医療高分子が血液などの生体成分に接触すると、異物反応が進行し不具合が生じる。病気の治療や超早期診断など、高齢社会においてニーズの大きい健康・医療技術や製品の開発には、製品性能を決定付ける製品の表面を形成する医療高分子の安全性と機能の向上が欠かせない。
受賞者らは、合成高分子であるpoly(2-methoxyethyl acrylate)（PMEA）が、中間水（材料表面に緩やかに結合した水分子）を豊富に含む材料表面を作り出し、この中間水がタンパク質や細胞などの吸着を防ぐことを示してきた。PMEAコーティング技術は、研究支援機器、医療機器として実用化され、厚生労働省の認可を受けている。例えば、PMEAコーティング人工心肺は世界No.1のシェアを取り続けているなど、我が国発の世界に誇る実績を有している。これにより、我が国の研究開発総合力のプレゼンス向上に貢献した。
一般に、合成高分子が生体に接触すると、直ちに水分子が材料表面に吸着する。吸着した水分子は、以下の2種類に分けられる。材料に強く結合し分子運動性が低下した不凍水と材料に弱く結合し分子運動性が高い自由水である。さらに、自由水と不凍水の中間的な性質を示す中間水が形成される。この中間水が生体親和性の発現に大きな影響を与えることが明らかにし、中間水に着目した生体親和性材料のスクリーニングにつながる「中間水コンセプト」を世界で初めて見出した。この中間水は、生体親和性を示す合成高分子と生体分子に共通して観測されることを見出した（図１）。
また、受賞者らは、独自に設計したPMEA誘導体により適切な中間水量を与えると、血球細胞などの血栓を作る生体成分の吸着は抑制されたまま、がん細胞が選択的に接着することを見出し、基本特許を取得した。がん細胞をダメージレスに分離回収可能なので、分離回収した癌細胞を培養し、抗がん剤の評価が可能となった。受賞者らが見出した合成高分子への生体成分の吸着性を制御可能な中間水のコンセプトは、新世代医療高分子開発に大きく貢献した。

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

Stem cell differentiation is an important issue in regenerative medicine and tissue engineering. It has been reported that cell shape is one of the factors that determine the lineage commitment of mesenchymal stem cells (MSCs). Therefore, the substrates have been developed to control their shapes. Recently, we found that poly(2-methoxyethyl acrylate) (PMEA) analogs can control tumor cell shape through the alteration of protein adsorption. Here, the adipogenesis of an adipocyte-progenitor cell, 3T3-L1 cells, was attempted; adipogenesis was to be regulated by surfaces coated with PMEA analogs through the control of their shape. The adipogenesis of 3T3-L1 cells was promoted on the surfaces coated with PMEA and its analogs, PMe3A and PMe2A. Evident focal adhesions were hardly observed on these surfaces, suggesting that integrin signal activation was suppressed. Additionally, actin assembly and cell spreading were suppressed on these surfaces. Therefore, the surfaces coated with PMEA analogs are expected to be suitable surfaces to regulate adipogenesis through the suppression of cell spreading. Additionally, we found that protein adsorption correlated with actin assembly and adipogenesis.

DOI： 10.1021/acs.biomac.6b01340

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

Highly regio-/stereoregular (trans-head-to-tail) polymers with amide side chains on every eighth backbone carbon were successfully synthesized by ring-opening metathesis polymerization (ROMP) of 3-substituted cis-cyclooctene (3RCOE) using Grubbs second-generation catalyst (G2). Regioregular linear ethylene-acrylamide copolymers were also prepared via hydrogenation of the obtained poly(3RCOE)s. The thermal properties and solubility of the obtained polymers were strongly influenced by the presence of amide hydrogen in the side chains, the presence of unsaturated bonds in the carbon backbone, and the side chain density. The presence of amide hydrogen in the side chains resulted in the formation of crystalline polymers and the lack of solubility of these polymers in common organic solvents. In contrast, the absence of amide hydrogen in the side chains led to the formation of amorphous polymers exhibiting good solubility in common organic solvents, and decreasing values of T_g were observed for amorphous polymers as a result of the saturation of double bonds in the backbone via hydrogenation.

DOI： 10.1021/acs.macromol.6b01829

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Allyl-substituted cyclooctenes with ether side-chains [methoxy, methoxy-terminated oligo(ethylene glycol)s, and tetrahydrofurfuryloxy group] were prepared as monomers and polymerized by ring-opening metathesis polymerization (ROMP) using Grubbs second-generation catalyst. In all cases, the ROMP of allyl-substituted monomers proceeded in a regio- and stereoselective manner to afford polymers with remarkably high head-to-tail regioregularity with high trans-stereoregularity. The regio- and stereoregularity of polymers were affected by the bulkiness of the substituent, and the ROMP of tetrahydrofurfuryloxy-substituted cyclooctene exhibited nearly perfect regio- (head-to-tail = 99%) and stereoselectivity (trans-double bond = 99%). Chemical hydrogenation of obtained polymers afforded model poly(ethylene-co-vinyl ether)s with precisely placed ether branches on every eighth backbone carbon. Differential scanning calorimetry (DSC) was used to study the thermal properties, and the hydrophilicity of polymers was evaluated by water contact angle measurement. The surface hydrophilicity of unsaturated polymers was effectively tuned by changing the side-chain length of oligo(ethylene glycol) groups while maintaining the hydrophobic character unchanged for saturated versions.

DOI： 10.1021/acs.macromol.6b00273

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The development of bioartificial liver (BAL) is expected because of the shortage of donor liver for transplantation. The substrates for BAL require the following criteria: (a) blood compatibility, (b) hepatocyte adhesiveness, and (c) the ability to maintain hepatocyte-specific functions. Here, we examined blood-compatible poly(2-methoxyethyl acrylate) (PMEA) and poly(tetrahydrofurfuryl acrylate) (PTHFA) (PTHFA) as the substrates for BAL. HepG2, a human hepatocyte model, could adhere on PMEA and PTHFA substrates. The spreading of HepG2 cells was suppressed on PMEA substrates because integrin contribution to cell adhesion on PMEA substrate was low and integrin signaling was not sufficiently activated. Hepatocyte-specific gene expression in HepG2 cells increased on PMEA substrate, whereas the expression decreased on PTHFA substrates due to the nuclear localization of Yes-associated protein (YAP). These results indicate that blood-compatible PMEA is suitable for BAL substrate. Also, PMEA is expected to be used to regulate cell functions for blood-contacting tissue engineering.

DOI： 10.1021/acsami.5b05210

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Intercorrelation among surface chemical composition, packing structure of molecules, water contact angles, amounts and structures of adsorbed proteins, and blood compatibility was systematically investigated with self-assembled monolayers (SAMs) with continuous chemical composition gradients. The SAMs were mixtures of two thiols: n-hexanethiol (hydrophobic and protein-adsorbing) and hydroxyl-tri(ethylene glycol)-terminated alkanethiol (hydrophilic and protein-resistant) with continuously changing mixing ratios. From the systematic analyses, we found that protein adsorption is governed both by sizes of proteins and hydrophobic domains of the substrate. Furthermore, we found a clear correlation between adsorption of fibrinogen and adhesion of platelets. Combined with the results of surface force measurements, we found that the interfacial behavior of water molecules is profoundly correlated with protein resistance and antiplatelet adhesion. On the basis of these results, we conclude that the structuring of water at the SAM-water interface is a critical factor in this context.

DOI： 10.1021/acs.langmuir.5b01216

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

Although many kinds of synthetic polymers have been investigated to construct blood-compatible materials, only a few have achieved success. To establish molecular designs for blood-compatible polymers, the chain structure and dynamics at the water interface must be understood using solid evidence as the first bench mark. Here we show that polymer dynamics at the water interface impacts on structure of the interfacial water, resulting in a change in protein adsorption and of platelet adhesion. As a particular material, a blend composed of poly(2-methoxyethyl acrylate) (PMEA) and poly(methyl methacrylate) was used. PMEA was segregated to the water interface. While the local conformation of PMEA at the water interface was insensitive to its molecular weight, the local dynamics became faster with decreasing molecular weight, resulting in a disturbance of the network structure of waters at the interface. This leads to the extreme suppression of protein adsorption and platelet adhesion.

DOI： 10.1021/acs.langmuir.5b00258

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The hydration structures of two different types of biomaterials, i.e., poly(2-methoxyethyl acrylate) (PMEA) and a random copolymer of 2-methacryloyloxyethyl phosphorylcholine and n-butyl methacrylate (P(MPC-r-BMA)), were investigated by means of attenuated total reflection infrared (ATR-IR) spectroscopy. The effects of the addition of sodium chloride to liquid water in contact with the surfaces of the polymer films were examined. The neutral polymer of PMEA was easily dehydrated by NaCl addition, whereas the zwitterionic polymer of P(MPC-r-BMA) was hardly dehydrated. More specifically, nonfreezing water having a strong interaction with the PMEA chain and freezing bound water having an intermediate interaction were hardly dehydrated by contacting with normal saline solution, whereas freezing water having a weak interaction with the PMEA chain was readily dehydrated. In contrast, freezing water in P(MPC-r-BMA) is exchanged for the saline solution contacting with the material surface without dehydration.

DOI： 10.1021/la502550d

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Recent advances in biomedical engineering require the development of new types of blood-compatible polymers that also allow non-blood cell attachment for the isolation of stem cells and circulating tumor cells (CTCs) from blood and for the development of artificial organs for use under blood-contact conditions. Poly(2-methoxyethyl acrylate) (PMEA) and poly(tetrafurfuryl acrylate) (PTHFA) were previously identified as blood-compatible polymers. Here, it is demonstrated that cancer cells can attach to the PMEA and PTHFA substrates, and the differences in the attachment mechanisms to the PMEA and PTHFA substrates between cancer cells and platelets are investigated. It is also found that the adsorption-induced deformation of fibrinogen, which is required for the attachment and activation of platelets, does not occur on the PMEA and PTHFA substrates. In contrast, fibronectin is deformed on the PMEA and PTHFA substrates. Therefore, it is concluded that cancer cells and not platelets can attach to the PMEA and PTHFA substrates based on this protein-deformation difference between these substrates. Moreover, it is observed that cancer cells attach to the PMEA substrate via both integrin-dependent and -independent mechanisms and attach to the PTHFA substrate only through an integrin-dependent mechanism. It is expected that PMEA and PTHFA will prove useful for blood-contact biomedical applications.

DOI： 10.1002/adhm.201300309

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DOI： 10.1016/j.neuroscience.2024.11.018

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DOI： 10.1021/acs.langmuir.4c04048

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DOI： 10.1111/jjns.12631

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DOI： 10.1038/s41538-024-00360-0

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DOI： 10.1007/s12185-024-03871-4

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DOI： 10.1002/chem.202403663

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DOI： 10.1111/bjh.19835

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DOI： 10.1186/s12893-024-02610-0

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Language：English   Publisher：(一社)日本医真菌学会  

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

Background: Acrylamide polymers with zwitterionic carboxybetaine (CB) side groups have attracted attention as stealth polymers that do not induce antibodies when conjugated to proteins. However, they induce antibodies when modified onto liposomes. We hypothesized that antibodies are produced against polymer backbones rather than CB side groups. Objectives: In this study, we designed and synthesized a polymer employing CB in its main chain, poly(N-acetic acid-N-methyl-propyleneimine) (PAMPI), and evaluated the blood retention of PAMPI-modified liposomes in mice. Results: The non-fouling nature of PAMPI-modified liposomes estimated from serum protein adsorption was found to be not inferior to PCB- and PEG-modified liposomes. However, to our surprise, the PAMPI-modified liposomes showed an instantaneous clearance less than 1 h post-injection, comparable to the naked liposomes. Conclusions: The extent of the blood retention of polymer-modified liposomes cannot be predicted by their susceptibility to serum protein adsorption and semi-flexible conformation.

DOI： 10.3390/pharmaceutics16101271

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

Advanced materials leveraging water control are garnering considerable interest, with the state of water emerging as a critical aspect of material design. This study explored the impact of microphase separation on water using aqueous solutions of double zwitterionic diblock copolymers, specifically poly(carboxybetaine methacrylate) and poly(sulfobetaine methacrylate) (PCB2-b-PSB4). These copolymers form a mesoscale periodic ordered lattice structure consisting of two distinct aqueous phases. Through differential scanning calorimetry and X-ray emission spectroscopy, it was found that water in these PCB2-b-PSB4 aqueous solutions exhibits pronounced cold crystallization and subtle distortions in hydrogen-bonding configurations.

DOI： 10.1021/acs.langmuir.4c02254

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Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

To reveal the synergic effects of movable and reversible cross-links, we fabricated movable cross-linked hydrogels with hydrophobic acetylated cyclodextrins (CDs). The obtained hydrogels showed high toughness based on the broad range of relaxation times achieved by the high mobility of movable cross-links and reversible hydrophobic interaction. The high mobility of movable cross-links resulted from the lack of hydrogen bonds between the triacetylated γCD (TAcγCD) units and main chains. High mobility also occurred because TAcγCD units were not hydrated. The localization of hydration forms hydrophobic domains with the distribution of TAcγCD units. The hydrophobic domains also disperse the stress upon tensile deformation. The low water content (Wc = 15 wt %) achieved further high toughness (36.8 MJ·m-3) by the triple-synergic effects of movable cross-links, reversible hydrophobic interaction, and craze/fibril-like structures upon deformation. The mobility of movable cross-links and the reformation of reversible hydrophobic interaction achieved high self-restoring properties.

DOI： 10.1021/acs.macromol.4c00732

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Language：English   Publisher：Advanced Healthcare Materials  

Novel adhesives for biological tissues offer an advanced surgical approach. Here, the authors report the development and application of solid-state adhesives consisting of porous hydroxyapatite (HAp) biocompatible ceramics as novel internal organ retractors. The operational principles of the porous solid-state adhesives are experimentally established in terms of water migration from biological soft tissues into the pores of the adhesives, and their performance is evaluated on several soft tissues with different hydration states. As an example of practical medical utility, HAp adhesive devices demonstrate the holding ability of porcine livers and on-demand detachability in vivo, showing great potential as internal organ retractors in laparoscopic surgery.

DOI： 10.1002/adhm.202304616

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Physical Chemistry B  

The behavior of water molecules around organic molecules has attracted considerable attention as a crucial factor influencing the properties and functions of soft matter and biomolecules. Recently, it has been suggested that the change in protein stability upon the addition of small organic molecules (osmolytes) is dominated by the change in the water dynamics caused by the osmolyte, where the dynamics of not only the directly interacting water molecules but also the long-range hydration layer affect the protein stability. However, the relation between the long-range structure of hydration water in various solutions and the water dynamics remains unclear at the molecular level. We performed density-functional tight-binding molecular dynamics simulations to elucidate the varying rotational dynamics of water molecules in 15 osmolyte solutions. A positive correlation was observed between the rotational relaxation time and our proposed normalized parameter obtained by dividing the number of hydrogen bonds between water molecules by the number of nearest-neighbor water molecules. For the 15 osmolyte solutions, an increase or a decrease in the value of the normalized parameter for the second hydration shell tended to result in water molecules with slow and fast rotational dynamics, respectively, thus illustrating the importance of the second hydration shell for the rotational dynamics of water molecules. Our simulation results are anticipated to advance the current understanding of water dynamics around organic molecules and the long-range structure of water molecules.

DOI： 10.1021/acs.jpcb.3c08470

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Sympathetic nerves play a pivotal role in promoting tumor growth through crosstalk with tumor and stromal cells. Chemotherapy exacerbates the infiltration of sympathetic nerves into tumors, thereby providing a rationale for inhibiting sympathetic innervation to enhance chemotherapy. Here, we discovered that doxorubicin increases the density and activity of sympathetic nerves in breast cancer mainly by upregulating the expression of nerve growth factors (NGFs) in cancer cells. To address this, we developed a combination therapy by co-encapsulating small interfering RNA (siRNA) and doxorubicin within breast cancer-targeted poly (lactic-co-glycolic acid) (PLGA) nanoparticles, aiming to suppress NGF expression post-chemotherapy. Incorporating NGF blockade into the nanoplatform for chemotherapy effectively mitigated the chemotherapy-induced proliferation of sympathetic nerves. This not only bolstered the tumoricidal activity of chemotherapy, but also amplified its stimulatory impact on the antitumor immune response by increasing the infiltration of immunostimulatory cells into tumors while concurrently reducing the frequency of immunosuppressive cells. Consequently, the combined nanodrug approach, when coupled with anti-PD-L1 treatment, exhibited a remarkable suppression of primary and deeply metastatic tumors with minimal systematic toxicity. Importantly, the nanoplatform relieved chemotherapy-induced peripheral neuropathic pain (CIPNP) by diminishing the expression of pain mediator NGFs. In summary, this research underscores the significant potential of NGF knockdown in enhancing immunochemotherapy outcomes and presents a nanoplatform for the highly efficient and low-toxicity treatment of breast cancer.

DOI： 10.1016/j.biomaterials.2024.122603

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Publisher：Journal of Applied Polymer Science  

Poly(ethylene glycol) (PEG) modification, also known as PEGylation, has been extensively used to improve the stability of nanoparticles for nanomedical applications. However, PEG exhibits antigenicity in some formulations, motivating researchers to explore alternative polymers. Herein, poly(vinyl ether) (PVE) derivatives are highlighted as promising alternatives to PEG because they form intermediate water molecules that suppress non-specific protein adsorption and platelet adhesion to the material surface. We prepared a water-soluble PVE derivative, poly(2-methoxyethyl vinyl ether) (PMOVE), and utilized it as a surface modifier for gold nanoparticles (AuNPs) as model nanoparticles. PMOVE with a thiol terminus was synthesized and confirmed to form an intermediate water molecule using differential scanning calorimetry. Similar to the synthesis of PEGylated AuNPs (PEG-AuNPs), PMOVE-modified AuNPs (PMOVE-AuNPs) were successfully fabricated with an appreciably high density of PMOVE palisades via a thiol-gold coordination reaction. Similar to PEG-AuNPs, PMOVE-AuNPs showed reduced serum protein adsorption and prolonged blood circulation. Additionally, no significant cytotoxicity was observed after incubation of a murine macrophage cell line, RAW264.7, with PMOVE-AuNPs. Our results indicate that the PMOVE modification increases the stealthiness of nanoparticles that is equivalent to that achieved by PEGylation.

DOI： 10.1002/app.55044

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：AIP Publishing  

Poly(ethylene oxide) (PEO) is a well-known biocompatible polymer and has widely been used for medical applications. Recently, we have investigated the dynamic behavior of hydration water in the vicinity of PEO chains at physiological temperature and shown the presence of slow water with diffusion coefficient one order of magnitude less than that of bulk water. This could be evidence for the intermediate water that is critical for biocompatibility; however, its detailed dynamical features were not established. In this article, we analyze the quasi-elastic neutron scattering from hydration water through mode distribution analysis and present a microscopic picture of hydration water as well as its relation to cold crystallization.

DOI： 10.1063/5.0185432

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Investigating polymer degradation mechanisms enables the establishment of controlled degradation techniques for the development of sustainable and recyclable materials. Hydration can play a crucial role in controlling the hydrolysis of polymers. Here, ether-functionalized aliphatic polycarbonates (APCs) susceptible to nonenzymatic hydrolysis were developed for application as biocompatible biomaterials. Among these polymers, those grafted with 2-methoxyethyl and 3-methoxypropyl side chains via an amide group were highly wettable, strongly interacted with water, and experienced almost complete hydrolysis in phosphate-buffered saline over 30 days, which was attributed to the hydrogen bonding between water and the amide/methoxy groups. In an alkaline medium, all amide-linked APCs were completely hydrolyzed within 30 days, regardless of the side-chain structure. In contrast, the nonamide-linked APCs and a representative aliphatic polycarbonate, poly(trimethylene carbonate), were minimally degraded in the buffer and experienced <31% degradation under alkaline conditions. The APC with the 3-methoxypropyl side chain exhibited platelet adhesion properties comparable to those of ether-functionalized APCs previously reported as blood-compatible polymers. Thus, our results demonstrate the effects of an amide linker on the hydration and hydrolytic properties of APCs and can help establish new design concepts for degradable polymers.

DOI： 10.1038/s41428-023-00874-6

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Other Link： https://www.nature.com/articles/s41428-023-00874-6

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACS Applied Bio Materials  

Isolating cancer cells from tissues and providing an appropriate culture environment are important for a better understanding of cancer behavior. Although various three-dimensional (3D) cell culture systems have been developed, techniques for collecting high-purity spheroids without strong stimulation are required. Herein, we report a 3D cell culture system for the isolation of cancer spheroids using enzymatically synthesized cellulose oligomers (COs) and demonstrate that this system isolates only cancer spheroids under coculture conditions with normal cells. CO suspensions in a serum-containing cell culture medium were prepared to suspend cells without settling. High-purity cancer spheroids could be separated by filtration without strong stimulation because the COs exhibited antibiofouling properties and a viscosity comparable to that of the culture medium. When human hepatocellular carcinoma (HepG2) cells, a model for cancer cells, were cultured in the CO suspensions, they proliferated clonally and efficiently with time. In addition, only developed cancer spheroids from HepG2 cells were collected in the presence of normal cells by using a mesh filter with an appropriate pore size. These results indicate that this approach has potential applications in basic cancer research and cancer drug screening.

DOI： 10.1021/acsabm.3c00901

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Language：English   Publisher：Surgery Today  

Purpose: Various polymers have been used as postsurgical antiadhesive materials; however, the mechanisms underlying their efficacy remain unclear. Intermediate water has been found to prevent the adhesion between polymer molecules and proteins or cells. The present study investigated the role of intermediate water retained in the polymer in alleviating postsurgical pericardial adhesion. Methods: Hydrophobic fabrics were prepared using biodegradable polyglycolic acid. To add intermediate water, the fabric fibers were coated with poly(oxyethylene)oleyl ethers. Intermediate water in the hydrated state was detected by a thermal analysis for each material, and cell attachment to the fibers with or without coating was observed in vitro. Using a canine model of postsurgical pericardial adhesion, the severity of adhesion was examined along with a histological assessment during treatment, with or without fabric coating. Results: Intermediate water was detected in the coating materials but not in polyglycolic acid. Coating significantly reduced the cell attachment to the fibers. Coating also alleviated adhesion by reducing inflammation in the fibrous layer and replacing the fabric and granulomas that develop around the surgical sutures in the pericardial space. Conclusions: Intermediate water in the hydrated polymer of anti-adhesives may play an important role in alleviating postoperative pericardial adhesion.

DOI： 10.1007/s00595-024-02953-4

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DOI： 10.3389/fnagi.2024.1486481

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry (RSC)  

Given that the hydration water of polymer matrices may differ from that of outermost polymer surfaces, processes at biomaterial–biofluid interfaces and role of hydration water therein cannot be adequately examined...

DOI： 10.1039/d4sm00977k

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Language：English   Publisher：Langmuir  

Optically transparent and colored elastomers with high toughness are expected to play an important role in the construction of advanced medical materials, wearable displays, and soft robots. In this study, we found that composite elastomers consisting of amorphous SiO2 particles homogeneously dispersed in high concentrations within a biocompatible acrylic polymer network exhibit optical transparency and bright structural colors. In the composite elastomers, the system in which the SiO2 particles form a colloidal amorphous array hardly changes its structural color hue despite deformation due to elongation. Furthermore, the composite elastomer of the SiO2 particles with the acrylic polymer network also results in high mechanical toughness. In summary, we have shown that the elastomer that exhibits fade-resistant structural coloration formed from safe materials can combine stable coloration and mechanical strength independent of their shape. This is expected to have new potential in future technologies to support our daily life.

DOI： 10.1021/acs.langmuir.3c02442

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Language：Japanese   Publisher：THE JAPAN SOCIETY OF DRUG DELIVERY SYSTEM  

When materials come into contact with biological fluids, water immediately adsorb onto the surface of materials. Water molecules play a crucial role in nanobiointerfacial interactions, including protein adsorption/desorption and cell adhesion/deadhesion on materials. To understand the role of water in the interaction of proteins and cells at biological interfaces, it is important to compare particular states of hydration water with various physicochemical properties of hydrated materials. Here, we discuss the fundamental concepts for determining the interactions of proteins and cells with hydrated materials along with selected examples corresponding to our recent studies, poly（2-methoxyethyl acrylate） （PMEA）, PMEA derivatives, zwitterionic polymers, poly（ethylene glycol）, and poly（2-oxazoline）s, and other polymers including biopolymers （DNA, RNA, proteins, and polysaccharides）. The states of water were analyzed by differential scanning calorimetry, time-resolved <i>in situ</i> attenuated total reflection infrared spectroscopy, solid-states NMR, surface force measurements, and wide variety of analytical techniques. We found that intermediate water which is loosely bound to a polymer, is a useful indicator of the biocompatibility of polymer surfaces. This finding on intermediate water provides novel insights and helps develop novel experimental models for understanding protein adsorption/cell adhesion in a wide range of polymers, and helps guiding principles to design functional polymers such as those used in biomedical applications.

DOI： 10.2745/dds.38.404

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DOI： 10.1016/j.scitotenv.2023.168173

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Hydrophilic materials display “bio-inert properties”, meaning that they are less recognized as foreign substances by proteins and cells. Such materials are often water soluble; therefore, one general approach to enable the use of these materials in various applications deals with copolymerizing hydrophilic monomers with hydrophobic ones to facilitate such resulting copolymers water insoluble. However, reducing the hydrophilic monomer amount may reduce the bio-inert properties of the material. The decrease in bio-inert properties can be avoided when small amounts of fluorine are used in copolymers with hydrophilic monomers, as presented in this article. Even in small quantities (7.9 wt%), the fluorinated monomer, 1,1,1,3,3,3-hexafluoropropan-2-yl 2-fluoroacrylate (FAHFiP), contributed to the improved hydrophobicity of the polymers of the long side-chain poly(ethylene glycol) methyl ether methacrylate (mPEGMA) bearing nine ethylene glycol units turning them water insoluble. As evidenced by the AFM deformation image, a phase separation between the FAHFiP and mPEGMA domains was observed. The copolymer with the highest amount of the fluorinated monomer (66.2 wt%) displayed also high (82 %) FAHFiP amount at the polymer–water interface. In contrast, the hydrated sample with the lowest FAHFiP/highest mPEGMA amount was enriched of three times more hydrophilic domains at the polymer–water interface compared to that of the sample with the highest FAHFiP content. Thus, by adding a small FAHFiP amount to mPEGMA copolymers, water insoluble in the bulk too, could be turned highly hydrophilic at the water interface. The high content of intermediate water contributed to their excellent bio-inert properties. Platelet adhesion and fibrinogen adsorption on their surfaces were even more decreased as compared to those on poly(2-methoxyethyl acrylate), which is typically used in medical devices.

DOI： 10.1016/j.bioadv.2023.213573

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry (RSC)  

γ-Carbonyl-substituted ε-caprolactones were found to predominantly isomerize to five-membered lactones rather than to form desired linear polyesters in ring-opening polymerization.

DOI： 10.1039/d3ra01025b

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：The Chemical Society of Japan  

Polymeric biomaterials are often used in water and hydration water molecules with different mobilities, such as non-freezing water, intermediate water, and free water, are formed on their surfaces. These water molecules affect biological responses between the biomaterials and biofluids. It is challenging to control the state of hydration waters by tuning chemical structures of the polymers toward advance of medical fields. This review describes and updates syntheses, analyses, and applications of the polymeric biomaterials based on the intermediate water concept. The concept provides significant opportunities for pioneering polymeric biomaterials.

DOI： 10.1246/bcsj.20230168

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Interdisciplinary Graduate School of Engineering Sciences, Kyushu University  

In recent years, human iPS cell-derived cardiomyocytes (hiPS-CMs) have attracted much attention in the arena of regenerative therapies. However, hiPS-CMs are known to be immature and have lower contractility than the adult heart. In this study, we investigated the effect of material properties of scaffold surfaces on hiPS-CMs with the aim of improving the contractility of hiPS-CMs. PMEA analogs with varying surface-bound water content, which affect cell adhesion/proliferation behavior, were selected as scaffold materials to coat PET substrates. The cell characteristics of the hiPS-CMs seeded on the scaffolds were evaluated. The initial cell adhesion area tended to be smaller on substrates with a higher amount of bound water. With further incubation, the hiPS-CMs formed self-pulsating aggregates on the substrate. On the substrates with high bound water content, the area of the hiPS-CMs aggregates tended to be smaller while the pulsation behavior became greater. The results indicate that PMEA analogues might affect the cellular properties of hiPS-CMs.

DOI： 10.15017/6786935

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Language：English   Publisher：International Journal of Biological Macromolecules  

Nature-derived or biologically encouraged hydrogels have attracted considerable interest in numerous biomedical applications owing to their multidimensional utility and effectiveness. The internal architecture of a hydrogel network, the chemistry of the raw materials involved, interaction across the interface of counter ions, and the ability to mimic the extracellular matrix (ECM) govern the clinical efficacy of the designed hydrogels. This review focuses on the mechanistic viewpoint of different biologically driven/inspired biomacromolecules that encourages the architectural development of hydrogel networks. In addition, the advantage of hydrogels by mimicking the ECM and the significance of the raw material selection as an indicator of bioinertness is deeply elaborated in the review. Furthermore, the article reviews and describes the application of polysaccharides, proteins, and synthetic polymer-based multimodal hydrogels inspired by or derived from nature in different biomedical areas. The review discusses the challenges and opportunities in biomaterials along with future prospects in terms of their applications in biodevices or functional components for human health issues. This review provides information on the strategy and inspiration from nature that can be used to develop a link between multimodal hydrogels as the main frame and its utility in biomedical applications as the primary target.

DOI： 10.1016/j.ijbiomac.2023.125606

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DOI： 10.1140/epjc/s10052-023-11837-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media {LLC}  

The microphase separation of double-hydrophilic block copolymers in water is of interest when these copolymers are utilized as molecular assemblies with mesoscale aqueous compartments. Diblock copolymers composed of a water-soluble zwitterionic polymer, poly(carboxybetaine acrylate) (PCBA2), and a hydrophilic water-insoluble nonionic polymer, poly(2-methoxyethyl acrylate) (PMEA), (PCBA2n-b-PMEAm) were synthesized, and their assembly characteristics were investigated in aqueous solutions. Well-defined PCBA2n-b-PMEAm block copolymers were synthesized by the reversible addition–fragmentation chain transfer polymerization of a carboxybetaine acrylate modified with a tert-butyl group and 2-methoxyethyl acrylate followed by tert-butyl group cleavage. PCBA2n-b-PMEAm produced particles in dilute aqueous solutions and microphase-separated structures in concentrated aqueous solutions. The hydrodynamic radius of the particles and the microphase-separated structure were associated with the block copolymer composition and degree of polymerization of the PMEA chain. The molecular assembly behavior was tolerant to NaCl concentration, providing molecular design guidelines for the use of double-hydrophilic microphase-separated compartments in physiological environments.

DOI： 10.1038/s41428-023-00831-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Advanced Drug Delivery Reviews  

The stealth effect plays a central role on capacitating nanomaterials for drug delivery applications through improving the pharmacokinetics such as blood circulation, biodistribution, and tissue targeting. Here based on a practical analysis of stealth efficiency and a theoretical discussion of relevant factors, we provide an integrated material and biological perspective in terms of engineering stealth nanomaterials. The analysis surprisingly shows that more than 85% of the reported stealth nanomaterials encounter a rapid drop of blood concentration to half of the administered dose within 1 h post administration although a relatively long β-phase is observed. A term, pseudo-stealth effect, is used to delineate this common pharmacokinetics behavior of nanomaterials, that is, dose-dependent nonlinear pharmacokinetics because of saturating or depressing bio-clearance of reticuloendothelial system (RES). We further propose structural holism can be a watershed to improve the stealth effect; that is, the whole surface structure and geometry play important roles, rather than solely relying on a single factor such as maximizing repulsion force through polymer-based steric stabilization (e.g., PEGylation) or inhibiting immune attack through a bio-inspired component. Consequently, engineering delicate structural hierarchies to minimize attractive binding sites, that is, minimal charges/dipole and hydrophobic domain, becomes crucial. In parallel, the pragmatic implementation of the pseudo-stealth effect and dynamic modulation of the stealth effect are discussed for future development.

