M2 macrophage-derived exosome-functionalized topological scaffolds regulate the foreign body response and the coupling of angio/osteoclasto/osteogenesis.

Designing scaffolds that can regulate the innate immune response and promote vascularized bone regeneration holds promise for bone tissue engineering. Herein, electrospun scaffolds that combined physical and biological cues were fabricated by anchoring reparative M2 macrophage-derived exosomes onto topological pore structured nanofibrous scaffolds. The topological pore structure of the fiber and the immobilization of exosomes increased the nanoscale roughness and hydrophilicity of the fibrous scaffold. In vitro cell experiments showed that exosomes could be internalized by target cells to promote cell migration, tube formation, osteogenic differentiation, and anti-inflammatory macrophage polarization. The activation of fibrosis, angiogenesis, and macrophage was elucidated during the exosome-functionalized fibrous scaffold-mediated foreign body response (FBR) in subcutaneous implantation in mice. The exosome-functionalized nanofibrous scaffolds also enhanced vascularized bone formation in a critical-sized rat cranial bone defect model. Importantly, histological analysis revealed that the biofunctional scaffolds regulated the coupling effect of angiogenesis, osteoclastogenesis, and osteogenesis by stimulating type H vessel formation. This study elaborated on the complex processes within the cell microenvironment niche during fibrous scaffold-mediated FBR and vascularized bone regeneration to guide the design of implants or devices used in orthopedics and maxillofacial surgery. STATEMENT OF SIGNIFICANCE: How to design scaffold materials that can regulate the local immune niche and truly achieve functional vascularized bone regeneration still remain an open question. Here, combining physical and biological cues, we proposed new insight to cell-free and growth factor-free therapy, anchoring reparative M2 macrophage-derived exosomes onto topological pore structured nanofibrous scaffolds. The exosomes functionalized-scaffold system mitigated foreign body response, including excessive fibrosis, tumor-like vascularization, and macrophage activation. Importantly, the biofunctional scaffolds regulated the coupling effect of angiogenesis, osteoclastogenesis, and osteogenesis by stimulating type H vessel formation.

The structure property and endothelial protective activity of fucoidan from Laminaria japonica.

Four antithrombotic fucoidan fractions F1, F2, LF1, and LF2 with different monosaccharide composition, molecular weight, and degree of sulfation and sulfate position were prepared from Laminaria japonica by hot water extraction and radical degradation. Their endothelial protective activity and possible action mechanism were studied using both cell- and rat-based models systematically. By comparison, the low molecular weight (LMW) fucoidan LF1 and LF2 were more potent than the medium molecular weight (MMW) fucoidan F1 and F2 in endothelial protection, down-regulation of von Willebrand Factor, CD31 and CD51 expressing endothelial microparticles in adrenalin-induced arterial endothelial injury rats and human umbilical vein endothelial cell system. However, the highly sulfated fucoidan fractions F2 and LF2 were better at inducing FGFR1c-expressing BaF3 cell proliferation in the presence of FGF-1, -2, -7, -8, -9 or -10. These results indicated that the chemical property of fucoidan was correlated to its specific biological activity tested. Therefore, defying fucoidan's monosaccharide composition, molecular weight, and degree of sulfation might be important in developing it into a medicine.

A comparative study of antithrombotic and antiplatelet activities of different fucoidans from Laminaria japonica.

INTRODUCTION: Fucoidans extracted from brown algae represent an intriguing group of natural fucose-enriched sulfated polysaccharide, with excellent anticoagulant, antimetastatic, antiangiogenic and anti-inflammatory activities. In the present study, we compared antithrombotic activities of four fucoidan fractions with different molecular weight and sulfated ester content from Laminaria japonica in an electrical induced arterial thrombosis and their potential mechanism underlying such activity. RESULTS AND CONCLUSIONS: In vivo middle molecular weight (MMW) fucoidan fractions with molecular weight about 28000 and 35000 exhibited better antithrombotic activity in electrical induced arterial thrombosis than low molecular weight (LMW) fucoidan LF1 and LF2 (Mw 7600 and 3900). Inhibition of arterial thrombosis occurred at dose of 0.1-0.25mg/kg for MMW fucoidans, accompanied with moderate anticoagulant activity and significant decrease of whole blood viscosity and hematocrit. The antithrombotic effects of MMW Fucoidans might be related with promotion of TFPI content and decrease of TXB2 content, without affecting platelet aggregation and 6-keto-PGF1α content in vivo. In contrast, LMW fucoidans showed a correlation among anticoagulant, antiplatelet and antithrombotic effects in vivo. Antithrombotic action of LF1 and LF2 required high dose of 2.5-10mg/kg, concomitantly with anticoagulant activity and specific inhibition of platelet aggregation in vivo. Their antithrombotic effect might be related to their promotion of TFPI and 6-keto-PGF1α, down regulation of TXB2, without affecting hemorheology. These findings suggested that fucoidan fractions with different molecular weight acted on the antithrombotic action by different mechanism. By comparison, highly sulfated fucoidan LF2 with molecular weight of 3900 seemed to be a more suitable choice of antithrombotic drug for its antithrombotic activity accompanied with specific inhibitory activity on platelet aggregation, low anticoagulant activity and low hemorrhagic risk in vivo.

Association between the presence of H pylori in the liver and hepatocellular carcinoma: a meta-analysis.

AIM: To evaluate the arguments for and against the possible roles of H pylori in hepatocellular carcinoma (HCC). METHODS: We performed a systematic review of all relevant studies published in the literature. A total of 103 clinical trials and reports were identified, but only 10 trials qualified under our selection criteria. A meta-analysis was carried out by a biostatistician according to the Cochrane Reviewers' Handbook recommended by The Cochrane Collaboration. RESULTS: Nine case-control studies and one retrospective cross sectional study were included in the final analysis. Overall the prevalence of H pylori infection was 53.3% (129 of 242) in cases and 10.4% (29 of 280) in controls, and the summary odds ratio for the association of H pylori infection with the risk for HCC (using the fixed-effects model, which accounted for the homogeneity across the 10 studies) was determined to be 13.63 (95% CI, 7.90-23.49). CONCLUSION: Our analysis showed a positive association between H pylori infection and the risk of HCC, with an indication of possible publication bias and possible confounders due to study designs that showed results of less pronounced associations.