The prevalence of Type 2 diabetes mellitus (T2DM) is escalating globally. Patients suffer from multiple complications including the development of chronic wounds that can lead to amputation. These wounds are characterised by an inflammatory environment including elevated tumour necrosis factor alpha (TNF-α). Dermal fibroblasts (DF) are critical for effective wound healing, so we sought to establish whether there were any differences in DF cultured from T2DM donors or those without diabetes (ND-DF). ND- and T2DM-DF when cultured similarly in vitro secreted comparable concentrations of TNF-α. Functionally, pre-treatment with TNF-α reduced the proliferation of ND-DF and transiently altered ND-DF morphology; however, T2DM-DF were resistant to these TNF-α induced changes. In contrast, TNF-α inhibited ND- and T2DM-DF migration and matrix metalloprotease expression to the same degree, although T2DM-DF expressed significantly higher levels of tissue inhibitor of metalloproteases (TIMP)-2. Finally, TNF-α significantly increased the secretion of pro-inflammatory cytokines (including CCL2, CXCL1 and SERPINE1) in ND-DF, whilst this effect in T2DM-DF was blunted, presumably due to the tendency to higher baseline pro-inflammatory cytokine expression observed in this cell type. Collectively, these data demonstrate that T2DM-DF exhibit a selective loss of responsiveness to TNF-α, particularly regarding proliferative and secretory functions. This highlights important phenotypic changes in T2DM-DF that may explain the susceptibility to chronic wounds in these patients.

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Epidermal growth factor (EGF) is known to stimulate skin cell growth and synthesis of extracellular matrix such as hyaluronan(HA) which is decreased with aging in skin. However, EGF is hard to penetrate the stratum corneum and permeate into skin due to its size and hydrophilicity. To improve the skin delivery of EGF, we have used multi-lamellar complexes consist of EGF and 1,2-dioleoyl-3-tirmethylammonium-propane (DOTAP). EGF-DOTAP complex showed higher permeation rate in human skin and synthesis of hyaluronan in human skin equivalent model than normal liposome. A randomized, double-blind, vehiclecontrolled, split-face study was designed to evaluate the anti-aging effects of a cream containing EGF-DOTAP complex on human skin. Twentyeone Korean women completed a 12weeks study and were applied twice daily to the face. As compared with the vehicle control, EGF-DOTAP cream significantly improved the facial photo-damage score, skin roughness (R1), maximum roughness (R2), average roughness (R3, Ra), arithmetic roughness average (R5), and dermal density at 12 weeks. In conclusion, this study suggests that topical application of EGF-DOTAP complex exhibited significant improvement on skin aging by enhancing the permeation of EGF. LB1548 A pro-inflammatory environment modulates the human dermal fibroblast secretory phenotype: Implications for chronic wounds