2022年06月, 公益社団法人日本セラミックス協会, 進歩賞
生体無機-高分子ゲル融合体による骨形成機序と骨再生誘導の研究

2020年09月, 公益社団法人日本セラミックス協会, 秋季シンポジウム若手優秀発表賞（先進セラミックバイオマテリアルの新展開と次世代型材料機能設計指針の構築）　　　　　　　　　　　　　　　
バイオミネラルをエネルギー散逸項とするハイドロゲルの強靭化
野々山貴行

2019年05月, 高分子学会, 高分子研究奨励賞
高靱性ゲル・バイオセラミックスの複合と骨形成誘導に関する研究
野々山貴行

2018年09月, 高分子学会, パブリシティ賞　　　　　　　　　　　　　　　
高温で瞬時に1000倍以上硬くなる温度応答性アクティブソフトマテリアル
野々山貴行

2017年09月, 公益社団法人日本セラミックス協会, 特定セッション若手優秀発表賞　　　　　　　　　　　　　　　
天然骨組織と合成ハイドロゲルとの相互侵入構造の解析
野々山貴行, 国内学会・会議・シンポジウム等の賞, 日本国

2014年10月, International Union of Materials Research Societies, International Union of Materials Research Societies- International Conference in Asia, The Award for Encouragement of Research in IUMRS-ICA2014　　　　　　　　　　　　　　　
野々山貴行

2013年03月, 名古屋工業大学, 学生基金奨励賞 学長賞　　　　　　　　　　　　　　　
野々山貴行

2012年05月, 日本セラミックス協会, 2012年セラミックス協会年会 最優秀賞　　　　　　　　　　　　　　　
野々山貴行

2012年03月, 名古屋工業大学, 学生基金奨励賞 学長賞　　　　　　　　　　　　　　　
野々山貴行

2011年12月, 日本セラミックス協会東海支部, 平成23年度日本セラミックス協会東海支部学術発表会 最優秀講演賞　　　　　　　　　　　　　　　
野々山貴行

2011年11月, 中部化学関係学協会支部連合(中化連), 中化連秋季大会 東海高分子優秀学生発表賞　　　　　　　　　　　　　　　
野々山貴行

2011年09月, 高分子学会東海支部, 第137回東海高分子研究会講演会 優秀発表賞　　　　　　　　　　　　　　　
野々山貴行

2011年07月, 日本セラミックス協会東海支部, 第41回東海若手セラミスト懇話会 ベスト質問賞　　　　　　　　　　　　　　　
野々山貴行

2011年07月, 日本セラミックス協会東海支部, 第41回東海若手セラミスト懇話会 優秀発表賞　　　　　　　　　　　　　　　
野々山貴行

2011年03月, 名古屋工業大学, 学生基金奨励賞 副学長賞　　　　　　　　　　　　　　　
野々山貴行

2011年01月, 日本セラミックス協会, 第49回セラミックス基礎科学討論会 World young fellow meeting 2011 Presentation award　　　　　　　　　　　　　　　
野々山貴行

2010年07月, 日本セラミックス協会東海支部, 第40回東海若手セラミスト懇話会 最優秀発表賞　　　　　　　　　　　　　　　
野々山貴行

Real-Space Visualization of Charged Polymer Network of Hydrogel by Double Network Strategy and Mineral Staining
Shinji Noguchi, Ryuji Kiyama, Masahiro Yoshida, Maradhana Agung Marsudi, Naohiro Kashimura, Kiyoharu Tadanaga, Jian Ping Gong, Takayuki Nonoyama
Nano Letters, American Chemical Society (ACS), 2024年07月09日, ［査読有り］, ［最終著者, 責任著者］
研究論文（学術雑誌）

血管系IVRシミュレーションに適した3Dプリントによる透明柔軟な樹脂を用いた血管モデルの可能性　　　　　　　　　　　　　　　
森田 亮, 野々山 貴行, 阿保 大介, 曽山 武士, 藤間 憲幸, 今井 哲秋, 高橋 文也, 木野田 直也, 加藤 大祐, 藤井 宝顕, 山崎 康之, 高柳 歩, 濱口 裕行, 亀田 拓人, 工藤 與亮
日本インターベンショナルラジオロジー学会雑誌, 39, Suppl., 253, 253, (一社)日本インターベンショナルラジオロジー学会, 2024年04月
日本語

Phase separation-induced glass transition under critical miscible conditions
Mayu Watanabe, Dong Shi, Ryuji Kiyama, Kagari Maruyama, Yuichiro Nishizawa, Takayuki Uchihashi, Jian Ping Gong, Takayuki Nonoyama
Materials Advances, Royal Society of Chemistry (RSC), 2024年, ［査読有り］, ［最終著者, 責任著者］
研究論文（学術雑誌）, A polymer material shows phase separation-induced glass transition under critical miscible conditions, where the miscible/immiscible state is altered by temperature variations predicted by temperature-corrected Hansen solubility parameters.