DOI： 10.1016/j.addr.2023.114895

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Molecular Systems Design and Engineering  

Ring-opening metathesis polymerisation (ROMP) has become a popular method for synthesising complex functional polymers owing to the high functional group tolerance of metathesis catalysts. In recent years, ROMP has emerged as an indispensable approach for the design and synthesis of polymeric biomaterials, allowing for precise control of polymer structure and introduction of complex polar functional groups that are challenging to access through conventional polymerisation methods. In this review, we present examples of precision polymer synthesis with polar functional groups and their utilisation as soft-biomaterials in biotechnology and biomedical fields. Specifically, we focus on two approaches: the underexplored ROMP of functionalised monocyclic alkenes and the dominant methods of synthesising biomaterials using functionalised norbornene.

DOI： 10.1039/D3ME00063J

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

The intermediate water (IW) concept has been hypothesized to predict the biocompatibility of polymers and inorganic materials. This study, for the first time, prepared the composite biomaterials of poly(2-hydroxyethyl methacrylate) (PHEMA)/titanium-doped bioactive glasses (BGT) for bone regeneration by applying the IW concept. The homogeneous distribution of BGT and the mechanical stability of the composites were confirmed using X-ray diffraction, infrared spectroscopy, scanning electron microscopy, energy dispersive X-ray spectrometry, and rheological characterization. In vitro tests with immersion in simulated body fluid showed that titanium doping improved the biomineralization properties. The IW level ranged from 10.4 wt% with 0% titanium doped to 25.6 wt% with 7.5% titanium doped. Cell viability tests on osteosarcoma cells revealed that the growth rate increased with increasing titanium concentration, reaching up to 150%. Based on single-cell force spectroscopy, an appropriate titanium concentration for cell adhesion was estimated to be 5%. The hydrated PHEMA gels with 5% BGT exhibited a high IW level of 19.3% and less hydrophilic wettability than the gels without titanium or with 10% BGT. The IW concept proved to be useful for predicting the bone regeneration potential on the interfaces of the PHEMA/BGT composite hydrogels.

DOI： 10.1016/j.ceramint.2022.12.221

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Polypropyleneimine (PPI) was examined as a transfection reagent comparing with most widely used polymer, polyethyleneimine (PEI). PPI had better responsiveness to the endosomal pH and showed more condensation ability of plasmid DNA than PEI. Although the cytotoxicity of PPI was somewhat higher than PEI, the transfection efficacy of PPI was comparable with PEI or higher than PEI in some cell line. Thus, PPI would be an alternative transfection reagent. Graphical abstract: [Figure not available: see fulltext.].

DOI： 10.1007/s44211-023-00284-x

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Other Link： https://link.springer.com/article/10.1007/s44211-023-00284-x/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Molecular Sciences  

Here we aimed to establish a simple detection method for detecting circulating tumor cells (CTCs) in the blood sample of colorectal cancer (CRC) patients using poly(2-methoxyethyl acrylate) (PMEA)-coated plates. Adhesion test and spike test using CRC cell lines assured efficacy of PMEA coating. A total of 41 patients with pathological stage II-IV CRC were enrolled between January 2018 and September 2022. Blood samples were concentrated by centrifugation by the OncoQuick tube, and then incubated overnight on PMEA-coated chamber slides. The next day, cell culture and immunocytochemistry with anti-EpCAM antibody were performed. Adhesion tests revealed good attachment of CRCs to PMEA-coated plates. Spike tests indicated that ~75% of CRCs from a 10-mL blood sample were recovered on the slides. By cytological examination, CTCs were identified in 18/41 CRC cases (43.9%). In cell cultures, spheroid-like structures or tumor-cell clusters were found in 18/33 tested cases (54.5%). Overall, CTCs and/or growing circulating tumor cells were found in 23/41 CRC cases (56.0%). History of chemotherapy or radiation was significantly negatively correlated with CTC detection (p = 0.02). In summary, we successfully captured CTCs from CRC patients using the unique biomaterial PMEA. Cultured tumor cells will provide important and timely information regarding the molecular basis of CTCs.

DOI： 10.3390/ijms24043949

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Publishing type：Research paper (scientific journal)   Publisher：Polymer Journal  

It has been reported that the hydration state of biocompatible polymers, such as poly(ethylene glycol) (PEG), affects their bioinertness. PEGylated dendrimers have been studied for use as drug carriers. In our previous study, the hydration behaviors of PEG and PEGylated dendrimers were analyzed using differential scanning calorimetry (DSC) to investigate the relationship between hydration and in vivo behaviors. In this study, the hydration behaviors of PEG and PEGylated dendrimer were analyzed using X-ray diffraction (XRD) and infrared (IR) spectroscopy. According to the XRD analysis, ice was formed and melted in the PEG/water mixture with a 20% water content below 0 °C during the heating process; however, PEG crystals were formed in the PEG/water mixture containing 70% water. The XRD and IR results of the PEGylated dendrimer/water mixture were similar to those of the PEG/water system containing 70% water. Our IR spectral studies indicated that the hydration state of the PEGylated dendrimer was different from that of PEG containing 20% water. These results suggested that a comprehensive study is important for the analysis of such eutectic mixtures of PEG compounds and water.

DOI： 10.1038/s41428-022-00700-5

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Authorship：Last author,　Corresponding author  

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Reversible or movable cross-links based on host-guest interactions in supramolecular materials create functions such as enhanced mechanical properties and stimulus responsiveness. A supramolecular complex on a polymer side chain achieves the described functions as a reversible cross-link. Generally, 1:1 complex is utilized as a cross-link for the host-guest interaction based-supramolecular materials, but herein, the 1:2 complex between γ-cyclodextrin (γCD) and methyl viologen terminated undecyl acrylate (VC11) was chosen to cross-link three polymeric chains. The obtained supramolecular hydrogels γCD-VC11 (x, y) (x and y represent the mol% of the γCD and VC11 units in feeding, respectively) was prepared by radical copolymerization with acrylamide as a mainchain monomer. Tensile test revealed that toughness (Gf) of γCD-VC11 (x, y) maximized at water content (Wc) ≈ 40 wt.%. The maxima of Gf depended on the amount of γCD and VC11 units. Through dynamic mechanical analysis, Arrhenius style plots between horizontal shift factors and temperature determined activation energies (Ea) of each γCD-VC11 (x, y) and MBAAm (0.5). Ea of MBAAm (0.5) monotonically decreased with the increasing Wc. On the other hand, slope of Ea of γCD-VC11 (x, y) changed at Wc ≈ 40 wt.%. Simultaneously considering results of the tensile tests and DMA, the reversible cross-links formed by γCD and VC11 in γCD-VC11 (x, y) function effectively at appropriate Wc.

DOI： 10.1016/j.supmat.2021.100001

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DOI： 10.3390/cancers15010237

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DOI： 10.3390/cancers15010237

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Colloids and Surfaces B: Biointerfaces  

Cellulose-based crystalline assemblies artificially constructed in a bottom-up manner are attracting increasing attention as chemically stable and functionally designable nano- to macroscale materials. However, basic knowledge of how such crystalline assemblies interact with biomolecules and how to control them via molecular design is still limited. In this study, we investigated the protein adsorption properties of crystalline lamella assemblies composed of alkyl β-cellulosides (namely, ethyl, n-butyl, and n-hexyl β-cellulosides) or plain cellulose, which all have an antiparallel molecular arrangement. It was found that the adsorption of proteins was observed only for the n-hexyl β-celluloside assembly, while it was hardly observed for other assemblies. The n-hexyl groups appeared to be ordinarily embedded in the assembly surface in an aqueous phase, while, when in contact with proteins, n-hexyl groups appeared to be tethered to promote protein adsorption. All-atom molecular dynamics simulations supported the contradictory protein adsorption properties. The basic knowledge obtained herein is highly valuable for controlling the interactions of cellulose-based synthetic assemblies with proteins for designing new biological applications.

DOI： 10.1016/j.colsurfb.2022.112898

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Advanced Materials Interfaces  

Poly(3,4-ethylenedioxythiophene) (PEDOT) and its derivatives have demonstrated potential in the development of bioelectrodes because of their superior conductivity. However, developing reliable implanted bioelectrodes requires improvements in biocompatibility and the prevention of nonspecific adhesion. In this study, a six ethylene glycol (EG)-functionalized EDOTs with three different EG lengths (tri-EG, tetra-EG, and hexa-EG) and two types of end groups, hydroxyl (−OH) and methoxy (−OCH3) is synthesized and systematically investigated. By coating them on gold electrodes using electropolymerization, the surface and electrochemical properties of these functionalized PEDOT-coated electrodes are investigated. Although PEDOT with −OH groups on the surface is more hydrophilic, those with −OCH3 groups on the surface exhibit higher electrochemical activity and lower impedance. The increase in EG units and −OCH3 groups on the surface effectively reduces the adhesion between the PEDOT and atomic force microscopy tips. PEDOT with longer EG lengths and −OCH3 groups exhibits relatively few adhered platelets, and the results of the analysis of hydrated states through differential scanning calorimetry are consistent with those of the platelet adhesion test. This study suggests that a tetra(EG)-functionalized PEDOT with −OCH3 groups on the surface is a promising coating for implanted bioelectrode applications.

DOI： 10.1002/admi.202200707

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

Blood-compatible and cell-adhering polymer materials are extremely useful for regenerative medicine and disease diagnosis. (Meth)acryl polymers with high hydrophilicity have been widely used in industries, and attempts to apply these polymers in the medical field are frequently reported. We focused on crosslinked polymer films prepared using bifunctional monomers, which are widely used as coating materials, and attempted to alter the cell adhesion behavior while maintaining blood compatibility by changing the chemical structure of the crosslinker. Four bifunctional monomers were studied, three of which were found to be blood-compatible polymers and to suppress platelet adhesion. The adhesion behavior of cancer cells to polymer films varied; moreover, the cancer model cells MCF-7 [EpCAM(+)] and MDA-MB-231 [EpCAM (-)], with different expression levels of epithelial cell adhesion molecule (EpCAM), showed distinct adhesion behavior for each material. We suggest that a combination of these materials has the potential to selectively capture and enrich highly metastatic cancer cells.

DOI： 10.1021/acsbiomaterials.2c00662

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Publisher：RSC Advances  

The demand for artificial blood vessels to treat vascular disease will continue to increase in the future. To expand the application of blood-compatible poly(2-methoxyethyl acrylate) (pMEA) to artificial blood vessels, control of the mechanical properties of pMEA is established using supramolecular cross-links based on inclusion complexation of acetylated cyclodextrin. The mechanical properties, such as Young's modulus and toughness, of these pMEA-based elastomers change with the amount of cross-links, maintaining tissue-like behavior (J-shaped stress-strain curve). Regardless of the cross-links, the pMEA-based elastomers exhibit low platelet adhesion properties (approximately 3% platelet adherence) compared with those of poly(ethylene terephthalate), which is one of the commercialized materials for artificial blood vessels. Contact angle measurements imply a shift of supramolecular cross-links in response to the surrounding environment. When immersed in water, hydrophobic supramolecular cross-links are buried within the interior of the materials, thereby exposing pMEA chains to the aqueous environment; this is why supramolecular cross-links do not affect the platelet adhesion properties. In addition, the elastomers exhibit stable adhesion to human umbilical vein endothelial cells. This report shows the potential of combining supramolecular cross-links and pMEA.

DOI： 10.1039/d2ra04885j

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DOI： 10.1039/d2ra04885j

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DOI： 10.1039/d2ra04885j

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Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry (RSC)  

A cyclic carbonate with an ammonium carboxylate residue was found to serve as a nucleophile for esterification with alkyl bromides via the S_N2 mechanism.

DOI： 10.1039/d2py00705c

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Language：Japanese   Publisher：The Chemical Society of Japan  

<p>医療製品の開発には，生体に接触する環境で安全に機能する生体親和性に優れたソフトバイオマテリアルが必須である。医療製品は，使用する前の滅菌済みの乾燥状態から，使用時にはウエットな状態に変化する。本講座では，製品使用環境で存在する水の視点を考慮し，材料と生体の接触点であるバイオ界面の設計における課題と進展について概説する。生体親和性に強く影響する材料—細胞間相互作用には，多くの因子が関与している。我々は，生体親和性合成材料と生体分子に形成される水の状態を調べ，特定の構造と運動性を有する中間水が共通点であることを明らかにした。中間水のバイオ界面における役割について考察する。</p>

DOI： 10.20665/kakyoshi.70.7_348

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Language：Others   Publisher：Advanced Drug Delivery Reviews  

When biomedical materials come into contact with body fluids, the first reaction that occurs on the material surface is hydration; proteins are then adsorbed and denatured on the hydrated material surface. The amount and degree of denaturation of adsorbed proteins affect subsequent cell behavior, including cell adhesion, migration, proliferation, and differentiation. Biomolecules are important for understanding the interactions and biological reactions of biomedical materials to elucidate the role of hydration in biomedical materials and their interaction partners. Analysis of the water states of hydrated materials is complicated and remains controversial; however, knowledge about interfacial water is useful for the design and development of advanced biomaterials. Herein, we summarize recent findings on the hydration of synthetic polymers, supramolecular materials, inorganic materials, proteins, and lipid membranes. Furthermore, we present recent advances in our understanding of the classification of interfacial water and advanced polymer biomaterials, based on the intermediate water concept.

DOI： 10.1016/j.addr.2022.114310

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Poly(2-methoxyethyl acrylate) (PMEA) is a US FDA-approved biocompatible polymer, although there is insufficient work on human umbilical vein endothelial cells (HUVECs) and platelet interaction analysis on PMEA-analogous polymers. In this study, we extensively investigated HUVEC–polymer and platelet–polymer interaction behavior by measuring the adhesion strength using single-cell force spectroscopy. Furthermore, the hydration layer of the polymer interface was observed using frequency-modulation atomic force microscopy. We found that endothelial cells can attach and spread on the PMEA surface with strong adhesion strength compared to other analogous polymers. We found that the hydration layers on the PMEA-analogous polymers were closely related to their weak platelet adhesion behavior. Based on our results, it can be concluded that PMEA is a promising candidate for the construction of artificial small-diameter blood vessels owing to the presence of IW and a hydration layer on the interface.

DOI： 10.3390/surfaces5030027

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

The hydration state of bioactive glass materials and its relationship with their biocompatibility have been receiving attention. In this research, silver-containing bioactive glasses (BGAgs) (Ag contents of 0.25, 0.5, and 1.0% in the glass system) were developed using the sol-gel method. Their physicochemical properties, size, morphology, and surface area were characterized by conducting X-rays diffraction (XRD), Fourier transform infrared (FTIR), Transmission electron microscopy (TEM), and Brunauer–Emmett–Teller (BET) surface area analyses. The surface charges of the developed BGAgs were evaluated using the Nano Zetasizer. Moreover, the antibacterial activities and intermediate water (IW) contents of hydrated BGAgs were determined. Finally, BGAgs disks were tested against osteosarcoma (MG63) cell line to evaluate their death modes. The physicochemical characteristics of the BGAgs revealed no modifications after Ag doping. In comparison, relative changes were recorded in the particle size (20–33 to 16–29 nm), surface area (4.3 to 3.7 m2/g), and particle charge (−24 to −14.6 mV). Doping the current glass system with silver produced impressive amounts of IW, consistent with recorded proliferation rates of the cells when treated with BGAgs. The determined hydration states correlated with other findings in this research might be helpful in predicting and assessing the biological behaviors of BGAgs.

DOI： 10.1016/j.bioadv.2022.212965

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Elucidating the state of interfacial water, especially the hydrogen-bond configurations, is considered to be key for a better understanding of the functions of polymers that are exhibited in the presence of water. Here, an analysis in this direction is conducted for two water-insoluble biocompatible polymers, poly(2-methoxyethyl acrylate) and cyclic(poly(2-methoxyethyl acrylate)), and a non-biocompatible polymer, poly(n-butyl acrylate), by measuring their IR spectra under humidified conditions and by carrying out theoretical calculations on model complex systems. It is found that the OH stretching bands of water are decomposed into four components, and while the higher-frequency components (with peaks at ∼3610 and ∼3540 cm-1) behave in parallel with the C═O and C-O-C stretching and CH deformation bands of the polymers, the lower-frequency components (with peaks at ∼3430 and ∼3260 cm-1) become pronounced to a greater extent with increasing humidity. From the theoretical calculations, it is shown that the OH stretching frequency that is distributed from ∼3650 to ∼3200 cm-1 is correlated to the hydrogen-bond configurations and is mainly controlled by the electric field that is sensed by the vibrating H atom. By combining these observed and calculated results, the configurations of water at the interface of the polymers are discussed.

DOI： 10.1021/acs.jpcb.2c01702

Language：Others   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

Zwitterionic methacrylate polymers with either choline phosphate (CP) (poly(MCP)) or phosphorylcholine (PC) (poly(MPC)) side groups were analyzed to characterize the bound hydration water molecules as nonfreezing water (NFW), intermediate water (IW), or free water (FW). This characterization was carried out by differential scanning calorimetry (DSC) of polymer/water systems, and the enthalpy changes of cold crystallization and melting were determined. The electron pair orientation of CP is opposite to that of PC, and the former binds the alkyl terminal groups at the phosphate esters. The numbers of NFW and IW molecules per monomer unit of poly(MCP) with an isopropyl terminal group were estimated to be 10.7 and 11.3 mol/mol, respectively, which were slightly greater than those of the poly(MCP) bearing an ethyl terminal group. More NFW and IW molecules hydrated the phosphobetaine polyzwitterions, poly(MCP) and poly(MPC), compared with carboxybetaine and sulfobetaine polymers. Moreover, the hydration states of polyelectrolytes were compared with the zwitterionic polymers. Finally, we discuss the relationship between the amount of hydration water and bio-inert properties.

DOI： 10.1021/acs.biomac.2c00484

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Coatings  

Confluent monolayers of human umbilical vein endothelial cells (HUVECs) on a poly(2-methoxyethyl acrylate) (PMEA) antithrombogenic surface play a major role in mimicking the inner surface of native blood vessels. In this study, we extensively investigated the behavior of cell–polymer and cell–cell interactions by measuring adhesion strength using single-cell force spectroscopy. In addition, the attachment and migration of HUVECs on PMEA-analogous substrates were detected, and the migration rate was estimated. Moreover, the bilateral migration of HUVECs between two adjacent surfaces was observed. Furthermore, the outer surface of HUVEC was exam-ined using frequency-modulation atomic force microscopy (FM-AFM). Hydration was found to be an indication of a healthy glycocalyx layer. The results were compared with the hydration states of individual PMEA-analogous polymers to understand the adhesion mechanism between the cells and substrates in the interface region. HUVECs could attach and spread on the PMEA surface with stronger adhesion strength than self-adhesion strength, and migration occurred over the surface of analogue polymers. We confirmed that platelets could not adhere to HUVEC monolayers cultured on the PMEA surface. FM-AFM images revealed a hydration layer on the HUVEC surfaces, indicating the presence of components of the glycocalyx layer in the presence of intermediate water. Our findings show that PMEA can mimic original blood vessels through an antithrombogenic HUVEC monolayer and is thus suitable for the construction of artificial small-diameter blood vessels.

DOI： 10.3390/coatings12060869

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Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry ({RSC})  

The biocompatible (co)polymers undergoes a thermal stimulus-driven liquid–liquid phase separation and form coacervates above the lower critical solution temperature (LCST). The LCSTs are able to be precisely controlled between 0 °C and 100 °C.

DOI： 10.1039/d2py00154c

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Polymer microparticles, composed of water-soluble hydrophilic monomers, are synthesized via surfactant-free suspension polymerization with an oil-in-water system. Microparticles formed from PMEA have potential as a platform to capture tumor cells.

DOI： 10.1039/D2MA00129B

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Regulation of protein adsorption on the surface of biomaterials is important for modulating cell adhesion. Two important proteins in this regard are fibrinogen and fibronectin. Poly(2-methoxyethyl acrylate) (PMEA) and its derivatives have been developed as promising coating materials for biomaterial surfaces. Previous studies have highlighted that PMEA-coated substrates suppress thrombogenicity but promote cell adhesiveness. However, it was unclear what was responsible for these differences in adhesion. In this study, we focused on the correlation between protein adsorption and the nanometer-scale structures on the surfaces of the PMEA substrates. An atomic force microscope using protein- or antibody-conjugated cantilevers was used to perform nanoscopic analyses of the adsorption forces and conformational changes in fibrinogen and fibronectin adsorbed on the nanometer-scale PMEA structures. The adsorption force of fibronectin in the polymer-poor region was higher than that of fibrinogen, whereas the polymer-rich region showed a negligible difference in adsorption force between the two proteins. Interestingly, a greater conformational change in the adsorbed fibronectin was induced in the polymer-poor region than that in fibronectin in the polymer-rich region or fibrinogen in either regions, resulting in the induction of cell adhesion. Nanoscopic analyses of protein adsorption on biomaterial surfaces provide promising insights into the design of novel biomaterials that control protein adsorption and cell adhesion.

DOI： 10.1039/d2bm00093h

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Selective targeting of specific cells without the use of biological ligands has not been achieved. In the present study, we revealed that the coacervate droplets formed from poly(2-methoxyethyl acrylate) (PMEA) and its derivatives selectively accumulated to tumor cells. PMEA derivatives, which are insoluble acrylate polymers, induced coacervation in water to form polymer-dense droplets via hydrophobic interaction. Interestingly, the accumulation of coacervate droplets to tumor cells was involved in the bound water content of PMEA derivatives. Coacervate droplets with a high bound water content accumulated and internalized up to 36.6-fold higher in HeLa cervical tumor cells than in normal human fibroblasts (NHDF). Moreover, the interactions between coacervate droplets and plasma membrane components such as CD44 played a key role in this accumulation process. Therefore, coacervate droplets formed from PMEA derivatives have great clinical potential in tumor cell detection, development of alternative tumor-targeting ligands, and optimization of drug delivery carriers.

DOI： 10.1021/acs.biomac.1c01343

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

There is a long, ongoing debate on how small molecules (osmolytes) affect the stability of proteins. The present study found that change in collective rotational dynamics of water in osmolyte solutions likely has a dominant effect on protein denaturation. According to THz spectroscopy analysis, osmolytes that stabilize proteins are accompanied by bound hydration water with slow dynamics, while the collective rotational dynamics of water is accelerated in the case of denaturant osmolytes. Among 15 osmolytes studied here, there is a good correlation between the change in mobility in terms of water rotational dynamics and the denaturation temperature of ribonuclease A. The changes in water dynamics due to osmolytes can be regarded as a pseudo-temperature-change, which agrees well with the change in protein denaturation temperature. These results indicate that the molecular dynamics of water around the protein is a key factor for protein denaturation.

DOI： 10.1021/acs.jpcb.1c10634

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Physical Chemistry B  

In some synthetic polymers used for medical applications, hydration water in the vicinity of the polymer chains is known to play an important role in biocompatibility and is referred to as intermediate water. The crystallization of water below 0 °C observed during thermal analysis has been considered as evidence of the presence of intermediate water. However, the origin and physicochemical properties of intermediate water have not yet been elucidated. In this study, as a typical biocompatible polymer, poly(ethylene oxide) and its hydration water were investigated with the use of terahertz time-domain spectroscopy and quasi-elastic neutron scattering. The obtained results prove the existence of a significant amount of mobile water that interacts with the polymer chains even when the water content is low at physiological temperatures.

DOI： 10.1021/acs.jpcb.1c09044

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Blood-compatible materials that do not promote reactions in contact with human blood are required to support emerging medical technologies. The interfaces of poly(2-methoxyethyl acrylate) (PMEA), a blood-compatible polymer, and its analogues were investigated by frequency modulation atomic force microscopy (FM-AFM). The grafted polymers exhibited phase separation into polymer-rich and water-rich domains. Thin repulsive layers of hydrated polymer chains were observed in the water-rich domains of the blood-compatible polymers; on the other hand, such layers were not observed for the non-blood-compatible polymers. We report for the first time that FM-AFM enables characteristic repulsive layers composed of hydrated polymer chains in water-rich domains to be observed, which is a significant design factor for blood-compatible polymers.

DOI： 10.1016/j.msec.2021.112596

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

Circulating tumor cells in body fluids are important biomarkers in cancer diagnosis. The culture of tumor cells isolated from body fluids can provide intrinsic information about tumors and can be used to screen for the best anticancer drugs. However, the culture of primary tumor cells has been hindered by their low viability and difficulties in recapitulating the phenotype of primary tumors in in vitro culture. The culture of tumor cells under serum-free conditions is one of the methodologies to maintain the phenotype and genotype of primary tumors. Poly(2-methoxyethyl acrylate) (PMEA)-coated substrates have been investigated to prolong the proliferation of tumor cells under serum-free conditions. In this study, we investigated the detailed behavior and the mechanism of the increase in tumor cell viability after adherence to PMEA substrates. The blebbing formation of tumor cells on PMEA was attributed not to apoptosis but to the low adhesion strength of cells on PMEA. Moreover, blebbing tumor cells showed amoeboid movement and formed clusters with other cells via N-cadherin, leading to an increase in tumor cell viability. Furthermore, the behaviors of tumor cells adhered to PMEA under serum-free conditions were involved in the activation of the PI3K and Rho-associated protein kinase pathways. Thus, we propose that PMEA would be suitable for the development of devices to cultivate primary tumor cells under serum-free conditions for the label-free diagnosis of cancer.

DOI： 10.1021/acsbiomaterials.1c01469

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry ({RSC})  

This peptide undergoes a pH-driven conformational switch between a random coil structure with a flexible linear RGD epitope and a β-hairpin structure with a rigid RGD loop. The β-hairpin-structured peptide is more readily internalized by tumor cells.

DOI： 10.1039/d1cc06218b

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

Fluorine-containing polymers are used not only in industrial processes but also in medical applications, because they exhibit excellent heat, weather, and chemical resistance. As these polymers are not easily degraded in our body, it is difficult to use them in applications that require antithrombotic properties, such as artificial blood vessels. The material used for medical applications should not only be stable in vivo, but it should also be inert to biomolecules such as proteins or cells. In this review, this property is defined as “bio-inert,” and previous studies in this field are summarized. Bio-inert materials are less recognized as foreign substances by proteins or cells in the living body, and they must be covered at interfaces designed with the concept of intermediate water (IW). On the basis of this concept, we present here the current understanding of bio-inertness and unusual blood compatibility found in fluoropolymers used in biomedical applications. IW is the water that interacts with materials with moderate strength and has been quantified by a variety of analytical methods and simulations. For example, by using differential scanning calorimetry (DSC) measurements, IW was defined as water frozen at around -40°C. To consider the role of the IW, quantification methods of the hydration state of polymers are also summarized. These investigations have been conducted independently because of the conflict between hydrophobic fluorine and bio-inert properties that require hydrophilicity. In recent years, not many materials have been developed that incorporate the good points of both aspects, and their properties have seldom been linked to the hydration state. This has been critically performed now. Furthermore, fluorine-containing polymers in medical use are reviewed. Finally, this review also describes the molecular design of the recently reported fluorine-containing bio-inert polymers for controlling their hydration state. Statement of significance: A material covered with a hydration layer known as intermediate water that interacts moderately with other objects is difficult to be recognized as a foreign substance and exhibits bio-inert properties. Fluoropolymers show high durability, but conflict with bio-inert characteristics requiring hydrophilicity as these research studies have been conducted independently. On the other hand, materials that combine the advantages of both hydrophobic and hydrophilic features have been developed recently. Here, we summarize the molecular architecture and analysis methods that control intermediate water and provide a guideline for designing novel fluorine-containing bio-inert materials.

DOI： 10.1016/j.actbio.2021.10.027

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

Poly(ethylene glycol)-conjugated amphiphilic block copolymers, which contain degradable hydrophobic blocks connected by a rigid hydrogen-bonding motif (RHM), are developed to yield anisotropic nanoassemblies in a manner independent of the crystalline nature of the hydrophobic block. The all-atom and coarse-grained molecular dynamics simulations suggest that the anisotropic alignment of the block copolymers can be attributed to the π-πinteractions of the RHM and the crystallizable hydrophobic blocks help maintain the aligned structure. Light scattering analysis of the polymer assemblies demonstrates the formation of nonspherical assemblies by the RHM-containing block copolymers with an amorphous hydrophobic block; this indicates the strong contribution of the RHM to the directed assembly of the block copolymers, unlike crystallization-driven self-assembly. Enhanced cell proliferation is observed in cell cultures containing normal human fibroblasts in the presence of the anisotropic polymer assemblies with aspect ratios greater than 12 or lengths greater than 310 nm.

DOI： 10.1021/acs.macromol.1c01894

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Interactions involving intermediate water are crucial for the design of novel blood-compatible materials. Herein, we use a combination of atomic force microscopy, quartz crystal microbalance measurements, and soft X-ray emission spectroscopy to investigate the local hydrogen-bonded configuration of water on blood-compatible poly(2-methoxyethyl acrylate) and non-blood-compatible poly(n-butyl acrylate) grafted on a gold substrate. We find that the initially incorporated water induces polymer-dependent phase separation, facilitating further water uptake. For the blood-compatible polymer, tetrahedrally coordinated water coexists with water adsorbed on C═O groups in low-density regions of the grafted polymer surface, providing a scaffold for the formation of intermediate water. The amount of intermediate water is determined by the type of functional groups, local polymer configuration, and polymer morphology. Thus, blood compatibility is governed by the complex water/polymer interactions.

DOI： 10.1021/acs.langmuir.1c02672

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DOI： 10.1038/s41428-021-00555-2

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DOI： 10.1039/D2RA04885J

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DOI： 10.1039/d2ra04885j

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DOI： 10.1002/pol.20210410

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DOI： 10.1002/pol.20210496

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A conformable microneedle biochemical detection platform that can diagnose metabolic disease has been developed.

DOI： 10.1126/sciadv.abi6290

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Peptide-based self-assembled monolayers (peptide-SAMs) with specific zwitterionic amino acid sequences express an anti-biofouling property. In this work, we performed protein adsorption and cell adhesion tests using peptide-SAMs with repeating units of various zwitterionic pairs of amino acids (EK, DK, ER, and DR). The SAMs with the repeating units of EK and DK (EK and DK SAMs) manifested excellent bioinertness, whereas the SAMs with the repeating units of ER and DR (ER and DR SAMs) adhered proteins and cells. We also performed surface force measurements using atomic force microscopy to elucidate the mechanism underlying the difference in the anti-biofouling property. Our measurements revealed that water-induced repulsion with a range of about 8 nm acts between EK SAMs (immobilized on both probe and substrate) and DK SAMs, whereas such repulsion was not observed for ER and DR SAMs. The strength of the repulsion exhibited a clear correlation with the protein- and cell-resistance of the SAMs, indicating that the interfacial water in the vicinity of EK and DK SAMs is considered as a physical barrier to deter protein and cells from their adsorption or adhesion. The range of the repulsion observed for EK and DK SAMs is longer than 8 nm, indicating that the hydrogen bonding state of the interfacial water with a thickness of 4 nm is modified by EK and DK SAMs, resulting in the expression of the anti-biofouling property.

