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Poly(dimethylsiloxane) (PDMS) is known as one of the most established polymers for making elastomers. Therefore, it is commonly used for the fabrication of biomedical devices. Many PDMS surface modification processes have been proposed recently to increase PDMS reliability in medical fields. However, the modified surface's long-term stability is still limited. Hydrophobic recovery of PDMS is widely recognized as a factor that reduces the efficacy of PDMS surface modification. The photoreactive zwitterionic polymer effectively suppresses the hydrophobic recovery of PDMS, according to the current analysis. The photoreactive zwitterionic monomer, 2-[2-(Methacryloyloxy)ethyldimethylanmmonium] ethyl benzophenoxy phosphate (MBPP) was polymerized by conventional radical polymerization and coated on O2-plasma-treated PDMS specimens. The specimens were immersed in an aqueous solution of 2-methacryloyloxyethyl phosphorylcholine (MPC) and exposed under ultraviolet (UV) radiation for 3 h. Instead, of poly(MBPP) (PMBPP), benzophenone (BP) was also used as a conventional photoinitiator. The time-dependent change in the wettability and elemental composition of the specimen surface was monitored for nine weeks after photo-grafting of poly[2-methacryloyloxyethyl phosphorylcholine (MPC)] (PMPC). The advancing and receding contact angles (θA/θR) of the pristine PDMS specimen were 112°/71° and significantly decreased immediately after the grafting of PMPC regardless of types of photoinitiator. However, the hydrophobicity of the surface gradually recovered, and θA was changed from 12° to 81° for nine weeks of storage under air atmosphere when BP was used as a photoinitiator for graft polymerization of MPC. However, surface hydrophilicity (θA ≅ 20°) of the surface grafted with PMPC with PMBPP as an initiator was effectively preserved for nine weeks. This surface also showed excellent lubricity and non-fouling properties regardless of the storage periods. Therefore, zwitterionic photoreactive polymer, PMBPP, is then used as a macrophotoinitiator for the surface modification of PDMS.

DOI： 10.1016/j.colsurfb.2021.111900

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Owing to their high spatiotemporal precision and adaptability to different host cells, organ-on-a-chip systems are showing great promise in drug discovery, developmental biology studies and disease modeling. However, many current micro-engineered biomimetic systems are limited in technological application because of culture media mixing that does not allow direct incorporation of techniques from stem cell biology, such as organoids. Here, we describe a detailed alternative method to cultivate millimeter-scale functional vascularized tissues on a biofabricated platform, termed ‘integrated vasculature for assessing dynamic events’, that enables facile incorporation of organoid technology. Utilizing the 3D stamping technique with a synthetic polymeric elastomer, a scaffold termed ‘AngioTube’ is generated with a central microchannel that has the mechanical stability to support a perfusable vascular system and the self-assembly of various parenchymal tissues. We demonstrate an increase in user familiarity and content analysis by situating the scaffold on a footprint of a 96-well plate. Uniquely, the platform can be used for facile connection of two or more tissue compartments in series through a common vasculature. Built-in micropores enable the studies of cell invasion involved in both angiogenesis and metastasis. We describe how this protocol can be applied to create both vascularized cardiac and hepatic tissues, metastatic breast cancer tissue and personalized pancreatic cancer tissue through incorporation of patient-derived organoids. Platform assembly to populating the scaffold with cells of interest into perfusable functional vascularized tissue will require 12–14 d and an additional 4 d if pre-polymer and master molds are needed.

DOI： 10.1038/s41596-020-00490-1

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In this study, oligo-prolines, (Pro)n (n = 6 and 9) inspired by the backbone structure of collagen, were evaluated as a novel non-ionic anti-fouling peptide. Two oligo-prolines with a cysteine residue were synthesized and immobilized on gold substrates via Au-thiol binding. The surfaces immobilized with oligo-prolines, and forming a polyproline-II conformation, indicated hydrophilic properties (water contact angle ≈ 25 degrees). The degree of adsorption of human serum albumin, human fibrinogen, and bovine serum components on these surfaces was quantified using a quartz crystal. The immobilization of oligo-prolines prevented the adsorption of proteins and serum components including small molecules, such as fatty acids. Pro9 specifically indicated good resistance to the adsorption of all components due to the highly-packed Pro9 chains on the surface. The adhesion of fibroblasts was drastically suppressed on the surfaces immobilized with oligo-prolines. Our findings suggest that oligo-proline-immobilized surfaces, specifically Pro9-s, are useful for the development of novel vascular devices that have ultra-low fouling properties.

DOI： 10.1039/d0tb00051e

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society ({ACS})  

DOI： 10.1021/acsabm.9b01040

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Improved thromboresistance of mechanical valves is desired to decrease the risk of thromboembolism and thrombosis and reduce the dosage of anticoagulation with a vitamin K antagonist (e.g., warfarin). For several mechanical valves, design-related features are responsible for their improved thromboresistance. However, it remains unclear whether material-related features provide a practical level of thromboresistance to mechanical valves. Here, we studied the effect of a bileaflet valve made of poly(ether ether ketone) (PEEK) with a poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)-grafted surface (PEEK-g-PMPC). PMPC is a well-known thromboresistant polymeric material. A short-term (<26 h) porcine aortic valve replacement model using neither an anticoagulant nor an antiplatelet agent showed that the PEEK-g-PMPC valve opened and closed normally with an allowable transvalvular gradient. Unlike an untreated PEEK valve, no thrombus formed on the PEEK-g-PMPC valves on gross anatomy examination in addition to the absence of traveled thrombi in the kidney and lung tissues. Material (PEEK-g-PMPC)-related thromboresistance appeared to decrease the risk of thromboembolism and thrombosis for patients with mechanical valves. However, thromboresistance of the PEEK-g-PMPC valve requires improvement because fibrous fouling was still observed on the leaflet. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1052-1063, 2019.

DOI： 10.1002/jbm.a.36628

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：Society for Biomaterials  

Statement of Purpose: Collagen is the major structural protein in the extracellular matrix and plays an essential role in providing a scaffold for cellular functions. A large part of a collagen molecule is composed of the backbone forming the triple helical structure which supports for active sites such as Arg-Gly-Asp sequences to interact with cell surface receptors unmolested. The collagen triple helical structure consists of three left-handed polyproline-II helices (PP-II) having Gly-Pro-Hyp repetitive sequences. Hence, we built a hypothesis that the oligo-proline might not possess any biological function resulting that it works as a bioinert biomolecule. In this study, we prepared oligo-proline immobilized surfaces and analyzed their fundamental characteristics and fibroblast adhesion behaviors.

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Heparin binds to and modulates various growth factors, potentially augmenting the bone-forming capability of biomaterials. Here, α-tricalcium phosphate (α-TCP) granules were modified with peptide containing the marine mussel-derived adhesive sequence, which reacts with α-TCP surface, and cationic sequence, which binds to heparin (α-Ph). α-Ph retained the α-TCP phase and intergranule spaces after the surface modification. The existence of heparin on α-Ph granules was confirmed using X-ray photoelectron spectroscopy. Granules of α-TCP and α-Ph were implanted into critical-size defects in rat calvaria for 4 weeks. Micro-computed tomography, histological evaluation, and Alcian blue staining revealed that α-Ph induced superior bone formation compared with α-TCP. Newly formed bone on α-Ph was preferentially in contact with the Alcian blue-stained surfaces of granules. These results suggested that heparinization enhanced the early osteogenic capacity of α-TCP, possibly by modulating the secretion of Alcian blue-stained extracellular matrixes.