Fractographic mirror law for brittle fracture of nonlinear elastic soft materials
Ryuji Kiyama, Yong Zheng, Takayuki Nonoyama, Jian Ping Gong
Soft Matter, 19, 40, 7724, 7730, Royal Society of Chemistry (RSC), 2023年09月, ［査読有り］
英語, 研究論文（学術雑誌）, The first fractographic mirror radius analysis for soft hydrogel materials was conducted. The universal −1 power law between fracture stress and mirror radius was established, in contrast to the different power law of linear elastic hard materials.

Engineering of an electrically charged hydrogel implanted into a traumatic brain injury model for stepwise neuronal tissue reconstruction
Satoshi Tanikawa, Yuki Ebisu, Tomáš Sedlačík, Shingo Semba, Takayuki Nonoyama, Takayuki Kurokawa, Akira Hirota, Taiga Takahashi, Kazushi Yamaguchi, Masamichi Imajo, Hinako Kato, Takuya Nishimura, Zen-ichi Tanei, Masumi Tsuda, Tomomi Nemoto, Jian Ping Gong, Shinya Tanaka
Scientific Reports, 13, 1, Springer Science and Business Media LLC, 2023年02月14日, ［査読有り］
研究論文（学術雑誌）, Abstract

Neural regeneration is extremely difficult to achieve. In traumatic brain injuries, the loss of brain parenchyma volume hinders neural regeneration. In this study, neuronal tissue engineering was performed by using electrically charged hydrogels composed of cationic and anionic monomers in a 1:1 ratio (C1A1 hydrogel), which served as an effective scaffold for the attachment of neural stem cells (NSCs). In the 3D environment of porous C1A1 hydrogels engineered by the cryogelation technique, NSCs differentiated into neuroglial cells. The C1A1 porous hydrogel was implanted into brain defects in a mouse traumatic damage model. The VEGF-immersed C1A1 porous hydrogel promoted host-derived vascular network formation together with the infiltration of macrophages/microglia and astrocytes into the gel. Furthermore, the stepwise transplantation of GFP-labeled NSCs supported differentiation towards glial and neuronal cells. Therefore, this two-step method for neural regeneration may become a new approach for therapeutic brain tissue reconstruction after brain damage in the future.

Tough Hydroxyapatite Hydrogels Based on Bone-like Self-Regulatory Sacrificial Bond Formation
Naohiro Kashimura, Yuki Suzuki, Takayuki Nonoyama, Jian Ping Gong
Chemistry of Materials, 2023年, ［査読有り］, ［責任著者］
研究論文（学術雑誌）, Learning from nature is a promising approach to achieving specific functions of synthetic materials. The high material functions, in turn, shed light on the fundamental mechanisms underlying the high performance of biological tissues. For instance, bone is an attractive metabolic tissue with fascinating capabilities from the perspective of both biochemical and biomechanical functionalities. Bone tissue exhibits exceptional mechanical performance as a skeleton, enabling to sustain the locomotion of mammals. In this study, we design coupled reactions for self-regulatory sacrificial bond formation in poly(acrylic acid) hydrogels by introducing biomineral hydroxyapatite (HAp) found in bones. We demonstrate that through five coupled reactions, HAp regulates the Ca2+ bridging to the acidic polymer and toughens the hydrogels in water by the sacrificial bonds effect. This work is expected not only to greatly contribute to the design of tough soft materials but also to give deep insights into the self-regulated bone-toughening mechanisms.

Mechanical Properties of a 3 Dimensional–Printed Transparent Flexible Resin Used for Vascular Model Simulation Compared with Those of Porcine Arteries
Ryo Morita, Takayuki Nonoyama, Daisuke Abo, Takeshi Soyama, Noriyuki Fujima, Tetsuaki Imai, Hiroyuki Hamaguchi, Takuto Kameda, Osamu Sugita, Bunya Takahashi, Naoya Kinota, Kohsuke Kudo
Journal of Vascular and Interventional Radiology, Elsevier BV, 2023年01月, ［査読有り］
研究論文（学術雑誌）