DOI： 10.3389/fchem.2021.748017

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

<jats:p>The dynamic behavior of water molecules and polymer chains in a hydrated poly(methyl methacrylate) (PMMA) matrix containing a small amount of water molecules was investigated. Water molecules have been widely recognized as plasticizers for activating the segmental motion of polymer chains owing to their ability to reduce the glass transition temperature. In this study, combined with judicious hydrogen/deuterium labeling, we conducted quasi-elastic neutron scattering (QENS) experiments on PMMA for its dry and hydrated states. Our results clearly indicate that the dynamics of hydrated polymer chains are accelerated, and that individual water molecules are slower than bulk water. It is therefore suggested that the hydration water affects the local motion of PMMA and activates the local relaxation process known as restricted rotation, which is widely accepted to be generally insensitive to changes in the microenvironment.</jats:p>

DOI： 10.3389/fchem.2021.728738

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DOI： 10.1021/acs.macromol.1c00970

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DOI： 10.1246/cl.210335

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

In this study, a blood-compatible polymer, poly(2-methoxyethyl acrylate) (PMEA), was grafted onto a gold substrate with various grafting densities (sigma) (sigma = 0-0.18 chains nm(-2)), and the amount of hydrated water and mobility of the polymer chain interacting with water molecules were quantitatively evaluated using a quartz crystal microbalance with an admittance system. The amount of hydrated water decreased with increasing sigma. By contrast, the mobility of the hydrated PMEA was maximum at sigma approximate to 0.12 chains nm(-2), revealing that the amount of high-mobility water at sigma = 0.12 was higher than that at other densities. The degree of denaturation of the adsorbed fibrinogen was evaluated based on the hydrodynamic water ratio and viscoelasticity, and was found to increase with increasing sigma. The denaturation of adsorbed fibrinogen was suppressed when both the amount of hydrated water and the mobility of hydrated PMEA were high. This study demonstrates that the interfacial state of the polymer chains hydrated in water is important for blood compatibility.

DOI： 10.1002/pol.20210496

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This study focuses on dendritic glycerols and investigates the construction of biocompatible surfaces by understanding how differences in the branching of these molecules change the interactions with the biological components. The two molecules, polyglycerol dendrimer (PGD), which has a completely branched structure, and hyperbranched polyglycerol (HPG), which has an incompletely branched structure, are compared and the differences in branching are evaluated. It is shown that PGD has a little bit more intermediate water than HPG, which reflects the differences in the branching. The effect of surface state on the adsorption of the plasma proteins, human serum albumin (HSA), fibrinogen (Fib), and fibronectin (FN), is discussed by modifying a glass surface using these molecules with different hydration states. The adsorption of HSA decreases to several percent for HPG and 10% for PGD compared to unmodified substrate. Although the adsorption of Fib decreases to 5% for HPG, an increase to 150% is observed for PGD. Since this specific Fib adsorption observed only onto PGD is suppressed in the cases of a mixed solution of HSA and Fib or sequentially using HSA solution and then Fib solution, it is thought that the Vroman effect is suppressed on the PGD-modified surface. Furthermore, when AFM measurements are performed in PBS to understand the surface roughness, PGD is found to be more highly non-uniform. Because of this, the nanometer scale roughness that is significantly observed only on the PGD-modified surface is thought to have an effect on the characteristic adsorption properties of Fib. Thus, although both PGD and HPG with different branching have intermediate water, the proportion differs between PGD and HPG. Therefore, it is found that differences occur in the plasma protein adsorption mechanisms depending on the coordinates and density of hydroxyl groups within the molecules.

DOI： 10.1021/acs.langmuir.1c01003

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DOI： 10.1021/acs.langmuir.1c01003

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DOI： 10.1021/acs.jpcb.1c01864

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DOI： 10.1002/pol.20210410

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DOI： 10.1016/j.actbio.2021.07.058

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DOI： 10.1021/acs.jpcb.1c01864

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DOI： 10.3390/ijms22158038

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DOI： 10.3390/ijms22158038

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DOI： 10.1021/acs.biomac.1c00411

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DOI： 10.1021/acsbiomaterials.1c00388

Language：Japanese   Publishing type：Research paper (scientific journal)  

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DOI： 10.1021/acs.biomac.1c0041

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DOI： 10.1055/a-1441-8239

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The regulation of adhesion and the subsequent behavior of fibroblast cells on the surface of biomaterials is important for successful tissue regeneration and wound healing by implanted biomaterials. We have synthesized poly(ω-methoxyalkyl acrylate)s (PMCxAs; x indicates the number of methylene carbons between the ester and ethyl oxygen), with a carbon chain length of x = 2–6, to investigate the regulation of fibroblast cell behavior including adhesion, proliferation, migration, differentiation and collagen production. We found that PMC2A suppressed the cell spreading, protein adsorption, formation of focal adhesion, and differentiation of normal human dermal fibroblasts, while PMC4A surfaces enhanced them compared to other PMCxAs. Our findings suggest that fibroblast activities attached to the PMCxA substrates can be modified by changing the number of methylene carbons in the side chains of the polymers. These results indicate that PMCxAs could be useful coating materials for use in skin regeneration and wound dressing applications.

DOI： 10.3390/coatings11040461

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Intermediate water (IW), which is formed not only by biocompatible polymers such as poly(2-methoxyethyl acrylate) (PMEA), but also by biomacromolecules, plays a key role in determining the biocompatibility of synthetic polymers. In this study, we compare the well-defined linear and cyclic PMEA using differential scanning calorimetry and atomic force microscopy. This study aims to clarify the role of the chain-end effect in IW formation to establish design guidelines for biomaterials.

DOI： 10.1055/a-1441-8239

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The regulation of adhesion and the subsequent behavior of fibroblast cells on the surface of biomaterials is important for successful tissue regeneration and wound healing by implanted biomaterials. We have synthesized poly(ω-methoxyalkyl acrylate)s (PMCxAs; x indicates the number of methylene carbons between the ester and ethyl oxygen), with a carbon chain length of x = 2–6, to investigate the regulation of fibroblast cell behavior including adhesion, proliferation, migration, differentiation and collagen production. We found that PMC2A suppressed the cell spreading, protein adsorption, formation of focal adhesion, and differentiation of normal human dermal fibroblasts, while PMC4A surfaces enhanced them compared to other PMCxAs. Our findings suggest that fibroblast activities attached to the PMCxA substrates can be modified by changing the number of methylene carbons in the side chains of the polymers. These results indicate that PMCxAs could be useful coating materials for use in skin regeneration and wound dressing applications.

DOI： 10.3390/coatings11040461

Language：Japanese   Publishing type：Research paper (scientific journal)  

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DOI： 10.1021/acs.macromol.0c02611

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An excellent blood-compatible polymer, poly(2-methoxyethyl acrylate) (PMEA), exhibits nanometer-scale phase-separated structures at the interface with water or phosphate-buffered saline (PBS), and fibrinogen adsorption is suppressed, especially on the water-rich region. To understand the correlation between the interfacial structure based on the grafting density of PMEA and blood compatibility, grafted PMEA (gPMEA) surfaces with controlled density were prepared by immobilizing thiol-terminated PMEA on a gold substrate. The amount of adsorbed fibrinogen and the number of adhered platelets on gPMEAs decreased first with the increasing grafting density (σ), but increased after showed minimum at σ of approximately 0.11 chains/nm . The interfacial structures of the gPMEA/PBS interface changed with grafting density, and the maximum area of water-rich region was obtained at σ = 0.11. The water contact angle at σ = 0.11 is smaller than that at the other grafting density. These results revealed that hydration to the polymer is very effective to suppress the platelet adhesion and water-rich region shows excellent blood compatibility on gPMEA surfaces. This work clearly indicated that the density of PMEA affects the interfacial structure and plays an important role in the blood compatibility of the material. 2

DOI： 10.1016/j.colsurfb.2020.111517

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

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Polymers that are biocompatible and degradable are desired for tissue engineering approaches in the treatment of vascular diseases, especially for those involving small-diameter blood vessels. Herein, we report the compatibility of a newly developed glycerol-based aliphatic polycarbonate possessing simple methoxy side groups, named poly(5-methoxy-1,3-dioxan-2-one) (PMDO), with blood cells and plasma proteins as well as its susceptibility to hydrolysis. As a consequence of the organocatalytic ring-opening polymerization (ROP) of a methoxy-functionalized cyclic carbonate derived from glycerol, PMDO with a sufficiently high molecular weight (Mn 14 kg/mol) and a narrow distribution (DM 1.12) was obtained for evaluation as a bulk biomaterial. This study demonstrates for the first time the organocatalytic ROP of a glycerol-based cyclic carbonate in a controlled manner. Compared with the clinically applied aliphatic polycarbonate poly(trimethylene carbonate) (PTMC), PMDO inhibits platelet adhesion by 33&#37; and denaturation of fibrinogen by 23&#37;. Although the wettability of PMDO based on water contact angle was almost comparable to those of PTMC and poly(ethylene terephthalate), the reason for the inhibited platelet adhesion and protein denaturation appeared to be related to the presence of specific hydrated water formed in the hydrated polymer. The improved hydration of PMDO also enhanced the susceptibility to hydrolysis, with PMDO demonstrating a slightly higher hydrolytic property than PTMC. This simple glycerol-based aliphatic polycarbonate has the following benefits: bio-based characteristics of glycerol and improved blood compatibility and hydrolytic biodegradability stemming from moderate hydration of the methoxy side groups.

DOI： 10.1021/acsbiomaterials.0c01460

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DOI： 10.1016/j.msec.2020.111386

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DOI： 10.1021/acsbiomaterials.0c01220

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DOI： 10.1021/acsbiomaterials.0c01220

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

Water molecules play a crucial role in biointerfacial interactions, including protein adsorption and desorption. To understand the role of water in the interaction of proteins and cells at biological interfaces, it is important to compare particular states of hydration water with various physicochemical properties of hydrated biomaterials. In this review, we discuss the fundamental concepts for determining the interactions of proteins and cells with hydrated materials along with selected examples corresponding to our recent studies, including poly(2-methoxyethyl acrylate) (PMEA), PMEA derivatives, and other biomaterials. The states of water were analyzed by differential scanning calorimetry, in situ attenuated total reflection infrared spectroscopy, and surface force measurements. We found that intermediate water which is loosely bound to a biomaterial, is a useful indicator of the bioinertness of material surfaces. This finding on intermediate water provides novel insights and helps develop novel experimental models for understanding protein adsorption in a wide range of materials, such as those used in biomedical applications.

DOI： 10.1016/j.colsurfb.2020.111449

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DOI： 10.1021/acsapm.0c00776

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DOI： 10.1021/acsapm.0c00776

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DOI： 10.1021/acs.macromol.0c01144

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DOI： 10.1021/acs.macromol.0c01144

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DOI： 10.1021/acsbiomaterials.0c00746

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DOI： 10.1021/acsbiomaterials.0c00746

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DOI： 10.1021/acsbiomaterials.0c00230

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DOI： 10.1021/acsbiomaterials.0c00230

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Circulating tumor cells (CTCs) are highly related to tumor metastasis and an effective technique of detecting/isolating CTCs has been expected to be established for tumor treatments. Previously, we reported that platelets cannot adhere but tumor cells can adhere on poly(2-methoxyethyl acrylate) (PMEA) substrate. In this study, we report that cell viability of human fibrosarcoma (HT-1080) cells was promoted on PMEA substrate in serum-free medium. The significant blebbing-like phenomenon and spontaneous formation of cell aggregation were observed on PMEA substrate. Moreover, cell viability was promoted by activation of Akt signaling pathway via N-cadherin-mediated cell-cell contact. These results suggest that not only capture efficiency and purity but also high cell viability of CTCs can be accomplished by using PMEA substrate. PMEA substrate can be a promising candidate for medical applications such as in vitro screening of anticancer drugs and is an excellent platform for studies and diagnoses of tumor migration and metastasis.

DOI： 10.1021/acsabm.9b00885

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DOI： 10.1021/acsabm.9b00885

Language：Others   Publishing type：Research paper (scientific journal)  

Copyright © 2020 American Chemical Society. Circulating tumor cells (CTCs) are highly related to tumor metastasis and an effective technique of detecting/isolating CTCs has been expected to be established for tumor treatments. Previously, we reported that platelets cannot adhere but tumor cells can adhere on poly(2-methoxyethyl acrylate) (PMEA) substrate. In this study, we report that cell viability of human fibrosarcoma (HT-1080) cells was promoted on PMEA substrate in serum-free medium. The significant blebbing-like phenomenon and spontaneous formation of cell aggregation were observed on PMEA substrate. Moreover, cell viability was promoted by activation of Akt signaling pathway via N-cadherin-mediated cell-cell contact. These results suggest that not only capture efficiency and purity but also high cell viability of CTCs can be accomplished by using PMEA substrate. PMEA substrate can be a promising candidate for medical applications such as in vitro screening of anticancer drugs and is an excellent platform for studies and diagnoses of tumor migration and metastasis.

DOI： 10.1021/acsabm.9b00885

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DOI： 10.1021/acsabm.9b00885

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

Circulating tumor cells (CTCs) are highly related to tumor metastasis and an effective technique of detecting/isolating CTCs has been expected to be established for tumor treatments. Previously, we reported that platelets cannot adhere but tumor cells can adhere on poly(2-methoxyethyl acrylate) (PMEA) substrate. In this study, we report that cell viability of human fibrosarcoma (HT-1080) cells was promoted on PMEA substrate in serum-free medium. The significant blebbing-like phenomenon and spontaneous formation of cell aggregation were observed on PMEA substrate. Moreover, cell viability was promoted by activation of Akt signaling pathway via N-cadherin-mediated cell-cell contact. These results suggest that not only capture efficiency and purity but also high cell viability of CTCs can be accomplished by using PMEA substrate. PMEA substrate can be a promising candidate for medical applications such as in vitro screening of anticancer drugs and is an excellent platform for studies and diagnoses of tumor migration and metastasis.

DOI： 10.1021/acsabm.9b00885

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

The effect of a magnetic field on the water contact angle for magnetic elastomers with various plasticizer contents was investigated. At a plasticizer content below 60 wt %, there was no change in contact angle when a magnetic field of 370 mT was applied. For magnetic elastomers with a plasticizer content above 65 wt %, a change in contact angle of approximately 8.0 degrees was observed (e.g. 38 degrees at 0 mT and 46 degrees at 370 mT for 65 wt % plasticizer content). Dynamic viscoelastic measurements showed that magnetic elastomers with a plasticizer content below 60 wt % demonstrate the magnetorheological (MR) effect with changes in storage modulus higher than similar to 1 MPa. Atomic force microscopy for magnetic elastomer with a plasticizer content of 50 wt % revealed that the averaged Young's modulus was 233 +/- 52.1 kPa at 370 mT and 83 +/- 5.4 kPa at 0 mT, indicating that the MR effect is caused not only on a bulk but also on a mesoscopic scale. Magnetic elastomers specialized for cell culture were obtained by optimizing the plasticizer content, that exhibit the MR effect with changes in storage modulus from 1.3 x 10(4) Pa to 9.4 x 10(5) without changing the surface properties.

DOI： 10.1246/cl.190929

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

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

The effect of a magnetic field on the water contact angle for magnetic elastomers with various plasticizer contents was investigated. At a plasticizer content below 60 wt %, there was no change in contact angle when a magnetic field of 370 mT was applied. For magnetic elastomers with a plasticizer content above 65 wt %, a change in contact angle of approximately 8.0° was observed (e.g. 38° at 0 mT and 46° at 370 mT for 65 wt % plasticizer content). Dynamic viscoelastic measurements showed that magnetic elastomers with a plasticizer content below 60 wt % demonstrate the magnetorheological (MR) effect with changes in storage modulus higher than ³1 MPa. Atomic force microscopy for magnetic elastomer with a plasticizer content of 50 wt % revealed that the averaged Young’s modulus was 233 « 52.1 kPa at 370 mT and 83 « 5.4 kPa at 0 mT, indicating that the MR effect is caused not only on a bulk but also on a mesoscopic scale. Magnetic elastomers specialized for cell culture were obtained by optimizing the plasticizer content, that exhibit the MR effect with changes in storage modulus from 1.3

DOI： 10.1246/cl.190929

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1080/09205063.2019.1680930

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

The effect of a magnetic field on the water contact angle for magnetic elastomers with various plasticizer contents was investigated. At a plasticizer content below 60 wt %, there was no change in contact angle when a magnetic field of 370 mT was applied. For magnetic elastomers with a plasticizer content above 65 wt %, a change in contact angle of approximately 8.0° was observed (e.g. 38° at 0 mT and 46° at 370 mT for 65 wt % plasticizer content). Dynamic viscoelastic measurements showed that magnetic elastomers with a plasticizer content below 60 wt % demonstrate the magnetorheological (MR) effect with changes in storage modulus higher than ³1 MPa. Atomic force microscopy for magnetic elastomer with a plasticizer content of 50 wt % revealed that the averaged Young’s modulus was 233 « 52.1 kPa at 370 mT and 83 « 5.4 kPa at 0 mT, indicating that the MR effect is caused not only on a bulk but also on a mesoscopic scale. Magnetic elastomers specialized for cell culture were obtained by optimizing the plasticizer content, that exhibit the MR effect with changes in storage modulus from 1.3

DOI： 10.1246/cl.190929

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

The practical use of the viscous liquid polymer, poly(2-methoxyethyl acrylate) (PMEA), was expanded from thin films with excellent blood compatibility to thick coatings and free-standing films without essentially sacrificing its blood compatibility. This was undertaken by creating multiple hydrogen-bonding polymer networks by introducing a functional methacrylic monomer bearing a 6-methyl-2-ureido-4[1H]-pyrimidone group in the PMEA backbone via free radical copolymerization. The hydrogen-bonded PMEA (H-PMEA) contained about 6 mol % of the functional monomer in the copolymer. These functional monomers as physical cross-links are distributed in the PMEA matrix with a T_g of -35 °C, making H-PMEA a solid rubber-like material with recoverable tensile strain. Additionally, mechanical tests revealed its tensile strength, and thermogravimetric analyses confirmed its higher thermostability. The dry and hydration states of H-PMEA were assessed by differential scanning calorimetry, contact angle, and atomic force microscopy measurements. Comparison with viscous PMEA was made. For the first time, we included PVC alongside PET, the surface we usually use as a negative control, in the platelet adhesion test with human blood, and found out that 1.5 times more platelets adhered onto the PVC surface than onto the PET surface, while H-PMEA proved to have a clear edge. Thus, H-PMEA may serve as a suitable replacement for polymers in products contacting blood as it shows potential for making free-standing films, thick coatings, implants, and articles with various geometries for the medicinal industry.

DOI： 10.1021/acsabm.9b00363

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DOI： 10.1021/acsabm.9b00363

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Hydration States and Blood Compatibility of Hydrogen-Bonded Supramolecular Poly(2-methoxyethyl acrylate)
Copyright © 2019 American Chemical Society. The practical use of the viscous liquid polymer, poly(2-methoxyethyl acrylate) (PMEA), was expanded from thin films with excellent blood compatibility to thick coatings and free-standing films without essentially sacrificing its blood compatibility. This was undertaken by creating multiple hydrogen-bonding polymer networks by introducing a functional methacrylic monomer bearing a 6-methyl-2-ureido-4[1H]-pyrimidone group in the PMEA backbone via free radical copolymerization. The hydrogen-bonded PMEA (H-PMEA) contained about 6 mol &#37; of the functional monomer in the copolymer. These functional monomers as physical cross-links are distributed in the PMEA matrix with a Tg of -35 °C, making H-PMEA a solid rubber-like material with recoverable tensile strain. Additionally, mechanical tests revealed its tensile strength, and thermogravimetric analyses confirmed its higher thermostability. The dry and hydration states of H-PMEA were assessed by differential scanning calorimetry, contact angle, and atomic force microscopy measurements. Comparison with viscous PMEA was made. For the first time, we included PVC alongside PET, the surface we usually use as a negative control, in the platelet adhesion test with human blood, and found out that 1.5 times more platelets adhered onto the PVC surface than onto the PET surface, while H-PMEA proved to have a clear edge. Thus, H-PMEA may serve as a suitable replacement for polymers in products contacting blood as it shows potential for making free-standing films, thick coatings, implants, and articles with various geometries for the medicinal industry.

DOI： 10.1021/acsabm.9b00363

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

The practical use of the viscous liquid polymer, poly(2-methoxyethyl acrylate) (PMEA), was expanded from thin films with excellent blood compatibility to thick coatings and free-standing films without essentially sacrificing its blood compatibility. This was undertaken by creating multiple hydrogen-bonding polymer networks by introducing a functional methacrylic monomer bearing a 6-methyl-2-ureido-4[1H]-pyrimidone group in the PMEA backbone via free radical copolymerization. The hydrogen-bonded PMEA (H-PMEA) contained about 6 mol % of the functional monomer in the copolymer. These functional monomers as physical cross-links are distributed in the PMEA matrix with a T_g of -35 °C, making H-PMEA a solid rubber-like material with recoverable tensile strain. Additionally, mechanical tests revealed its tensile strength, and thermogravimetric analyses confirmed its higher thermostability. The dry and hydration states of H-PMEA were assessed by differential scanning calorimetry, contact angle, and atomic force microscopy measurements. Comparison with viscous PMEA was made. For the first time, we included PVC alongside PET, the surface we usually use as a negative control, in the platelet adhesion test with human blood, and found out that 1.5 times more platelets adhered onto the PVC surface than onto the PET surface, while H-PMEA proved to have a clear edge. Thus, H-PMEA may serve as a suitable replacement for polymers in products contacting blood as it shows potential for making free-standing films, thick coatings, implants, and articles with various geometries for the medicinal industry.

DOI： 10.1021/acsabm.9b00363

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

Poly(2-methoxyethyl acrylate) (PMEA) shows excellent blood compatibility because of the existence of intermediate water. Various modifications of PMEA by changing its main or side chain's chemical structure allowed tuning of the water content and the blood compatibility of numerous novel polymers. Here, we exploit a possibility of manipulating the surface hydration structure of PMEA by incorporation of small amounts of hydrophobic fluorine groups in MEA polymers using atom-transfer radical polymerization and the (macro) initiator concept. Two kinds of fluorinated MEA polymers with similar molecular weights and the same 5.5 mol % of fluorine content were synthesized using the bromoester of 2,2,3,3,4,4,5,5,6,6,7,7,8,8-pentadecafluoro-1-octanol (F15) and poly(2,2,2-trifluoroethyl methacrylate) (PTFEMA) as (macro) initiators, appearing liquid and solid at room temperature, respectively. The fibrinogen adsorption of the two varieties of fluorinated MEA polymers was different, which could not be explained only by the bulk hydration structure. Both polymers show a nanostructured morphology in the hydrated state with different sizes of the features. The measured elastic modulus of the domains appearing in atomic force microscopy and the intermediate water content shed light on the distinct mechanism of blood compatibility. Contact angle measurements reveal the surface hydration dynamics - while in the hydrated state, F15-b-PMEA reorients easily to the surface exposing its PMEA part to the water, the small solid PTFEMA block with high glass-transition temperature suppresses the movement of PTFEMA-b-PMEA and its reconstruction on the surface. These findings illustrate that in order to make a better blood compatible polymer, the chains containing sufficient intermediate water need to be mobile and efficiently oriented to the water surface.

DOI： 10.1021/acs.biomac.9b00201

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1021/acs.biomac.9b00201

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

Poly(2-methoxyethyl acrylate) (PMEA) shows excellent blood compatibility because of the existence of intermediate water. Various modifications of PMEA by changing its main or side chain's chemical structure allowed tuning of the water content and the blood compatibility of numerous novel polymers. Here, we exploit a possibility of manipulating the surface hydration structure of PMEA by incorporation of small amounts of hydrophobic fluorine groups in MEA polymers using atom-transfer radical polymerization and the (macro) initiator concept. Two kinds of fluorinated MEA polymers with similar molecular weights and the same 5.5 mol % of fluorine content were synthesized using the bromoester of 2,2,3,3,4,4,5,5,6,6,7,7,8,8-pentadecafluoro-1-octanol (F15) and poly(2,2,2-trifluoroethyl methacrylate) (PTFEMA) as (macro) initiators, appearing liquid and solid at room temperature, respectively. The fibrinogen adsorption of the two varieties of fluorinated MEA polymers was different, which could not be explained only by the bulk hydration structure. Both polymers show a nanostructured morphology in the hydrated state with different sizes of the features. The measured elastic modulus of the domains appearing in atomic force microscopy and the intermediate water content shed light on the distinct mechanism of blood compatibility. Contact angle measurements reveal the surface hydration dynamics - while in the hydrated state, F15-b-PMEA reorients easily to the surface exposing its PMEA part to the water, the small solid PTFEMA block with high glass-transition temperature suppresses the movement of PTFEMA-b-PMEA and its reconstruction on the surface. These findings illustrate that in order to make a better blood compatible polymer, the chains containing sufficient intermediate water need to be mobile and efficiently oriented to the water surface.

DOI： 10.1021/acs.biomac.9b00201

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

Neural interfaces enabling light transmittance rely on optogenetics to control and monitor specific neural activity, thereby facilitating deeper understanding of intractable diseases. This study reports the material strategy underlying an optogenetic neural interface comprising stretchable and transparent conductive tracks and capable of demonstrating high biocompatibility after long-term (5-month) implantation. Ag/Au core–shell nanowires contribute toward improving track performance in terms of stretchability (<60% strain), transparency (<83%), and electrical resistance (15 Ω sq⁻¹). The neural interface integrated with gel-coated exterior microelectrodes preserves low impedance (1.1–3.2 Ω cm²) in a saline solution over the evaluated 5-month period. Besides the use of efficient conductive materials, surface treatment using antithrombogenic polymer tends to prevent the growth of granulation tissue, thereby facilitating clear monitoring of electrocorticograms (ECoG) in a rodent during chronic implantation. The flexible and transparent neural interface pathologically exhibits noncytotoxicity and low inflammatory response while efficiently recording evoked ECoG in a nonhuman primate via optogenetic stimulation. The proposed highly reliable interface can be employed in multifaceted approaches for translational research based on chronic implants.

DOI： 10.1002/adhm.201900130

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

© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Neural interfaces enabling light transmittance rely on optogenetics to control and monitor specific neural activity, thereby facilitating deeper understanding of intractable diseases. This study reports the material strategy underlying an optogenetic neural interface comprising stretchable and transparent conductive tracks and capable of demonstrating high biocompatibility after long-term (5-month) implantation. Ag/Au core–shell nanowires contribute toward improving track performance in terms of stretchability (<60% strain), transparency (<83%), and electrical resistance (15 Ω sq−1). The neural interface integrated with gel-coated exterior microelectrodes preserves low impedance (1.1–3.2 Ω cm2) in a saline solution over the evaluated 5-month period. Besides the use of efficient conductive materials, surface treatment using antithrombogenic polymer tends to prevent the growth of granulation tissue, thereby facilitating clear monitoring of electrocorticograms (ECoG) in a rodent during chronic implantation. The flexible and transparent neural interface pathologically exhibits noncytotoxicity and low inflammatory response while efficiently recording evoked ECoG in a nonhuman primate via optogenetic stimulation. The proposed highly reliable interface can be employed in multifaceted approaches for translational research based on chronic implants.

DOI： 10.1002/adhm.201900130

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

DOI： 10.1021/acs.biomac.9b00201

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

Neural interfaces enabling light transmittance rely on optogenetics to control and monitor specific neural activity, thereby facilitating deeper understanding of intractable diseases. This study reports the material strategy underlying an optogenetic neural interface comprising stretchable and transparent conductive tracks and capable of demonstrating high biocompatibility after long-term (5-month) implantation. Ag/Au core–shell nanowires contribute toward improving track performance in terms of stretchability (<60% strain), transparency (<83%), and electrical resistance (15 Ω sq⁻¹). The neural interface integrated with gel-coated exterior microelectrodes preserves low impedance (1.1–3.2 Ω cm²) in a saline solution over the evaluated 5-month period. Besides the use of efficient conductive materials, surface treatment using antithrombogenic polymer tends to prevent the growth of granulation tissue, thereby facilitating clear monitoring of electrocorticograms (ECoG) in a rodent during chronic implantation. The flexible and transparent neural interface pathologically exhibits noncytotoxicity and low inflammatory response while efficiently recording evoked ECoG in a nonhuman primate via optogenetic stimulation. The proposed highly reliable interface can be employed in multifaceted approaches for translational research based on chronic implants.

DOI： 10.1002/adhm.201900130

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

Water structures of hydrated polymers have been suggested to directly influence the biomolecules’ adsorption. We conducted a serial of molecular dynamics simulations to investigate the water structures of hydrated poly(2-methoxyethyl acrylate) (PMEA). According to the calculated IR spectra of water molecules categorized into four binding sites in hydrated PMEA, most of water molecules at water content less than 3 wt% are water molecules interacting with two carbonyl groups, corresponding to experimental observed non-freezing water. In addition, we found two-stage variation of the non-bound water content with increasing the water content. The turnover point can be regarded as the saturation point and be used to estimate the equilibrium water content (EWC). Furthermore, the ratio of bound water content to polymer oxygen content was found to be a possible index for predicting the platelet adhesion of polymers. The findings will be useful for developing new biomaterials containing oxygen moieties in the medical applications.

DOI： 10.1016/j.polymer.2019.03.001

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.polymer.2019.03.001

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

Water structures of hydrated polymers have been suggested to directly influence the biomolecules’ adsorption. We conducted a serial of molecular dynamics simulations to investigate the water structures of hydrated poly(2-methoxyethyl acrylate) (PMEA). According to the calculated IR spectra of water molecules categorized into four binding sites in hydrated PMEA, most of water molecules at water content less than 3 wt% are water molecules interacting with two carbonyl groups, corresponding to experimental observed non-freezing water. In addition, we found two-stage variation of the non-bound water content with increasing the water content. The turnover point can be regarded as the saturation point and be used to estimate the equilibrium water content (EWC). Furthermore, the ratio of bound water content to polymer oxygen content was found to be a possible index for predicting the platelet adhesion of polymers. The findings will be useful for developing new biomaterials containing oxygen moieties in the medical applications.

DOI： 10.1016/j.polymer.2019.03.001

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

Water molecules are known to play crucial roles both in the formation and biological function of materials. Herein, we show the presence of “intermediate water” on an inorganic solid material, hydroxyapatite. In vitro experiments revealed that Mg substitution of apatite significantly enriched the amount of intermediate water, possibly due to the proton transfer to a hydrogen-bonded network of water around HPO₄²⁻ on divalent-cation-deficient apatite surfaces. The intermediate water formation related to a markedl su ressed rotein adsor tion on a atite Anal sis of bone a atites suggested that the intermediate water on minerals could play crucial roles in regulating crystal growth.

DOI： 10.1021/acsabm.9b00014

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1021/acsabm.9b00014

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1021/acsabm.9b00014

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

Water molecules are known to play crucial roles both in the formation and biological function of materials. Herein, we show the presence of “intermediate water” on an inorganic solid material, hydroxyapatite. In vitro experiments revealed that Mg substitution of apatite significantly enriched the amount of intermediate water, possibly due to the proton transfer to a hydrogen-bonded network of water around HPO₄²⁻ on divalent-cation-deficient apatite surfaces. The intermediate water formation related to a markedl su ressed rotein adsor tion on a atite Anal sis of bone a atites suggested that the intermediate water on minerals could play crucial roles in regulating crystal growth.

