilla offer a unique reconstructive challenge to the maxillofacial reconstructive surgeon. Traditionally, reconstruction and replacement of lost tissues have been achieved with a variety of methods including obturators, local/regional flaps, and microvascular free tissue transfer. All these techniques have distinct disadvantages. We present a novel approach to palatomaxillary reconstruction using a combination of free tissue transfer and zygomaticus implants. To our knowledge, this specific technique has not been previously reported.

OBJECTIVE: Determine long-term loss of mandible height with use of stress-shielding reconstruction plates for free fibula flap mandible reconstruction. DESIGN: Retrospective single-blinded medical record review. SUBJECTS: Seventy patients who had fibula free flap mandible reconstructions performed for 10 years. Patients who underwent radiotherapy were excluded. METHODS: Review of 70 fibula free flap mandible reconstructions performed for the last 10 years in a city hospital revealed 7 patients (10%) who had resections for benign odontogenic diseases. All had a three-dimensional cast model made, on which the reconstruction plate was bent to the desired shape preoperatively. Free fibula height on panoramic x-ray images taken preoperatively and at 2 and 12 months postoperatively. RESULTS: Seven (10%) patients met criteria for the study. Bone height was maintained at 2 months postoperatively, but at 12 months, there was a statistically significant loss of fibular bone height averaging 20% in the anterior, body, and ramus areas (P < 0.05). Despite this, all patients were considered eligible for dental rehabilitation, and 4 of 7 patients have had osseointegrated implants placed. CONCLUSIONS: As opposed to miniplates, increased resorption may have been due to the stress-shielding phenomenon unique to a reconstruction plates. However, this did not seem to affect the ability to place osseointegrated implants.

The success of lower extremity microsurgical reconstructions may be compromised postoperatively secondary to several factors, including thrombosis, infection, bleeding, and edema. To address edema, surgeons may use protocols for gradually dangling and/or wrapping the affected extremity. Such protocols vary widely among surgeons and are typically based on training and/or prior experience. To that end, we distributed surveys to five plastic surgeons who are experienced in microvascular lower extremity reconstruction at five different institutions. The surveys inquired about postoperative management protocols for lower extremity free flaps with regard to positioning, compression, initiation and progression of postoperative mobilization, nonweightbearing and weightbearing ambulation, assessment of flap viability, and flap success rate. These protocols were then evaluated for similarities to create a consensus of postoperative management guidelines. Progressive periods of leg dependency and compression therapy emerged as important elements. Although the consensus protocol developed in this study is considered safe by each participant, we do not intend for these recommendations to serve as a standard of care, nor do we suggest that any one particular protocol leads to improved outcomes. However, these recommendations may serve as a guide for less experienced surgeons or those without a protocol in place