BackgroundMacrophages play important roles in the immune response to, and successful implantation of, biomaterials. Titanium nanotubes are considered promising heart valve stent materials owing to their effects on modulation of macrophage behavior. However, the effects of nanotube-regulated macrophages on endothelial cells, which are essential for stent endothelialization, are unknown. Therefore, in this study we evaluated the inflammatory responses of endothelial cells to titanium nanotubes prepared at different voltages.Methods and resultsIn this study we used three different voltages (20, 40, and 60 V) to produce titania nanotubes with three different diameters by anodic oxidation. The state of macrophages on the samples was assessed, and the supernatants were collected as conditioned media (CM) to stimulate human umbilical vein endothelial cells (HUVECs), with pure titanium as a control group. The results indicated that titanium dioxide (TiO2) nanotubes induced macrophage polarization toward the anti-inflammatory M2 state and increased the expression of arginase-1, mannose receptor, and interleukin 10. Further mechanistic analysis revealed that M2 macrophage polarization controlled by the TiO2 nanotube surface activated the phosphatidylinositol 3-kinase/AKT and extracellular signal-regulated kinase 1/2 pathways through release of vascular endothelial growth factor to influence endothelialization.ConclusionOur findings expanded our understanding of the complex influence of nanotubes in implants and the macrophage inflammatory response. Furthermore, CM generated from culture on the TiO2 nanotube surface may represent an integrated research model for studying the interactions of two different cell types and may be a promising approach for accelerating stent endothelialization through immunoregulation.

Background Hepatocellular carcinoma (HCC) incidences have been increasing in the United States. This study aimed to examine temporal trend of HCC survival and determine prognostic factors influencing HCC survival within the U.S. population. Methods The Surveillance Epidemiology, and End Results (SEER) database was used to identify patients diagnosed with primary HCC from 1988 to 2015. Overall survival (OS) and disease-specific survival (DSS) were calculated by the Kaplan-Meier method. Univariate and multivariate Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for prognostic factors and comparing survival between patients diagnosed at different periods (per 5-year interval). Results A total of 80,347 patients were included. The proportions of both young patients (< 45 years) and old patients (≥75 years) decreased over time (P < 0.001) and the male-to-female ratio increased over time (P < 0.001). Significant decreasing temporal trends were observed for HCC severity at diagnosis, including SEER stage, tumor size, tumor extent, and lymph node involvement (P < 0.001 for all). OS and DSS of patients with HCC improved over time (P < 0.001). After adjusting for patient and tumor characteristics and treatment difference, period of diagnosis retained an independent factor for improved DSS and its prognostic significance was evident for localized and regional HCC (P < 0.001), but not for distant HCC. On multivariate analyses, young age, female gender, Hispanic ethnicity, and married status were predictors favoring DSS, whereas a worse DSS was observed for patients with tumor > 5 cm, with vascular invasion, and with lymph node involvement. Patients treated with liver-directed therapy (HR = 0.54, 95% CI: 0.35–0.56), hepatic resection (HR = 0.35, 95% CI: 0.33–0.37), and transplantation (HR = 0.14, 95% CI: 0.13–0.15) had significantly longer DSS compared with those who received no surgery. In stratified analyses, the beneficial effects of surgical approach, regardless therapy type, were significant across all stages. Conclusions Our results indicate a significant improvement in survival for HCC patients from 1988 to 2015, which may be attributable to advances in early diagnosis and therapeutic approaches.

BackgroundPoly (ethylene glycol) (PEG) has attracted broad interest for tissue engineering applications. The aim of this study was to synthesize 4-arm -PEG-20kDa with the terminal group of diacrylate (4-arm-PEG-DA) and evaluate its dual functionality for decellularized porcine aortic valve (DAV) based on its mechanical and biological properties.Methods4-arm-PEG-DA was synthesized by graft copolymerization of linear PEG 20,000 monomers, and characterized by IR1H NMR and 13C NMR; PEGylation of DAV was achieved by the Michael addition reaction between propylene acyl and thiol, its effect was tested by uniaxial planar tensile testing, hematoxylin and eosin (HE) and scanning electron microscopy (SEM). Gly-Arg-Gly-Asp-Ser-Pro-Cys (GRGDSPC) peptides and vascular endothelial growth factor-165 (VEGF165) were conjugated onto DAV by branched PEG-DA (GRGDSPC-PEG-DAV-PEG-VEGF165).ResultsMechanical testing confirmed that PEG-cross-linking significantly enhanced the tensile strength of DAV. Immunofluoresce confirmed the GRGDSPC peptides and VEGF165 were conjugated effectively onto DAV; the quantification of conjunction was completed roughly using spectrophotometry and ELISA. The human umbilical vein endothelial cells (HUVECs) grew and spread well on the GRGDSPC-PEG-DAV-PEG-VEGF165.ConclusionsTherefore, PEGylation of DAV not only can improve the tensile strength of DAV, and can also mediate the conjugation of bioactive molecule (VEGF165 and GRGDSPC peptides) on DAV, which might be suitable for further development of tissue engineered heart valve.

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