DOI： 10.1021/acsabm.9b00014

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

The blood-compatible polymer poly(2-methoxyethyl acrylate) (PMEA) is composed of nanometer-scale interfacial structures because of the phase separation of the polymer and water at the PMEA/phosphate-buffered saline (PBS) interface. We synthesized PMEA with four different molecular weights (19, 30, 44, and 183 kg/mol) to investigate the effect of the molecular weight on the interfacial structures and blood compatibility. The amounts of intermediate water and fibrinogen adsorption were not affected by the molecular weight of PMEA. In contrast, the degree of denaturation of adsorbed fibrinogen molecules and platelet adhesion increased as the molecular weight increased. Atomic force microscopy observation revealed that the domain size of the microphase separation structures observed at the PMEA/PBS interfaces drastically (nearly 3 times in the mean area of a domain) changed with the molecular weight. PMEA with a lower molecular weight showed a smaller polymer-rich domain size, as expected on the basis of the microphase separation of polymer-rich and water-rich domains. The small domain size suppressed the aggregation and denaturation of adsorbed fibrinogen molecules because only a few fibrinogen molecules were adsorbed on a domain. Increasing the domain size enhanced the denaturation of adsorbed fibrinogen molecules. Controlling the interfacial structures is crucial for ensuring the blood compatibility of polymer interfaces.

DOI： 10.1021/acs.langmuir.8b02971

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1021/acs.langmuir.8b02971

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1021/acs.langmuir.8b02971

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

The blood-compatible polymer poly(2-methoxyethyl acrylate) (PMEA) is composed of nanometer-scale interfacial structures because of the phase separation of the polymer and water at the PMEA/phosphate-buffered saline (PBS) interface. We synthesized PMEA with four different molecular weights (19, 30, 44, and 183 kg/mol) to investigate the effect of the molecular weight on the interfacial structures and blood compatibility. The amounts of intermediate water and fibrinogen adsorption were not affected by the molecular weight of PMEA. In contrast, the degree of denaturation of adsorbed fibrinogen molecules and platelet adhesion increased as the molecular weight increased. Atomic force microscopy observation revealed that the domain size of the microphase separation structures observed at the PMEA/PBS interfaces drastically (nearly 3 times in the mean area of a domain) changed with the molecular weight. PMEA with a lower molecular weight showed a smaller polymer-rich domain size, as expected on the basis of the microphase separation of polymer-rich and water-rich domains. The small domain size suppressed the aggregation and denaturation of adsorbed fibrinogen molecules because only a few fibrinogen molecules were adsorbed on a domain. Increasing the domain size enhanced the denaturation of adsorbed fibrinogen molecules. Controlling the interfacial structures is crucial for ensuring the blood compatibility of polymer interfaces.

DOI： 10.1021/acs.langmuir.8b02971

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

Fibrinogen adsorption behavior on the blood-compatible polymer, poly(2-methoxyethyl acrylate) (PMEA), non-blood-compatible polymer, poly(n-butyl acrylate) (PBA), and random copolymers of both were examined. Adsorption and denaturation of fibrinogen on the polymers increased as the ratio of PBA increased. The incremental change corresponded to the amount of intermediate water included in the hydrated polymers. The composition of PBA altered the features of the phase-separated structures observed on the polymer/phosphate-buffered saline interfaces. Microscopically, the denaturation of fibrinogen was observed as the formation of fibrous networks on the interfaces by atomic force microscopy. Fibrinogen adsorption and denaturation were enhanced on the water-rich domains in the phase-separated structures on the non-blood-compatible polymers. This suggested that the excellent blood compatibility of PMEA is caused by the constrained adsorption and denaturation of fibrinogen in water-rich domains, possibly due to the high content of intermediate water in this region. This work provides essential scientific foundations for the design and fabrication of highly functional biomaterials.

DOI： 10.1080/09205063.2019.1680930

Language：Others   Publishing type：Research paper (scientific journal)  

Design of Polymeric Biomaterials: The "Intermediate Water Concept"
© 2019 The Chemical Society of Japan. When biomaterials come into contact with biological fluids, water molecules immediately adsorb onto the surface of the materials. To understand the origin of the crucial roles of water molecules in biological interfaces, it is necessary to relate particular states of hydration water to various physicochemical properties of hydrated polymers. Here, advances in the inter-mediate water concept are reviewed. This account provides an overview of the progress made in the design of multi-functional biomedical polymers by controlling the bio-interfacial water states. Using principles of intermediate water, which is common in hydrated biopolymers and only biocompatible synthetic polymers, we found the synthetic methodology to create novel biocompatible polymers moves toward a more high-throughput way.

DOI： 10.1246/bcsj.20190274

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

When biomaterials come into contact with biological fluids, water molecules immediately adsorb onto the surface of the materials. To understand the origin of the crucial roles of water molecules in biological interfaces, it is necessary to relate particular states of hydration water to various physicochemical properties of hydrated polymers. Here, advances in the inter-mediate water concept are reviewed. This account provides an overview of the progress made in the design of multi-functional biomedical polymers by controlling the bio-interfacial water states. Using principles of intermediate water, which is common in hydrated biopolymers and only biocompatible synthetic polymers, we found the synthetic methodology to create novel biocompatible polymers moves toward a more high-throughput way.

DOI： 10.1246/bcsj.20190274

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

Fibrinogen adsorption behavior on the blood-compatible polymer, poly(2-methoxyethyl acrylate) (PMEA), non-blood-compatible polymer, poly(n-butyl acrylate) (PBA), and random copolymers of both were examined. Adsorption and denaturation of fibrinogen on the polymers increased as the ratio of PBA increased. The incremental change corresponded to the amount of intermediate water included in the hydrated polymers. The composition of PBA altered the features of the phase-separated structures observed on the polymer/phosphate-buffered saline interfaces. Microscopically, the denaturation of fibrinogen was observed as the formation of fibrous networks on the interfaces by atomic force microscopy. Fibrinogen adsorption and denaturation were enhanced on the water-rich domains in the phase-separated structures on the non-blood-compatible polymers. This suggested that the excellent blood compatibility of PMEA is caused by the constrained adsorption and denaturation of fibrinogen in water-rich domains, possibly due to the high content of intermediate water in this region. This work provides essential scientific foundations for the design and fabrication of highly functional biomaterials.

DOI： 10.1080/09205063.2019.1680930

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

When biomaterials come into contact with biological fluids, water molecules immediately adsorb onto the surface of the materials. To understand the origin of the crucial roles of water molecules in biological interfaces, it is necessary to relate particular states of hydration water to various physicochemical properties of hydrated polymers. Here, advances in the inter-mediate water concept are reviewed. This account provides an overview of the progress made in the design of multi-functional biomedical polymers by controlling the bio-interfacial water states. Using principles of intermediate water, which is common in hydrated biopolymers and only biocompatible synthetic polymers, we found the synthetic methodology to create novel biocompatible polymers moves toward a more high-throughput way.

DOI： 10.1246/bcsj.20190274

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

Science Advances誌　High-precision monitoring of electrophysiological signals with high spatial and temporal resolutions is one of the most important subjects for elucidating physiology functions. Recently, ultraflexible multielectrode arrays (MEAs) have been fabricated to establish conformal contacts with the surface of organs and to measure propagation of electrophysiological signals with high spatial-temporal resolution; however, plastic substrates have high Young's modulus, causing difficulties in creating appropriate stretchability and blood compatibility for applying them on the dynamically moving and surgical bleeding surface of the heart. Here, we have successfully fabricated an active MEA that simultaneously achieves nonthrombogenicity, stretchability, and stability, which allows long-term electrocardiographic (ECG) monitoring of the dynamically moving hearts of rats even with capillary bleeding. Because of the active data readout, the measured ECG signals exhibit a high signal-to-noise ratio of 52 dB. The novel stretchable MEA is carefully designed using state-of-the-art engineering techniques by combining extraordinarily high gain organic electrochemical transistors processed on microgrid substrates and a coating of poly(3-methoxypropyl acrylate), which exhibits significant antithrombotic properties while maintaining excellent ionic conductivity.

DOI： 10.1126/sciadv.aau2426

Language：Others   Publishing type：Research paper (scientific journal)  

Language：Others   Publishing type：Research paper (scientific journal)  

© 2018 The Authors. High-precision monitoring of electrophysiological signals with high spatial and temporal resolutions is one of the most important subjects for elucidating physiology functions. Recently, ultraflexible multielectrode arrays (MEAs) have been fabricated to establish conformal contacts with the surface of organs and to measure propagation of electrophysiological signals with high spatial-temporal resolution; however, plastic substrates have high Young's modulus, causing difficulties in creating appropriate stretchability and blood compatibility for applying them on the dynamically moving and surgical bleeding surface of the heart. Here, we have successfully fabricated an active MEA that simultaneously achieves nonthrombogenicity, stretchability, and stability, which allows long-term electrocardiographic (ECG) monitoring of the dynamically moving hearts of rats even with capillary bleeding. Because of the active data readout, the measured ECG signals exhibit a high signal-to-noise ratio of 52 dB. The novel stretchable MEA is carefully designed using state-of-the-art engineering techniques by combining extraordinarily high gain organic electrochemical transistors processed on microgrid substrates and a coating of poly(3-methoxypropyl acrylate), which exhibits significant antithrombotic properties while maintaining excellent ionic conductivity.

DOI： 10.1126/sciadv.aau2426

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

A Nonthrombogenic, Stretchable, Active Multielectrode Array using Organic Electrochemical Transistors

DOI： 10.1126/sciadv.aau2426

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

High-precision monitoring of electrophysiological signals with high spatial and temporal resolutions is one of the most important subjects for elucidating physiology functions. Recently, ultraflexible multielectrode arrays (MEAs) have been fabricated to establish conformal contacts with the surface of organs and to measure propagation of electrophysiological signals with high spatial-temporal resolution; however, plastic substrates have high Young's modulus, causing difficulties in creating appropriate stretchability and blood compatibility for applying them on the dynamically moving and surgical bleeding surface of the heart. Here, we have successfully fabricated an active MEA that simultaneously achieves nonthrombogenicity, stretchability, and stability, which allows long-term electrocardiographic (ECG) monitoring of the dynamically moving hearts of rats even with capillary bleeding. Because of the active data readout, the measured ECG signals exhibit a high signal-to-noise ratio of 52 dB. The novel stretchable MEA is carefully designed using state-of-the-art engineering techniques by combining extraordinarily high gain organic electrochemical transistors processed on microgrid substrates and a coating of poly(3-methoxypropyl acrylate), which exhibits significant antithrombotic properties while maintaining excellent ionic conductivity.

DOI： 10.1126/sciadv.aau2426

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

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

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

This study presents a drug delivery system of poly (Ɛ-caprolactone) (PCL) ribbons to optimize the pharmaceutical action of tramadol for the first time according to our knowledge. PCL ribbons were fabricated and loaded with tramadol HCl. Ribbons were prepared by slip casting technique and coated with dipping technique with β-cyclodextrin. The chemical integrity and surface morphology of the ribbons were confirmed using FTIR and SEM coupled with EDX. In addition, thermodynamic behavior of the fabricated ribbons was investigated using DSC/TGA. Tramadol loading into PCL ribbons, biodegradation of ribbons and tramadol release kinetics were studied in PBS.The results revealed that the formulated composition did not affect the chemical integrity of the drug. Furthermore, SEM/EDX confirmed the inclusion of tramadol into the PCL matrix in homogenous distribution pattern without any observation of porous structure. The particle size of loaded tramadol was found to be in the range of (2–4 nm). The formulated composition did not affect the chemical integrity of the drug and should be further investigated for bioavailability. Tramadol exhibited controlled release behavior from PCL ribbons up to 45 days governed mainly by diffusion mechanism. The fabricated ribbons have a great potentiality to be implemented in the long term subcutaneous delivery of tramadol.

DOI： 10.1016/j.jsps.2018.01.014

Language：Others   Publishing type：Research paper (scientific journal)  

© 2018 American Chemical Society. The interfacial structure of a thermosensitive biocompatible polymer, poly[2-(2-methoxyethoxy)ethyl methacrylate] (PMe2MA), at the polymer/phosphate-buffered saline (PBS) interface was investigated by atomic force microscopy. A number of nanometer scale protrusions appeared at 37 °C and disappeared at 22 °C, reversibly. This structural change occurred above the lower critical solution temperature of PMe2MA in PBS (19 °C), indicating that the formation of protrusions was explained by the microphase separation of polymer and water at the interfacial region. The protein adsorption and platelet adhesion onto PMe2MA interface were drastically restrained at 22 °C compared to that at 37 °C. Detachment of NIH3T3 cells accompanied by the dissipation of protrusions on the PMe2MA interface was also demonstrated. These results indicate that the protrusions act as the scaffold for the protein adsorption and cell adhesion.

DOI： 10.1021/acsbiomaterials.8b00081

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

This study presents a drug delivery system of poly (Ɛ-caprolactone) (PCL) ribbons to optimize the pharmaceutical action of tramadol for the first time according to our knowledge. PCL ribbons were fabricated and loaded with tramadol HCl. Ribbons were prepared by slip casting technique and coated with dipping technique with β-cyclodextrin. The chemical integrity and surface morphology of the ribbons were confirmed using FTIR and SEM coupled with EDX. In addition, thermodynamic behavior of the fabricated ribbons was investigated using DSC/TGA. Tramadol loading into PCL ribbons, biodegradation of ribbons and tramadol release kinetics were studied in PBS.The results revealed that the formulated composition did not affect the chemical integrity of the drug. Furthermore, SEM/EDX confirmed the inclusion of tramadol into the PCL matrix in homogenous distribution pattern without any observation of porous structure. The particle size of loaded tramadol was found to be in the range of (2–4 nm). The formulated composition did not affect the chemical integrity of the drug and should be further investigated for bioavailability. Tramadol exhibited controlled release behavior from PCL ribbons up to 45 days governed mainly by diffusion mechanism. The fabricated ribbons have a great potentiality to be implemented in the long term subcutaneous delivery of tramadol.

DOI： 10.1016/j.jsps.2018.01.014

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

The interfacial structure of a thermosensitive biocompatible polymer, poly[2-(2-methoxyethoxy)ethyl methacrylate] (PMe2MA), at the polymer/phosphate-buffered saline (PBS) interface was investigated by atomic force microscopy. A number of nanometer scale protrusions appeared at 37 °C and disappeared at 22 °C, reversibly. This structural change occurred above the lower critical solution temperature of PMe2MA in PBS (19 °C), indicating that the formation of protrusions was explained by the microphase separation of polymer and water at the interfacial region. The protein adsorption and platelet adhesion onto PMe2MA interface were drastically restrained at 22 °C compared to that at 37 °C. Detachment of NIH3T3 cells accompanied by the dissipation of protrusions on the PMe2MA interface was also demonstrated. These results indicate that the protrusions act as the scaffold for the protein adsorption and cell adhesion.

DOI： 10.1021/acsbiomaterials.8b00081

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

This study presents a drug delivery system of poly (Ɛ-caprolactone) (PCL) ribbons to optimize the pharmaceutical action of tramadol for the first time according to our knowledge. PCL ribbons were fabricated and loaded with tramadol HCl. Ribbons were prepared by slip casting technique and coated with dipping technique with β-cyclodextrin. The chemical integrity and surface morphology of the ribbons were confirmed using FTIR and SEM coupled with EDX. In addition, thermodynamic behavior of the fabricated ribbons was investigated using DSC/TGA. Tramadol loading into PCL ribbons, biodegradation of ribbons and tramadol release kinetics were studied in PBS.The results revealed that the formulated composition did not affect the chemical integrity of the drug. Furthermore, SEM/EDX confirmed the inclusion of tramadol into the PCL matrix in homogenous distribution pattern without any observation of porous structure. The particle size of loaded tramadol was found to be in the range of (2–4 nm). The formulated composition did not affect the chemical integrity of the drug and should be further investigated for bioavailability. Tramadol exhibited controlled release behavior from PCL ribbons up to 45 days governed mainly by diffusion mechanism. The fabricated ribbons have a great potentiality to be implemented in the long term subcutaneous delivery of tramadol.

DOI： 10.1016/j.jsps.2018.01.014

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1021/acsbiomaterials.8b00081

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

Chondrocyte dedifferentiation during subculture prevents cartilage tissue engineering. The dedifferentiation is generally caused by cell spreading and trypsin treatment. Thus, it is expected that chondrocytes maintain their specific functions when the cells are subcultured on a substrate that can suppress cell spreading and allow the cells to detach without trypsin treatment. Here, we showed that thermoresponsive poly(2-methoxyethyl acrylate) and analogous polymers can be used to suppress cell spreading and detachment without trypsin treatment.

DOI： 10.1246/cl.170889

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

The engineering of human tissues to cure diseases is an interdisciplinary and a very attractive field of research both in academia and the biotechnology industrial sector. Three-dimensional (3D) biomaterial scaffolds can play a critical role in the development of new tissue morphogenesis via interacting with human cells. Although simple polymeric biomaterials can provide mechanical and physical properties required for tissue development, insufficient biomimetic property and lack of interactions with human progenitor cells remain problematic for the promotion of functional tissue formation. Therefore, the developments of advanced functional biomaterials that respond to stimulus could be the next choice to generate smart 3D biomimetic scaffolds, actively interacting with human stem cells and progenitors along with structural integrity to form functional tissue within a short period. To date, smart biomaterials are designed to interact with biological systems for a wide range of biomedical applications, from the delivery of bioactive molecules and cell adhesion mediators to cellular functioning for the engineering of functional tissues to treat diseases.

DOI： 10.3390/ijms19010017

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

The engineering of human tissues to cure diseases is an interdisciplinary and a very attractive field of research both in academia and the biotechnology industrial sector. Three-dimensional (3D) biomaterial scaffolds can play a critical role in the development of new tissue morphogenesis via interacting with human cells. Although simple polymeric biomaterials can provide mechanical and physical properties required for tissue development, insufficient biomimetic property and lack of interactions with human progenitor cells remain problematic for the promotion of functional tissue formation. Therefore, the developments of advanced functional biomaterials that respond to stimulus could be the next choice to generate smart 3D biomimetic scaffolds, actively interacting with human stem cells and progenitors along with structural integrity to form functional tissue within a short period. To date, smart biomaterials are designed to interact with biological systems for a wide range of biomedical applications, from the delivery of bioactive molecules and cell adhesion mediators to cellular functioning for the engineering of functional tissues to treat diseases.

DOI： 10.3390/ijms19010017

Language：English  

There are numerous parameters of polymeric biomaterials that can affect the protein adsorption and cell adhesion. The mechanisms responsible for the polymer/protein/cell interactions at the molecular level have not been clearly demonstrated, although many experimental and theoretical efforts have been made to understand these mechanisms. Water interactions have been recognized as fundamental for the protein and cell response to contact with polymers. This chapter focuses on the interfacial water at the polymer/protein/cell interfaces and specific water structure in hydrated biopolymers and bio-inspired water in hydrated synthetic polymers. Additionally, it highlights recent developments in the use of biocompatible polymeric biomaterials for medical devices and provides an overview of the progress made in the design of multifunctional element-block polymers by controlling the bio-inspired water structure through precision polymer synthesis.

DOI： 10.1007/978-981-13-2889-3_23

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

Chondrocyte dedifferentiation during subculture prevents cartilage tissue engineering. The dedifferentiation is generally caused by cell spreading and trypsin treatment. Thus, it is expected that chondrocytes maintain their specific functions when the cells are subcultured on a substrate that can suppress cell spreading and allow the cells to detach without trypsin treatment. Here, we showed that thermoresponsive poly(2-methoxyethyl acrylate) and analogous polymers can be used to suppress cell spreading and detachment without trypsin treatment.

DOI： 10.1246/cl.170889

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

The correlation between the interfacial structure and protein adsorption at a polymer/water interface was investigated. Poly(2-methoxyethyl acrylate)(PMEA), which is one of the best blood compatible polymers available, was employed. Nanometer-scale structures generated through the phase separation of polymer and water were observed at the PMEA/phosphate buffered saline interface. The interaction between the interfacial structures and fibrinogen (FNG) was measured using atomic force microscopy. Attraction was observed in the polymer-rich domains as well as in the non-blood compatible polymer. In contrast, no attractive interactions were observed, and only a repulsion occurred in the water-rich domains. The non-adsorption of FNG into the water rich domains was also clarified through topographic and phase image analyses. Furthermore, the FNG molecules adsorbed on the surface of PMEA were easily desorbed, even in the polymer-rich domains. Water molecules in the water-rich domains are anticipated to be the dominant factor in preventing FNG adsorption and thrombogenesis on a PMEA interface.

DOI： 10.3389/fchem.2018.00542

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

Molecular interactions of amino functional (AF) monomers with chitosan (CS) lead to the formation of external stimuli responsive hydrogels (HGs). These have the potential to produce biomaterials with novel properties by a simple blending approach. Six independent AF monomers such as diethylenetriamine (DETA), bis(3-aminopropyl)amine (BAPA), 3,3′-diamino-N-methyldipropyleamine (DAMPA), hexamethylenediamine (HMDA), N,N-dimethylethylamine (DMEA) and diethylamine (DEA) with distinct functional groups and chain lengths were designed to form stable HGs at physiological pH. Such AF monomers are able to form HGs within a short time (in the range from 10 to 19 seconds) by physically interacting with CS. This is an alternative to the covalently crosslinking reaction process, providing cost effective HG biomaterials. HG complexes were characterized by rheometry, differential scanning calorimetry (DSC), and Fourier transform infrared (FTIR) spectroscopy. The interaction between AF monomers and the CS polymer has been discussed and the results have been confirmed by FTIR analysis. The storage modulus (G′), loss modulus (G′′) and complex viscosity (η∗) were evaluated for all HGs using a rheometer, and the ratios of CS and the particular AF monomer were optimized for stable HG formation. The swelling ratio was evaluated using a simple method and was found to be directly related to the structure of the AF monomer, pH and temperature. These HGs were utilised for encapsulation, and the release of active molecules (e.g., reactive red 120 (RR120) as a model compound) was measured at low pH 5.5, physiological pH 7.4 and high pH 9.5. The cell viability and cellular compatibility of the HGs were evaluated in vitro cell culture, demonstrating that all the five different types of HGs support cellular compatibility, attachment and growth. The physical mixing of AF monomers with CS is expedited for the development of new bespoke economically viable biomaterials.

DOI： 10.1039/c8tb00865e

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

The engineering of human tissues to cure diseases is an interdisciplinary and a very attractive field of research both in academia and the biotechnology industrial sector. Three-dimensional (3D) biomaterial scaffolds can play a critical role in the development of new tissue morphogenesis via interacting with human cells. Although simple polymeric biomaterials can provide mechanical and physical properties required for tissue development, insufficient biomimetic property and lack of interactions with human progenitor cells remain problematic for the promotion of functional tissue formation. Therefore, the developments of advanced functional biomaterials that respond to stimulus could be the next choice to generate smart 3D biomimetic scaffolds, actively interacting with human stem cells and progenitors along with structural integrity to form functional tissue within a short period. To date, smart biomaterials are designed to interact with biological systems for a wide range of biomedical applications, from the delivery of bioactive molecules and cell adhesion mediators to cellular functioning for the engineering of functional tissues to treat diseases.

DOI： 10.3390/ijms19010017

Language：English  

There are numerous parameters of polymeric biomaterials that can affect the protein adsorption and cell adhesion. The mechanisms responsible for the polymer/protein/cell interactions at the molecular level have not been clearly demonstrated, although many experimental and theoretical efforts have been made to understand these mechanisms. Water interactions have been recognized as fundamental for the protein and cell response to contact with polymers. This chapter focuses on the interfacial water at the polymer/protein/cell interfaces and specific water structure in hydrated biopolymers and bio-inspired water in hydrated synthetic polymers. Additionally, it highlights recent developments in the use of biocompatible polymeric biomaterials for medical devices and provides an overview of the progress made in the design of multifunctional element-block polymers by controlling the bio-inspired water structure through precision polymer synthesis.

DOI： 10.1007/978-981-13-2889-3_23

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

Chondrocyte dedifferentiation during subculture prevents cartilage tissue engineering. The dedifferentiation is generally caused by cell spreading and trypsin treatment. Thus, it is expected that chondrocytes maintain their specific functions when the cells are subcultured on a substrate that can suppress cell spreading and allow the cells to detach without trypsin treatment. Here, we showed that thermoresponsive poly(2-methoxyethyl acrylate) and analogous polymers can be used to suppress cell spreading and detachment without trypsin treatment.

DOI： 10.1246/cl.170889

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

The correlation between the interfacial structure and protein adsorption at a polymer/water interface was investigated. Poly(2-methoxyethyl acrylate)(PMEA), which is one of the best blood compatible polymers available, was employed. Nanometer-scale structures generated through the phase separation of polymer and water were observed at the PMEA/phosphate buffered saline interface. The interaction between the interfacial structures and fibrinogen (FNG) was measured using atomic force microscopy. Attraction was observed in the polymer-rich domains as well as in the non-blood compatible polymer. In contrast, no attractive interactions were observed, and only a repulsion occurred in the water-rich domains. The non-adsorption of FNG into the water rich domains was also clarified through topographic and phase image analyses. Furthermore, the FNG molecules adsorbed on the surface of PMEA were easily desorbed, even in the polymer-rich domains. Water molecules in the water-rich domains are anticipated to be the dominant factor in preventing FNG adsorption and thrombogenesis on a PMEA interface.

DOI： 10.3389/fchem.2018.00542

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

Molecular interactions of amino functional (AF) monomers with chitosan (CS) lead to the formation of external stimuli responsive hydrogels (HGs). These have the potential to produce biomaterials with novel properties by a simple blending approach. Six independent AF monomers such as diethylenetriamine (DETA), bis(3-aminopropyl)amine (BAPA), 3,3′-diamino-N-methyldipropyleamine (DAMPA), hexamethylenediamine (HMDA), N,N-dimethylethylamine (DMEA) and diethylamine (DEA) with distinct functional groups and chain lengths were designed to form stable HGs at physiological pH. Such AF monomers are able to form HGs within a short time (in the range from 10 to 19 seconds) by physically interacting with CS. This is an alternative to the covalently crosslinking reaction process, providing cost effective HG biomaterials. HG complexes were characterized by rheometry, differential scanning calorimetry (DSC), and Fourier transform infrared (FTIR) spectroscopy. The interaction between AF monomers and the CS polymer has been discussed and the results have been confirmed by FTIR analysis. The storage modulus (G′), loss modulus (G′′) and complex viscosity (η∗) were evaluated for all HGs using a rheometer, and the ratios of CS and the particular AF monomer were optimized for stable HG formation. The swelling ratio was evaluated using a simple method and was found to be directly related to the structure of the AF monomer, pH and temperature. These HGs were utilised for encapsulation, and the release of active molecules (e.g., reactive red 120 (RR120) as a model compound) was measured at low pH 5.5, physiological pH 7.4 and high pH 9.5. The cell viability and cellular compatibility of the HGs were evaluated in vitro cell culture, demonstrating that all the five different types of HGs support cellular compatibility, attachment and growth. The physical mixing of AF monomers with CS is expedited for the development of new bespoke economically viable biomaterials.

DOI： 10.1039/c8tb00865e

Language：English  

There are numerous parameters of polymeric biomaterials that can affect the protein adsorption and cell adhesion. The mechanisms responsible for the polymer/protein/cell interactions at the molecular level have not been clearly demonstrated, although many experimental and theoretical efforts have been made to understand these mechanisms. Water interactions have been recognized as fundamental for the protein and cell response to contact with polymers. This chapter focuses on the interfacial water at the polymer/protein/cell interfaces and specific water structure in hydrated biopolymers and bio-inspired water in hydrated synthetic polymers. Additionally, it highlights recent developments in the use of biocompatible polymeric biomaterials for medical devices and provides an overview of the progress made in the design of multifunctional element-block polymers by controlling the bio-inspired water structure through precision polymer synthesis.

DOI： 10.1007/978-981-13-2889-3_23

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

The correlation between the interfacial structure and protein adsorption at a polymer/water interface was investigated. Poly(2-methoxyethyl acrylate)(PMEA), which is one of the best blood compatible polymers available, was employed. Nanometer-scale structures generated through the phase separation of polymer and water were observed at the PMEA/phosphate buffered saline interface. The interaction between the interfacial structures and fibrinogen (FNG) was measured using atomic force microscopy. Attraction was observed in the polymer-rich domains as well as in the non-blood compatible polymer. In contrast, no attractive interactions were observed, and only a repulsion occurred in the water-rich domains. The non-adsorption of FNG into the water rich domains was also clarified through topographic and phase image analyses. Furthermore, the FNG molecules adsorbed on the surface of PMEA were easily desorbed, even in the polymer-rich domains. Water molecules in the water-rich domains are anticipated to be the dominant factor in preventing FNG adsorption and thrombogenesis on a PMEA interface.

DOI： 10.3389/fchem.2018.00542

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

Molecular interactions of amino functional (AF) monomers with chitosan (CS) lead to the formation of external stimuli responsive hydrogels (HGs). These have the potential to produce biomaterials with novel properties by a simple blending approach. Six independent AF monomers such as diethylenetriamine (DETA), bis(3-aminopropyl)amine (BAPA), 3,3′-diamino-N-methyldipropyleamine (DAMPA), hexamethylenediamine (HMDA), N,N-dimethylethylamine (DMEA) and diethylamine (DEA) with distinct functional groups and chain lengths were designed to form stable HGs at physiological pH. Such AF monomers are able to form HGs within a short time (in the range from 10 to 19 seconds) by physically interacting with CS. This is an alternative to the covalently crosslinking reaction process, providing cost effective HG biomaterials. HG complexes were characterized by rheometry, differential scanning calorimetry (DSC), and Fourier transform infrared (FTIR) spectroscopy. The interaction between AF monomers and the CS polymer has been discussed and the results have been confirmed by FTIR analysis. The storage modulus (G′), loss modulus (G′′) and complex viscosity (η∗) were evaluated for all HGs using a rheometer, and the ratios of CS and the particular AF monomer were optimized for stable HG formation. The swelling ratio was evaluated using a simple method and was found to be directly related to the structure of the AF monomer, pH and temperature. These HGs were utilised for encapsulation, and the release of active molecules (e.g., reactive red 120 (RR120) as a model compound) was measured at low pH 5.5, physiological pH 7.4 and high pH 9.5. The cell viability and cellular compatibility of the HGs were evaluated in vitro cell culture, demonstrating that all the five different types of HGs support cellular compatibility, attachment and growth. The physical mixing of AF monomers with CS is expedited for the development of new bespoke economically viable biomaterials.

DOI： 10.1039/c8tb00865e

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

The engineering of human tissues to cure diseases is an interdisciplinary and a very attractive field of research both in academia and the biotechnology industrial sector. Three-dimensional (3D) biomaterial scaffolds can play a critical role in the development of new tissue morphogenesis via interacting with human cells. Although simple polymeric biomaterials can provide mechanical and physical properties required for tissue development, insufficient biomimetic property and lack of interactions with human progenitor cells remain problematic for the promotion of functional tissue formation. Therefore, the developments of advanced functional biomaterials that respond to stimulus could be the next choice to generate smart 3D biomimetic scaffolds, actively interacting with human stem cells and progenitors along with structural integrity to form functional tissue within a short period. To date, smart biomaterials are designed to interact with biological systems for a wide range of biomedical applications, from the delivery of bioactive molecules and cell adhesion mediators to cellular functioning for the engineering of functional tissues to treat diseases.