ERK MAP Kinase Signaling Regulates RAR Signaling to Confer Retinoid Resistance on Breast Cancer Cells
Akira Hirota, Jean-Emmanuel Clément, Satoshi Tanikawa, Takayuki Nonoyama, Tamiki Komatsuzaki, Jian Ping Gong, Shinya Tanaka, Masamichi Imajo
Cancers, 14, 23, 5890, 5890, MDPI AG, 2022年11月29日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Retinoic acid (RA) and its synthetic derivatives, retinoids, have been established as promising anticancer agents based on their ability to regulate cell proliferation and survival. Clinical trials, however, have revealed that cancer cells often acquire resistance to retinoid therapy. Therefore, elucidation of underlying mechanisms of retinoid resistance has been considered key to developing more effective use of retinoids in cancer treatment. In this study, we show that constitutive activation of ERK MAP kinase signaling, which is often caused by oncogenic mutations in RAS or RAF genes, suppresses RA receptor (RAR) signaling in breast cancer cells. We show that activation of the ERK pathway suppresses, whereas its inhibition promotes, RA-induced transcriptional activation of RAR and the resultant upregulation of RAR-target genes in breast cancer cells. Importantly, ERK inhibition potentiates the tumor-suppressive activity of RA in breast cancer cells. Moreover, we also reveal that suppression of RAR signaling and activation of ERK signaling are associated with poor prognoses in breast cancer patients and represent hallmarks of specific subtypes of breast cancers, such as basal-like, HER2-enriched and luminal B. These results indicate that ERK-dependent suppression of RAR activity underlies retinoid resistance and is associated with cancer subtypes and patient prognosis in breast cancers.

Nanoscale TEM Imaging of Hydrogel Network Architecture
Ryuji Kiyama, Masahiro Yoshida, Takayuki Nonoyama, Tomáš Sedlačík, Hiroshi Jinnai, Takayuki Kurokawa, Tasuku Nakajima, Jian Ping Gong
Advanced Materials, 35, 1, 2208902, 2208902, Wiley, 2022年11月09日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, In this work, the authors succeed in direct visualization of the network structure of synthetic hydrogels with transmission electron microscopy (TEM) by developing a novel staining and network fixation method. Such a direct visualization is not carried out because sample preparation and obtaining sufficient contrast are challenging for these soft materials. TEM images reveal robust heterogeneous network architectures at mesh size scale and defects at micro-scale. TEM images also reveal the presence of abundant dangling chains on the surface of the hydrogel network. The real space structural information provides a comprehensive perspective that links bulk properties with a nanoscale network structure, including fracture, adhesion, sliding friction, and lubrication. The presented method has the potential to advance the field.

Force-triggered rapid microstructure growth on hydrogel surface for on-demand functions
Mu, Q., Cui, K., Wang, Z.J., Matsuda, T., Cui, W., Kato, H., Namiki, S., Yamazaki, T., Frauenlob, M., Nonoyama, T., Tsuda, M., Tanaka, S., Nakajima, T., Gong, J.P.
Nature Communications, 13, 1, Springer Science and Business Media LLC, 2022年10月20日, ［査読有り］
研究論文（学術雑誌）, Abstract

Living organisms share the ability to grow various microstructures on their surface to achieve functions. Here we present a force stamp method to grow microstructures on the surface of hydrogels based on a force-triggered polymerisation mechanism of double-network hydrogels. This method allows fast spatial modulation of the morphology and chemistry of the hydrogel surface within seconds for on-demand functions. We demonstrate the oriented growth of cells and directional transportation of water droplets on the engineered hydrogel surfaces. This force-triggered method to chemically engineer the hydrogel surfaces provides a new tool in addition to the conventional methods using light or heat, and will promote the wide application of hydrogels in various fields.

Gluing blood into gel by electrostatic interaction using a water-soluble polymer as an embolic agent.
Zhiping Jin, Hailong Fan, Toshiya Osanai, Takayuki Nonoyama, Takayuki Kurokawa, Hideki Hyodoh, Kotaro Matoba, Akiko Takeuchi, Jian Ping Gong, Miki Fujimura
Proceedings of the National Academy of Sciences of the United States of America, 119, 42, e2206685119, 2022年10月18日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Liquid embolic agents are widely used for the endovascular embolization of vascular conditions. However, embolization based on phase transition is limited by the adhesion of the microcatheter to the embolic agent, use of an organic solvent, unintentional catheter retention, and other complications. By mimicking thrombus formation, a water-soluble polymer that rapidly glues blood into a gel without triggering coagulation was developed. The polymer, which consists of cationic and aromatic residues with adjacent sequences, shows electrostatic adhesion with negatively charged blood substances in a physiological environment, while common polycations cannot. Aqueous polymer solutions are injectable through clinical microcatheters and needles. The formed blood gel neither adhered to the catheter nor blocked the port. Postoperative computed tomography imaging showed that the polymer can block the rat femoral artery in vivo and remain at the injection site without nontarget embolization. This study provides an alternative for the development of waterborne embolic agents.