DOI： 10.4012/dmj.2017-305

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We evaluated the effect of porous alpha-tricalcium phosphate (α-TCP) with immobilized basic fibroblast growth factor (bFGF) on periodontal regeneration in a canine model of 2-wall periodontal defects. Identical bone defects were made in the canine mandible; six defects in each animal were filled with porous α-TCP with bFGF bound via heparin (bFGF group), and the remaining defects were filled with unmodified porous α-TCP (control group). Micro-computed tomography and histological evaluation were performed at 2, 4, and 8 weeks post-implantation. The bone mineral content of the bFGF group was higher than that of the control group at 2 and 4 weeks (p < 0.05). Histological evaluation at 2 weeks post-implantation revealed degradation of the porous α-TCP, and bone had formed on the surface of α-TCP particles in the bFGF group. Some of these collagen fibers connected the newly formed cementum with the alveolar bone, revealing the formation of new periodontal ligaments with Sharpey's fibers. At 8 weeks, continuous cortical bone with a Haversian structure covered the top of the bone defects in the bFGF group. These findings indicate that porous α-TCP with immobilized bFGF could promote periodontal regeneration at the early regeneration phase in a canine model of 2-wall periodontal defects.

DOI： 10.1007/s00795-017-0172-9

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Rapid in-situ re-endothelialization of coronary stents is one of the most effective approaches to inhibit late thrombosis and restenosis. Strut surfaces allowing excellent adhesion and migration of endothelial cells and endothelial progenitor cells may accelerate in-situ re-endothelialization. Here, a well-known endothelial cell adhesive peptide, Arg-Glu-Asp-Val (REDV), was directly immobilized onto metallic surfaces by means of single-step tyrosine oxidation with copper chloride (II) and hydrogen peroxide, which we recently reported as a new biomaterial modification technique. REDV immobilization on a 316L stainless steel plate improved endothelial cell adhesion and effectively suppressed platelet adhesion in vitro. In addition, a Co-Cr stent immobilized with Ac-Tyr-Gly-Gly-Gly-Arg-Glu-Asp-Val (Y-REDV) was implanted into a rabbit abdominal aorta. On 7 days postimplantation, 80% of the strut surface of the Y-REDV-immobilized stent was covered by a thin neointimal layer and was similar in appearance to native endothelium. Restenosis and late thrombosis were not observed in the Y-REDV-immobilized stent for 42 days. These findings suggest that direct immobilization of Y-REDV peptide onto metallic biomaterials by tyrosine oxidation is effective for promoting in-situ re-endothelialization in vascular stents. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 491-499, 2018.

DOI： 10.1002/jbm.a.36258

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Cell-based therapies using self-beating cardiomyocytes have been attracting great attention for use in cardiac regeneration, although an effective procedure to improve cardiac differentiation and self-beating induction is required. The purpose of this study is to clarify the effect of the culture substrate on cardiac maturation by separately evaluating the cardiac differentiation step and the beating induction step in vitro. To this end, the well-studied cardiomyocyte-like progenitor cell line P19CL6 and neonatal cardiomyocytes (NCMs) were selected and cultured on substrates coated with collagen type I (Col-I), gelatin (Gel), fibronectin (FN), or poly-l-lysine (PLL). It was found that the cardiac differentiation step, which was assessed using cardiac marker gene expression (GATA-binding protein 4 (GATA4), myocyte-specific enhancer factor 2D (MEF2D), and hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4)) in the P19CL6 embryonal carcinoma cells, was greatly enhanced on Col-I, Gel, and PLL. In contrast, the spontaneous beating step, which was directly assessed by counting the beating colonies and measuring contractile protein gene expression (α-myosin heavy chain (α-MHC), troponin C type 1 (TnC1), and troponin T type 2 (TnT2)) in the rat NCMs, was enhanced on the FN and PLL surfaces. In the present study, for the first time, it was found that PLL enhances both the cardiac differentiation and the beating induction steps of cardiac maturation, which can aid in preparing beating cardiomyocytes for regenerative medicine. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1166-1174, 2017.

DOI： 10.1002/jbm.a.35977

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Language：Japanese   Publisher：日本バイオマテリアル学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL SOC CHEMISTRY  

The effect of increasing molecular mobility, on hydrated polyrotaxane (PRX)-coated surfaces, on differentiation of mouse induced pluripotent stem cells (iPS cells) into cardiomyocytes was examined. PRX is composed of a-cyclodextrin (alpha-CD) threaded on linear poly(ethylene glycol) (PEG)-capped terminals with bulky end-groups. The degree of molecular mobility at the hydrated state (Mf) on the PRX surfaces can be varied by changing the number of threaded alpha-CDs. Rac1 expression was significantly upregulated for adhering iPS cells on the PRX surface with high Mf value, while it was downregulated on surfaces with low Mf value. Furthermore, the expression of N-cadherin, which is an important marker protein for cardiomyogenic differentiation of stem cells, was greatly upregulated for adhering iPS cells on the PRX surface with high Mf value, while those on surfaces with low Mf value showed low Ncadherin expression. Finally, the PRX surface with higher Mf value was found to be higher in cardiomyogenesis and beating colony formation from iPS cells, the extent of which was much higher than that on gelatin-coated surfaces. This suggests that surface hydrated molecular mobility, varied by varying a supramolecular PRX architecture on materials, plays a significant role in controlling cytoskeletal signaling pathways, eventually contributing to the direction of stem cell commitment.

DOI： 10.1039/c6ra03967g

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Soft tissue integration into a porous structure is important to prevent bacterial infection of percutaneous devices and improve tissue regeneration using porous scaffolds. Here, basic fibroblast growth factor (bFGF) was immobilized on porous polymer materials using a mild and biologically safe three-step reaction: (1) modification with a novel surface-modification peptide (penta-lysine-mussel adhesive sequence, which reacts with various matrices), (2) electrostatic binding of heparin with introduced penta-lysine, and (3) biologically specific binding of bFGF to heparin. Porous polyethylene specimens (PPSs) (D = 6.0 mm, H = 2.0 mm) with a good size for tissue integration were selected as a base material, immobilized with bFGF, and subcutaneously implanted into mice. Half of the unmodified PPSs extruded out of the body on day 112 postimplantation; however, the three-step reaction completely prevented sample rejection. Tissue integration was greatly accelerated by immobilizing bFGF. Direct physical coating of bFGF on PPS resulted in greater immobilization but lesser tissue integration than that after the three-step bFGF immobilization, indicating that heparin binds and enhances bFGF efficacy. This three-step bFGF immobilization reaction will be applicable to various polymeric, metallic, and ceramic materials and is a simple strategy to integrate tissue on porous medical devices or scaffolds for tissue regeneration.

DOI： 10.1002/jbm.a.35516

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Immobilization of biologically active peptides which were isolated from extracellular matrix proteins is a powerful strategy for the design and functionalization of biomaterial substrates. However, the method of peptide immobilization was restricted, that is, peptide is often immobilized through the reactive groups inherent in substrates with multistep reactions. Here, we report a single-step immobilization of fibronectin-derived cell adhesive peptide (Arg-Glu-Asp-Val; REDV) onto polymer materials by use of tyrosine oxidation with copper catalyst and hydrogen peroxide. REDV peptide was successfully immobilized on tissue culture polystyrene, poly(ethylene terephthalate), poly(vinyl chloride), expanded-poly(tetrafluoroethylene), and poly(l-lactic acid), resulting in enhanced adhesion of human umbilical vein endothelial cells. This method is a single-step reaction under very mild conditions and is available for the biological functionalization of various medical devices.