DOI： 10.3390/ijms19010017

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

Chondrocytes are important for cartilage tissue engineering. However, dedifferentiation during chondrocyte subculture prevents the application of cartilage tissue engineering. Therefore, prevention of this dedifferentiation is required. Here, the possibility of poly(2-methoxyethyl acrylate) (PMEA) and its analogous polymers, poly(tetrahydrofurfuryl acrylate) (PTHFA) and poly(2-(2-methoxyethoxy) ethyl acrylate-co-butyl acrylate) (PMe2A), for chondrocyte subculture without dedifferentiation is examined. Chondrocytes spread on PTHFA and polyethylene terephthalate (PET), whereas their spreading is delayed on PMEA and PMe2A. When primary chondrocytes are subcultured on these polymers, the expression levels of cartilaginous genes are higher on PMEA and PMe2A than on PET and PTHFA. Integrin contribution to the initial cell adhesion is lower on PMEA and PMe2A than on PTHFA and PET. This low level of integrin contribution to cell adhesion may cause a delay in cell spreading and the maintenance of cartilaginous gene expression. These results indicate that PMEA and PMe2A may be favorable substrates for chondrocyte subculture and cartilage tissue engineering.

DOI： 10.1002/mabi.201700297

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

Poly(omega-methoxyalkyl acrylate)s: Nonthrombogenic Polymer Family with Tunable Protein Adsorption
A series of polyacrylates with different n-alkyl side chain lengths (1 to 6, and 12 carbons) and a omega-methoxy terminal group (poly(omega-methoxyalkyl acrylate): PMCxA) were prepared to study their nonthrombogenicity using human platelet adhesion, micro bicinchoninic acid (micro BCA) protein assay, and enzyme-linked immunosorbent assay (ELISA) tests. In all cases, human platelet adhesion was suppressed on the PMCxA-coated substrates, and the number of human platelets adhered to thePMCxA(poly(3-methoxypropylacrylate))-coated surface was comparable to that of commercialized nonthrombogenic coating agent poly(2-methoxyethyl acrylate) (PMEA, equal to PMC2A). The amount of protein adsorbed onto the PMCxA was investigated by micro BCA using bovine serum albumin (BSA) and human fibrinogen (hFbn), revealing that PMC3A exhibited significantly high resistance to nonspecific BSA adsorption. Additionally, the amount of hFbn adsorbed onto the PMC3A was suppressed to the same extent as PMEA. The exposure degree of platelet adhesion sites in adsorbed hFbn was evaluated using an ELISA test, and the degree on the PMCxA with three to six methylene carbons was comparable to the PMEA. The hydration water structure in the hydrated PMCxA was also characterized using differential scanning calorimetry (DSC). The amount of intermediate water, which is the hydration water molecules that moderately interact with the polymer matrix, was maximum in the PMEA with two methylene run lengths, whereas the amount decreased by increasing the number of methyelnes in the side chain. The amount of adsorbed protein increased with a decrease in the amount of intermediate water, suggesting that the protein adsorption amount is tunable by simply changing the number of methylene carbons in the side chain. The present study revealed that poly(omega-methoxyalkyl acrylate)s are useful for blood-contacting medical devices, and PMC3A is the best mode of PMCxA to apply as an antiprotein adsorption coating agent.

DOI： 10.1021/acs.biomac.7b01247

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

Chondrocytes are important for cartilage tissue engineering. However, dedifferentiation during chondrocyte subculture prevents the application of cartilage tissue engineering. Therefore, prevention of this dedifferentiation is required. Here, the possibility of poly(2-methoxyethyl acrylate) (PMEA) and its analogous polymers, poly(tetrahydrofurfuryl acrylate) (PTHFA) and poly(2-(2-methoxyethoxy) ethyl acrylate-co-butyl acrylate) (PMe2A), for chondrocyte subculture without dedifferentiation is examined. Chondrocytes spread on PTHFA and polyethylene terephthalate (PET), whereas their spreading is delayed on PMEA and PMe2A. When primary chondrocytes are subcultured on these polymers, the expression levels of cartilaginous genes are higher on PMEA and PMe2A than on PET and PTHFA. Integrin contribution to the initial cell adhesion is lower on PMEA and PMe2A than on PTHFA and PET. This low level of integrin contribution to cell adhesion may cause a delay in cell spreading and the maintenance of cartilaginous gene expression. These results indicate that PMEA and PMe2A may be favorable substrates for chondrocyte subculture and cartilage tissue engineering.

DOI： 10.1002/mabi.201700304

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

A series of polyacrylates with different n-alkyl side chain lengths (1 to 6, and 12 carbons) and a ω-methoxy terminal group (poly(ω-methoxyalkyl acrylate): PMCxA) were prepared to study their nonthrombogenicity using human platelet adhesion, micro bicinchoninic acid (micro BCA) protein assay, and enzyme-linked immunosorbent assay (ELISA) tests. In all cases, human platelet adhesion was suppressed on the PMCxA-coated substrates, and the number of human platelets adhered to the PMC3A (poly(3-methoxypropyl acrylate))-coated surface was comparable to that of commercialized nonthrombogenic coating agent poly(2-methoxyethyl acrylate) (PMEA, equal to PMC2A). The amount of protein adsorbed onto the PMCxA was investigated by micro BCA using bovine serum albumin (BSA) and human fibrinogen (hFbn), revealing that PMC3A exhibited significantly high resistance to nonspecific BSA adsorption. Additionally, the amount of hFbn adsorbed onto the PMC3A was suppressed to the same extent as PMEA. The exposure degree of platelet adhesion sites in adsorbed hFbn was evaluated using an ELISA test, and the degree on the PMCxA with three to six methylene carbons was comparable to the PMEA. The hydration water structure in the hydrated PMCxA was also characterized using differential scanning calorimetry (DSC). The amount of intermediate water, which is the hydration water molecules that moderately interact with the polymer matrix, was maximum in the PMEA with two methylene run lengths, whereas the amount decreased by increasing the number of methyelnes in the side chain. The amount of adsorbed protein increased with a decrease in the amount of intermediate water, suggesting that the protein adsorption amount is tunable by simply changing the number of methylene carbons in the side chain. The present study revealed that poly(ω-methoxyalkyl acrylate)s are useful for blood-contacting medical devices, and PMC3A is the best mode of PMCxA to apply as an antiprotein adsorption coating agent.

DOI： 10.1021/acs.biomac.7b01247

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

Chondrocytes are important for cartilage tissue engineering. However, dedifferentiation during chondrocyte subculture prevents the application of cartilage tissue engineering. Therefore, prevention of this dedifferentiation is required. Here, the possibility of poly(2-methoxyethyl acrylate) (PMEA) and its analogous polymers, poly(tetrahydrofurfuryl acrylate) (PTHFA) and poly(2-(2-methoxyethoxy) ethyl acrylate-co-butyl acrylate) (PMe2A), for chondrocyte subculture without dedifferentiation is examined. Chondrocytes spread on PTHFA and polyethylene terephthalate (PET), whereas their spreading is delayed on PMEA and PMe2A. When primary chondrocytes are subcultured on these polymers, the expression levels of cartilaginous genes are higher on PMEA and PMe2A than on PET and PTHFA. Integrin contribution to the initial cell adhesion is lower on PMEA and PMe2A than on PTHFA and PET. This low level of integrin contribution to cell adhesion may cause a delay in cell spreading and the maintenance of cartilaginous gene expression. These results indicate that PMEA and PMe2A may be favorable substrates for chondrocyte subculture and cartilage tissue engineering.

DOI： 10.1002/mabi.201700297

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

A series of polyacrylates with different n-alkyl side chain lengths (1 to 6, and 12 carbons) and a ω-methoxy terminal group (poly(ω-methoxyalkyl acrylate): PMCxA) were prepared to study their nonthrombogenicity using human platelet adhesion, micro bicinchoninic acid (micro BCA) protein assay, and enzyme-linked immunosorbent assay (ELISA) tests. In all cases, human platelet adhesion was suppressed on the PMCxA-coated substrates, and the number of human platelets adhered to the PMC3A (poly(3-methoxypropyl acrylate))-coated surface was comparable to that of commercialized nonthrombogenic coating agent poly(2-methoxyethyl acrylate) (PMEA, equal to PMC2A). The amount of protein adsorbed onto the PMCxA was investigated by micro BCA using bovine serum albumin (BSA) and human fibrinogen (hFbn), revealing that PMC3A exhibited significantly high resistance to nonspecific BSA adsorption. Additionally, the amount of hFbn adsorbed onto the PMC3A was suppressed to the same extent as PMEA. The exposure degree of platelet adhesion sites in adsorbed hFbn was evaluated using an ELISA test, and the degree on the PMCxA with three to six methylene carbons was comparable to the PMEA. The hydration water structure in the hydrated PMCxA was also characterized using differential scanning calorimetry (DSC). The amount of intermediate water, which is the hydration water molecules that moderately interact with the polymer matrix, was maximum in the PMEA with two methylene run lengths, whereas the amount decreased by increasing the number of methyelnes in the side chain. The amount of adsorbed protein increased with a decrease in the amount of intermediate water, suggesting that the protein adsorption amount is tunable by simply changing the number of methylene carbons in the side chain. The present study revealed that poly(ω-methoxyalkyl acrylate)s are useful for blood-contacting medical devices, and PMC3A is the best mode of PMCxA to apply as an antiprotein adsorption coating agent.

DOI： 10.1021/acs.biomac.7b01247

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

Chondrocytes are important for cartilage tissue engineering. However, dedifferentiation during chondrocyte subculture prevents the application of cartilage tissue engineering. Therefore, prevention of this dedifferentiation is required. Here, the possibility of poly(2-methoxyethyl acrylate) (PMEA) and its analogous polymers, poly(tetrahydrofurfuryl acrylate) (PTHFA) and poly(2-(2-methoxyethoxy) ethyl acrylate-co-butyl acrylate) (PMe2A), for chondrocyte subculture without dedifferentiation is examined. Chondrocytes spread on PTHFA and polyethylene terephthalate (PET), whereas their spreading is delayed on PMEA and PMe2A. When primary chondrocytes are subcultured on these polymers, the expression levels of cartilaginous genes are higher on PMEA and PMe2A than on PET and PTHFA. Integrin contribution to the initial cell adhesion is lower on PMEA and PMe2A than on PTHFA and PET. This low level of integrin contribution to cell adhesion may cause a delay in cell spreading and the maintenance of cartilaginous gene expression. These results indicate that PMEA and PMe2A may be favorable substrates for chondrocyte subculture and cartilage tissue engineering.

DOI： 10.1002/mabi.201700297

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

We developed a biodegradable polycarbonate that demonstrates antithrombogenicity and vascular cell adhesion via organocatalytic ring-opening polymerization of a trimethylene carbonate (TMC) analogue bearing a methoxy group. The monoether-tagged polycarbonate demonstrates a platelet adhesion property that is 93 and 89% lower than those of poly(ethylene terephthalate) and polyTMC, respectively. In contrast, vascular cell adhesion properties of the polycarbonate are comparable to those controls, indicating a potential for selective cell adhesion properties. This difference in the cell adhesion property is well associated with surface hydration, which affects protein adsorption and denaturation. Fibrinogen is slightly denatured on the monoether-tagged polycarbonate, whereas fibronectin is highly activated to expose the RGD motif for favorable vascular cell adhesion. The surface hydration, mainly induced by the methoxy side chain, also contributes to slowing the enzymatic degradation. Consequently, the polycarbonate exhibits decent blood compatibility, vascular cell adhesion properties, and biodegradability, which is promising for applications in resorbable vascular grafts and stents.

DOI： 10.1021/acs.biomac.7b01210

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

We developed a biodegradable polycarbonate that demonstrates antithrombogenicity and vascular cell adhesion via organocatalytic ring-opening polymerization of a trimethylene carbonate (TMC) analogue bearing a methoxy group. The monoether-tagged polycarbonate demonstrates a platelet adhesion property that is 93 and 89% lower than those of poly(ethylene terephthalate) and polyTMC, respectively. In contrast, vascular cell adhesion properties of the polycarbonate are comparable to those controls, indicating a potential for selective cell adhesion properties. This difference in the cell adhesion property is well associated with surface hydration, which affects protein adsorption and denaturation. Fibrinogen is slightly denatured on the monoether-tagged polycarbonate, whereas fibronectin is highly activated to expose the RGD motif for favorable vascular cell adhesion. The surface hydration, mainly induced by the methoxy side chain, also contributes to slowing the enzymatic degradation. Consequently, the polycarbonate exhibits decent blood compatibility, vascular cell adhesion properties, and biodegradability, which is promising for applications in resorbable vascular grafts and stents.

DOI： 10.1021/acs.biomac.7b01210

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

We developed a biodegradable polycarbonate that demonstrates antithrombogenicity and vascular cell adhesion via organocatalytic ring-opening polymerization of a trimethylene carbonate (TMC) analogue bearing a methoxy group. The monoether-tagged polycarbonate demonstrates a platelet adhesion property that is 93 and 89% lower than those of poly(ethylene terephthalate) and polyTMC, respectively. In contrast, vascular cell adhesion properties of the polycarbonate are comparable to those controls, indicating a potential for selective cell adhesion properties. This difference in the cell adhesion property is well associated with surface hydration, which affects protein adsorption and denaturation. Fibrinogen is slightly denatured on the monoether-tagged polycarbonate, whereas fibronectin is highly activated to expose the RGD motif for favorable vascular cell adhesion. The surface hydration, mainly induced by the methoxy side chain, also contributes to slowing the enzymatic degradation. Consequently, the polycarbonate exhibits decent blood compatibility, vascular cell adhesion properties, and biodegradability, which is promising for applications in resorbable vascular grafts and stents.

DOI： 10.1021/acs.biomac.7b01210

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

We have first confirmed that an organic acid, diphenyl phosphate (DPP) is effective in a sequential process of ring-opening polymerization (ROP) of a cyclic carbonate and polyaddition with a diisocyanate. More potent triflic acid (TfOH) exhibited higher catalytic activities for both ROP and polyaddition than DPP and pairs of thiourea and basic catalysts such as cyclic amidines and sparteine. However, DPP-catalyzed ROP was more manageable than that using TfOH regarding control over the molar-mass dispersity of the resultant polycarbonates that matters to the final polyurethanes. As a consequence of DPP-catalyzed one-pot synthesis of poly(carbonate-urethane)s, we have obtained segmented polyurethanes comprising a poly(trimethylene carbonate) analog with ether side chains as a soft segment and hexamethylene diisocyanate as a hard segment. Although the whole reaction took a few days, high molecular weight over 50 k was achieved for the resultant polyurethanes whose texture suggested improved physical properties. Nevertheless, the polyuretahnes maintained low platelet adhesion properties. This antithrombotic polyurethane became more promising as a candidate base material for resorbable artificial blood vessels. Furthermore, this sequential synthesis by single organocatalysts enables the efficient production of functionalized poly(carbonate-urethane)s.

DOI： 10.1016/j.eurpolymj.2017.07.001

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

We have first confirmed that an organic acid, diphenyl phosphate (DPP) is effective in a sequential process of ring-opening polymerization (ROP) of a cyclic carbonate and polyaddition with a diisocyanate. More potent triflic acid (TfOH) exhibited higher catalytic activities for both ROP and polyaddition than DPP and pairs of thiourea and basic catalysts such as cyclic amidines and sparteine. However, DPP-catalyzed ROP was more manageable than that using TfOH regarding control over the molar-mass dispersity of the resultant polycarbonates that matters to the final polyurethanes. As a consequence of DPP-catalyzed one-pot synthesis of poly(carbonateurethane)s, we have obtained segmented polyurethanes comprising a poly(trimethylene carbonate) analog with ether side chains as a soft segment and hexamethylene diisocyanate as a hard segment. Although the whole reaction took a few days, high molecular weight over 50 k was achieved for the resultant polyurethanes whose texture suggested improved physical properties. Nevertheless, the polyuretahnes maintained low platelet adhesion properties. This antithrombotic polyurethane became more promising as a candidate base material for resorbable artificial blood vessels. Furthermore, this sequential synthesis by single organocatalysts enables the efficient production of functionalized poly(carbonate-urethane)s.

DOI： 10.1016/j.eurpolymj.2017.07.001

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

We have first confirmed that an organic acid, diphenyl phosphate (DPP) is effective in a sequential process of ring-opening polymerization (ROP) of a cyclic carbonate and polyaddition with a diisocyanate. More potent triflic acid (TfOH) exhibited higher catalytic activities for both ROP and polyaddition than DPP and pairs of thiourea and basic catalysts such as cyclic amidines and sparteine. However, DPP-catalyzed ROP was more manageable than that using TfOH regarding control over the molar-mass dispersity of the resultant polycarbonates that matters to the final polyurethanes. As a consequence of DPP-catalyzed one-pot synthesis of poly(carbonate-urethane)s, we have obtained segmented polyurethanes comprising a poly(trimethylene carbonate) analog with ether side chains as a soft segment and hexamethylene diisocyanate as a hard segment. Although the whole reaction took a few days, high molecular weight over 50 k was achieved for the resultant polyurethanes whose texture suggested improved physical properties. Nevertheless, the polyuretahnes maintained low platelet adhesion properties. This antithrombotic polyurethane became more promising as a candidate base material for resorbable artificial blood vessels. Furthermore, this sequential synthesis by single organocatalysts enables the efficient production of functionalized poly(carbonate-urethane)s.

DOI： 10.1016/j.eurpolymj.2017.07.001

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

We have first confirmed that an organic acid, diphenyl phosphate (DPP) is effective in a sequential process of ring-opening polymerization (ROP) of a cyclic carbonate and polyaddition with a diisocyanate. More potent triflic acid (TfOH) exhibited higher catalytic activities for both ROP and polyaddition than DPP and pairs of thiourea and basic catalysts such as cyclic amidines and sparteine. However, DPP-catalyzed ROP was more manageable than that using TfOH regarding control over the molar-mass dispersity of the resultant polycarbonates that matters to the final polyurethanes. As a consequence of DPP-catalyzed one-pot synthesis of poly(carbonate-urethane)s, we have obtained segmented polyurethanes comprising a poly(trimethylene carbonate) analog with ether side chains as a soft segment and hexamethylene diisocyanate as a hard segment. Although the whole reaction took a few days, high molecular weight over 50 k was achieved for the resultant polyurethanes whose texture suggested improved physical properties. Nevertheless, the polyuretahnes maintained low platelet adhesion properties. This antithrombotic polyurethane became more promising as a candidate base material for resorbable artificial blood vessels. Furthermore, this sequential synthesis by single organocatalysts enables the efficient production of functionalized poly(carbonate-urethane)s.

DOI： 10.1016/j.eurpolymj.2017.07.001

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

Cell adhesion is a major concern in biomaterial development. Generally, cells adhere to polymeric substrates via the interaction between integrins and proteins adsorbed on the substrates. Previously, it was reported that poly (2-methoxyethyl acrylate) (PMEA) and its analogous polymers can alter the integrin dependency for cell adhesion. In particular, integrin-independent adhesion was observed on PMEA. However, initial adhesion mechanisms, including integrin-independent adhesion mechanisms, on PMEA are not well characterized. In this study, initial cell adhesion within 10 min was characterized on PMEA analogous polymers. Protein adsorption was suppressed on PMEA compared with tissue culture polystyrene, but the cell adhesion site in adsorbed fibronectin was exposed to the cells similarly. HT-1080 cells adhered on PMEA in a serum medium even in the presence of EDTA, suggesting that the cells adhered via both integrin-dependent and integrin-independent mechanisms. Finally, the cell adhesion force was measured by single-cell force spectroscopy. The cell adhesion force was not changed on PMEA in serum and serum-free media, suggesting that the cells adhered on PMEA directly. In conclusion, the control of protein adsorption is useful for regulating integrin dependency for cell adhesion and following the expression of cell functions regulated by integrins.

DOI： 10.1080/09205063.2017.1312738

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

Unequivocal dependence of bioinertness of self-assembled monolayers of methoxy-tri(ethylene glycol)-terminated alkanethiol (EG3-OMe SAMs) on their packing density has been a mystery for more than two decades. We tackled this long-standing question by performing surface force and surface-enhanced infrared absorption (SEIRA) spectroscopic measurements. Our surface force measurements revealed a physical barrier of interfacial water in the vicinity of the Au-supported EG3-OMe SAM (low packing density), whereas the Ag-supported one (high packing density) did not possess such interfacial water. In addition, the results of SEIRA measurements clearly exhibited that hydrogen bonding states of the interfacial water differ depending on the substrates. We also characterized the bioinertness of these SAMs by protein adsorption tests and adhesion assays of platelet and human umbilical vein endothelial cells. The hydrogen bonding states of the interfacial water and water-induced interaction clearly correlated with the bioinertness of the SAMs, suggesting that the interfacial water plays an important role determining the interaction of the SAMs with biomolecules and cells.

DOI： 10.1080/09205063.2017.1303120

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

Cell adhesion is a major concern in biomaterial development. Generally, cells adhere to polymeric substrates via the interaction between integrins and proteins adsorbed on the substrates. Previously, it was reported that poly (2-methoxyethyl acrylate) (PMEA) and its analogous polymers can alter the integrin dependency for cell adhesion. In particular, integrin-independent adhesion was observed on PMEA. However, initial adhesion mechanisms, including integrin-independent adhesion mechanisms, on PMEA are not well characterized. In this study, initial cell adhesion within 10 min was characterized on PMEA analogous polymers. Protein adsorption was suppressed on PMEA compared with tissue culture polystyrene, but the cell adhesion site in adsorbed fibronectin was exposed to the cells similarly. HT-1080 cells adhered on PMEA in a serum medium even in the presence of EDTA, suggesting that the cells adhered via both integrin-dependent and integrin-independent mechanisms. Finally, the cell adhesion force was measured by single-cell force spectroscopy. The cell adhesion force was not changed on PMEA in serum and serum-free media, suggesting that the cells adhered on PMEA directly. In conclusion, the control of protein adsorption is useful for regulating integrin dependency for cell adhesion and following the expression of cell functions regulated by integrins.

DOI： 10.1080/09205063.2017.1312738

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

Unequivocal dependence of bioinertness of self-assembled monolayers of methoxy-tri(ethylene glycol)-terminated alkanethiol (EG3-OMe SAMs) on their packing density has been a mystery for more than two decades. We tackled this long-standing question by performing surface force and surface-enhanced infrared absorption (SEIRA) spectroscopic measurements. Our surface force measurements revealed a physical barrier of interfacial water in the vicinity of the Au-supported EG3-OMe SAM (low packing density), whereas the Ag-supported one (high packing density) did not possess such interfacial water. In addition, the results of SEIRA measurements clearly exhibited that hydrogen bonding states of the interfacial water differ depending on the substrates. We also characterized the bioinertness of these SAMs by protein adsorption tests and adhesion assays of platelet and human umbilical vein endothelial cells. The hydrogen bonding states of the interfacial water and water-induced interaction clearly correlated with the bioinertness of the SAMs, suggesting that the interfacial water plays an important role determining the interaction of the SAMs with biomolecules and cells.

DOI： 10.1080/09205063.2017.1303120

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

Cell adhesion is a major concern in biomaterial development. Generally, cells adhere to polymeric substrates via the interaction between integrins and proteins adsorbed on the substrates. Previously, it was reported that poly (2-methoxyethyl acrylate) (PMEA) and its analogous polymers can alter the integrin dependency for cell adhesion. In particular, integrin-independent adhesion was observed on PMEA. However, initial adhesion mechanisms, including integrin-independent adhesion mechanisms, on PMEA are not well characterized. In this study, initial cell adhesion within 10 min was characterized on PMEA analogous polymers. Protein adsorption was suppressed on PMEA compared with tissue culture polystyrene, but the cell adhesion site in adsorbed fibronectin was exposed to the cells similarly. HT-1080 cells adhered on PMEA in a serum medium even in the presence of EDTA, suggesting that the cells adhered via both integrin-dependent and integrin-independent mechanisms. Finally, the cell adhesion force was measured by single-cell force spectroscopy. The cell adhesion force was not changed on PMEA in serum and serum-free media, suggesting that the cells adhered on PMEA directly. In conclusion, the control of protein adsorption is useful for regulating integrin dependency for cell adhesion and following the expression of cell functions regulated by integrins.

DOI： 10.1080/09205063.2017.1312738

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

Unequivocal dependence of bioinertness of self-assembled monolayers of methoxy-tri(ethylene glycol)-terminated alkanethiol (EG3-OMe SAMs) on their packing density has been a mystery for more than two decades. We tackled this long-standing question by performing surface force and surface-enhanced infrared absorption (SEIRA) spectroscopic measurements. Our surface force measurements revealed a physical barrier of interfacial water in the vicinity of the Au-supported EG3-OMe SAM (low packing density), whereas the Ag-supported one (high packing density) did not possess such interfacial water. In addition, the results of SEIRA measurements clearly exhibited that hydrogen bonding states of the interfacial water differ depending on the substrates. We also characterized the bioinertness of these SAMs by protein adsorption tests and adhesion assays of platelet and human umbilical vein endothelial cells. The hydrogen bonding states of the interfacial water and water-induced interaction clearly correlated with the bioinertness of the SAMs, suggesting that the interfacial water plays an important role determining the interaction of the SAMs with biomolecules and cells.

DOI： 10.1080/09205063.2017.1303120

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

There are recent reports of hybrid tissue–fabric materials with good performance—high biocompatibility and high mechanical strength. In this study, we demonstrate the capability of a hybrid material as a long-term filter for blood proteins. Polyester fabrics were implanted into rats to fabricate hybrid tissue–fabric material sheets. The hybrid materials comprised biological tissue grown on the fabric. The materials were extracted from the rat’s body, approximately 100 days post-implantation. The tissues were decellularized to prevent immunological rejection. An antithrombogenicity test was performed by dropping blood onto the hybrid material surface. The hybrid material showed lesser blood coagulation than polysulfone and cellulose. Blood plasma was filtered using the hybrid material to evaluate the protein removal percentage and the lifetime of the hybrid material in vitro. The hybrid material showed a comparable performance to conventional filters for protein removal. Moreover, the hybrid material could work as a protein filter for 1 month, which is six times the lifetime of polysulfone.

DOI： 10.1007/s10439-016-1781-5

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

A poly(vinyl acetate) derivative, poly(3-methoxypropionic acid vinyl ester) (PMePVE), was synthesized to develop a new candidate for blood compatible polymers. The monomer MePVE was synthesized by a simple two-step reaction, and then the MePVE was polymerized via free radical polymerization to obtain PMePVE. Human platelet adhesion tests were performed to evaluate the thrombogenicity, and the platelet adhesion was suppressed on the PMePVE-coated substrate. To determine the expression of the nonthrombogenicity of the PMePVE, the plasma protein adsorption and a conformationally altered state of fibrinogen were analyzed by a microBCA assay and enzyme-linked immunosorbent assay. The adsorption and denaturation of the plasma proteins were inhibited on the PMePVE; thus, PMePVE exhibited blood compatibility. A distinctive hydration water structure in the nonthrombogenic polymer, intermediate water (IW), was observed in the hydrated PMePVE by differential scanning calorimetry analysis. The nonthrombogenicity of PMePVE is considered to be brought about by the presence of IW.

DOI： 10.1021/acs.biomac.7b00221

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

There are recent reports of hybrid tissue-fabric materials with good performance-high biocompatibility and high mechanical strength. In this study, we demonstrate the capability of a hybrid material as a long-term filter for blood proteins. Polyester fabrics were implanted into rats to fabricate hybrid tissue-fabric material sheets. The hybrid materials comprised biological tissue grown on the fabric. The materials were extracted from the rat's body, approximately 100 days post-implantation. The tissues were decellularized to prevent immunological rejection. An antithrombogenicity test was performed by dropping blood onto the hybrid material surface. The hybrid material showed lesser blood coagulation than polysulfone and cellulose. Blood plasma was filtered using the hybrid material to evaluate the protein removal percentage and the lifetime of the hybrid material in vitro. The hybrid material showed a comparable performance to conventional filters for protein removal. Moreover, the hybrid material could work as a protein filter for 1 month, which is six times the lifetime of polysulfone.

DOI： 10.1007/s10439-016-1781-5

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

A poly(vinyl acetate) derivative, poly(3-methoxypropionic acid vinyl ester) (PMePVE), was synthesized to develop a new candidate for blood compatible polymers. The monomer MePVE was synthesized by a simple two-step reaction, and then the MePVE was polymerized via free radical polymerization to obtain PMePVE. Human platelet adhesion tests were performed to evaluate the thrombogenicity, and the platelet adhesion was suppressed on the PMePVE-coated substrate. To determine the expression of the nonthrombogenicity of the PMePVE, the plasma protein adsorption and a conformationally altered state of fibrinogen were analyzed by a microBCA assay and enzyme-linked immunosorbent assay. The adsorption and denaturation of the plasma proteins were inhibited on the PMePVE; thus, PMePVE exhibited blood compatibility. A distinctive hydration water structure in the nonthrombogenic polymer, intermediate water (IW), was observed in the hydrated PMePVE by differential scanning calorimetry analysis. The nonthrombogenicity of PMePVE is considered to be brought about by the presence of IW.

DOI： 10.1021/acs.biomac.7b00221

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

There are recent reports of hybrid tissue–fabric materials with good performance—high biocompatibility and high mechanical strength. In this study, we demonstrate the capability of a hybrid material as a long-term filter for blood proteins. Polyester fabrics were implanted into rats to fabricate hybrid tissue–fabric material sheets. The hybrid materials comprised biological tissue grown on the fabric. The materials were extracted from the rat’s body, approximately 100 days post-implantation. The tissues were decellularized to prevent immunological rejection. An antithrombogenicity test was performed by dropping blood onto the hybrid material surface. The hybrid material showed lesser blood coagulation than polysulfone and cellulose. Blood plasma was filtered using the hybrid material to evaluate the protein removal percentage and the lifetime of the hybrid material in vitro. The hybrid material showed a comparable performance to conventional filters for protein removal. Moreover, the hybrid material could work as a protein filter for 1 month, which is six times the lifetime of polysulfone.

DOI： 10.1007/s10439-016-1781-5

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

A poly(vinyl acetate) derivative, poly(3-methoxypropionic acid vinyl ester) (PMePVE), was synthesized to develop a new candidate for blood compatible polymers. The monomer MePVE was synthesized by a simple two-step reaction, and then the MePVE was polymerized via free radical polymerization to obtain PMePVE. Human platelet adhesion tests were performed to evaluate the thrombogenicity, and the platelet adhesion was suppressed on the PMePVE-coated substrate. To determine the expression of the nonthrombogenicity of the PMePVE, the plasma protein adsorption and a conformationally altered state of fibrinogen were analyzed by a microBCA assay and enzyme-linked immunosorbent assay. The adsorption and denaturation of the plasma proteins were inhibited on the PMePVE; thus, PMePVE exhibited blood compatibility. A distinctive hydration water structure in the nonthrombogenic polymer, intermediate water (IW), was observed in the hydrated PMePVE by differential scanning calorimetry analysis. The nonthrombogenicity of PMePVE is considered to be brought about by the presence of IW.

DOI： 10.1021/acs.biomac.7b00221

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

There are recent reports of hybrid tissue–fabric materials with good performance—high biocompatibility and high mechanical strength. In this study, we demonstrate the capability of a hybrid material as a long-term filter for blood proteins. Polyester fabrics were implanted into rats to fabricate hybrid tissue–fabric material sheets. The hybrid materials comprised biological tissue grown on the fabric. The materials were extracted from the rat’s body, approximately 100 days post-implantation. The tissues were decellularized to prevent immunological rejection. An antithrombogenicity test was performed by dropping blood onto the hybrid material surface. The hybrid material showed lesser blood coagulation than polysulfone and cellulose. Blood plasma was filtered using the hybrid material to evaluate the protein removal percentage and the lifetime of the hybrid material in vitro. The hybrid material showed a comparable performance to conventional filters for protein removal. Moreover, the hybrid material could work as a protein filter for 1 month, which is six times the lifetime of polysulfone.