Bioceramics x soft material as a simple model to mimic functions in bones
Nonoyama, T.
Journal of the Ceramic Society of Japan, 130, 10, 817, 824, Ceramic Society of Japan, 2022年10月01日, ［査読有り］, ［招待有り］, ［筆頭著者, 責任著者］
研究論文（学術雑誌）

The mechanosensitive ion channel PIEZO1 is expressed in tendons and regulates physical performance.
Ryo Nakamichi, Shang Ma, Takayuki Nonoyama, Tomoki Chiba, Ryota Kurimoto, Hiroki Ohzono, Merissa Olmer, Chisa Shukunami, Noriyuki Fuku, Guan Wang, Errol Morrison, Yannis P Pitsiladis, Toshifumi Ozaki, Darryl D'Lima, Martin Lotz, Ardem Patapoutian, Hiroshi Asahara
Science translational medicine, 14, 647, eabj5557, 2022年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, How mechanical stress affects physical performance via tendons is not fully understood. Piezo1 is a mechanosensitive ion channel, and E756del PIEZO1 was recently found as a gain-of-function variant that is common in individuals of African descent. We generated tendon-specific knock-in mice using R2482H Piezo1, a mouse gain-of-function variant, and found that they had higher jumping abilities and faster running speeds than wild-type or muscle-specific knock-in mice. These phenotypes were associated with enhanced tendon anabolism via an increase in tendon-specific transcription factors, Mohawk and Scleraxis, but there was no evidence of changes in muscle. Biomechanical analysis showed that the tendons of R2482H Piezo1 mice were more compliant and stored more elastic energy, consistent with the enhancement of jumping ability. These phenotypes were replicated in mice with tendon-specific R2482H Piezo1 replacement after tendon maturation, indicating that PIEZO1 could be a target for promoting physical performance by enhancing function in mature tendon. The frequency of E756del PIEZO1 was higher in sprinters than in population-matched nonathletic controls in a small Jamaican cohort, suggesting a similar function in humans. Together, this human and mouse genetic and physiological evidence revealed a critical function of tendons in physical performance, which is tightly and robustly regulated by PIEZO1 in tenocytes.

Evaluation of biological responses to micro-particles derived from a double network hydrogel.
Gen Matsumae, Mohamad Alaa Terkawi, Takayuki Nonoyama, Takayuki Kurokawa, Daisuke Takahashi, Tomohiro Shimizu, Ken Kadoya, Jian Ping Gong, Kazunori Yasuda, Norimasa Iwasaki
Biomaterials science, 10, 9, 2182, 2187, 2022年05月04日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Double network hydrogels (DN gels) composed of poly (2-acrylamido-2-methyl propanesulfonic acid) (PAMPS) as the brittle first network and poly (N,N-dimethylacrylamide) (PDMA) as the ductile second network have been proven to be a substitute biomaterial for cartilage, with promising biocompatibility and low toxicity, when they are used as bulk materials. For their further applications as articular cartilages, it is essential to understand the biological reactions and adverse events that might be initiated by wear particles derived from these materials. In this study, we used DN gel micro-particles of sizes 4 μm and 10 μm generated by the grinding method to mimic wearing debris of DN gels. The biological responses to particles were then evaluated in a macrophage-cultured system and an inflammatory osteolysis murine model. Our results demonstrated that DN gel particles have the ability to activate macrophages and promote the expression of Tnf-α, both in vitro and in vivo. Furthermore, the implantation of these particles onto calvarial bone triggered local inflammation and bone loss in a mouse model. Our data reveal that the potential foreign body responses to the generated particles from artificial cartilage should receive more attention in artificial cartilage engineering with the goal of developing a safer biocompatible substitute.