DOI： 10.1021/acs.bioconjchem.5b00032

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Mechanotransduction in the regulation of cellular responses has been previously studied using elastic hydrogels. Because cells interact only with the surface of biomaterials, we are focusing on the molecular mobility at the outermost surface of biomaterials. In this study, surfaces with the mobile Arg-Gly-Asp-Ser (RGDS) peptide have been constructed. Cell culture substrates were coated with ABA-type block copolymers composed of poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) segments (A) and a polyrotaxane (PRX) unit with RGDS bound to α-cyclodextrin (B). Adhesion, morphological changes and actin filament formation of human umbilical vein endothelial cells were reduced on the surfaces containing mobile PRX-RGDS in comparison to the immobile RGDS surfaces constructed from random copolymers with RGDS side groups (Prop-andom-RGDS). In the neurite outgrowth assay using rat adrenal pheochromocytoma cells (PC12), only ∼20% of adherent PC12 cells had neurites on PRX-RGDS surfaces, but more than 50% did on the Random-RGDS surface. The beating colony of dimethyl-sulfoxide-treated mouse embryonic carcinoma cells (P19CL6) were found 10 and 14 days after induction on PRX-RGDS and Random-RGDS surfaces, respectively. After 22 days, the beating colony disappeared on PRX-RGDS surfaces, but many colonies remained on Random-RGDS surfaces. These data suggest that the molecular mobility of the cell-binding ligand on the outermost surface of materials effectively suppresses the actin filament formation and differentiation of these functional cell lines, and may be used as a culture substrate for immature stem cells or progenitor cells.

DOI： 10.1016/j.actbio.2014.11.020

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Polymer surfaces with a wide range of hydrated surface mobility are developed by a simple deposition method with supramolecular block copolymers. The morphologies of adhering stem cells are greatly dependent on the surface mobility of polymers, and this induces significant changes in the cytoskeletal signaling pathway to direct the downstream stem cell differentiation.

DOI： 10.1002/adhm.201400173

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Language：Japanese   Publisher：The Materials Research Society of Japan  

To modify the surface properties of segmented polyurethane (SPU), 2-methacryloyloxyethyl phosphorylcholine (MPC) polymers were applied. We prepared different molecular architectures of the MPC polymers, that is, random-type, block-type, and graft-type to investigate durability of the MPC polymer layer on the SPU. The SPU membranes modified with the MPC polymers were characterized using X-ray photoelectron spectroscopy. The better stability was observed in the poly(MPC-<i>graft</i>-2-ethylhexyl methacrylate (EHMA))(gPMEH) polymer layer on the SPU membrane after immersion in an aqueous medium, the possible reason would be the intermiscibility of the poly(EHMA) segments and the soft segments in the SPU. Each SPU/MPC polymer membrane demonstrated a dramatic suppression of protein adsorption from human plasma. From these results, the antithrombogenicity of the 2.0 mm diameter SPU/gPMEH tubings was investigated. We concluded that the SPU membrane modified with the gPMEH was one of the promising polymeric biomaterials for making blood-contacting medical devices.

DOI： 10.14723/tmrsj.40.137

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Biomaterials that contact with soft tissues such as postoperative adhesion prevention membrane or tissue-regenerative scaffolds should possess specific features such as hydrophilicity, mild to no immunogenicity, and quick degradability. The inflammation reaction to multiblock copolymers of poly(L-lactic acid) (PLLA) and poly(ethylene glycol), named as Multi, which we developed as a good adhesion prevention materials with a very high degradation rate were investigated and compared with usual PLLA, non-degradable polyethylene (PE), and acellular collagenous tissue (COL). Tissue encapsulation, inflammatory cell recruitment, and expression of four cytokines (IL-1β, IL-6, IL-10, and TGFβ) affecting the promotion or inhibition of inflammation and wound healing were evaluated. The thick encapsulation for PE might have related to high expression of TGFβ, and it was largely reduced in the cases of PLLA and Multi. The cytokine expression pattern in PE was dominantly alternatively activated macrophage (M2) type, while expression patterns to Multi were classically activated macrophage (M1)-type dominant, as with the COL specimen. Thus, multi is a tissue compatible material in spite of the large degradability. By introducing low molecular weight PEG into PLLA as multiblock-type sequence, we successfully prepared biocompatible PLLA derivatives with high molecular weight, large degradation rate, and mild tissue responses.

DOI： 10.1007/s10047-014-0791-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL SOC CHEMISTRY  

Poly(l-lactic acid) (PLLA) is widely used as a scaffold but does not possess biological functions. Here, we described the biosynthesis of the elastin-like repetitive polypeptide (VPGIG)30 containing a laminin-derived neurite outgrowth-promoting sequence (RKRLQVQLSIRT: AG73) (AG73-(VPGIG)30). The expression vector for AG73-(VPGIG)30 was constructed using the self-ligation technique to elongate the VPGIG repetitive sequence. The coacervation temperature of the purified AG73-(VPGIG)30 protein was 20 and 14 °C in water and phosphate-buffered saline (PBS), respectively. AG73-(VPGIG)30 was quickly adsorbed on PLLA films via a hydrophobic interaction by raising the temperature from 4 °C to 37 °C. On the AG73-(VPGIG)30-modified PLLA surface, the neurite outgrowth of PC12 cells was strongly promoted. We successfully induced the neurite outgrowth activity on PLLA films by treating the novel surface modifier AG73-(VPGIG)30, which could be applicable in developing PLLA scaffolds for nerve regeneration.

DOI： 10.1039/c4tb00305e

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Poly(l-lactic acid) (PLLA) is widely used as a scaffold but does not possess biological functions. Here, we described the biosynthesis of the elastin-like repetitive polypeptide (VPGIG)30 containing a laminin-derived neurite outgrowth-promoting sequence (RKRLQVQLSIRT: AG73) (AG73-(VPGIG)30). The expression vector for AG73-(VPGIG)30 was constructed using the self-ligation technique to elongate the VPGIG repetitive sequence. The coacervation temperature of the purified AG73-(VPGIG)30 protein was 20 and 14 °C in water and phosphate-buffered saline (PBS), respectively. AG73-(VPGIG)30 was quickly adsorbed on PLLA films via a hydrophobic interaction by raising the temperature from 4 °C to 37 °C. On the AG73-(VPGIG)30- modified PLLA surface, the neurite outgrowth of PC12 cells was strongly promoted. We successfully induced the neurite outgrowth activity on PLLA films by treating the novel surface modifier AG73-(VPGIG)30, which could be applicable in developing PLLA scaffolds for nerve regeneration. © 2014 the Partner Organisations.

DOI： 10.1039/c4tb00305e

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Aromatic poly(ether ether ketone) (PEEK) is a super engineering plastic, which has good mechanical properties and is resistant to physical and chemical stimuli. We have, therefore, attempted to use PEEK in cardiovascular devices. Synthetic cardiovascular devices require both high hemocompatibility and anti-inflammatory activity in addition to the mechanical properties. We modified the PEEK surface by photoinduced and self-initiated graft polymerization with 2-methacryloyloxyethyl phosphorylcholine (MPC; PMPC-grafted PEEK) for obtaining good antithrombogenicity. Polymerization was carried out on the surface of PEEK under radiation of ultraviolet (UV) light during which we controlled monomer concentrations, temperatures, and UV intensities. The biological performance of the PMPC-grafted PEEK was examined and compared with that of unmodified PEEK. With increase in the thickness of the PMPC layer, the amount of fibrinogen adsorption decreased significantly in comparison to that in the case of unmodified PEEK. When placed in contact with human platelet-rich plasma, surface of the PMPC-grafted PEEK clearly showed inhibition of platelet adhesion and activation. Also, bacterial adhesion was reduced dramatically on the PMPC-grafted PEEK. Thus, the PMPC grafting on PEEK improved the antithrombogenicity.