DOI： 10.1007/s10439-016-1781-5

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

The chain dynamics of well-defined poly(2-methoxyethyl acrylate) (PMEA), which has been used in practice as a bioinert coating for heart-lung machines, was examined as a function of water content by dielectric relaxation spectroscopy (DRS). Two relaxation processes observed in both dried and hydrated films were assigned to the segmental motion (α-process) and the relatively smaller scale motion such as the hindered rotation of side chains (β-process). Water molecules adsorbed on PMEA made the α-process faster, meaning that water molecules in PMEA played the role of a plasticizer. Combining the above knowledge with the depth dependence of water content in the PMEA film previously obtained by neutron reflectivity, the segmental dynamics of PMEA at the water interface, which should be crucial to bio-inertness, is discussed. We found that the segmental motion was markedly faster than that in the bulk and almost comparable to the side chain motion.

DOI： 10.1039/c6cp07322k

Language：Others  

Applications of functionalized biodegradable polymers in tissue engineering and regenerative medicine

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

Background: Although various types of materials have been used widely in dialyzers, most biomaterials lack the desired functional properties to interface with blood and have not been engineered for optimum performance. Therefore, there is increasing demand to develop novel materials to address such problems in the dialysis arena. Numerous parameters of polymeric biomaterials can affect biocompatibility in a controlled manner. The mechanisms responsible for the biocompatibility of polymers at the molecular level have not been clearly demonstrated, although many theoretical and experimental efforts have been made to try and understand them. Moreover, water interactions have been recognized as fundamental for the blood response to contact with polymers. Summary: We have proposed the 'intermediate water' concept and hypothesized that intermediate water, which prevents the proteins and blood cells from directly contacting the polymer surface, or nonfreezing water on the polymer surface, plays an important role in the biocompatibility of polymers. This chapter provides an overview of the recent experimental progress of biocompatible polymers measured by thermal, spectroscopic, and surface force techniques. Additionally, it highlights recent developments in the use of biocompatible polymeric biomaterials for dialyzers and provides an overview of the progress made in the design of multifunctional biomedical polymers by controlling the biointerfacial water structure through precision polymer synthesis. Key Messages: Intermediate water was found only in hydrated biopolymers (proteins, polysaccharides, and nucleic acids, DNA and RNA) and hydrated biocompatible synthetic polymers. Intermediate water could be one of the main screening factors for the design of appropriate dialyzer materials.

DOI： 10.1159/000451043

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

The chain dynamics of well-defined poly(2-methoxyethyl acrylate) (PMEA), which has been used in practice as a bioinert coating for heart-lung machines, was examined as a function of water content by dielectric relaxation spectroscopy (DRS). Two relaxation processes observed in both dried and hydrated films were assigned to the segmental motion (alpha-process) and the relatively smaller scale motion such as the hindered rotation of side chains (beta-process). Water molecules adsorbed on PMEA made the alpha-process faster, meaning that water molecules in PMEA played the role of a plasticizer. Combining the above knowledge with the depth dependence of water content in the PMEA film previously obtained by neutron reflectivity, the segmental dynamics of PMEA at the water interface, which should be crucial to bio-inertness, is discussed. We found that the segmental motion was markedly faster than that in the bulk and almost comparable to the side chain motion.

DOI： 10.1039/c6cp07322k

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

The chain dynamics of well-defined poly(2-methoxyethyl acrylate) (PMEA), which has been used in practice as a bioinert coating for heart-lung machines, was examined as a function of water content by dielectric relaxation spectroscopy (DRS). Two relaxation processes observed in both dried and hydrated films were assigned to the segmental motion (α-process) and the relatively smaller scale motion such as the hindered rotation of side chains (β-process). Water molecules adsorbed on PMEA made the α-process faster, meaning that water molecules in PMEA played the role of a plasticizer. Combining the above knowledge with the depth dependence of water content in the PMEA film previously obtained by neutron reflectivity, the segmental dynamics of PMEA at the water interface, which should be crucial to bio-inertness, is discussed. We found that the segmental motion was markedly faster than that in the bulk and almost comparable to the side chain motion.

DOI： 10.1039/c6cp07322k

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

Background: Although various types of materials have been used widely in dialyzers, most biomaterials lack the desired functional properties to interface with blood and have not been engineered for optimum performance. Therefore, there is increasing demand to develop novel materials to address such problems in the dialysis arena. Numerous parameters of polymeric biomaterials can affect biocompatibility in a controlled manner. The mechanisms responsible for the biocompatibility of polymers at the molecular level have not been clearly demonstrated, although many theoretical and experimental efforts have been made to try and understand them. Moreover, water interactions have been recognized as fundamental for the blood response to contact with polymers. Summary: We have proposed the 'intermediate water' concept and hypothesized that intermediate water, which prevents the proteins and blood cells from directly contacting the polymer surface, or nonfreezing water on the polymer surface, plays an important role in the biocompatibility of polymers. This chapter provides an overview of the recent experimental progress of biocompatible polymers measured by thermal, spectroscopic, and surface force techniques. Additionally, it highlights recent developments in the use of biocompatible polymeric biomaterials for dialyzers and provides an overview of the progress made in the design of multifunctional biomedical polymers by controlling the biointerfacial water structure through precision polymer synthesis. Key Messages: Intermediate water was found only in hydrated biopolymers (proteins, polysaccharides, and nucleic acids, DNA and RNA) and hydrated biocompatible synthetic polymers. Intermediate water could be one of the main screening factors for the design of appropriate dialyzer materials.

DOI： 10.1159/000451043

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

The chain dynamics of well-defined poly(2-methoxyethyl acrylate) (PMEA), which has been used in practice as a bioinert coating for heart-lung machines, was examined as a function of water content by dielectric relaxation spectroscopy (DRS). Two relaxation processes observed in both dried and hydrated films were assigned to the segmental motion (α-process) and the relatively smaller scale motion such as the hindered rotation of side chains (β-process). Water molecules adsorbed on PMEA made the α-process faster, meaning that water molecules in PMEA played the role of a plasticizer. Combining the above knowledge with the depth dependence of water content in the PMEA film previously obtained by neutron reflectivity, the segmental dynamics of PMEA at the water interface, which should be crucial to bio-inertness, is discussed. We found that the segmental motion was markedly faster than that in the bulk and almost comparable to the side chain motion.

DOI： 10.1039/c6cp07322k

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

The interfacial structures of a blood-compatible polymer, poly(2-methoxyethyl acrylate) (PMEA), and several analogues were investigated by atomic force microscopy (AFM). The blood-compatible polymers exhibited nanometer-scale protrusions that spontaneously and homogeneously formed at polymer/water and polymer/phosphate-buffered saline interfaces. AFM observation also revealed that fibrinogen adsorption occurred locally on the protrusions rather than uniformly at the interface, with the regions adjacent to the protrusions apparently preventing the adsorption of fibrinogen. The formation of these interfacial structures may be due to in-plane microphase separation of polymer and water at the interface.

DOI： 10.1021/acsbiomaterials.6b00415

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

The interfacial structures of a blood-compatible polymer, poly(2-methoxyethyl acrylate) (PMEA), and several analogues were investigated by atomic force microscopy (AFM). The blood-compatible polymers exhibited nano meter-scale protrusions that spontaneously and homogeneously formed at polymer/water and polymer/phosphatebuffered saline interfaces. AFM observation also revealed that fibrinogen adsorption occurred locally on the protrusions rather than uniformly at the interface, with the regions adjacent to the protrusions apparently preventing the adsorption of fibrinogen. The formation of these interfacial structures may be due to in-plane microphase separation of polymer and water at the interface.

DOI： 10.1021/acsbiomaterials.6b00415

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

The interfacial structures of a blood-compatible polymer, poly(2-methoxyethyl acrylate) (PMEA), and several analogues were investigated by atomic force microscopy (AFM). The blood-compatible polymers exhibited nanometer-scale protrusions that spontaneously and homogeneously formed at polymer/water and polymer/phosphate-buffered saline interfaces. AFM observation also revealed that fibrinogen adsorption occurred locally on the protrusions rather than uniformly at the interface, with the regions adjacent to the protrusions apparently preventing the adsorption of fibrinogen. The formation of these interfacial structures may be due to in-plane microphase separation of polymer and water at the interface.

DOI： 10.1021/acsbiomaterials.6b00415

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

Biomaterials must fulfill some requirements before moving into in vivo application. In vitro test is usually conducted as a preliminary screening evaluation. Although most of the studies are focused in the cytotoxicity, interactions between blood elements and the biomaterials or hemocompatibility must also be considered. Aliphatic polyurethanes have been always considered ideal candidates for in-vivo application due to their versatility. However, the utilization of metal catalyst to promote the polymerization have limited their use. Recently, some organocatalysts have shown to be competitive to tin based catalyst for the preparation of polyurethanes and have relaunched their use in biomedicine. In the present study we carried out the organocatalyzed polymerization of 5 commercially available isocyanates, hexamethylene diisocyanate, isophorone diisocyanate, trans-1,4-cyclohexylene diisocyanate, 4,4′-methylenebis(cyclohexyl isocyanate) and L-lysine diisocyanate to analyze the cytotoxicity and hemocompatibility of the resultant polymers as a function of the employed diisocyanate. The diisocyanates were polymerized with hydroxy end-capped oligomeric poly (tetramethylene glycol) (PT2K) as the long chain diol and 1,3-propanediol as the short chain diol. We demonstrated that from selected diisocyanates, lysine diisocyanate based polyurethanes possessed lower cytotoxicity and better hemocompatibility than the other polyurethanes. In comparison with a well known blood compatible polymer such as poly(2-methoxyethyl acrylate), the lysine diisocyanate based polyurethanes showed remarkable values in terms of cytotoxicity and platelet adhesion, but major levels of protein adsorption.

DOI： 10.1016/j.eurpolymj.2016.08.008

Language：Japanese  

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

Highly regio-/stereoregular (trans-head-to-tail) polymers with amide side chains on every eighth backbone carbon were successfully synthesized by ring-opening metathesis polymerization (ROMP) of 3-substituted cis-cyclooctene (3RCOE) using Grubbs second-generation catalyst (G2). Regioregular linear ethylene acrylamide copolymers were also prepared via hydrogenation of the obtained poly(3RCOE)s. The thermal properties and solubility of the obtained polymers were strongly influenced by the presence of amide hydrogen in the side chains, the presence of unsaturated bonds in the carbon backbone, and the side chain density. The presence of amide hydrogen in the side chains resulted in the formation of crystalline polymers and the lack of solubility of these polymers in common organic solvents. In contrast, the absence of amide hydrogen in the side chains led to the formation of amorphous polymers exhibiting good solubility in common organic solvents, and decreasing values of T-g were observed for amorphous polymers as a result of the saturation of double bonds in the backbone via hydrogenation.

DOI： 10.1021/acs.macromol.6b01829

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

Stem cell differentiation is an important issue in regenerative medicine and tissue engineering. It has been reported that cell shape is one of the factors that determine the lineage commitment of mesenchymal stem cells (MSCs). Therefore, the substrates have been developed to control their shapes. Recently, we found that poly(2-methoxyethyl acrylate) (PMEA) analogs can control tumor cell shape through the alteration of protein adsorption. Here, the adipogenesis of an adipocyte-progenitor cell, 3T3-L1 cells, was attempted; adipogenesis was to be regulated by surfaces coated with PMEA analogs through the control of their shape. The adipogenesis of 3T3-L1 cells was promoted on the surfaces coated with PMEA and its analogs, PMe3A and PMe2A. Evident focal adhesions were hardly observed on these surfaces, suggesting that integrin signal activation was suppressed. Additionally, actin assembly and cell spreading were suppressed on these surfaces. Therefore, the surfaces coated with PMEA analogs are expected to be suitable surfaces to regulate adipogenesis through the suppression of cell spreading. Additionally, we found that protein adsorption correlated with actin assembly and adipogenesis.

DOI： 10.1021/acs.biomac.6b01340

Language：English  

Cells can mainly sense mechanical cues from the extracellular matrix via integrins. Because mechanical cues can strongly influence cellular functions, understanding the roles of integrins in the sensing of mechanical cues is a key for the achievement of tissue engineering. The analyses to determine the roles of integrins in the sensing of mechanical cues have been performed by many methods based on molecular- and cell-biological techniques, atomic force microscopy, and optical tweezers. Integrin-dependent cell adhesion substrates have been also used for this purpose. Additionally, the cells can adhere on several substrates via integrin-independent mechanisms. There are two types of integrin-independent cell adhesion substrates; 1) the substrates immobilized with ligands against the receptors on cell surface and 2) the substrates suppressing protein adsorption. Cells can exhibit specific functions on these substrates. Here, the examples of integrin-independent cell adhesion substrates were reviewed, and their possible applications in mechanobiology research are discussed.

DOI： 10.2116/analsci.32.1151

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

Chemoresistance is a major barrier for tumor chemotherapy. It is well-known that chemoresistance increases with tumor progression. Chemoresistance is altered by both genetic mutations and the alteration of extracellular microenvironment. Particularly, the extracellular matrix (ECM) is remodeled during tumor progression. Therefore, ECM remodeling is expected to cause the acquisition of chemoresistance in highly malignant tumor tissue. Here, we prepared cultured cell-derived decellularized matrices that mimic native ECM in tumor tissues at different stages of malignancy, and 5-fluorouracil (5-FU) resistance was compared among these matrices. 5-FU resistance of colorectal tumor cells increased on the matrices derived from highly malignant tumor HT-29 cells, although the resistance did not increase on the matrices derived from low malignant tumor SW480 cells and normal CCD-841-CoN cells. The resistance on HT-29 cell-derived matrices increased through the activation of Akt and the upregulation of ABCB1 and ABCC1 without cell growth promotion, suggesting that ECM remodeling plays important roles in the acquisition of chemoresistance during tumor progression. It is expected that our decellularized matrices, or "staged tumorigenesis-mimicking matrices", will become preferred cell culture substrates for in vitro analysis of comprehensive ECM roles in chemoresistance and the screening and pharmacokinetic analysis of anti-cancer drugs. (C) 2016 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.bbamcr.2016.08.009

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

Biomaterials must fulfill some requirements before moving into in vivo application. In vitro test is usually conducted as a preliminary screening evaluation. Although most of the studies are focused in the cytotoxicity, interactions between blood elements and the bio-materials or hemocompatibility must also be considered. Aliphatic polyurethanes have been always considered ideal candidates for in-vivo application due to their versatility. However, the utilization of metal catalyst to promote the polymerization have limited their use. Recently, some organocatalysts have shown to be competitive to tin based catalyst for the preparation of polyurethanes and have relaunched their use in biomedicine. In the present study we carried out the organocatalyzed polymerization of 5 commercially available isocyanates, hexamethylene diisocyanate, isophorone diisocyanate, trans-1,4-cyclohexylene diisocyanate, 4,4'-methylenebis(cyclohexyl isocyanate) and L-lysine diisocyanate to analyze the cytotoxicity and hemocompatibility of the resultant polymers as a function of the employed diisocyanate. The diisocyanates were polymerized with hydroxy end-capped oligomeric poly (tetramethylene glycol) (PT2K) as the long chain diol and 1,3-propanediol as the short chain diol. We demonstrated that from selected diisocyanates, lysine diisocyanate based polyurethanes possessed lower cytotoxicity and better hemocompatibility than the other polyurethanes. In comparison with a well known blood compatible polymer such as poly(2-methoxyethyl acrylate), the lysine diisocyanate based polyurethanes showed remarkable values in terms of cytotoxicity and platelet adhesion, but major levels of protein adsorption. (C) 2016 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.eurpolymj.2016.08.008

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

Highly regio-/stereoregular (trans-head-to-tail) polymers with amide side chains on every eighth backbone carbon were successfully synthesized by ring-opening metathesis polymerization (ROMP) of 3-substituted cis-cyclooctene (3RCOE) using Grubbs second-generation catalyst (G2). Regioregular linear ethylene-acrylamide copolymers were also prepared via hydrogenation of the obtained poly(3RCOE)s. The thermal properties and solubility of the obtained polymers were strongly influenced by the presence of amide hydrogen in the side chains, the presence of unsaturated bonds in the carbon backbone, and the side chain density. The presence of amide hydrogen in the side chains resulted in the formation of crystalline polymers and the lack of solubility of these polymers in common organic solvents. In contrast, the absence of amide hydrogen in the side chains led to the formation of amorphous polymers exhibiting good solubility in common organic solvents, and decreasing values of T
_g
were observed for amorphous polymers as a result of the saturation of double bonds in the backbone via hydrogenation.

DOI： 10.1021/acs.macromol.6b01829

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

Stem cell differentiation is an important issue in regenerative medicine and tissue engineering. It has been reported that cell shape is one of the factors that determine the lineage commitment of mesenchymal stem cells (MSCs). Therefore, the substrates have been developed to control their shapes. Recently, we found that poly(2-methoxyethyl acrylate) (PMEA) analogs can control tumor cell shape through the alteration of protein adsorption. Here, the adipogenesis of an adipocyte-progenitor cell, 3T3-L1 cells, was attempted; adipogenesis was to be regulated by surfaces coated with PMEA analogs through the control of their shape. The adipogenesis of 3T3-L1 cells was promoted on the surfaces coated with PMEA and its analogs, PMe3A and PMe2A. Evident focal adhesions were hardly observed on these surfaces, suggesting that integrin signal activation was suppressed. Additionally, actin assembly and cell spreading were suppressed on these surfaces. Therefore, the surfaces coated with PMEA analogs are expected to be suitable surfaces to regulate adipogenesis through the suppression of cell spreading. Additionally, we found that protein adsorption correlated with actin assembly and adipogenesis.

DOI： 10.1021/acs.biomac.6b01340

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

Chemoresistance is a major barrier for tumor chemotherapy. It is well-known that chemoresistance increases with tumor progression. Chemoresistance is altered by both genetic mutations and the alteration of extracellular microenvironment. Particularly, the extracellular matrix (ECM) is remodeled during tumor progression. Therefore, ECM remodeling is expected to cause the acquisition of chemoresistance in highly malignant tumor tissue. Here, we prepared cultured cell-derived decellularized matrices that mimic native ECM in tumor tissues at different stages of malignancy, and 5-fluorouracil (5-FU) resistance was compared among these matrices. 5-FU resistance of colorectal tumor cells increased on the matrices derived from highly malignant tumor HT-29 cells, although the resistance did not increase on the matrices derived from low malignant tumor SW480 cells and normal CCD-841-CoN cells. The resistance on HT-29 cell-derived matrices increased through the activation of Akt and the upregulation of ABCB1 and ABCC1 without cell growth promotion, suggesting that ECM remodeling plays important roles in the acquisition of chemoresistance during tumor progression. It is expected that our decellularized matrices, or “staged tumorigenesis-mimicking matrices”, will become preferred cell culture substrates for in vitro analysis of comprehensive ECM roles in chemoresistance and the screening and pharmacokinetic analysis of anti-cancer drugs.

DOI： 10.1016/j.bbamcr.2016.08.009

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

Biomaterials must fulfill some requirements before moving into in vivo application. In vitro test is usually conducted as a preliminary screening evaluation. Although most of the studies are focused in the cytotoxicity, interactions between blood elements and the biomaterials or hemocompatibility must also be considered. Aliphatic polyurethanes have been always considered ideal candidates for in-vivo application due to their versatility. However, the utilization of metal catalyst to promote the polymerization have limited their use. Recently, some organocatalysts have shown to be competitive to tin based catalyst for the preparation of polyurethanes and have relaunched their use in biomedicine. In the present study we carried out the organocatalyzed polymerization of 5 commercially available isocyanates, hexamethylene diisocyanate, isophorone diisocyanate, trans-1,4-cyclohexylene diisocyanate, 4,4′-methylenebis(cyclohexyl isocyanate) and L-lysine diisocyanate to analyze the cytotoxicity and hemocompatibility of the resultant polymers as a function of the employed diisocyanate. The diisocyanates were polymerized with hydroxy end-capped oligomeric poly (tetramethylene glycol) (PT2K) as the long chain diol and 1,3-propanediol as the short chain diol. We demonstrated that from selected diisocyanates, lysine diisocyanate based polyurethanes possessed lower cytotoxicity and better hemocompatibility than the other polyurethanes. In comparison with a well known blood compatible polymer such as poly(2-methoxyethyl acrylate), the lysine diisocyanate based polyurethanes showed remarkable values in terms of cytotoxicity and platelet adhesion, but major levels of protein adsorption.

DOI： 10.1016/j.eurpolymj.2016.08.008

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

Highly regio-/stereoregular (trans-head-to-tail) polymers with amide side chains on every eighth backbone carbon were successfully synthesized by ring-opening metathesis polymerization (ROMP) of 3-substituted cis-cyclooctene (3RCOE) using Grubbs second-generation catalyst (G2). Regioregular linear ethylene-acrylamide copolymers were also prepared via hydrogenation of the obtained poly(3RCOE)s. The thermal properties and solubility of the obtained polymers were strongly influenced by the presence of amide hydrogen in the side chains, the presence of unsaturated bonds in the carbon backbone, and the side chain density. The presence of amide hydrogen in the side chains resulted in the formation of crystalline polymers and the lack of solubility of these polymers in common organic solvents. In contrast, the absence of amide hydrogen in the side chains led to the formation of amorphous polymers exhibiting good solubility in common organic solvents, and decreasing values of T
_g
were observed for amorphous polymers as a result of the saturation of double bonds in the backbone via hydrogenation.

DOI： 10.1021/acs.macromol.6b01829

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

Stem cell differentiation is an important issue in regenerative medicine and tissue engineering. It has been reported that cell shape is one of the factors that determine the lineage commitment of mesenchymal stem cells (MSCs). Therefore, the substrates have been developed to control their shapes. Recently, we found that poly(2-methoxyethyl acrylate) (PMEA) analogs can control tumor cell shape through the alteration of protein adsorption. Here, the adipogenesis of an adipocyte-progenitor cell, 3T3-L1 cells, was attempted; adipogenesis was to be regulated by surfaces coated with PMEA analogs through the control of their shape. The adipogenesis of 3T3-L1 cells was promoted on the surfaces coated with PMEA and its analogs, PMe3A and PMe2A. Evident focal adhesions were hardly observed on these surfaces, suggesting that integrin signal activation was suppressed. Additionally, actin assembly and cell spreading were suppressed on these surfaces. Therefore, the surfaces coated with PMEA analogs are expected to be suitable surfaces to regulate adipogenesis through the suppression of cell spreading. Additionally, we found that protein adsorption correlated with actin assembly and adipogenesis.

DOI： 10.1021/acs.biomac.6b01340

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

Chemoresistance is a major barrier for tumor chemotherapy. It is well-known that chemoresistance increases with tumor progression. Chemoresistance is altered by both genetic mutations and the alteration of extracellular microenvironment. Particularly, the extracellular matrix (ECM) is remodeled during tumor progression. Therefore, ECM remodeling is expected to cause the acquisition of chemoresistance in highly malignant tumor tissue. Here, we prepared cultured cell-derived decellularized matrices that mimic native ECM in tumor tissues at different stages of malignancy, and 5-fluorouracil (5-FU) resistance was compared among these matrices. 5-FU resistance of colorectal tumor cells increased on the matrices derived from highly malignant tumor HT-29 cells, although the resistance did not increase on the matrices derived from low malignant tumor SW480 cells and normal CCD-841-CoN cells. The resistance on HT-29 cell-derived matrices increased through the activation of Akt and the upregulation of ABCB1 and ABCC1 without cell growth promotion, suggesting that ECM remodeling plays important roles in the acquisition of chemoresistance during tumor progression. It is expected that our decellularized matrices, or “staged tumorigenesis-mimicking matrices”, will become preferred cell culture substrates for in vitro analysis of comprehensive ECM roles in chemoresistance and the screening and pharmacokinetic analysis of anti-cancer drugs.

DOI： 10.1016/j.bbamcr.2016.08.009

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

Biomaterials must fulfill some requirements before moving into in vivo application. In vitro test is usually conducted as a preliminary screening evaluation. Although most of the studies are focused in the cytotoxicity, interactions between blood elements and the biomaterials or hemocompatibility must also be considered. Aliphatic polyurethanes have been always considered ideal candidates for in-vivo application due to their versatility. However, the utilization of metal catalyst to promote the polymerization have limited their use. Recently, some organocatalysts have shown to be competitive to tin based catalyst for the preparation of polyurethanes and have relaunched their use in biomedicine. In the present study we carried out the organocatalyzed polymerization of 5 commercially available isocyanates, hexamethylene diisocyanate, isophorone diisocyanate, trans-1,4-cyclohexylene diisocyanate, 4,4′-methylenebis(cyclohexyl isocyanate) and L-lysine diisocyanate to analyze the cytotoxicity and hemocompatibility of the resultant polymers as a function of the employed diisocyanate. The diisocyanates were polymerized with hydroxy end-capped oligomeric poly (tetramethylene glycol) (PT2K) as the long chain diol and 1,3-propanediol as the short chain diol. We demonstrated that from selected diisocyanates, lysine diisocyanate based polyurethanes possessed lower cytotoxicity and better hemocompatibility than the other polyurethanes. In comparison with a well known blood compatible polymer such as poly(2-methoxyethyl acrylate), the lysine diisocyanate based polyurethanes showed remarkable values in terms of cytotoxicity and platelet adhesion, but major levels of protein adsorption.

DOI： 10.1016/j.eurpolymj.2016.08.008

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

Chemoresistance is a major barrier for tumor chemotherapy. It is well-known that chemoresistance increases with tumor progression. Chemoresistance is altered by both genetic mutations and the alteration of extracellular microenvironment. Particularly, the extracellular matrix (ECM) is remodeled during tumor progression. Therefore, ECM remodeling is expected to cause the acquisition of chemoresistance in highly malignant tumor tissue. Here, we prepared cultured cell-derived decellularized matrices that mimic native ECM in tumor tissues at different stages of malignancy, and 5-fluorouracil (5-FU) resistance was compared among these matrices. 5-FU resistance of colorectal tumor cells increased on the matrices derived from highly malignant tumor HT-29 cells, although the resistance did not increase on the matrices derived from low malignant tumor SW480 cells and normal CCD-841-CoN cells. The resistance on HT-29 cell-derived matrices increased through the activation of Akt and the upregulation of ABCB1 and ABCC1 without cell growth promotion, suggesting that ECM remodeling plays important roles in the acquisition of chemoresistance during tumor progression. It is expected that our decellularized matrices, or “staged tumorigenesis-mimicking matrices”, will become preferred cell culture substrates for in vitro analysis of comprehensive ECM roles in chemoresistance and the screening and pharmacokinetic analysis of anti-cancer drugs.

DOI： 10.1016/j.bbamcr.2016.08.009

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

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

Thrombus formation presents a serious hindrance in the development of functional artificial blood vessels, especially those with a small diameter. Endothelialization can prevent thrombus formation; however, the adhesion of endothelial cells to existing polymer materials is generally weak. Therefore, polymers that have both anti-thrombotic and endothelialization properties do not currently exist. We previously reported that platelets do not adhere to poly(2-methoxyethyl acrylate) (PMEA) or poly(tetrahydrofurfuryl acrylate)(PTHFA). Here, we investigated whether endothelial cells and smooth muscle cells, both of which are blood vessel components, could adhere to these synthetic polymers. Polyethylene terephthalate films were coated with PMEA and PTHFA using a spin-coater. Human umbilical vein endothelial cells or aorta smooth muscle cells were seeded on the polymer surfaces, after which we analyzed the number of adherent cells, their morphologies and vinculin expression. We found that both endothelial and smooth muscle cells adhered to PMEA and PTHFA, while platelets did not. We propose that, by using PMEA and PTHFA with no modifications, it should be possible to develop artificial blood vessels with both anti-thrombotic and endothelialization properties. In addition, we discuss the mechanism of selective cell adhesion in PMEA and PTHFA.

DOI： 10.1016/j.colsurfb.2016.05.057

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

Thrombus formation presents a serious hindrance in the development of functional artificial blood vessels, especially those with a small diameter. Endothelialization can prevent thrombus formation; however, the adhesion of endothelial cells to existing polymer materials is generally weak. Therefore, polymers that have both anti-thrombotic and endothelialization properties do not currently exist. We previously reported that platelets do not adhere to poly(2-methoxyethyl acrylate) (PMEA) or poly(tetrahydrofurfuryl acrylate)(PTHFA). Here, we investigated whether endothelial cells and smooth muscle cells, both of which are blood vessel components, could adhere to these synthetic polymers. Polyethylene terephthalate films were coated with PMEA and PTHFA using a spin-coater. Human umbilical vein endothelial cells or aorta smooth muscle cells were seeded on the polymer surfaces, after which we analyzed the number of adherent cells, their morphologies and vinculin expression. We found that both endothelial and smooth muscle cells adhered to PMEA and PTHFA, while platelets did not. We propose that, by using PMEA and PTHFA with no modifications, it should be possible to develop artificial blood vessels with both anti-thrombotic and endothelialization properties. In addition, we discuss the mechanism of selective cell adhesion in PMEA and PTHFA. (C) 2016 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.colsurfb.2016.05.057

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

Thrombus formation presents a serious hindrance in the development of functional artificial blood vessels, especially those with a small diameter. Endothelialization can prevent thrombus formation; however, the adhesion of endothelial cells to existing polymer materials is generally weak. Therefore, polymers that have both anti-thrombotic and endothelialization properties do not currently exist. We previously reported that platelets do not adhere to poly(2-methoxyethyl acrylate) (PMEA) or poly(tetrahydrofurfuryl acrylate)(PTHFA). Here, we investigated whether endothelial cells and smooth muscle cells, both of which are blood vessel components, could adhere to these synthetic polymers. Polyethylene terephthalate films were coated with PMEA and PTHFA using a spin-coater. Human umbilical vein endothelial cells or aorta smooth muscle cells were seeded on the polymer surfaces, after which we analyzed the number of adherent cells, their morphologies and vinculin expression. We found that both endothelial and smooth muscle cells adhered to PMEA and PTHFA, while platelets did not. We propose that, by using PMEA and PTHFA with no modifications, it should be possible to develop artificial blood vessels with both anti-thrombotic and endothelialization properties. In addition, we discuss the mechanism of selective cell adhesion in PMEA and PTHFA.

DOI： 10.1016/j.colsurfb.2016.05.057

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

Thrombus formation presents a serious hindrance in the development of functional artificial blood vessels, especially those with a small diameter. Endothelialization can prevent thrombus formation; however, the adhesion of endothelial cells to existing polymer materials is generally weak. Therefore, polymers that have both anti-thrombotic and endothelialization properties do not currently exist. We previously reported that platelets do not adhere to poly(2-methoxyethyl acrylate) (PMEA) or poly(tetrahydrofurfuryl acrylate)(PTHFA). Here, we investigated whether endothelial cells and smooth muscle cells, both of which are blood vessel components, could adhere to these synthetic polymers. Polyethylene terephthalate films were coated with PMEA and PTHFA using a spin-coater. Human umbilical vein endothelial cells or aorta smooth muscle cells were seeded on the polymer surfaces, after which we analyzed the number of adherent cells, their morphologies and vinculin expression. We found that both endothelial and smooth muscle cells adhered to PMEA and PTHFA, while platelets did not. We propose that, by using PMEA and PTHFA with no modifications, it should be possible to develop artificial blood vessels with both anti-thrombotic and endothelialization properties. In addition, we discuss the mechanism of selective cell adhesion in PMEA and PTHFA.