細胞外基質の電位変化に伴うJCウイルス増殖の制御　　　　　　　　　　　　　　　
谷川 聖, 野々山 貴行, 津田 真寿美, 王 磊, 種井 善一, Gong Jian Ping, 田中 伸哉
日本病理学会会誌, 111, 1, 263, 263, (一社)日本病理学会, 2022年03月
日本語

細胞外基質の電位変化に伴うJCウイルス増殖の制御　　　　　　　　　　　　　　　
谷川 聖, 野々山 貴行, 津田 真寿美, 王 磊, 種井 善一, Gong Jian Ping, 田中 伸哉
日本病理学会会誌, 111, 1, 263, 263, (一社)日本病理学会, 2022年03月
日本語

Combination of ultra-purified stem cells with an in situ-forming bioresorbable gel enhances intervertebral disc regeneration.
Daisuke Ukeba, Katsuhisa Yamada, Takashi Suyama, Darren R Lebl, Takeru Tsujimoto, Takayuki Nonoyama, Hirokazu Sugino, Norimasa Iwasaki, Masatoki Watanabe, Yumi Matsuzaki, Hideki Sudo
EBioMedicine, 76, 103845, 103845, 2022年01月24日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Lumbar intervertebral disc (IVD) herniations are associated with significant disability. Discectomy is the conventional treatment option for IVD herniations but causes a defect in the IVD, which has low self-repair ability, thereby representing a risk of further IVD degeneration. An acellular, bioresorbable, and good manufacturing practice (GMP)-compliant in situ-forming gel, which corrects discectomy-associated IVD defects and prevents further IVD degeneration had been developed. However, this acellular matrix-based strategy has certain limitations, particularly in elderly patients, whose tissues have low self-repair ability. The aim of this study was to investigate the therapeutic efficacy of using a combination of newly-developed, ultra-purified, GMP-compliant, human bone marrow mesenchymal stem cells (rapidly expanding clones; RECs) and the gel for IVD regeneration after discectomy in a sheep model of severe IVD degeneration. METHODS: RECs and nucleus pulposus cells (NPCs) were co-cultured in the gel. In addition, RECs combined with the gel were implanted into IVDs following discectomy in sheep with degenerated IVDs. FINDINGS: Gene expression of NPC markers, growth factors, and extracellular matrix increased significantly in the co-culture compared to that in each mono-culture. The REC and gel combination enhanced IVD regeneration after discectomy (up to 24 weeks) in the severe IVD degeneration sheep model. INTERPRETATION: These findings demonstrate the translational potential of the combination of RECs with an in situ-forming gel for the treatment of herniations in degenerative human IVDs. FUNDING: Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan Agency for Medical Research and Development, and the Mochida Pharmaceutical Co., Ltd.

Hydroxyapatite-hybridized double-network hydrogel surface enhances differentiation of bone marrow-derived mesenchymal stem cells to osteogenic cells.
Takuma Kaibara, Lei Wang, Masumi Tsuda, Takayuki Nonoyama, Takayuki Kurokawa, Norimasa Iwasaki, Jian Ping Gong, Shinya Tanaka, Kazunori Yasuda
Journal of biomedical materials research. Part A, 110, 4, 747, 760, 2021年10月28日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Recently, we have developed a hydroxyapatite (HAp)-hybridized double-network (DN) hydrogel (HAp/DN gel), which can robustly bond to the bone tissue in the living body. The purpose of this study is to clarify whether the HAp/DN gel surface can differentiate the bone marrow-derived mesenchymal stem cells (MSCs) to osteogenic cells. We used the MSCs which were harvested from the rabbit bone marrow and cultured on the polystyrene (PS) dish using the autogenous serum-supplemented medium. First, we confirmed the properties of MSCs by evaluating colony forming unit capacity, expression of MSC markers using flow cytometry, and multidifferential capacity. Secondly, polymerase chain reaction analysis demonstrated that the HAp/DN gel surface significantly enhanced mRNA expression of the eight osteogenic markers (TGF-β1, BMP-2, Runx2, Col-1, ALP, OPN, BSP, and OCN) in the cultured MSCs at 7 days than the PS surfaces (p < 0.0001), while the DN gel and HAp surfaces provided no or only a slight effect on the expression of these markers except for Runx2. Additionally, the alkaline phosphatase activity was significantly higher in the cells cultured on the HAp/DN gel surface than in the other three material surfaces (p < 0.0001). Thirdly, when the HAp/DN gel plug was implanted into the rabbit bone marrow, MSC marker-positive cells were recruited in the tissue generated around the plug at 3 days, and Runx2 and OCN were highly expressed in these cells. In conclusion, this study demonstrated that the HAp/DN gel surface can differentiate the MSCs into osteogenic cells.