DOI： 10.1002/jbm.a.34809

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FRONTIERS MEDIA SA  

We developed a microfibrous poly(L-lactic acid) (PLLA) nerve conduit with a three-layered structure to simultaneously enhance nerve regeneration and prevent adhesion of surrounding tissue. The inner layer was composed of PLLA microfiber containing 25% elastin-laminin mimetic protein (AG73-(VPGIG)30) that promotes neurite outgrowth. The thickest middle layer was constructed of pure PLLA microfibers that impart the large mechanical strength to the conduit. A 10% poly(ethylene glycol) was added to the outer layer to prevent the adhesion with the surrounding tissue. The AG73-(VPGIG)30 compositing of an elastin-like repetitive sequence (VPGIG)30 and a laminin-derived sequence (RKRLQVQLSIRT: AG73) was biosynthesized using Escherichia coli. The PLLA microfibrous conduits were fabricated using an electrospinning procedure. AG73-(VPGIG)30 was successfully mixed in the PLLA microfibers, and the PLLA/AG73-(VPGIG)30 microfibers were stable under physiological conditions. The PLLA/AG73-(VPGIG)30 microfibers enhanced adhesion and neurite outgrowth of PC12 cells. The electrospun microfibrous conduit with a three-layered structure was implanted for bridging a 2.0-cm gap in the tibial nerve of a rabbit. Two months after implantation, no adhesion of surrounding tissue was observed, and the action potential was slightly improved in the nerve conduit with the PLLA/AG73-(VPGIG)30 inner layer.

DOI： 10.3389/fchem.2014.00052

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

We propose a novel application of 2-methacryloyloxyethyl phosphorylcholine (MPC) polymers for enhancing the performance of modified segmented polyurethane (SPU) surfaces for the development of a small-diameter vascular prosthesis. The SPU membranes were modified by random-type, block-type, and graft-type MPC polymers that were prepared using a double-solution casting procedure on stainless steel substrates. Among these MPC polymers, the graft-type poly(MPC-graft-2-ethylhexyl methacrylate [EHMA]), which is composed of a poly(MPC) segment as the main chain and poly(EHMA) segments as side chains, indicated a higher stability on the SPU membrane after being peeled off from the stainless steel substrate, as well as after immersion in an aqueous medium. This stability was caused by the intermiscibility in the domain of the poly(EHMA) segments and the soft segments of the SPU membrane. Each SPU/MPC polymer membrane exhibited a dramatic suppression of protein adsorption from human plasma and endothelium cell adhesion. Based on these results, the performance of SPU/poly(MPC-graft-EHMA) tubings 2 mm in diameter as vascular prostheses was investigated. Even after blood was passed through the tubings for 2 min, the graft-type MPC polymers effectively protected the blood-contacting surfaces from thrombus formation. In summary, SPU modified by graft-type MPC polymers has the potential for practical application in the form of a non-endothelium, small-diameter vascular prosthesis.

DOI： 10.1080/09205063.2014.920172

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

To modify the surface properties of segmented polyurethane (SPU), effects of the molecular architecture of the 2-methacryloyloxyethyl phosphorylcholine (MPC) polymers on the performance of the SPU/MPC polymer membrane were investigated. We combined the random-type, block-type, and graft-type of the MPC polymers with a typical SPU, Tecoflex(®) using double solution casting procedure. The graft-type MPC polymers composed of a poly(MPC) main chain and poly(2-ethylhexyl methacrylate (EHMA)) side chains were synthesized through the combination of two different living radical polymerization techniques to regulate the density and chain length of the side chains. The SPU membranes modified with the MPC polymers were characterized using X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy. The results revealed that the MPC units were located on the SPU surface. Although the breaking strength of the SPU membranes modified with block-type poly(MPC-block-EHMA) and graft-type poly(MPC-graft-EHMA) was lower than that of SPU membranes modified with random-type poly(MPC-random-EHMA), their breaking strengths were adequate for manufacturing medical devices. On the other hand, better stability was observed in the MPC polymer layer on the SPU membrane after immersion in an aqueous medium, wherein the SPU membrane had been modified with the poly(MPC-graft-EHMA). This was because of the intermixing of the hydrophobic poly(EHMA) segments in the domain of the hard segments in the SPU membrane. After this modification, each SPU/MPC polymer membrane showed hydrophilic nature based on the MPC polymers and a dramatic suppression of protein adsorption. From these results, we concluded that the SPU membrane modified with the poly(MPC-graft-EHMA) was one of the promising polymeric biomaterials for making blood-contacting medical devices.

DOI： 10.1080/09205063.2013.873282

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

To evaluate the in vivo foreign body reaction to bio-inert 2-methacryloyloxyethyl phosphorylcholine (MPC) polymers, MPC polymer-coated porous substrates, with large surface area, were implanted subcutaneously in mice for 7 and 28 days, and the surrounding tissue response and cells infiltrating into the porous structure were evaluated. The MPC polymer surface induced low angiogenesis and thin encapsulation around the porous substrate, and slightly suppressed cell infiltration into the porous substrate. M1-type macrophage specific gene (CCR7) expression was suppressed by the MPC polymer surface after 7 days, resulting in the suppression of inflammatory cytokine/chemokine gene expression. However, the expression of these genes on the MPC polymer surface was higher than on the non-coated surface after 28 days. These findings suggest that MPC polymer surfaces successfully inhibit inflammatory responses during the early stage of tissue response, and seem to retard its occurrence over time.

DOI： 10.1080/09205063.2014.939917

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS LTD  

Four different dynamic biomaterial surfaces with different molecular architectures were prepared using two hydrophilic polymers: poly(ethylene glycol) and polyrotaxanes containing α-cyclodextrin. Either one or both terminals of the poly(ethylene glycol) or polyrotaxanes were immobilized onto a gold substrate via Au-S bonds, resulting in poly(ethylene glycol)-graft, polyrotaxanes-graft, poly(ethylene glycol)-loop, and polyrotaxanes-loop structures. Human platelet adhesion was suppressed more effectively on the graft surfaces than on the loop surfaces for both poly(ethylene glycol) and polyrotaxanes due to the high mobility of graft polymer chains with a free terminal. Moreover, the platelets adhered to the polyrotaxane surfaces much less than the poly(ethylene glycol) surfaces, possibly because of the mobile nature of the α-cyclodextrin molecules that were threaded on the poly(ethylene glycol) chain. Actin filament assembly in adherent platelets was also greatly prevented on the poly(ethylene glycol)/polyrotaxanes-graft surfaces in comparison with the corresponding loop surfaces. A clear correlation between the numbers and areas of adherent platelets on these surfaces suggests that platelet adhesion and activation were dominated by the platelet GPIIb/IIIa-adsorbed fibrinogen interaction. These results indicate that both of the different modes of dynamic features, sliding/rotation of α-cyclodextrin and polymer chain mobility, effectively suppressed platelet adhesion in spite of the similar hydrophilicity. This research affords a novel chemical strategy for designing hemocompatible biomaterial surfaces.

DOI： 10.1177/0885328212462260

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Tissue adhesions cause severe and life-threatening conditions, including pain, infertility, and heart defects. The purpose of this study is to develop an anti-adhesion membrane that sticks onto the injured tissues or organs in order to avoid the suturing of the membrane which may lead to the unnecessary tissue adhesion. We previously developed poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) multiblock copolymers as soft, water absorbable, and quickly degradable biomaterials. The copolymer with the highest PEG content adsorbs body fluid in vivo and sticks to the tissues. In the present study thin film and nanofiber mat were prepared from the copolymer and evaluated in vitro and in vivo. The hydrophilicity and the degradation rate increased with the increased PEG content of the multiblock copolymers. The copolymer with PEG content of 88% (LE(m)-88) was quickly swollen, become viscous, and rapidly collapsed in PBS, which was suitable feature for adhesion prevention material without suturing. Various double layered membranes with different characteristics were evaluated in vivo by applying onto the cecum scrubbed with abrasive paper, and onto the heart surface after pericardium removal. LE(m)-88 was swollen with tissue fluid and had a hydrogel-like nature. LE(m)-88 film/LE(m)-32 film double layered membrane was found to be the most effective in preventing tissue adhesion in cecum model. This excellent performance was confirmed in the rat heart adhesion model. In both models, the LE(m)-32 support film was detached from the site of application, which leads to the healing without adhesion. (C) 2013 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.polymdegradstab.2013.08.026

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

The rapid response of integrin β1 molecules to an RGD peptide on a dynamic polyrotaxane surface was successfully induced. As a result, RGD peptides introduced on a highly dynamic cyclodextrin molecule enhanced the frequency of contact with specific integrin molecules on the cell membrane at the early stage of material-cell interactions.