DOI： 10.1016/j.colsurfb.2016.05.057

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

Circulating tumor cells have received attention for their role in cancer diagnosis and the decision on which chemotherapeutic course to take. For these purposes, the isolation of circulating tumor cells has been important. Previously, we reported that non-blood cells can adhere on blood-compatible polymer substrates, such as poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate). In this study, we examined whether blood-compatible poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) allow the adhesion and growth of A549 lung cancer cells for isolating circulating tumor cells by adhesion-mediated manner to diagnose metastatic cancer and to decide on the chemotherapeutic course. A549 cells can adhere on poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates via an integrin-dependent mechanism after 1 h of incubation, suggesting that blood-compatible poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates possess the ability to capture circulating tumor cells selectively from peripheral blood. After 1 day of culture, A549 cells started to spread on poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates. A549 can also grow on poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates. Additionally, the chemoresistance of A549 cells against 5-fluorouracil on poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates was similar to that on the conventional cell culture substrate, tissue culture polystyrene. These results indicate that circulating tumor cells can be cultured on poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates after they are isolated from peripheral blood, and poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates can be used as circulating tumor cell culture substrates for screening anti-cancer drugs. Therefore, poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates might be able to be applied to the development of a new device for a circulating tumor cell-based diagnosis of metastatic cancer and a personalized medicine approach regarding the decision of which chemotherapeutic course should be taken.

DOI： 10.1177/0883911515618976

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

Circulating tumor cells have received attention for their role in cancer diagnosis and the decision on which chemotherapeutic course to take. For these purposes, the isolation of circulating tumor cells has been important. Previously, we reported that non-blood cells can adhere on blood-compatible polymer substrates, such as poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate). In this study, we examined whether blood-compatible poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) allow the adhesion and growth of A549 lung cancer cells for isolating circulating tumor cells by adhesion-mediated manner to diagnose metastatic cancer and to decide on the chemotherapeutic course. A549 cells can adhere on poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates via an integrin-dependent mechanism after 1h of incubation, suggesting that blood-compatible poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates possess the ability to capture circulating tumor cells selectively from peripheral blood. After 1day of culture, A549 cells started to spread on poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates. A549 can also grow on poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates. Additionally, the chemoresistance of A549 cells against 5-fluorouracil on poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates was similar to that on the conventional cell culture substrate, tissue culture polystyrene. These results indicate that circulating tumor cells can be cultured on poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates after they are isolated from peripheral blood, and poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates can be used as circulating tumor cell culture substrates for screening anti-cancer drugs. Therefore, poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates might be able to be applied to the development of a new device for a circulating tumor cell-based diagnosis of metastatic cancer and a personalized medicine approach regarding the decision of which chemotherapeutic course should be taken.

DOI： 10.1177/0883911515618976

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

Circulating tumor cells have received attention for their role in cancer diagnosis and the decision on which chemotherapeutic course to take. For these purposes, the isolation of circulating tumor cells has been important. Previously, we reported that non-blood cells can adhere on blood-compatible polymer substrates, such as poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate). In this study, we examined whether blood-compatible poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) allow the adhesion and growth of A549 lung cancer cells for isolating circulating tumor cells by adhesion-mediated manner to diagnose metastatic cancer and to decide on the chemotherapeutic course. A549 cells can adhere on poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates via an integrin-dependent mechanism after 1 h of incubation, suggesting that blood-compatible poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates possess the ability to capture circulating tumor cells selectively from peripheral blood. After 1 day of culture, A549 cells started to spread on poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates. A549 can also grow on poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates. Additionally, the chemoresistance of A549 cells against 5-fluorouracil on poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates was similar to that on the conventional cell culture substrate, tissue culture polystyrene. These results indicate that circulating tumor cells can be cultured on poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates after they are isolated from peripheral blood, and poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates can be used as circulating tumor cell culture substrates for screening anti-cancer drugs. Therefore, poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates might be able to be applied to the development of a new device for a circulating tumor cell-based diagnosis of metastatic cancer and a personalized medicine approach regarding the decision of which chemotherapeutic course should be taken.

DOI： 10.1177/0883911515618976

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

Circulating tumor cells have received attention for their role in cancer diagnosis and the decision on which chemotherapeutic course to take. For these purposes, the isolation of circulating tumor cells has been important. Previously, we reported that non-blood cells can adhere on blood-compatible polymer substrates, such as poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate). In this study, we examined whether blood-compatible poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) allow the adhesion and growth of A549 lung cancer cells for isolating circulating tumor cells by adhesion-mediated manner to diagnose metastatic cancer and to decide on the chemotherapeutic course. A549 cells can adhere on poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates via an integrin-dependent mechanism after 1 h of incubation, suggesting that blood-compatible poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates possess the ability to capture circulating tumor cells selectively from peripheral blood. After 1 day of culture, A549 cells started to spread on poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates. A549 can also grow on poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates. Additionally, the chemoresistance of A549 cells against 5-fluorouracil on poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates was similar to that on the conventional cell culture substrate, tissue culture polystyrene. These results indicate that circulating tumor cells can be cultured on poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates after they are isolated from peripheral blood, and poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates can be used as circulating tumor cell culture substrates for screening anti-cancer drugs. Therefore, poly(2-methoxyethyl acrylate) and poly(tetrahydrofurfuryl acrylate) substrates might be able to be applied to the development of a new device for a circulating tumor cell-based diagnosis of metastatic cancer and a personalized medicine approach regarding the decision of which chemotherapeutic course should be taken.

DOI： 10.1177/0883911515618976

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

Functionalizing biomaterials with peptides or polymers that enhance recruitment of endothelial cells (ECs) can reduce blood coagulation and thrombosis. To assess endothelialization of materials in vitro, primary ECs are generally used, although the characteristics of these cells vary among the donors and change with time in culture. Recently, primary cell lines immortalized by transduction of simian vacuolating virus 40 large T antigen or human telomerase reverse transcriptase have been developed. To determine whether immortalized ECs can substitute for primary ECs in material testing, we investigated endothelialization on biocompatible polymers using three lots of primary human umbilical vein endothelial cells (HUVEC) and immortalized microvascular ECs, TIME-GFP. Attachment to and growth on polymer surfaces were comparable between cell types, but results were more consistent with TIME-GFP. Our findings indicate that TIME-GFP is more suitable for in vitro endothelialization testing of biomaterials.

DOI： 10.1371/journal.pone.0158289

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

Functionalizing biomaterials with peptides or polymers that enhance recruitment of endothelial cells (ECs) can reduce blood coagulation and thrombosis. To assess endothelialization of materials in vitro, primary ECs are generally used, although the characteristics of these cells vary among the donors and change with time in culture. Recently, primary cell lines immortalized by transduction of simian vacuolating virus 40 large T antigen or human telomerase reverse transcriptase have been developed. To determine whether immortalized ECs can substitute for primary ECs in material testing, we investigated endothelialization on biocompatible polymers using three lots of primary human umbilical vein endothelial cells (HUVEC) and immortalized microvascular ECs, TIME-GFP. Attachment to and growth on polymer surfaces were comparable between cell types, but results were more consistent with TIME-GFP. Our findings indicate that TIME-GFP is more suitable for in vitro endothelialization testing of biomaterials.

DOI： 10.1371/journal.pone.0158289

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

Functionalizing biomaterials with peptides or polymers that enhance recruitment of endothelial cells (ECs) can reduce blood coagulation and thrombosis. To assess endothelialization of materials in vitro, primary ECs are generally used, although the characteristics of these cells vary among the donors and change with time in culture. Recently, primary cell lines immortalized by transduction of simian vacuolating virus 40 large T antigen or human telomerase reverse transcriptase have been developed. To determine whether immortalized ECs can substitute for primary ECs in material testing, we investigated endothelialization on biocompatible polymers using three lots of primary human umbilical vein endothelial cells (HUVEC) and immortalized microvascular ECs, TIME-GFP. Attachment to and growth on polymer surfaces were comparable between cell types, but results were more consistent with TIME-GFP. Our findings indicate that TIME-GFP is more suitable for in vitro endothelialization testing of biomaterials.

DOI： 10.1371/journal.pone.0158289

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

Functionalizing biomaterials with peptides or polymers that enhance recruitment of endothelial cells (ECs) can reduce blood coagulation and thrombosis. To assess endothelialization of materials in vitro, primary ECs are generally used, although the characteristics of these cells vary among the donors and change with time in culture. Recently, primary cell lines immortalized by transduction of simian vacuolating virus 40 large T antigen or human telomerase reverse transcriptase have been developed. To determine whether immortalized ECs can substitute for primary ECs in material testing, we investigated endothelialization on biocompatible polymers using three lots of primary human umbilical vein endothelial cells (HUVEC) and immortalized microvascular ECs, TIME-GFP. Attachment to and growth on polymer surfaces were comparable between cell types, but results were more consistent with TIME-GFP. Our findings indicate that TIME-GFP is more suitable for in vitro endothelialization testing of biomaterials.

DOI： 10.1371/journal.pone.0158289

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

Allyl-substituted cyclooctenes with ether side-chains [methoxy, methoxy-terminated oligo(ethylene glycol)s, and tetrahydrofurfuryloxy group] were prepared as monomers and polymerized by ring-opening metathesis polymerization (ROMP) using Grubbs second-generation catalyst. In all cases, the ROMP of allyl-substituted monomers proceeded in a regio- and stereoselective manner to afford polymers with remarkably high head-to-tail regioregularity with high trans-stereoregularity. The regio- and stereoregularity of polymers were affected by the bulkiness of the substituent, and the ROMP of tetrahydrofurfuryloxy-substituted cyclooctene exhibited nearly perfect regio- (head-to-tail = 99%) and stereoselectivity (trans-double bond = 99%). Chemical hydrogenation of obtained polymers afforded model poly(ethylene-co-vinyl ether)s with precisely placed ether branches on every eighth backbone carbon. Differential scanning calorimetry (DSC) was used to study the thermal properties, and the hydrophilicity of polymers was evaluated by water contact angle measurement. The surface hydrophilicity of unsaturated polymers was effectively tuned by changing the side-chain length of oligo(ethylene glycol) groups while maintaining the hydrophobic character unchanged for saturated versions.

DOI： 10.1021/acs.macromol.6b00273

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

Allyl-substituted cyclooctenes with ether side chains [methoxy, methoxy-terminated oligo(ethylene glycol)s, and tetrahydrofurfuryloxy group] were prepared as monomers and polymerized by ring-opening metathesis polymerization (ROMP) using Grubbs second-generation catalyst. In all cases, the ROMP of allyl-substituted monomers proceeded in a regio- and stereoselective manner to afford polymers with remarkably high head-to-tail regioregularity with high transstereoregularity. The regio- and stereoregularity of polymers were affected by the bulkiness of the substituent, and the ROMP of tetrahydrofurfuryloxy-substituted cyclooctene exhibited nearly perfect regio- (head-to-tail = 99%) and stereoselectivity (trans double bond = 99%). Chemical hydrogenation of obtained polymers afforded model poly(ethylene-co-vinyl ether)s with precisely placed ether branches on every eighth backbone carbon. Differential scanning calorimetry (DSC) was used to study the thermal properties, and the hydrophilicity of polymers was evaluated by water contact angle measurement. The surface hydrophilicity of unsaturated polymers was effectively tuned by changing the side-chain length of oligo(ethylene glycol) groups while maintaining the hydrophobic character unchanged for saturated versions.

DOI： 10.1021/acs.macromol.6b00273

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

Allyl-substituted cyclooctenes with ether side-chains [methoxy, methoxy-terminated oligo(ethylene glycol)s, and tetrahydrofurfuryloxy group] were prepared as monomers and polymerized by ring-opening metathesis polymerization (ROMP) using Grubbs second-generation catalyst. In all cases, the ROMP of allyl-substituted monomers proceeded in a regio- and stereoselective manner to afford polymers with remarkably high head-to-tail regioregularity with high trans-stereoregularity. The regio- and stereoregularity of polymers were affected by the bulkiness of the substituent, and the ROMP of tetrahydrofurfuryloxy-substituted cyclooctene exhibited nearly perfect regio- (head-to-tail = 99%) and stereoselectivity (trans-double bond = 99%). Chemical hydrogenation of obtained polymers afforded model poly(ethylene-co-vinyl ether)s with precisely placed ether branches on every eighth backbone carbon. Differential scanning calorimetry (DSC) was used to study the thermal properties, and the hydrophilicity of polymers was evaluated by water contact angle measurement. The surface hydrophilicity of unsaturated polymers was effectively tuned by changing the side-chain length of oligo(ethylene glycol) groups while maintaining the hydrophobic character unchanged for saturated versions.

DOI： 10.1021/acs.macromol.6b00273

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

Circulating tumor cells (CTCs) have been a focus of study for metastatic cancer diagnostics, in in vitro anti-cancer drug screening to decide the chemotherapeutic course, and cancer biology research. For these purposes, there have been efforts made to collect CTCs from the peripheral blood of cancer patients. Here, we explore the possibility of collecting CTCs using blood-compatible and thermo-responsive poly(2-(2-ethoxyethoxy) ethyl acrylate-co-2-(2-methoxyethoxy) ethyl methacrylate) (P(Et2A-Me2MA)) through adhesion and detachment by incubation under a lower critical solution temperature of P(Et2A-Me2MA). A P(Et2A-Me2MA)-coated substrate is dissolved by incubation under 15 °C. A P(Et2A-Me2MA)-coated substrate can suppress platelet adhesion whereas it allows the cancer cells to adhere by an epithelial cell adhesion molecule (EpCAM) expression-independent mechanism. These results suggest that cancer cells can specifically adhere to a P(Et2A-Me2MA)-coated substrate, which can be used to isolate CTCs from peripheral blood. Moreover, approximately 90% of the adherent cells can be detached by incubation at 10 and 15 °C for 30 and 90 min, respectively. The collected cells can be cultured healthily in the presence of dissolved P(Et2A-Me2MA), suggesting that the cytotoxicity of P(Et2A-Me2MA) is low. In conclusion, P(Et2A-Me2MA) is suitable for the development of devices that collect intact CTCs via an adhesion-based method.

DOI： 10.1039/c6ra15229e

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

Cells can mainly sense mechanical cues from the extracellular matrix via integrins. Because mechanical cues can strongly influence cellular functions, understanding the roles of integrins in the sensing of mechanical cues is a key for the achievement of tissue engineering. The analyses to determine the roles of integrins in the sensing of mechanical cues have been performed by many methods based on molecular- and cell-biological techniques, atomic force microscopy, and optical tweezers. Integrin-dependent cell adhesion substrates have been also used for this purpose. Additionally, the cells can adhere on several substrates via integrin-independent mechanisms. There are two types of integrin-independent cell adhesion substrates; 1) the substrates immobilized with ligands against the receptors on cell surface and 2) the substrates suppressing protein adsorption. Cells can exhibit specific functions on these substrates. Here, the examples of integrinindependent cell adhesion substrates were reviewed, and their possible applications in mechanobiology research are discussed.

DOI： 10.2116/analsci.32.1151

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

Stem cells are a promising cell source for regenerative medicine. Stem cell differentiation must be regulated for applications in regenerative medicine. Stem cells are surrounded by extracellular matrix (ECM) in vivo. The ECM is composed of many types of proteins and glycosaminoglycans that assemble into a complex structure. The assembly of ECM molecules influences stem cell differentiation through orchestrated intracellular signaling activated by many ECM molecules. Therefore, it is important to understand the comprehensive role of the ECM in stem cell differentiation as well as the functions of the individual ECM molecules. Decellularized ECM is a useful in vitro model for studying the comprehensive roles of ECM because it retains a native-like structure and composition. Decellularized ECM can be obtained from in vivo tissue ECM or ECM fabricated by cells cultured in vitro. It is important to select the correct decellularized ECM because each type has different properties. In this review, tissue-derived and cell-derived decellularized ECMs are compared as in vitro ECM models to examine the comprehensive roles of the ECM in stem cell differentiation. We also summarize recent studies using decellularized ECM to determine the comprehensive roles of the ECM in stem cell differentiation.

DOI： 10.1155/2016/6397820

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

Circulating tumor cells (CTCs) have been a focus of study for metastatic cancer diagnostics, in in vitro anti-cancer drug screening to decide the chemotherapeutic course, and cancer biology research. For these purposes, there have been efforts made to collect CTCs from the peripheral blood of cancer patients. Here, we explore the possibility of collecting CTCs using blood-compatible and thermo-responsive poly(2-(2-ethoxyethoxy) ethyl acrylate-co-2-(2-methoxyethoxy) ethyl methacrylate) (P(Et2A-Me2MA)) through adhesion and detachment by incubation under a lower critical solution temperature of P(Et2A-Me2MA). A P(Et2A-Me2MA)-coated substrate is dissolved by incubation under 15 °C. A P(Et2A-Me2MA)-coated substrate can suppress platelet adhesion whereas it allows the cancer cells to adhere by an epithelial cell adhesion molecule (EpCAM) expression-independent mechanism. These results suggest that cancer cells can specifically adhere to a P(Et2A-Me2MA)-coated substrate, which can be used to isolate CTCs from peripheral blood. Moreover, approximately 90% of the adherent cells can be detached by incubation at 10 and 15 °C for 30 and 90 min, respectively. The collected cells can be cultured healthily in the presence of dissolved P(Et2A-Me2MA), suggesting that the cytotoxicity of P(Et2A-Me2MA) is low. In conclusion, P(Et2A-Me2MA) is suitable for the development of devices that collect intact CTCs via an adhesion-based method.

DOI： 10.1039/c6ra15229e

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

Cells can mainly sense mechanical cues from the extracellular matrix via integrins. Because mechanical cues can strongly influence cellular functions, understanding the roles of integrins in the sensing of mechanical cues is a key for the achievement of tissue engineering. The analyses to determine the roles of integrins in the sensing of mechanical cues have been performed by many methods based on molecular- and cell-biological techniques, atomic force microscopy, and optical tweezers. Integrin-dependent cell adhesion substrates have been also used for this purpose. Additionally, the cells can adhere on several substrates via integrin-independent mechanisms. There are two types of integrin-independent cell adhesion substrates; 1) the substrates immobilized with ligands against the receptors on cell surface and 2) the substrates suppressing protein adsorption. Cells can exhibit specific functions on these substrates. Here, the examples of integrinindependent cell adhesion substrates were reviewed, and their possible applications in mechanobiology research are discussed.

DOI： 10.2116/analsci.32.1151

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

Stem cells are a promising cell source for regenerative medicine. Stem cell differentiation must be regulated for applications in regenerative medicine. Stem cells are surrounded by extracellular matrix (ECM) in vivo. The ECM is composed of many types of proteins and glycosaminoglycans that assemble into a complex structure. The assembly of ECM molecules influences stem cell differentiation through orchestrated intracellular signaling activated by many ECM molecules. Therefore, it is important to understand the comprehensive role of the ECM in stem cell differentiation as well as the functions of the individual ECM molecules. Decellularized ECM is a useful in vitro model for studying the comprehensive roles of ECM because it retains a native-like structure and composition. Decellularized ECM can be obtained from in vivo tissue ECM or ECM fabricated by cells cultured in vitro. It is important to select the correct decellularized ECM because each type has different properties. In this review, tissue-derived and cell-derived decellularized ECMs are compared as in vitro ECM models to examine the comprehensive roles of the ECM in stem cell differentiation. We also summarize recent studies using decellularized ECM to determine the comprehensive roles of the ECM in stem cell differentiation.

DOI： 10.1155/2016/6397820

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

Circulating tumor cells (CTCs) have been a focus of study for metastatic cancer diagnostics, in in vitro anti-cancer drug screening to decide the chemotherapeutic course, and cancer biology research. For these purposes, there have been efforts made to collect CTCs from the peripheral blood of cancer patients. Here, we explore the possibility of collecting CTCs using blood-compatible and thermo-responsive poly(2-(2-ethoxyethoxy) ethyl acrylate-co-2-(2-methoxyethoxy) ethyl methacrylate) (P(Et2A-Me2MA)) through adhesion and detachment by incubation under a lower critical solution temperature of P(Et2A-Me2MA). A P(Et2A-Me2MA)-coated substrate is dissolved by incubation under 15 °C. A P(Et2A-Me2MA)-coated substrate can suppress platelet adhesion whereas it allows the cancer cells to adhere by an epithelial cell adhesion molecule (EpCAM) expression-independent mechanism. These results suggest that cancer cells can specifically adhere to a P(Et2A-Me2MA)-coated substrate, which can be used to isolate CTCs from peripheral blood. Moreover, approximately 90% of the adherent cells can be detached by incubation at 10 and 15 °C for 30 and 90 min, respectively. The collected cells can be cultured healthily in the presence of dissolved P(Et2A-Me2MA), suggesting that the cytotoxicity of P(Et2A-Me2MA) is low. In conclusion, P(Et2A-Me2MA) is suitable for the development of devices that collect intact CTCs via an adhesion-based method.

DOI： 10.1039/c6ra15229e

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

Cells can mainly sense mechanical cues from the extracellular matrix via integrins. Because mechanical cues can strongly influence cellular functions, understanding the roles of integrins in the sensing of mechanical cues is a key for the achievement of tissue engineering. The analyses to determine the roles of integrins in the sensing of mechanical cues have been performed by many methods based on molecular- and cell-biological techniques, atomic force microscopy, and optical tweezers. Integrin-dependent cell adhesion substrates have been also used for this purpose. Additionally, the cells can adhere on several substrates via integrin-independent mechanisms. There are two types of integrin-independent cell adhesion substrates; 1) the substrates immobilized with ligands against the receptors on cell surface and 2) the substrates suppressing protein adsorption. Cells can exhibit specific functions on these substrates. Here, the examples of integrinindependent cell adhesion substrates were reviewed, and their possible applications in mechanobiology research are discussed.

DOI： 10.2116/analsci.32.1151

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

Background: Although various types of materials have been used widely in dialyzers, most biomaterials lack the desired functional properties to interface with blood and have not been engineered for optimum performance. Therefore, there is increasing demand to develop novel materials to address such problems in the dialysis arena. Numerous parameters of polymeric biomaterials can affect biocompatibility in a controlled manner. The mechanisms responsible for the biocompatibility of polymers at the molecular level have not been clearly demonstrated, although many theoretical and experimental efforts have been made to try and understand them. Moreover, water interactions have been recognized as fundamental for the blood response to contact with polymers. Summary: We have proposed the 'intermediate water' concept and hypothesized that intermediate water, which prevents the proteins and blood cells from directly contacting the polymer surface, or nonfreezing water on the polymer surface, plays an important role in the biocompatibility of polymers. This chapter provides an overview of the recent experimental progress of biocompatible polymers measured by thermal, spectroscopic, and surface force techniques. Additionally, it highlights recent developments in the use of biocompatible polymeric biomaterials for dialyzers and provides an overview of the progress made in the design of multifunctional biomedical polymers by controlling the biointerfacial water structure through precision polymer synthesis. Key Messages: Intermediate water was found only in hydrated biopolymers (proteins, polysaccharides, and nucleic acids, DNA and RNA) and hydrated biocompatible synthetic polymers. Intermediate water could be one of the main screening factors for the design of appropriate dialyzer materials.

DOI： 10.1159/000451043

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

Stem cells are a promising cell source for regenerative medicine. Stem cell differentiation must be regulated for applications in regenerative medicine. Stem cells are surrounded by extracellular matrix (ECM) in vivo. The ECM is composed of many types of proteins and glycosaminoglycans that assemble into a complex structure. The assembly of ECM molecules influences stem cell differentiation through orchestrated intracellular signaling activated by many ECM molecules. Therefore, it is important to understand the comprehensive role of the ECM in stem cell differentiation as well as the functions of the individual ECM molecules. Decellularized ECM is a useful in vitro model for studying the comprehensive roles of ECM because it retains a native-like structure and composition. Decellularized ECM can be obtained from in vivo tissue ECM or ECM fabricated by cells cultured in vitro. It is important to select the correct decellularized ECM because each type has different properties. In this review, tissue-derived and cell-derived decellularized ECMs are compared as in vitro ECM models to examine the comprehensive roles of the ECM in stem cell differentiation. We also summarize recent studies using decellularized ECM to determine the comprehensive roles of the ECM in stem cell differentiation.

DOI： 10.1155/2016/6397820

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

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

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

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

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

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

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

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

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

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

The technique of surface segregation was applied to prepare a bio-inert polymer interface. A small amount, 10 wt%, of poly(2-methoxyethyl acrylate) (PMEA), which exhibits excellent bio-inertness properties, fed into a matrix polymer was able to suppress platelet adhesion sufficiently to be of practical use. PMEA was effective because it was preferentially segregated at the outermost region of the polymer blend. Combining interfacial-sensitive analyses such as the air bubble contact angle and neutron reflectivity measurements and sum-frequency generation spectroscopy with the platelet adhesion test gives a better understanding of how the bio-inert property is expressed at the water interface.

DOI： 10.1016/j.polymer.2015.10.001

Language：Japanese  

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

The technique of surface segregation was applied to prepare a bio-inert polymer interface. A small amount, 10 wt%, of poly(2-methoxyethyl acrylate) (PMEA), which exhibits excellent bio-inertness properties, fed into a matrix polymer was able to suppress platelet adhesion sufficiently to be of practical use. PMEA was effective because it was preferentially segregated at the outermost region of the polymer blend. Combining interfacial-sensitive analyses such as the air bubble contact angle and neutron reflectivity measurements and sum-frequency generation spectroscopy with the platelet adhesion test gives a better understanding of how the bio-inert property is expressed at the water interface. (C) 2015 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.polymer.2015.10.001

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

The technique of surface segregation was applied to prepare a bio-inert polymer interface. A small amount, 10 wt%, of poly(2-methoxyethyl acrylate) (PMEA), which exhibits excellent bio-inertness properties, fed into a matrix polymer was able to suppress platelet adhesion sufficiently to be of practical use. PMEA was effective because it was preferentially segregated at the outermost region of the polymer blend. Combining interfacial-sensitive analyses such as the air bubble contact angle and neutron reflectivity measurements and sum-frequency generation spectroscopy with the platelet adhesion test gives a better understanding of how the bio-inert property is expressed at the water interface.

DOI： 10.1016/j.polymer.2015.10.001

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

The technique of surface segregation was applied to prepare a bio-inert polymer interface. A small amount, 10 wt%, of poly(2-methoxyethyl acrylate) (PMEA), which exhibits excellent bio-inertness properties, fed into a matrix polymer was able to suppress platelet adhesion sufficiently to be of practical use. PMEA was effective because it was preferentially segregated at the outermost region of the polymer blend. Combining interfacial-sensitive analyses such as the air bubble contact angle and neutron reflectivity measurements and sum-frequency generation spectroscopy with the platelet adhesion test gives a better understanding of how the bio-inert property is expressed at the water interface.

DOI： 10.1016/j.polymer.2015.10.001

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

Six types of poly(2-methoxyethyl acrylate) (PMEA) analogues were synthesized and the water structure in the hydrated polymers was characterized using differential scanning calorimetry (DSC). The hydrated PMEA analogues exhibited the different amounts of intermediate water. Non-thrombogenicity evaluation was performed on PMEA analogues for platelet adhesion and protein adsorption. Platelet adhesion was suppressed on PMEA analogues. In addition, the protein adsorption and deformation were suppressed by increasing the amount of intermediate water. This study demonstrates that the amount of intermediate water might play a key role in expressing the blood compatibility of polymeric materials.

DOI： 10.1002/mabi.201500078

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

Six types of poly(2-methoxyethyl acrylate) (PMEA) analogues were synthesized and the water structure in the hydrated polymers was characterized using differential scanning calorimetry (DSC). The hydrated PMEA analogues exhibited the different amounts of intermediate water. Non-thrombogenicity evaluation was performed on PMEA analogues for platelet adhesion and protein adsorption. Platelet adhesion was suppressed on PMEA analogues. In addition, the protein adsorption and deformation were suppressed by increasing the amount of intermediate water. This study demonstrates that the amount of intermediate water might play a key role in expressing the blood compatibility of polymeric materials.

DOI： 10.1002/mabi.201500078

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

Six types of poly(2-methoxyethyl acrylate) (PMEA) analogues were synthesized and the water structure in the hydrated polymers was characterized using differential scanning calorimetry (DSC). The hydrated PMEA analogues exhibited the different amounts of intermediate water. Non-thrombogenicity evaluation was performed on PMEA analogues for platelet adhesion and protein adsorption. Platelet adhesion was suppressed on PMEA analogues. In addition, the protein adsorption and deformation were suppressed by increasing the amount of intermediate water. This study demonstrates that the amount of intermediate water might play a key role in expressing the blood compatibility of polymeric materials.

DOI： 10.1002/mabi.201500078

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

Six types of poly(2-methoxyethyl acrylate) (PMEA) analogues were synthesized and the water structure in the hydrated polymers was characterized using differential scanning calorimetry (DSC). The hydrated PMEA analogues exhibited the different amounts of intermediate water. Non-thrombogenicity evaluation was performed on PMEA analogues for platelet adhesion and protein adsorption. Platelet adhesion was suppressed on PMEA analogues. In addition, the protein adsorption and deformation were suppressed by increasing the amount of intermediate water. This study demonstrates that the amount of intermediate water might play a key role in expressing the blood compatibility of polymeric materials.

DOI： 10.1002/mabi.201500078

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

Polymeric biomaterials have a significant impact in today's health care technology. Polymer hydrogels were the first experimentally designed biomaterials for human use. In this article the design, synthesis and properties of hydrogels, derived from synthetic and natural polymers, and their use as biomaterials in tissue engineering are reviewed. The stimuli-responsive hydrogels with controlled degradability and examples of suitable methods for designing such biomaterials, using multidisciplinary approaches from traditional polymer chemistry, materials engineering to molecular biology, have been discussed. Examples of the fabrication of polymer-based biomaterials, utilized for various cell type manipulations for tissue re-generation are also elaborated. Since a highly porous three-dimensional scaffold is crucially important in the cellular process, for tissue engineering, recent advances in the effective methods of scaffold fabrication are described. Additionally, the incorporation of factor molecules for the enhancement of tissue formation and their controlled release is also elucidated in this article. Finally, the future challenges in the efficient fabrication of effective polymeric biomaterials for tissue regeneration and medical device applications are discussed.

DOI： 10.1039/c5tb01370d

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

Cell enrichment is currently in high demand in medical engineering. We have reported that non-blood cells can attach to a blood-compatible poly(2-methoxyethyl acrylate) (PMEA) substrate through integrin-dependent and integrin-independent mechanisms because the PMEA substrate suppresses protein adsorption. Therefore, we assumed that PMEA analogous polymers can change the contribution of integrin to cell attachment through the regulation of protein adsorption. In the present study, we investigated protein adsorption, cell attachment profiles, and attachment mechanisms on PMEA analogous polymer substrates. Additionally, we demonstrated the possibility of attachment-based cell enrichment on PMEA analogous polymer substrates. HT-1080 and MDA-MB-231 cells started to attach to poly(butyl acrylate) (PBA) and poly(tetrahydrofurfuryl acrylate) (PTHFA), on which proteins could adsorb well, within 1 h. HepG2 cells started to attach after 1 h. HT-1080, MDA-MB-231, and HepG2 cells started to attach within 30 min to PMEA, poly(2-(2-methoxyethoxy) ethyl acrylate-co-butyl acrylate) (30:70 mol%, PMe2A) and poly(2-(2-methoxyethoxy) ethoxy ethyl acrylate-co-butyl acrylate) (30:70 mol%, PMe3A), which suppress protein adsorption. Moreover, the ratio of attached cells from a cell mixture can be changed on PMEA analogous polymers. These findings suggested that PMEA analogous polymers can be used for attachment-based cell enrichment.