Fast in vivo fixation of double network hydrogel to bone by monetite surface hybridization
Takayuki Nonoyama, Lei Wang, Ryuji Kiyama, Naohiro Kashimura, Kazunori Yasuda, Shinya Tanaka, Takayuki Kurokawa, Jian Ping Gong
JOURNAL OF THE CERAMIC SOCIETY OF JAPAN, 129, 9, 584, 589, CERAMIC SOC JAPAN-NIPPON SERAMIKKUSU KYOKAI, 2021年09月, ［査読有り］, ［筆頭著者, 責任著者］
英語, 研究論文（学術雑誌）, Double network (DN) hydrogels, possessing biocompatibility, low sliding friction, high strength and toughness, are promising as artificial cartilages for next-generation joint disease treatment. For such application, a fast and robust fixation of DN hydrogel to bone tissue in vivo is indispensable. However, bonding the DN hydrogel that contains similar to 90 wt % of water to bone is a grand challenge since glues do not work on hydrated surfaces. Recently, we reported that a DN hydrogel of its subsurface hybridized with low crystalline hydroxyapatite (HAp) can achieve robust fixation to bone after 4 weeks implantation in rabbit knees, owing to the HAp-induced osteogenesis penetration into the hydrogel matrix. For clinical application, achieving a quick fixation at the early stage of implantation remains as a next subject. In this study, instead of HAp, we hybridized calcium monohydrogen phosphate (monetite), which is a HAp precursor calcium phosphate salt, in the subsurface of the DN hydrogel and we observed an increase in the pushout resistance of the DN hydrogel to bone after 1 week implantation, prior to the HAp-induced osteogenesis penetration. In physiological environment, the monetite hybridized in the subsurface of the DN gel spontaneously dissolved to calcium and phosphate ions and then recrystallized to more stable HAp. We consider that the HAp formed in the boundary between the gel and the bone forms physical interlocking that significantly enhances the frictional resistance against the pushout force. The fast temporally pre-fixation to the bone by monetite surface hybridization makes one step closer to the clinical application of the DN gels as artificial cartilages. (C) 2021 The Ceramic Society of Japan. All rights reserved.

ハイドロキシアパタイト複合化ダブルネットワークゲル上での骨髄間葉系幹細胞の骨分化能評価
甲斐原 拓真, 王 磊, 津田 真寿美, 野々山 貴行, 黒川 孝幸, きょう 剣萍, 岩崎 倫政, 田中 伸哉, 安田 和則
日本整形外科学会雑誌, 95, 8, S1561, S1561, (公社)日本整形外科学会, 2021年08月
日本語

Ultrapurified Alginate Gel Containing Bone Marrow Aspirate Concentrate Enhances Cartilage and Bone Regeneration on Osteochondral Defects in a Rabbit Model
Liang Xu, Atsushi Urita, Tomohiro Onodera, Ryosuke Hishimura, Takayuki Nonoyama, Masanari Hamasaki, Dawei Liang, Kentaro Homan, Jian Ping Gong, Norimasa Iwasaki
The American Journal of Sports Medicine, 036354652110141, 036354652110141, SAGE Publications, 2021年06月01日, ［査読有り］
研究論文（学術雑誌）, Ultrapurified alginate (UPAL) gel implantation has been demonstrated as effective in cartilage repair for osteochondral defects; however, cell transplantation within UPAL gels would be required to treat larger defects.

The combination of UPAL gel and bone marrow aspirate concentrate (BMAC) would enhance cartilage repair and subchondral bone repair for large osteochondral defects.

Controlled laboratory study.

A total of 104 osteochondral defects (1 defect per knee) of 52 rabbits were randomly divided into 4 groups (26 defects per group): defects without any treatment (Defect group), defects treated using UPAL gel alone (UPAL group), defects treated using UPAL gel containing allogenic bone marrow mesenchymal stromal cells (UPAL-MSC group), and defects treated using UPAL gel containing BMAC (UPAL-BMAC group). At 4 and 16 weeks postoperatively, macroscopic and histologic evaluations and measurements of repaired subchondral bone volumes of reparative tissues were performed. Collagen orientation and mechanical properties of the reparative tissue were assessed at 16 weeks.

The defects in the UPAL-BMAC group were repaired with hyaline-like cartilage with well-organized collagen structures. The histologic scores at 4 weeks were significantly higher in the UPAL-BMAC group (16.9 ± 2.0) than in the Defect group (4.7 ± 1.9; P < .05), the UPAL group (10.0 ± 3.3; P < .05), and the UPAL-MSC group (12.2 ± 2.9; P < .05). At 16 weeks, the score in the UPAL-BMAC group (24.4 ± 1.7) was significantly higher than those in the Defect group (9.0 ± 3.7; P < .05), the UPAL group (14.2 ± 3.9; P < .05), and the UPAL-MSC group (16.3 ± 3.6; P < .05). At 4 and 16 weeks, the macroscopic evaluations were significantly superior in the UPAL-BMAC group compared with the other groups, and the values of repaired subchondral bone volumes in the UPAL-BMAC group were significantly higher than those in the Defect and UPAL groups. The mechanical properties of the reparative tissues were significantly better in the UPAL-BMAC group than in the other groups.