DOI： 10.1021/ja400817q

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The effects of the hydrated molecular mobility and the surface free energy of polymer surfaces on fibronectin adsorption and fibroblast adhesion were investigated. ABA-type block copolymers composed of polyrotaxane (PRX) with different number of threaded α-cyclodextrin (α-CD), random copolymers with similar chemical composition to the PRX block copolymers, and conventional polymers were prepared to determine a wide range of hydrated molecular mobility (Mf) values estimated by quartz crystal microbalance-dissipation (QCM-D) measurements. Fibronectin adsorption was highly dependent on surface free energy, and high surface fibronectin density resulted in a large projected cell area on the polymer surfaces. However, the morphology of adhering fibroblasts was not explained by the surface free energy, but it was found to be strongly dependent on the Mf values of the polymer surfaces in aqueous media. These results emphasize the importance of Mf in the discussion of the elongated morphology of adhering fibroblasts on various polymer surfaces.

DOI： 10.1016/j.biomaterials.2013.01.080

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：TRANS TECH PUBLICATIONS LTD  

Immobilizing bioactive molecules on the materials surfaces is one of the main strategies for creating functional bio-interfaces. In these kinds of bio-interfaces, the density of immobilized functional groups and the following physicochemical factors such as roughness, polarity and electrical charge have been thought important variables for regulating biological responses such as cell adhesion and differentiations. Here in this study, differences between rigidity and dynamically immobilized bioactive molecules on the biological responses will be discussed. In order to develop dynamic bio-interfaces, a polyrotaxane based block-copolymer containing clickable azide groups for conjugating various bioactive molecules was designed. Cell adhesive RGD peptide was then conjugated with the azide group by click reaction on both dynamic and rigid surfaces. As a result, cell adhesive RGD peptide immobilized on the dynamic bio-interfaces shows larger initial cell adhesion area, indicating that molecular dynamics of surface chemical groups is another important variable for the regulation of biological responses.

DOI： 10.4028/www.scientific.net/AST.86.59

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHARMACEUTICAL SOC JAPAN  

MicroRNAs (miRNAs) are endogenous small RNAs that are 18-23 nucleotides long. Recently, plasma miRNAs were reported to be sensitive and specific biomarkers of various pathological conditions. In the present study, we focused on miR-210, which is known to be induced by hypoxia and might therefore be an excellent biomarker for congestive heart failure. Plasma miR-210 levels and expression levels in mononuclear cells and skeletal muscles were elevated in Dahl salt-sensitive rats with heart failure. We also assessed miR-210 expression in patients with heart failure. The miR-210 expression levels in the mononuclear cells of patients with NYHA III and IV heart failure according to the New York Heart Association (NYHA) functional classification system were significantly higher than those with NYHA II heart failure and controls. Although no significant correlation was observed between plasma brain natriuretic peptide (BNP) and plasma miR-210 levels in patients with NYHA II heart failure, patients with an improved BNP profile at the subsequent hospital visit were classified in a subgroup of patients with low plasma miR-210 levels. Plasma miR-210 levels may reflect a mismatch between the pump function of the heart and oxygen demand in the peripheral tissues, and be a new biomarker for chronic heart failure in addition to plasma BNP concentrations.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

Adhesion behaviors of human umbilical vein endothelial cells (HUVECs) are interestingly affected by the mobility of hydrophilic chains on the material surfaces. Surfaces with different molecular mobilities were prepared using ABA-type block copolymers consisting polyrotaxane (PRX) or poly(ethylene glycol) (PEG) central block (A block), and amphiphilic anchoring B blocks of poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) (PMB). Two different molecular mobilities of the PRX chains were designed by using normal α-cyclodextrin (α-CD) or α-CD whose hydroxyl groups were converted to methoxy groups in a given ratio to improve its molecular mobility (PRX-PMB and OMe-PRX-PMB). The surface mobility of these materials was assessed as the mobility factor (Mf), which is measured by quartz crystal microbalance with dissipation monitoring system. HUVECs adhered on OMe-PRX-PMB surface much more than PRX-PMB and PMB-block-PEG-block-PMB (PEG-PMB) surfaces. These different HUVEC adhesions were correlated with the density of cell-binding site of adsorbed fibronectin. In addition, the alignment of the actin cytoskeleton of adhered HUVECs was strongly suppressed on the PEG-PMB, PRX-PMB, and OMe-PRX-PMB in response to the increased Mf value. Remarkably, the HUVECs adhered on the OMe-PRX-PMB surface with much less actin organization. We concluded that not only the cell adhesion but also the cellular function are regulated by the molecular mobility of the outmost material surfaces.

DOI： 10.1080/09205063.2012.757726

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL SOC CHEMISTRY  

ABA block copolymers composed of highly methylated polyrotaxane and hydrophobic anchoring terminal segments containing 2-methacryloyloxyethyl phosphorylcholine (MPC) and n-butyl methacrylate (PMB) (OMe-PRX-PMB) were synthesized as a platform of molecularly dynamic biomaterials. A contact angle measurement indicated that polymer surfaces with higher molecular mobility factors (M-f) estimated from quartz crystal microbalance with dissipation (QCM-D) measurements showed more significant changes in hydrophilicity in response to an environmental change between air and water; the OMe-PRX-PMB surface showed the highest M-f among the prepared polymer surfaces. Fibrinogen adsorption and its conformational analysis estimated by QCM-D and enzyme-linked immunosorbent assay revealed that large amounts of fibrinogen adsorption occurred in a soft manner on the OMe-PRX-PMB surface and that the antibody binding to the C-terminus of the fibrinogen gamma chains responsible for platelet adhesion and activation decreased as the M-f value increased. Furthermore, it was found that the OMe-PRX-PMB surface showed low platelet adhesion and high fibroblast adhesion, suggesting that molecular movement on biomaterial surfaces could be one of the key parameters in the regulation of a non-specific biological response.

DOI： 10.1039/c2sm25318f

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

In some traumatic nerve injuries, autologous nerve grafting is the first choice for bridging the gap between the severed nerve ends. However, this therapeutic strategy has some disadvantages, including permanent loss of donor function and requirement of multiple surgeries. An attractive alternative to this therapeutic technique is the use of artificial nerve conduit. Poly (L-lactic acid) (PLLA) is widely used as a substrate for artificial nerve conduit because it is readily biodegradable, but it is not inherently biologically active. In this study, we developed a PLLA nanofibrous nerve conduit, modified with a conjugate of oligo (D-lactic acid) (ODLA) and the neurite outgrowth, thereby promoting peptide AG73 (RKRLQVQLSIRT) to improve nerve regeneration. PLA/ODLA-AG73 nanofibrous conduit was fabricated by electrospinning and then transplanted at the 10 mm gap of rat sciatic nerve. After six months, electrophysiological evaluation revealed that it achieved better functional reinnervation than silicone tube (used as a reference) or unmodified PLLA nanofibrous conduit.