DOI： 10.1371/journal.pone.0136066

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

Cell enrichment is currently in high demand in medical engineering. We have reported that non-blood cells can attach to a blood-compatible poly(2-methoxyethyl acrylate) (PMEA) substrate through integrin-dependent and integrin-independent mechanisms because the PMEA substrate suppresses protein adsorption. Therefore, we assumed that PMEA analogous polymers can change the contribution of integrin to cell attachment through the regulation of protein adsorption. In the present study, we investigated protein adsorption, cell attachment profiles, and attachment mechanisms on PMEA analogous polymer substrates. Additionally, we demonstrated the possibility of attachment-based cell enrichment on PMEA analogous polymer substrates. HT-1080 and MDA-MB-231 cells started to attach to poly(butyl acrylate) (PBA) and poly(tetrahydrofurfuryl acrylate) (PTHFA), on which proteins could adsorb well, within 1 h. HepG2 cells started to attach after 1 h. HT-1080, MDA-MB-231, and HepG2 cells started to attach within 30 min to PMEA, poly(2-(2-methoxyethoxy) ethyl acrylate-co-butyl acrylate) (30:70 mol%, PMe2A) and poly(2-(2-methoxyethoxy) ethoxy ethyl acrylate-co-butyl acrylate) (30: 70 mol%, PMe3A), which suppress protein adsorption. Moreover, the ratio of attached cells from a cell mixture can be changed on PMEA analogous polymers. These findings suggested that PMEA analogous polymers can be used for attachment-based cell enrichment.

DOI： 10.1371/journal.pone.0136066

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

The development of bioartificial liver (BAL) is expected because of the shortage of donor liver for transplantation. The substrates for BAL require the following criteria: (a) blood compatibility, (b) hepatocyte adhesiveness, and (c) the ability to maintain hepatocyte-specific functions. Here, we examined blood-compatible poly(2-methoxyethyl acrylate) (PMEA) and poly(tetrahydrofurfuryl acrylate) (PTHFA) (PTHFA) as the substrates for BAL. HepG2, a human hepatocyte model, could adhere on PMEA and PTHFA substrates. The spreading of HepG2 cells was suppressed on PMEA substrates because integrin contribution to cell adhesion on PMEA substrate was low and integrin signaling was not sufficiently activated. Hepatocyte-specific gene expression in HepG2 cells increased on PMEA substrate, whereas the expression decreased on PTHFA substrates due to the nuclear localization of Yes-associated protein (YAP). These results indicate that blood-compatible PMEA is suitable for BAL substrate. Also, PMEA is expected to be used to regulate cell functions for blood-contacting tissue engineering.

DOI： 10.1021/acsami.5b05210

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

Cell enrichment is currently in high demand in medical engineering. We have reported that non-blood cells can attach to a blood-compatible poly(2-methoxyethyl acrylate) (PMEA) substrate through integrin-dependent and integrin-independent mechanisms because the PMEA substrate suppresses protein adsorption. Therefore, we assumed that PMEA analogous polymers can change the contribution of integrin to cell attachment through the regulation of protein adsorption. In the present study, we investigated protein adsorption, cell attachment profiles, and attachment mechanisms on PMEA analogous polymer substrates. Additionally, we demonstrated the possibility of attachment-based cell enrichment on PMEA analogous polymer substrates. HT-1080 and MDA-MB-231 cells started to attach to poly(butyl acrylate) (PBA) and poly(tetrahydrofurfuryl acrylate) (PTHFA), on which proteins could adsorb well, within 1 h. HepG2 cells started to attach after 1 h. HT-1080, MDA-MB-231, and HepG2 cells started to attach within 30 min to PMEA, poly(2-(2-methoxyethoxy) ethyl acrylate-co-butyl acrylate) (30:70 mol%, PMe2A) and poly(2-(2-methoxyethoxy) ethoxy ethyl acrylate-co-butyl acrylate) (30:70 mol%, PMe3A), which suppress protein adsorption. Moreover, the ratio of attached cells from a cell mixture can be changed on PMEA analogous polymers. These findings suggested that PMEA analogous polymers can be used for attachment-based cell enrichment.

DOI： 10.1371/journal.pone.0136066

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

Polymeric biomaterials have a significant impact in today's health care technology. Polymer hydrogels were the first experimentally designed biomaterials for human use. In this article the design, synthesis and properties of hydrogels, derived from synthetic and natural polymers, and their use as biomaterials in tissue engineering are reviewed. The stimuli-responsive hydrogels with controlled degradability and examples of suitable methods for designing such biomaterials, using multidisciplinary approaches from traditional polymer chemistry, materials engineering to molecular biology, have been discussed. Examples of the fabrication of polymer-based biomaterials, utilized for various cell type manipulations for tissue re-generation are also elaborated. Since a highly porous three-dimensional scaffold is crucially important in the cellular process, for tissue engineering, recent advances in the effective methods of scaffold fabrication are described. Additionally, the incorporation of factor molecules for the enhancement of tissue formation and their controlled release is also elucidated in this article. Finally, the future challenges in the efficient fabrication of effective polymeric biomaterials for tissue regeneration and medical device applications are discussed.

DOI： 10.1039/c5tb01370d

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

The development of bioartificial liver (BAL) is expected because of the shortage of donor liver for transplantation. The substrates for BAL require the following criteria: (a) blood compatibility, (b) hepatocyte adhesiveness, and (c) the ability to maintain hepatocyte-specific functions. Here, we examined blood-compatible poly(2-methoxyethyl acrylate) (PMEA) and poly(tetrahydrofurfuryl acrylate) (PTHFA) (PTHFA) as the substrates for BAL. HepG2, a human hepatocyte model, could adhere on PMEA and PTHFA substrates. The spreading of HepG2 cells was suppressed on PMEA substrates because integrin contribution to cell adhesion on PMEA substrate was low and integrin signaling was not sufficiently activated. Hepatocyte-specific gene expression in HepG2 cells increased on PMEA substrate, whereas the expression decreased on PTHFA substrates due to the nuclear localization of Yes-associated protein (YAP). These results indicate that blood-compatible PMEA is suitable for BAL substrate. Also, PMEA is expected to be used to regulate cell functions for blood-contacting tissue engineering.

DOI： 10.1021/acsami.5b05210

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

Cell enrichment is currently in high demand in medical engineering. We have reported that non-blood cells can attach to a blood-compatible poly(2-methoxyethyl acrylate) (PMEA) substrate through integrin-dependent and integrin-independent mechanisms because the PMEA substrate suppresses protein adsorption. Therefore, we assumed that PMEA analogous polymers can change the contribution of integrin to cell attachment through the regulation of protein adsorption. In the present study, we investigated protein adsorption, cell attachment profiles, and attachment mechanisms on PMEA analogous polymer substrates. Additionally, we demonstrated the possibility of attachment-based cell enrichment on PMEA analogous polymer substrates. HT-1080 and MDA-MB-231 cells started to attach to poly(butyl acrylate) (PBA) and poly(tetrahydrofurfuryl acrylate) (PTHFA), on which proteins could adsorb well, within 1 h. HepG2 cells started to attach after 1 h. HT-1080, MDA-MB-231, and HepG2 cells started to attach within 30 min to PMEA, poly(2-(2-methoxyethoxy) ethyl acrylate-co-butyl acrylate) (30:70 mol%, PMe2A) and poly(2-(2-methoxyethoxy) ethoxy ethyl acrylate-co-butyl acrylate) (30:70 mol%, PMe3A), which suppress protein adsorption. Moreover, the ratio of attached cells from a cell mixture can be changed on PMEA analogous polymers. These findings suggested that PMEA analogous polymers can be used for attachment-based cell enrichment.

DOI： 10.1371/journal.pone.0136066

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

Polymeric biomaterials have a significant impact in today's health care technology. Polymer hydrogels were the first experimentally designed biomaterials for human use. In this article the design, synthesis and properties of hydrogels, derived from synthetic and natural polymers, and their use as biomaterials in tissue engineering are reviewed. The stimuli-responsive hydrogels with controlled degradability and examples of suitable methods for designing such biomaterials, using multidisciplinary approaches from traditional polymer chemistry, materials engineering to molecular biology, have been discussed. Examples of the fabrication of polymer-based biomaterials, utilized for various cell type manipulations for tissue re-generation are also elaborated. Since a highly porous three-dimensional scaffold is crucially important in the cellular process, for tissue engineering, recent advances in the effective methods of scaffold fabrication are described. Additionally, the incorporation of factor molecules for the enhancement of tissue formation and their controlled release is also elucidated in this article. Finally, the future challenges in the efficient fabrication of effective polymeric biomaterials for tissue regeneration and medical device applications are discussed.

DOI： 10.1039/c5tb01370d

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

The development of bioartificial liver (BAL) is expected because of the shortage of donor liver for transplantation. The substrates for BAL require the following criteria: (a) blood compatibility, (b) hepatocyte adhesiveness, and (c) the ability to maintain hepatocyte-specific functions. Here, we examined blood-compatible poly(2-methoxyethyl acrylate) (PMEA) and poly(tetrahydrofurfuryl acrylate) (PTHFA) (PTHFA) as the substrates for BAL. HepG2, a human hepatocyte model, could adhere on PMEA and PTHFA substrates. The spreading of HepG2 cells was suppressed on PMEA substrates because integrin contribution to cell adhesion on PMEA substrate was low and integrin signaling was not sufficiently activated. Hepatocyte-specific gene expression in HepG2 cells increased on PMEA substrate, whereas the expression decreased on PTHFA substrates due to the nuclear localization of Yes-associated protein (YAP). These results indicate that blood-compatible PMEA is suitable for BAL substrate. Also, PMEA is expected to be used to regulate cell functions for blood-contacting tissue engineering.

DOI： 10.1021/acsami.5b05210

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

In this study, we found that the surface made of a mixture of poly(2-methoxyethyl acrylate) (PMEA) and poly(methyl methacrylate) (PMMA) exhibited excellent blood compatibility by inhibiting platelet adhesion. To obtain a better understanding of this bioinertness, the polymer/water interface was characterized by neutron reflectivity measurements and sum frequency generation spectroscopy, in conjunction with bubble contact angle measurements. Based on the results, we can say that the outermost region of the blend film was reorganized in water. When the orientation of PMEA segments at the water interface became random with increasing immersion time, the fractional amount of lower-coordinated water molecules increased at the interface. Such an interfacial structure caused the suppression of platelet adhesion.

DOI： 10.1039/c5cp01972a

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

DOI： 10.1038/pj.2015.22

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

The hydration behavior, intermediate water content and platelet adhesion level of poly(trimethylene carbonate) (PTMC) and three other aliphatic carbonyl polymers (PDO, PCL and poly(δ -valerolactone) (PVL))was investigated to elucidate the influence of subtle differences in the backbone structure on hydration and hemocompatibility. PTMC and PVL were synthesized and used as DSC specimens. A spin-coated surface was used for the platelet adhesion test and contact angle measurements. The cast coatings and films were used for the infrared spectroscopy (IR). All hydrated surfaces and films were prepared by immersion in deionized water for 24 h. The phase transitions of water in the hydrated polymers were measured using DSC. The overall water content in the polymer was determined. The roughness of the spin-coated surfaces was evaluated using atomic force microscopy. The static contact angles of the polymer surface against water were measured using both a sessile drop and a captive bubble. By investigating the differences in hydration behavior of the polymer backbones with ester and carbonate bonds, we found that the carbonate bonds favor conformational change compared with ester bonds because of their stronger capacities as hydrogen bond acceptors and the less-regulated C=O on the surface based on its amorphous nature.

DOI： 10.1038/pj.2015.22

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

In this study, we found that the surface made of a mixture of poly(2-methoxyethyl acrylate) (PMEA) and poly(methyl methacrylate) (PMMA) exhibited excellent blood compatibility by inhibiting platelet adhesion. To obtain a better understanding of this bioinertness, the polymer/water interface was characterized by neutron reflectivity measurements and sum frequency generation spectroscopy, in conjunction with bubble contact angle measurements. Based on the results, we can say that the outermost region of the blend film was reorganized in water. When the orientation of PMEA segments at the water interface became random with increasing immersion time, the fractional amount of lower-coordinated water molecules increased at the interface. Such an interfacial structure caused the suppression of platelet adhesion.

DOI： 10.1039/c5cp01972a

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

The hydration behavior, intermediate water content and platelet adhesion level of poly(trimethylene carbonate) (PTMC) and three other aliphatic carbonyl polymers (PDO, PCL and poly(δ -valerolactone) (PVL))was investigated to elucidate the influence of subtle differences in the backbone structure on hydration and hemocompatibility. PTMC and PVL were synthesized and used as DSC specimens. A spin-coated surface was used for the platelet adhesion test and contact angle measurements. The cast coatings and films were used for the infrared spectroscopy (IR). All hydrated surfaces and films were prepared by immersion in deionized water for 24 h. The phase transitions of water in the hydrated polymers were measured using DSC. The overall water content in the polymer was determined. The roughness of the spin-coated surfaces was evaluated using atomic force microscopy. The static contact angles of the polymer surface against water were measured using both a sessile drop and a captive bubble. By investigating the differences in hydration behavior of the polymer backbones with ester and carbonate bonds, we found that the carbonate bonds favor conformational change compared with ester bonds because of their stronger capacities as hydrogen bond acceptors and the less-regulated C=O on the surface based on its amorphous nature.

DOI： 10.1038/pj.2015.22

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

In this study, we found that the surface made of a mixture of poly(2-methoxyethyl acrylate) (PMEA) and poly(methyl methacrylate) (PMMA) exhibited excellent blood compatibility by inhibiting platelet adhesion. To obtain a better understanding of this bioinertness, the polymer/water interface was characterized by neutron reflectivity measurements and sum frequency generation spectroscopy, in conjunction with bubble contact angle measurements. Based on the results, we can say that the outermost region of the blend film was reorganized in water. When the orientation of PMEA segments at the water interface became random with increasing immersion time, the fractional amount of lower-coordinated water molecules increased at the interface. Such an interfacial structure caused the suppression of platelet adhesion.

DOI： 10.1039/c5cp01972a

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

The hydration behavior, intermediate water content and platelet adhesion level of poly(trimethylene carbonate) (PTMC) and three other aliphatic carbonyl polymers (PDO, PCL and poly(δ -valerolactone) (PVL))was investigated to elucidate the influence of subtle differences in the backbone structure on hydration and hemocompatibility. PTMC and PVL were synthesized and used as DSC specimens. A spin-coated surface was used for the platelet adhesion test and contact angle measurements. The cast coatings and films were used for the infrared spectroscopy (IR). All hydrated surfaces and films were prepared by immersion in deionized water for 24 h. The phase transitions of water in the hydrated polymers were measured using DSC. The overall water content in the polymer was determined. The roughness of the spin-coated surfaces was evaluated using atomic force microscopy. The static contact angles of the polymer surface against water were measured using both a sessile drop and a captive bubble. By investigating the differences in hydration behavior of the polymer backbones with ester and carbonate bonds, we found that the carbonate bonds favor conformational change compared with ester bonds because of their stronger capacities as hydrogen bond acceptors and the less-regulated C=O on the surface based on its amorphous nature.

DOI： 10.1038/pj.2015.22

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

Intercorrelation among surface chemical composition, packing structure of molecules, water contact angles, amounts and structures of adsorbed proteins, and blood compatibility was systematically investigated with self-assembled monolayers (SAMs) with continuous chemical composition gradients. The SAMs were mixtures of two thiols: n-hexanethiol (hydrophobic and protein-adsorbing) and hydroxyl-tri(ethylene glycol)-terminated alkanethiol (hydrophilic and protein-resistant) with continuously changing mixing ratios. From the systematic analyses, we found that protein adsorption is governed both by sizes of proteins and hydrophobic domains of the substrate. Furthermore, we found a clear correlation between adsorption of fibrinogen and adhesion of platelets. Combined with the results of surface force measurements, we found that the interfacial behavior of water molecules is profoundly correlated with protein resistance and antiplatelet adhesion. On the basis of these results, we conclude that the structuring of water at the SAM-water interface is a critical factor in this context.

DOI： 10.1021/acs.langmuir.5b01216

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

Intercorrelation among surface chemical composition, packing structure of molecules, water contact angles, amounts and structures of adsorbed proteins, and blood compatibility was systematically investigated with self-assembled monolayers (SAMs) with continuous chemical composition gradients. The SAMs were mixtures of two thiols: n=hexanethiol (hydrophobic and protein-adsorbing) and hydroxyl-tri(ethylene glycol)-terminated alkanethiol (hydrophilic and protein-resistant) with continuously changing mixing ratios. From the systematic analyses, we found that protein adsorption is governed both by sizes of proteins and hydrophobic domains of the substrate, Furthermore, we found a clear correlation between adsorption of fibrinogen and adhesion of platelets. Combined with the results of surface force measurements, we found that the interfacial behavior of water molecules is profoundly correlated with protein resistance and antiplatelet adhesion. On the basis of these results, we conclude that the structuring of water at the SAM-water interface is a critical factor in this context.

DOI： 10.1021/acs.langmuir.5b01216

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

Intercorrelation among surface chemical composition, packing structure of molecules, water contact angles, amounts and structures of adsorbed proteins, and blood compatibility was systematically investigated with self-assembled monolayers (SAMs) with continuous chemical composition gradients. The SAMs were mixtures of two thiols: n-hexanethiol (hydrophobic and protein-adsorbing) and hydroxyl-tri(ethylene glycol)-terminated alkanethiol (hydrophilic and protein-resistant) with continuously changing mixing ratios. From the systematic analyses, we found that protein adsorption is governed both by sizes of proteins and hydrophobic domains of the substrate. Furthermore, we found a clear correlation between adsorption of fibrinogen and adhesion of platelets. Combined with the results of surface force measurements, we found that the interfacial behavior of water molecules is profoundly correlated with protein resistance and antiplatelet adhesion. On the basis of these results, we conclude that the structuring of water at the SAM-water interface is a critical factor in this context.

DOI： 10.1021/acs.langmuir.5b01216

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

Although many kinds of synthetic polymers have been investigated to construct blood-compatible materials, only a few have achieved success. To establish molecular designs for blood-compatible polymers, the chain structure and dynamics at the water interface must be understood using solid evidence as the first bench mark. Here we show that polymer dynamics at the water interface impacts on structure of the interfacial water, resulting in a change in protein adsorption and of platelet adhesion. As a particular material, a blend composed of poly(2-methoxyethyl acrylate) (PMEA) and poly(methyl methacrylate) was used. PMEA was segregated to the water interface. While the local conformation of PMEA at the water interface was insensitive to its molecular weight, the local dynamics became faster with decreasing molecular weight, resulting in a disturbance of the network structure of waters at the interface. This leads to the extreme suppression of protein adsorption and platelet adhesion.

DOI： 10.1021/acs.langmuir.5b00258

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

Although many kinds of synthetic polymers have been investigated to construct blood-compatible materials, only a few have achieved success. To establish molecular designs for blood-compatible polymers, the chain structure and dynamics at the water interface must be understood using solid evidence as the first bench mark. Here we show that polymer dynamics at the water interface impacts on structure of the interfacial water, resulting in a change in protein adsorption and of platelet adhesion. As a particular material, a blend composed of poly(2-methoxyethyl acrylate) (PMEA) and poly(methyl methacrylate) was used. PMEA was segregated to the water interface. While the local conformation of PMEA at the water interface was insensitive to its molecular weight, the local dynamics became faster with decreasing molecular weight, resulting in a disturbance of the network structure of waters at the interface. This leads to the extreme suppression of protein adsorption and platelet adhesion.

DOI： 10.1021/acs.langmuir.5b00258

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

Although many kinds of synthetic polymers have been investigated to construct blood-compatible materials, only a few have achieved success. To establish molecular designs for blood-compatible polymers, the chain structure and dynamics at the water interface must be understood using solid evidence as the first bench mark. Here we show that polymer dynamics at the water interface impacts on structure of the interfacial water, resulting in a change in protein adsorption and of platelet adhesion. As a particular material, a blend composed of poly(2-methoxyethyl acrylate) (PMEA) and poly(methyl methacrylate) was used. PMEA was segregated to the water interface. While the local conformation of PMEA at the water interface was insensitive to its molecular weight, the local dynamics became faster with decreasing molecular weight, resulting in a disturbance of the network structure of waters at the interface. This leads to the extreme suppression of protein adsorption and platelet adhesion.

DOI： 10.1021/acs.langmuir.5b00258

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

The low chemoresistance of in vitro cancer cells inhibits the development of new anti-cancer drugs. Thus, development of a new in vitro culture system is required to increase the chemoresistance of in vitro cancer cells. Tumor cell-derived matrices have been reported to increase the chemoresistance of in vitro cancer cells. However, it remains unclear how tissue sources and the malignancy of cells used for the preparation of matrices affect the chemoresistance of tumor cell-derived matrices. Moreover, it remains unclear how the initial substrates used for the preparation of matrices affect the chemoresistance. In this study, we compared the effects of tissue sources and the malignancy of tumor cells, as well as the effect of the initial substrates on chemoresistance against 5-fluorouracil (5-FU). The chemoresistance of breast and colon cancer cells against 5-FU increased on matrices prepared with cells derived from the corresponding original tissues with higher malignancy. Moreover, the chemoresistance against 5-FU was altered on matrices prepared using different initial substrates that exhibited different characteristics of protein adsorption. Taken together, these results indicated that the appropriate selection of tissue sources, malignancy of tumor cells, and initial substrates used for matrix preparation is important for the preparation of tumor cell-derived matrices for chemoresistance assays.

DOI： 10.1016/j.bbrc.2014.12.116

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

The low chemoresistance of in vitro cancer cells inhibits the development of new anti-cancer drugs. Thus, development of a new in vitro culture system is required to increase the chemoresistance of in vitro cancer cells. Tumor cell-derived matrices have been reported to increase the chemoresistance of in vitro cancer cells. However, it remains unclear how tissue sources and the malignancy of cells used for the preparation of matrices affect the chemoresistance of tumor cell-derived matrices. Moreover, it remains unclear how the initial substrates used for the preparation of matrices affect the chemoresistance. In this study, we compared the effects of tissue sources and the malignancy of tumor cells, as well as the effect of the initial substrates on chemoresistance against 5-fluorouracil (5-FU). The chemoresistance of breast and colon cancer cells against 5-FU increased on matrices prepared with cells derived from the corresponding original tissues with higher malignancy. Moreover, the chemoresistance against 5-FU was altered on matrices prepared using different initial substrates that exhibited different characteristics of protein adsorption. Taken together, these results indicated that the appropriate selection of tissue sources, malignancy of tumor cells, and initial substrates used for matrix preparation is important for the preparation of tumor cell-derived matrices for chemoresistance assays. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2014.12.116

Language：English  

Polymeric biomaterials have significant impact in the aged society. Biocompatible and biodegradable polymers have emerged during the past decades to promise extraordinary breakthroughs in a wide range of diagnostic and therapeutic medical devices. Understanding and controlling the interfacial interactions of the polymeric biomaterials with biological elements, such as water, ions, proteins, bacteria, fungai and cells, are essential toward their successful implementation in biomedical applications. Here we highlight the recent developments of biocompatible and biodegradable fusion polymeric biomaterials for medical devices and provide an overview of the recent progress of the design of the multi-functional biomedical polymers by controlling bio-interfacial water structure through precision polymer synthesis and supramolecular chemistry.

DOI： 10.1038/pj.2014.129

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

The low chemoresistance of in vitro cancer cells inhibits the development of new anti-cancer drugs. Thus, development of a new in vitro culture system is required to increase the chemoresistance of in vitro cancer cells. Tumor cell-derived matrices have been reported to increase the chemoresistance of in vitro cancer cells. However, it remains unclear how tissue sources and the malignancy of cells used for the preparation of matrices affect the chemoresistance of tumor cell-derived matrices. Moreover, it remains unclear how the initial substrates used for the preparation of matrices affect the chemoresistance. In this study, we compared the effects of tissue sources and the malignancy of tumor cells, as well as the effect of the initial substrates on chemoresistance against 5-fluorouracil (5-FU). The chemoresistance of breast and colon cancer cells against 5-FU increased on matrices prepared with cells derived from the corresponding original tissues with higher malignancy. Moreover, the chemoresistance against 5-FU was altered on matrices prepared using different initial substrates that exhibited different characteristics of protein adsorption. Taken together, these results indicated that the appropriate selection of tissue sources, malignancy of tumor cells, and initial substrates used for matrix preparation is important for the preparation of tumor cell-derived matrices for chemoresistance assays.

DOI： 10.1016/j.bbrc.2014.12.116

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

Polymeric biomaterials have significant impact in the aged society. Biocompatible and biodegradable polymers have emerged during the past decades to promise extraordinary breakthroughs in a wide range of diagnostic and therapeutic medical devices. Understanding and controlling the interfacial interactions of the polymeric biomaterials with biological elements, such as water, ions, proteins, bacteria, fungai and cells, are essential toward their successful implementation in biomedical applications. Here we highlight the recent developments of biocompatible and biodegradable fusion polymeric biomaterials for medical devices and provide an overview of the recent progress of the design of the multi-functional biomedical polymers by controlling bio-interfacial water structure through precision polymer synthesis and supramolecular chemistry.

DOI： 10.1038/pj.2014.129

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

The low chemoresistance of in vitro cancer cells inhibits the development of new anti-cancer drugs. Thus, development of a new in vitro culture system is required to increase the chemoresistance of in vitro cancer cells. Tumor cell-derived matrices have been reported to increase the chemoresistance of in vitro cancer cells. However, it remains unclear how tissue sources and the malignancy of cells used for the preparation of matrices affect the chemoresistance of tumor cell-derived matrices. Moreover, it remains unclear how the initial substrates used for the preparation of matrices affect the chemoresistance. In this study, we compared the effects of tissue sources and the malignancy of tumor cells, as well as the effect of the initial substrates on chemoresistance against 5-fluorouracil (5-FU). The chemoresistance of breast and colon cancer cells against 5-FU increased on matrices prepared with cells derived from the corresponding original tissues with higher malignancy. Moreover, the chemoresistance against 5-FU was altered on matrices prepared using different initial substrates that exhibited different characteristics of protein adsorption. Taken together, these results indicated that the appropriate selection of tissue sources, malignancy of tumor cells, and initial substrates used for matrix preparation is important for the preparation of tumor cell-derived matrices for chemoresistance assays.

DOI： 10.1016/j.bbrc.2014.12.116

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

Polymeric biomaterials have significant impact in the aged society. Biocompatible and biodegradable polymers have emerged during the past decades to promise extraordinary breakthroughs in a wide range of diagnostic and therapeutic medical devices. Understanding and controlling the interfacial interactions of the polymeric biomaterials with biological elements, such as water, ions, proteins, bacteria, fungai and cells, are essential toward their successful implementation in biomedical applications. Here we highlight the recent developments of biocompatible and biodegradable fusion polymeric biomaterials for medical devices and provide an overview of the recent progress of the design of the multi-functional biomedical polymers by controlling bio-interfacial water structure through precision polymer synthesis and supramolecular chemistry.

DOI： 10.1038/pj.2014.129

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

Polymeric biomaterials have significant impact in the aged society. Biocompatible and biodegradable polymers have emerged during the past decades to promise extraordinary breakthroughs in a wide range of diagnostic and therapeutic medical devices. Understanding and controlling the interfacial interactions of the polymeric biomaterials with biological elements, such as water, ions, proteins, bacteria, fungai and cells, are essential toward their successful implementation in biomedical applications. Here we highlight the recent developments of biocompatible and biodegradable fusion polymeric biomaterials for medical devices and provide an overview of the recent progress of the design of the multi-functional biomedical polymers by controlling bio-interfacial water structure through precision polymer synthesis and supramolecular chemistry.

DOI： 10.1038/pj.2014.129

Language：Japanese  

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

The hydration structures of two different types of biomaterials, i.e., poly(2-methoxyethyl acrylate) (PMEA) and a random copolymer of 2-methacryloyloxyethyl phosphorylcholine and n-butyl methacrylate (P(MPC-r-BMA)), were investigated by means of attenuated total reflection infrared (ATR-IR) spectroscopy. The effects of the addition of sodium chloride to liquid water in contact with the surfaces of the polymer films were examined. The neutral polymer of PMEA was easily dehydrated by NaCl addition, whereas the zwitterionic polymer of P(MPC-r-BMA) was hardly dehydrated. More specifically, nonfreezing water having a strong interaction with the PMEA chain and freezing bound water having an intermediate interaction were hardly dehydrated by contacting with normal saline solution, whereas freezing water having a weak interaction with the PMEA chain was readily dehydrated. In contrast, freezing water in P(MPC-r-BMA) is exchanged for the saline solution contacting with the material surface without dehydration.

DOI： 10.1021/la502550d

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

The hydration structures of two different types of biomaterials, i.e., poly(2-methoxyethyl acrylate) (PMEA) and a random copolymer of 2-methacryloyloxyethyl phosphorylcholine and n-butyl methacrylate (P(MPC-r-BMA)), were investigated by means of attenuated total reflection infrared (ATR-IR) spectroscopy. The effects of the addition of sodium chloride to liquid water in contact with the surfaces of the polymer films were examined. The neutral polymer of PMEA was easily dehydrated by NaCl addition, whereas the zwitterionic polymer of P(MPC-r-BMA) was hardly dehydrated. More specifically, nonfreezing water having a strong interaction with the PMEA chain and freezing bound water having an intermediate interaction were hardly dehydrated by contacting with normal saline solution, whereas freezing water having a weak interaction with the PMEA chain was readily dehydrated. In contrast, freezing water in P(MPC-r-BMA) is exchanged for the saline solution contacting with the material surface without dehydration.

DOI： 10.1021/la502550d

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

The hydration structures of two different types of biomaterials, i.e., poly(2-methoxyethyl acrylate) (PMEA) and a random copolymer of 2-methacryloyloxyethyl phosphorylcholine and n-butyl methacrylate (P(MPC-r-BMA)), were investigated by means of attenuated total reflection infrared (ATR-IR) spectroscopy. The effects of the addition of sodium chloride to liquid water in contact with the surfaces of the polymer films were examined. The neutral polymer of PMEA was easily dehydrated by NaCl addition, whereas the zwitterionic polymer of P(MPC-r-BMA) was hardly dehydrated. More specifically, nonfreezing water having a strong interaction with the PMEA chain and freezing bound water having an intermediate interaction were hardly dehydrated by contacting with normal saline solution, whereas freezing water having a weak interaction with the PMEA chain was readily dehydrated. In contrast, freezing water in P(MPC-r-BMA) is exchanged for the saline solution contacting with the material surface without dehydration.

DOI： 10.1021/la502550d

Language：Others  

Facile and practical route to a versatile intermediate of substituted cyclic carbonates offering diverse smart biomaterials

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

Recent advances in biomedical engineering require the development of new types of blood-compatible polymers that also allow non-blood cell attachment for the isolation of stem cells and circulating tumor cells (CTCs) from blood and for the development of artificial organs for use under blood-contact conditions. Poly(2-methoxyethyl acrylate) (PMEA) and poly(tetrafurfuryl acrylate) (PTHFA) were previously identified as blood-compatible polymers. Here, it is demonstrated that cancer cells can attach to the PMEA and PTHFA substrates, and the differences in the attachment mechanisms to the PMEA and PTHFA substrates between cancer cells and platelets are investigated. It is also found that the adsorption-induced deformation of fibrinogen, which is required for the attachment and activation of platelets, does not occur on the PMEA and PTHFA substrates. In contrast, fibronectin is deformed on the PMEA and PTHFA substrates. Therefore, it is concluded that cancer cells and not platelets can attach to the PMEA and PTHFA substrates based on this protein-deformation difference between these substrates. Moreover, it is observed that cancer cells attach to the PMEA substrate via both integrin-dependent and -independent mechanisms and attach to the PTHFA substrate only through an integrin-dependent mechanism. It is expected that PMEA and PTHFA will prove useful for blood-contact biomedical applications.

DOI： 10.1002/adhm.201300309