The implantation of UPAL gel containing BMAC-enhanced hyaline-like cartilage repair and subchondral bone repair of osteochondral defects in a rabbit knee model.

These data support the potential clinical application of 1-step treatment for large osteochondral defects using biomaterial implantation with cell transplantation.

Tough Double Network Hydrogel and Its Biomedical Applications.
Takayuki Nonoyama, Jian Ping Gong
Annual review of chemical and biomolecular engineering, 2021年03月26日, ［査読有り］, ［筆頭著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Soft and wet hydrogels have many similarities to biological tissues, though their mechanical fragility had been one of the biggest obstacles in biomedical applications. Studies and developments in double network (DN) hydrogels have elucidated how to create tough gels universally based on sacrificial bond principles and opened a path for biomedical application of hydrogels in regenerative medicine and artificial soft connective tissues, such as cartilage, tendon, and ligament, which endure high tension and compression. This review explores a universal toughening mechanism for and biomedical studies of DN hydrogels. Moreover, because the term sacrificial bonds has been mentioned often in studies of bone tissues, consisting of biomacromolecules and biominerals, recent studies of gel-biomineral composites to understand early-stage osteogenesis and to simulate bony sacrificial bonds are also summarized. Expected final online publication date for the Annual Review of Chemical and Biomolecular Engineering, Volume 12 is June 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Bone Marrow Aspirate Concentrate Combined with in Situ Forming Bioresorbable Gel Enhances Intervertebral Disc Regeneration in Rabbits.
Daisuke Ukeba, Katsuhisa Yamada, Takeru Tsujimoto, Katsuro Ura, Takayuki Nonoyama, Norimasa Iwasaki, Hideki Sudo
The Journal of bone and joint surgery. American volume, 103, 8, e31, 2021年01月21日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The current surgical procedure of choice for intervertebral disc (IVD) herniation is discectomy, which induces postoperative IVD degeneration. Thus, cell-based therapies, as a 1-step simple procedure, are desired because of the poor capacity of IVDs for self-repair. The aim of this study was to investigate the repair efficacy of ultra-purified alginate (UPAL) gels containing bone marrow aspirate concentrate (BMAC) for the treatment of discectomy-associated IVD degeneration in rabbits. METHODS: The mechanical properties of 3 types of gels-UPAL, UPAL containing bone marrow-derived mesenchymal stem cells (BMSCs), and UPAL containing BMAC-were evaluated. Forty rabbits were assigned to 5 groups: intact control, discectomy (to make the cavity), UPAL (implantation of the UPAL gel after discectomy), BMSCs-UPAL (implantation of a combination of autogenic BMSCs and UPAL gel after discectomy), and BMAC-UPAL (implantation of a combination of BMAC and UPAL gel after discectomy). The gels were implanted at 4 weeks after induction of IVD degeneration. At 4 and 12 weeks, magnetic resonance imaging (MRI) as well as histological and immunohistochemical analyses were performed to analyze IVD degeneration qualitatively and the viability of the implanted cells. RESULTS: There was no significant difference among the 3 types of gels in terms of the results of unconfined compression tests. The implanted cells survived for 12 weeks. The histological grades of the BMSCs-UPAL (mean and standard deviation, 2.50 ± 0.53; p < 0.001) and BMAC-UPAL (2.75 ± 0.64, p = 0.001) showed them to be more effective in preventing degeneration than UPAL gel alone (3.63 ± 0.52). The effectiveness of BMAC-UPAL was not significantly different from that of BMSCs-UPAL, except with respect to type-II collagen synthesis. CONCLUSIONS: BMAC-UPAL significantly enhanced the repair of IVD defects created by discectomy. This approach could be an effective therapeutic strategy owing to its simplicity and cost-effectiveness compared with cell therapy using culture-expanded BMSCs. CLINICAL RELEVANCE: Local administration of the BMAC combined with UPAL gel could be an effective therapeutic strategy to enhance IVD repair after discectomy.