DOI： 10.3390/polym3020820

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Surface modification of poly(dl-lactic acid) (PLA) scaffolds has been performed using a biofunctional small peptide composed of collagen-like repetitive sequence and laminin-derived sequence (AG73-G(3)-(PPG)(5)) via hydrophobic interaction. The results of surface analysis suggest that AG73-G(3)-(PPG)(5) can be stably adsorbed onto PLA films via hydrophobic interaction at the (PPG)(5) region, and form an extracellular matrix-like layer composed of both structural and biosignalling sequences. In addition, neurite outgrowth of PC12 cells was observed on the AG73-G(3)-(PPG)(5)-adsorbed PLA film. These results indicate that AG73-G(3)-(PPG)(5) very effectively enhances neurite outgrowth activity on PLA films. The hydrophobic adsorption of collagen-like peptide bound to biosignalling molecules may be widely applied as a surface modifier of PLA films for tissue engineering.

DOI： 10.1016/j.actbio.2009.12.001

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TNP-470 (AGM-1470, O-(chloroacetylcarbamoyl) fumagillol), which strongly inhibits the angiogenesis, is promising as a new drug for tumor dormancy therapy; however, TNP-470 is very unstable in vitro and in vivo. We previously prepared TNP-470 containing microspheres composed of poly (lactic acid) with medium-chain triglyceride, and demonstrated that the microspheres released TNP-470 over the long-term in vitro. The present study was undertaken to evaluate the release profile of TNP-470 in vivo and the inhibitory effect on hepatic metastasis of neuroblastoma. It was found that the microspheres could maintain high levels of TNP-470 in the blood plasma for over 4 weeks in vivo. In addition, hepatic metastasis of neuroblastoma was strongly inhibited at 2 weeks after intraperitoneal injection of the microspheres. Following 2 weeks of treatment, the liver weights of mice injected with TNP-DDS (TNP-DDS (H), and TNP-DDS (L) groups) and those injected with only physiological saline (C-1300 group) after implantation of neuroblastoma cells were 1.18+/-0.13g, 1.28+/-0.10g, and 2.54+/-0.97g, respectively (p<0.05; C-1300 group compared with the TNP-DDS (H) and the TNP-DDS (L) groups, respectively). It was evident that microspheres containing TNP-470 have an excellent potential for clinical application in tumor dormancy therapy.

DOI： 10.1016/j.pathophys.2009.04.003

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Our group has developed a novel tissue adhesive composed of biomacromolecules and organic acid derivatives which have good biocompatibility and exhibit high bonding strength to living tissues. We propose to use this tissue adhesive for in-situ forming drug delivery system (DDS) for cancer chemotherapy. In a previous work, we had prepared a novel in-situ forming DDS composed of human serum albumin (HSA) and tartaric acid derivative (TAD) containing doxorubicin hydrochloride (DOX), and we had demonstrated an in vitro release profile of DOX from HSA-TAD gel for approximately up to 100h. Here, we report on antitumor effect of this injectable in-situ forming DDS. Local injection of DOX by the HSA-TAD was administered to human colon carcinoma (WiDr) implanted subcutaneously onto the immunodeficient mouse. The results of the in vivo experiments showed that the presence of DOX in blood of mice was detectable for up to 3days, and that the tumor volume was effectively minimized with injection of HSA-TAD containing DOX. The in-situ forming DDS with the novel tissue adhesive containing DOX, therefore, is a useful technique for cancer chemotherapy.

DOI： 10.1016/j.ejpb.2007.03.020

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Injectable polymers that are biocompatible and biodegradable are important biomaterials for drug delivery system (DDS) and tissue engineering. We have already developed novel tissue adhesives consisting of biomacromolecules and organic acid derivatives with active ester groups. The resulting tissue adhesive forms in situ as a gel and has high bonding strength for living tissue as well as it has good biocompatibility and biodegradability. Here, we report on the physicochemical properties and in vitro evaluation of this novel tissue adhesive consisting of human serum albumin (HSA) and tartaric acid derivative (TAD) containing doxorubicin hydrochloride (DOX). The results of the measurement of physicochemical characteristics indicate that the gelation time and gel strength of HSA-TAD gels can be controlled according to the material composition. The bonding strength of HSA-TAD adhesives was found to be sufficient to adhere at focus and to correspond with the cross-linking density of HSA-TAD gels. Furthermore, the release of DOX from HSA-TAD gels was sustained for approximately 100 h in an in vitro evaluation. The novel tissue adhesive, therefore, is expected to be applicable for use as an injectable in situ forming DDS.

DOI： 10.1016/j.ejpb.2006.11.022

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SCIENTIFIC PUBLISHERS  

A novel glue consisting of human serum albumin (HSA) and citric acid derivative (CAD) was developed where the glue is named as CAD-A glue. In this adhesive, CAD works as a crosslinking reagent of HSA. For preparing crosslinking reagent CAD, using citric acid as a starting material, three carboxyl groups of a citric acid were modified with N-hydroxysuccinimide in the presence of 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride. From 1H-NMR spectrum, CAD with three active ester groups in a molecule was successfully synthesized with a high yield (more than 80%). The boding time of CAD-A glue to collagen-based casing was saturated within 15 minutes. The bonding strength of this glue to collagen-based casings increased with increasing of HSA concentration. The maximum bonding strength of CAD-A glue was a slightly low level compared to the bonding strength of cyanoacrylate adhesive and was 9 times higher than that of fibrin glue. The CAD-A glue showed excellent biocompatibility and high ability of wound closure similar to that of cyanoacrylate-based adhesive when glues were applied to the mouse skin. These results suggested that this developed adhesive had both tissue compatibility and bonding strength for use in clinical field.

DOI： 10.1166/jnn.2007.515

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Poly(proline) and random copolypeptide composed of Pro and Ala residues were synthesized, and their solution properties and molecular conformation were investigated. Aqueous solutions of the polypeptide were irradiated with gamma-rays above the transition temperature. It was shown that the transition temperature of the aqueous solution of the copolypeptide is influenced by Ala-residue content and gamma-ray irradiation.

DOI： 10.1007/s00289-006-0666-4

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：TRANS TECH PUBLICATIONS LTD  

A biocompatible glue consisting of human serum albumin (HSA) and citric acid derivative (CAD), named CAD-A glue was developed. CAD was successfully synthesized by the reaction between citric acid and N-hydroxysuccinimide in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride. When the CAD-A glue was applied to the collagen-based casings, it took 7 min to obtain half of maximum bonding strength (760 g/cm2). The bonding strength of this glue to collagen-based casings increased with increasing of HSA concentration. The bonding strength of CAD-A glue increased with increasing CAD concentration up to 200 mM, and then decreased with increasing CAD concentration under the fixed HSA concentration (50 w/w%). The CAD-A glue showed excellent wound closure ability rather than fibrin glue when applied to the mouse skin. These results suggested that this developed glue had both tissue compatibility and bonding strength for use in clinical field.

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Language：Japanese   Publishing type：Research paper (international conference proceedings)  

Recently, percutaneous coronary intervention (PCI) with percutaneous transluminal coronary angioplasty (PICA) is widely used for the ischemic heart diseases. Coronary artery metal stents, especially, represent one of the latest treatments in the field of interventional cardiology. However, in-stent restenosis occurs in 15 ∼ 40 % patients. Therefore, drug-eluting stents (DES) have been applied to many patents, because this device can improve the in-stent restenosis compared with bare-metal stent. However, non-biodegradable polymers or polymers with low degradation rate have been employed in DES. In this report, we attempted to modify the SUS316 surface in order to conduct amino groups, and to immobilize the biocompatible polymer matrix. Results of the measurement of contact angle and XPS spectrum indicated that amino groups were effectively introduced on the surface of SUS316 with γ-APS and condensation of lysine residues. Furthermore, we succeeded in the coating of HSA-TAD matrix uniformly on the modified SUS316.

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In order to investigate the chain-length dependence of conformational property of (Pro)n were synthesized by solid-phase procedure. Their conformations were analyzed by CD measurements in water and in trifluoroethanol. It was shown that polyproline-II conformation is stable conformation in water and trifuluoroethnol, and also that its stability increases with number of proline residues in both solvents. Moreover, the differential CD spectra indicated that the poly(proline) forms fluctuated polyproline-II conformation in the N- and C-terminal portions, but that it forms stable polyproline-II one at the central portion for n ≧ 12.

