The resistance of random copolymers of BMA and CMB against biofouling was evaluated. The amount of proteins adsorbed onto the CMB copolymers was smaller than that onto other polymers (non-ionic polymers and copolymers of ordinary ionic monomers and BMA) and decreased with an increase in the content of CMB residues. Furthermore, there was a dramatic decrease in the number of cells (platelets and fibroblasts) that adhered to the CMB copolymers compared with that to other polymers. In contrast with this, CMB copolymers were slightly perturbative to both complement and coagulation systems. However, the overall results suggest that zwitterionic moieties are effective for making polymer materials biocompatible due to their excellent anti-biofouling property.
The effect of a thin film of a zwitterionic random copolymer composed of carboxybetaine [1-carboxy-N,Ndimethyl-N-(2 -methacryloyloxyethyl)methanaminium inner salt] (CMB) and n-butyl methacrylate (BMA), poly(CMB-r-BMA) (CMB, 30 mol%), on the healing of a full-thickness excisional and incisional wound in hairless rats was examined. The poly(CMB-r-BMA) film significantly enhanced wound closure and complete healing of a full-thickness excisional wound compared with the effect of the poly(n-butyl methacrylate) (PBMA) and the poly(ethylene terephthalate) (PET) films. However, the poly(CMB-r-BMA) film did not enhance healing of a fullthickness incisional wound in hairless rats. The amount of proteins adsorbed and that of neutrophiles adhered onto the poly(CMB-r-BMA) film were significantly smaller than those onto the PBMA and PET films. The results suggested that various cells and growth factors in the wound exudate are utilized effectively by covering an excisional wound with the poly(CMB-r-BMA) film, resulting in acceleration of healing. In addition, the poly(CMB-r-BMA) film significantly enhanced healing of a full-thickness excisional wound in hairless rats compared with the effect of Tegaderm ® as wound dressings. The poly(CMB-r-BMA) film has potential as a new wound dressing.
The Toll-like receptor 4 (TLR4)/myeloid differentiation factor-2 (MD-2) complex is essential for LPS recognition and induces innate immune responses against Gram-negative bacteria. As activation of TLR4/MD-2 is also critical for the induction of adaptive immune responses, TLR4/MD-2 agonists have been developed as vaccine adjuvants, but their efficacy has not yet been ascertained. Here, we demonstrate that a funiculosin (FNC) variant, FNC-RED, and FNC-RED and FNC derivatives are agonists for both murine and human TLR4/MD-2. FNC-RED induced nuclear factor-κB (NF-κB) activation via murine TLR4/MD-2, whereas FNC had no TLR4/MD-2 stimulatory activity. Biacore analysis revealed that FNC-RED binds to murine TLR4/MD-2 but not murine radioprotective 105 (RP105)/myeloid differentiation factor-1 (MD-1), another LPS sensor. FNC-RED induced CD14-independent expressions of pro-inflammatory cytokines and co-stimulatory molecules in murine macrophages and dendritic cells. In contrast, FNC-RED stimulation was reduced in CD14-dependent LPS responses, including dimerization and internalization of TLR4/MD-2 and IFN-β expression. FNC-RED-induced IL-12p40 production from murine dendritic cells was dependent on NF-κB but not MAPK pathway. In addition, fetal bovine serum augmented lipid A-induced NF-κB activation but blocked FNC-RED-mediated responses. Two synthetic phosphate group-containing FNC-RED and FNC derivatives, FNC-RED-P01 and FNC-P01, respectively, activated human TLR4/MD-2, unlike FNC-RED. Finally, computational analysis revealed that this species-specific activation by FNC-RED and FNC-RED-P01 resulted from differences in electrostatic surface potentials between murine and human TLR4/MD-2. We conclude that FNC-RED and its synthetic derivative represent a novel category of murine and human TLR4/MD-2 agonist.
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