In vivo perfusion of human skin substitutes with microvessels formed by adult circulating endothelial progenitor cells.

BACKGROUND: At present, tissue-engineered human skin substitutes (HSSs) mainly function as temporary bioactive dressings due to inadequate perfusion. Failure to form functional vascular networks within the initial posttransplantation period compromises cell survival of the graft and its long-term viability in the wound bed. OBJECTIVES: Our goal was to demonstrate that adult circulating endothelial progenitor cells (EPCs) seeded onto HSS can form functional microvessels capable of graft neovascularization and perfusion. MATERIALS AND METHODS: Adult peripheral blood mononuclear cells (PBMCs) underwent CD34 selection and endothelial cell (EC) culture conditions. After in vitro expansion, flow cytometry verified EC phenotype before their incorporation into HSS. After 2 weeks in vivo, immunohistochemical analysis, immunofluorescent microscopy, and microfil polymer perfusion were performed. RESULTS: CD34+ PBMCs differentiated into EPC demonstrating characteristic EC morphology and expression of CD31, Tie-2, and E-selectin after TNFalpha-induction. Numerous human CD31 and Ulex europaeus agglutinin-1 (UEA-1) microvessels within the engineered grafts (HSS/EPCs) inosculated with recipient murine circulation. Limitation of murine CD31 immunoreactivity to HSS margins showed angiogenesis was attributable to human EPC at 2 weeks posttransplantation. Delivery of intravenous rhodamine-conjugated UEA-1 and microfil polymer to HSS/EPCs demonstrated enhanced perfusion by functional microvessels compared to HSS control without EPCs. CONCLUSION: We successfully engineered functional microvessels in HSS by incorporating adult circulating EPCs. This autologous EC source can form vascular conduits enabling perfusion and survival of human bioengineered tissues.

Cutaneous drug eruptions induced by sorafenib: a case series.

Sorafenib, an epidermal growth factor receptor inhibitor, is a novel treatment used for malignancies resistant to traditional chemotherapy. Epidermal growth factor receptors (EGFR) are a family of 4 transmembrane tyrosine kinase receptors that, via signal transduction pathways, mediate cell growth, differentiation, and survival. Sorafenib is a targeted drug specifically engineered to inhibit Raf serine/threonine kinases, which are part of the reticular activating system (RAS) oncogene pathway. In addition, in vitro studies have shown sorafenib to be a potent multikinase inhibitor, targeting receptor tyrosine kinases associated with tumor angiogenesis (VEGFR-2, VEGFR-3, and PDGFR-beta) and progression. Initially, approved for use in advanced renal cell carcinoma, sorafenib is being studied for the treatment of other solid tumors at our institution. During the clinical trial, 4 patients were referred to the dermatology clinic for evaluation and treatment of diffuse erythematous eruptions all occurring 8 to 10 days after initiating sorafenib at a dose of 400 mg twice daily. These eruptions occurred in demographically similar patients and displayed similar clinical characteristics and histopathological findings. Clinically, 3 of 4 patients had facial erythema, 3 of 4 had generalized macular erythema, 3 of 4 had widespread follicular-based papular eruption, and 4 of 4 had palmoplantar erythrodysesthesia. Half of the patients had cutaneous eruptions without systemic effects, while the other half had hypersensitivity reactions requiring withdrawal from clinical trial. This is the first case series illustrating drug eruptions induced by sorafenib.