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Conformational transition from polyproline-II to polyproline-I was analyzed by CD measurements for the poly(proline)s whose number of residues 13 in various alcohols. Then, the activation enthalpy (ΔH‡) and activation entropy(ΔS‡)for each system was estimated by the first-order reaction mechanism. It was shown that ΔH‡ decreases with an increase in number of carbon atom of alcohols, and also that ΔH‡ in 2-alcohols is less than in 1-alcohols. Moreover, it was also shown that ΔS‡ decreases with an increase in number of carbon atom of alcohols, and also that ΔS‡ in 2-alcohols is less than in 1-alcohols.These results would provide interesting information on the pathway-mechanism relating to the cis-trans isomerism at the Xaa-Pro peptide bond in protein folding.

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We have developed the novel tissue adhesives consisting of biomacromolecules and organic acid derivatives with active ester groups as cross-linking reagents. The bonding strength and compatibility of this tissue adhesive to soft tissues were superior to that of clinically-available tissue adhesives. In this report, in situ forming injectable drug delivery system (DDS) containing antitumor agent has been prepared using the novel tissue adhesives. In order to demonstrate the fundamental characteristics of the DDS conjugated with antitumor agent, doxorubicin hydrochloride (DOX), the measurement of physicochemical properties and in vitro eluting test of DOX were performed. It was possible to control the physicochemical characteristics and the release of antitumor agent by changing the composition of carrier, and to realize the local release because of the good bonding strength to living-tissue. The in situ forming injectable DDS composed of the novel tissue adhesive, thus, is expected to apply in the clinical medicine as minimum invasive cancer chemotherapy.

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In order to investigate the effect of a successive Ala residue on the conformational property of the proline-rich block polypeptide, Pro6-Ala3-Pro6 and Pro6-Ala5-Pro6 were synthesized, and their conformations were analyzed by CD measurement. The CD spectra of these polypeptides showed that they would separately form polyproline-II conformation in the both sides of the central Ala-block portion, that is, they would not form a straight-rod like polyproline-II conformation. It is also supposed that the Ala-block portion would form disordered conformations in water, and also that it would locally form the type I β -bend or α -helical conformation in TFE.

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Conformational transition from polyproline-II to polyproline-I was analyzed by CD measurements for the poly(proline)s whose number of residues 13 and 8 in various alcohols. Then, the activation enthalpy(ΔH ‡) for each system was estimated by Arrhenius plot. It was shown that ΔH ‡ decreases with an increase in number of carbon atom of alcohols, and also that ΔH ‡ in 2-alcohols is less than in 1-alcohols. Moreover, It was shown that ΔH ‡ decreases with an increase in number of residue of poly(proline). These results would provide interesting information on the pathway-mechanism relating to the cis-trans isomerism at the Xaa-Pro peptide bond in protein folding.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Several types of poly(Gly-co-Pro) and poly(Ala-co-Pro) were synthesized. Their molecular conformations and thermosensitive properties were investigated in an attempt to find new thermosensitive materials. These polypeptides were assumed the polyproline-II structure in the temperature range of 20 to 80 degrees C. They also exhibited cloud points in light transmittance, indicating the phase transition. The transition temperatures increased with decrease in hydrophobicity of the polypeptides, that is, in the order poly(proline), poly(Ala-co-Pro) and poly(Gly-co-Pro).

DOI： 10.1007/s00289-005-0384-3

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Proline oligopeptides composed of 13, 6 and 4 Pro residues were synthesized by solid-phase procedure. The circular dichroism spectra showed that the proline oligopeptides form the polyproline-II helix in water and in trifluoroethnol. However, it was shown that the oligopeptide composed of 13 Pro residues remarkably presents conformational transition from the polyproline-II to the polyproline-I helix in methanol and 1-propanol. This result is the first spectrum evidence that proline oligopeptides can form the polyproline-I helix in pure aliphatic alcohol such as methanol and 1-propanol. It was also shown that the propensity forming polyproline-I helix is more favorable in 1-propanol than in methanol, and also that the longer the chain-length is, the greater the stability of the polyproline-I helix is. Such a chain-length dependency of the conformational stability is also supported by the theoretical calculation using molecular mechanics.

DOI： 10.1007/s00289-004-0317-6

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In order to investigate the effect of a (Ala)n sequence on the conformational property of the proline-rich block oligopeptide, (Pro)5-(Ala)3-(Pro)5 (P5A3P5), (Pro)4-(Ala)5-(Pro)4 (P4A5P4) and (Pro)3-(Ala)6-(Pro)4 (P3A6P4) were synthesized, and their conformations were analyzed by CD measurement, molecular mechanics and molecular dynamics calculations. It was shown that two proline-block-sequences would separately form polyproline-II conformation. That is, block copoly peptides would not form a straight-rod like polyproline-II conformation, but form a hairpin-like structure composed of the packing of two PPII conformation (PPII-hairpin structure).

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Theoretical conformation analysis was carried out for poly(Lys-Pro-Ala), poly(Ala-Pro-Lys) and poly(Lys-Pro-Lys). All conformational energy calculations were carried out with the energy function of ECEPP and Powell minimization procedure. All combinations of the single-residue minima of Pro, Lys and Ala residues were selected as starting conformations. A left-handed β 13.7-helix and a left-handed β 14.2-helix werw obtained as the lowest-energy conformation for poly(Lys-Pro-Ala) and poly(Ala-Pro-Lys). A right-handed β 13.6-helix was obtained as the lowest-energy conformation for poly(Lys-Pro-Lys). The Lys side-chains are exposed to the outside of helix, and do not contribute to stabilize the helical conformation.

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In order to investigate the conformational character of the proline-rich block oligopeptides which have a successive Ala residues in the interior of two successive Pro sequence, the proline-rich block oligopeptides were synthesized, and their conformations were analyzed by CD and NMR measurements and by molecular mechanics and molecular dynamics calculations. The change of CD spectra of these polypeptides showed that they would separately form polyproline-II conformation in the both sides of the central Ala residue, that is, they would not form a straight-rod like polyproline-II conformation. Theoretical results indicated that the proline-rich block oligopeptides form a hairpin-like structure composed of the packing of two PPII conformation (PPII-hairpin structure).

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Poly(proline)s composed of 13, 6 and 4 residues(abbreviated as P13, P6 and P4, respectively) were synthesized, and their conformations were analyzed by CD measurement, molecular mechanics and molecular dynamics calculations. It was shown that relative stability of polyproline-I(PPI) and polyproline-II(PPII) conformations depends on the solvents and number of proline residue. The conformational transition from PPII conformation to PPI conformation was found in pure alcohols such as methanol, 1-propanol and 2-propanol. The transition enthalpy was also estimated in such solvent systems. The experimental results were supported by the theoretical results. It was also theoretically shown that PPII conformation is relaxed conformation fluctuated around the standard conformation.

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Theoretical conformation analysis was carried out for poly(Ile-Pro-Ala) and poly(Ala-Pro-Ile). All conformational energy calculations were carried out with the energy function of ECEPP and Powell minimization procedure. All combinations of the single-residue minima of He, Ala and Pro residues were selected as starting conformations. A right-handed β 13.3-helix was obtained as the lowest-energy conformation for poly(Ile-Pro-Ala). Conformational character of poly(Ile-Pro-Ala) is analogous to that of poly(Val-Pro-Ala), but is different from that of poly(Ilu-Pro-Ala). A left-handed β 12.1-helix was obtained as the lowest-energy conformation for poly(Ala-Pro-Ile). Conformational character of poly(Ala-Pro-Ile) is analogous to that of poly(Ala-Pro-Val), but is different from that of poly(Ala-Pro-Leu). These results indicate that stable helical conformations of periodic polypeptides significantly depend on their repetitive amino-acid sequences.

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We tried condensation polymerization using alanine and proline as monomer amino-acid, and the thermoresponsive properties of their solutions were investigated from the viewpoint of irradiation effects. Synthesized proline-rich copolypeptides composed of Ala and Pro residues represented the CD spectrum which resembles that of polyproline-II conformation, and also exhibited thermo-responsive property in aqueous solution state. It was shown that the transition temperature of polypeptide increased with the Ala content, and also that γ-irradiation effect appeared in different manner for each polypeptide.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Stimuli-responsive polyampholyte hydrogels were synthesized by the copolymerization of dimethylaminoethyl methacrylate (DMAA) and acrylic acid (AAc) or itaconic acid (IAc) by UV-irradiation. Temperature and pH responsiveness of these hydrogels were studied. The temperature responsiveness of poly-(DMAA-co-AAc, lAc) hydrogels shown in change of water content became dull compared to that of DMAA homo-polymer hydrogel. The water content of the poly-(DMAA-co-AAc, IAc) hydrogels showed a minimum at pH 8, and increased in more acidic and alkaline regions. This fact can be attributed to the coexistence of anions and cations in the poly-(DMAA-co-AAc, lAc) hydrogels. The poly-(DMAA-co-AAc, IAc) hydrogels were polyampholyte having both temperature responsiveness and pH responsiveness. (C) 2002 Elsevier Science Ltd. All rights reserved.

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TNP-470 (AGM-1470, 6-0-(N-chloroacetylcarbamoyl)-fumagillol), a derivative of fumagillin, is a promising angiogenesis inhibitor. However, as TNP-470 is very unstable in in vitro and in vivo, it has been difficult to verify its pharmacological efficacy in the clinical medicine. The preparation of a drug delivery system (DDS) in a microsphere form was studied for the stable inclusion and controlled release of TNP-470. Medium-chain triglyceride (MCTG) as an effective stabilizer and poly-lactic acid (PLA) as a biodegradable carrier were used for this purpose. The release of TNP-470 from the MCTG containing DDS continued for approximately 2 weeks, while the release of TNP-470 from the one without MCTG stopped after only 5 days. It was proved that TNP-470 could be released much more stable for much longer period from the MCTG containing DDS compared to the one without DDS.

DOI： 10.1016/S0939-6411(02)00156-X

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

A drug delivery system (DDS) consisting of lipopolysaccharide (LPS) as a drug and 2-hydroxyethyl methacrylate (HEMA)-diethylene glycol dimethacrylate (2G) or -polyethylene glycol dimethacrylate (4G, 9G) copolymer was prepared, and used for the efficient preparation of an experimental animal model of chronic hyper-endotoxemia. The release profiles of LPS in the in-vitro test were greatly influenced by the composition of HEMA-2G, 4G, 9G in the copolymer. It was found that LPS release from the DDS continued gradually and constantly throughout 2 weeks. In the in-vivo experiment with rats, the DDS maintained a high blood concentration level of LYS for 3 days. These results strongly suggest the possibility of convenient and reproducible preparation of a chronic hyper-endotoxemia animal model. (C) 2001 Elsevier Science BY All rights reserved.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER-VERLAG  

There has not: been an ideal reproducible small-animal model of chronic hyperendotoxemia to date. Our drug delivery system (DDS) is a new technology that call deliver a drug conveniently to a target organ at an optional rate. 2-Hydroxyethyl methacrylate (HEMA) was used as a carrier of lipopolysaccharide (LPS), and diethylene glycol and polyethylene glycol dimethacrylates (2G, 4G, 9G) were used as cross-linking agents. A mixed solution of HEMA and di(poly)ethylene glycol dimethacrylate was charged into a glass tube with or without LPS and polymerized by ultraviolet irradiation. This polymer was cut into DDS tablets of the same size with or without LPS. A mixture with HEMA:4G = 1:3 was the most suitable composition to release a constant concentration of LPS. We also developed a novel rat model of chronic hyperendotoxemia. Four DDS tablets, each containing 15 mg LPS, were implanted into the abdominal cavity of rats in the LPS group. The control group was implanted with four DDS tablets without: LPS. Plasma levels of LPS in the study group were maintained at more than 2,000 pg/ml for 72 h after implantation. Weight gain was lower and body temperature was higher in the LPS group than in the control group. Plasma levels of inter leukin (IL)-6 in the LPS group were higher than in the control group only during the initial 12 h after implantation of DDS tablets. The white blood cell count at 24 h and platelet counts at 24, 48, and 72 h in the LPS group were lower than these in the control group. These results indicate that chronic hyperendotoxemia was maintained for 72 h by continuous release of LPS from the DDS. Moreover, the intensity of endotoxemia could be varied by varying the number of DDS tablets. It is concluded that our new rat model using LPS-DDS will be applicable and useful as a model of chronic hyperendotoxemia.

Web of Science

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Language：Japanese   Publisher：SOC FIBER SCIENCE TECHNOLOGY  

DOI： 10.2115/fiber.68.P_314

Web of Science

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Language：Japanese  

CiNii Books

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER CHEMICAL SOC  

Web of Science

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J-GLOBAL

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Language：Japanese  

CiNii Books

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Language：Japanese  

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2011326319

Language：English  

CiNii Books

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Language：English  

CiNii Books

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Language：English  

CiNii Books

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Language：English  

CiNii Books

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Language：English  

CiNii Books

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J-GLOBAL

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Language：Japanese   Publisher：化学工業社  

CiNii Books

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：MARY ANN LIEBERT INC  

Web of Science

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：MARY ANN LIEBERT INC  

Web of Science

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Language：English  

CiNii Books

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Language：English  

CiNii Books

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Language：English  

CiNii Books

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Language：Japanese   Publisher：一般社団法人日本外科学会  

CiNii Books

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Language：Japanese   Publisher：一般社団法人日本外科学会  

CiNii Books

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Event date： 2012.7

Venue：Singapore  

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Event date： 2012.6

Venue：Chendgu, China  

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Event date： 2012.6

Venue：Chendgu, China  

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Event date： 2012.3

Venue：Tsukuba, Japan  

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Event date： 2011.12

Venue：Delhi, India  

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Event date： 2011.9

Venue：Busan, Korea  

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Event date： 2011.9

Venue：Busan, Korea  

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Event date： 2011.4

Venue：Orlando, Florida, USA  

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Event date： 2011.4

Venue：Orlando, Florida, USA  

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Event date： 2010.12

Venue：Kyoto, Japan  

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Event date： 2009.11

Venue：Tokyo, Japan  

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Event date： 2009.5

Venue：Mishima, Japan  

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Event date： 2008.12

Venue：San Diego, USA  

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Event date： 2007.12

Venue：Tsukuba, Japan  

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Event date： 2006.11

Venue：Okinawa, Japan  

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Event date： 2006.6

Venue：Capri, Italy  

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Event date： 2005.12

Venue：Honolulu, USA  

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Event date： 2005.10

Venue：Shanghai, China  

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Applicant：独立行政法人物質・材料研究機構

Application no：特願2006-160776  Date applied：2006.6

Announcement no：特開2007-325824  Date announced：2007.12

J-GLOBAL

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Applicant：独立行政法人物質・材料研究機構

Application no：特願2005-306815  Date applied：2005.10

Announcement no：特開2007-111300  Date announced：2007.5

J-GLOBAL

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Applicant：独立行政法人物質・材料研究機構, フルウチ化学株式会社

Application no：特願2005-174414  Date applied：2005.6

Announcement no：特開2006-346049  Date announced：2006.12

J-GLOBAL

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