Isotope Microscopic Observation of Osteogenesis Process Forming Robust Bonding of Double Network Hydrogel to Bone.
Takayuki Nonoyama, Lei Wang, Masumi Tsuda, Yuki Suzuki, Ryuji Kiyama, Kazunori Yasuda, Shinya Tanaka, Kousuke Nagata, Ryosuke Fujita, Naoya Sakamoto, Noriyuki Kawasaki, Hisayoshi Yurimoto, Jian Ping Gong
Advanced healthcare materials, 10, 3, e2001731, 2020年11月16日, ［査読有り］, ［筆頭著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Tough double network (DN) hydrogels are promising substitutes of soft supporting tissues such as cartilage and ligaments. For such applications, it is indispensable to robustly fix the hydrogels to bones with medically feasible methods. Recently, robustly bonding the DN hydrogels to defected bones of rabbits in vivo has been proved successful. The low crystalline hydroxyapatite (HAp) of calcium-phosphate-hydroxide salt coated on the surface layer of the DN hydrogels induced spontaneous osteogenesis penetrating into the semi-permeable hydrogels to form a gel/bone composite layer. In this work, the 44 Ca isotope-doped HAp/DN hydrogel is implanted in a defect of rabbit femoral bone and the dynamic osteogenesis process at the gel/bone interface is analyzed by tracing the calcium isotope ratio using isotope microscopy. The synthetic HAp hybridized on the surface layer of DN gel dissolves rapidly in the first two weeks by inflammation, and then the immature bone with a gradient structure starts to form in the gel region, reutilizing the dissolved Ca ions. These results reveal, for the first time, that synthetic HAp is reutilized for osteogenesis. These facts help to understand the lifetime of bone absorbable materials and to elucidate the mechanism of spontaneous, non-toxic, but strong fixation of hydrogels to bones.

Preparation of Tough Double- And Triple-Network Supermacroporous Hydrogels through Repeated Cryogelation
Tomáš Sedlačík, Takayuki Nonoyama, Honglei Guo, Ryuji Kiyama, Tasuku Nakajima, Yoshihiro Takeda, Takayuki Kurokawa, Jian Ping Gong
Chemistry of Materials, 32, 19, 8576, 8586, 2020年10月13日, ［査読有り］
研究論文（学術雑誌）, Copyright © 2020 American Chemical Society. Supermacroporous hydrogels, possessing a spongelike structure and permeability, have drawn significant attention for their bioengineering and biomedical applications. However, their mechanical weakness due to the low-density structure is one of their biggest limitations. This work reports a multistep cryogelation technique, which does not require special equipment, for preparing tough supermacroporous hydrogels on the basis of the double-network (DN) strategy. The produced supermacroporous DN gels possess interconnected pores with pore sizes of 50-230 μm. They also show a compressive modulus of up to ∼100 kPa, which is 2-4 times higher than that of the corresponding supermacroporous single-network (SN) gels, and a compressive strength of up to 1 MPa at 80% compression. The supermacroporous DN cryogels are also stretchable with a work of extension of up to 38 kJ m-3, which is 1-2 orders larger than that of the SN cryogels. Their high stiffness and stretchability distinguish them from other types of cryogels. Supermacroporous triple-network (TN) gels and DN gels composed of different polymer combinations are also prepared. The technique presented herein is suitable for preparing supermacroporous DN gels from various polymers; hence, it is promising in meeting bioengineering and biomedical demands.

Chitin-based double-network hydrogel as potential superficial soft tissue repairing materials.
Junchao Huang, Martin Frauenlob, Yuki Shibata, Lei Wang, Tasuku Nakajima, Takayuki Nonoyama, Masumi Tsuda, Shinya Tanaka, Takayuki Kurokawa, Jian Ping Gong
Biomacromolecules, 21, 10, 4220, 4230, 2020年09月16日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Chitin is a biopolymer which has been proved to be a candidate as biomedical materials, yet the weak mechanical properties limited their potentials seriously. In this work, a chitin-based double-network (DN) hydrogel was designed as a potential superficial repairing material. The hydrogel was synthesized through double-network (DN) strategy composing hybrid regenerated chitin nanofibers (RCNs)-poly (ethylene glycol diglycidyl ether) (PEGDE) as the first network and polyacrylamide (PAAm) as the second network. The hybrid RCNs-PEGDE/PAAm DN hydrogel was strong and tough, possessing Young's modulus (elasticity) E 0.097 ± 0.020 MPa, fracture stress σf 0.449 ± 0.025 MPa, and work of fracture Wf 5.75 ± 0.35 MJ·m-3. The obtained DN hydrogel was strong enough for surgical requirements in the usage of soft tissue scaffolds. In addition, the chitin endowed the DN hydrogel with good bacteria resistance and accelerated fibroblast proliferation, which NIH3T3 cell number increased nearly 5 times within 3 days. Subcutaneous implantation studies showed that the DN hydrogel did not induce inflammation after 4 weeks, suggesting a good biosafety in vivo. These results indicated that the hybrid RCNs-PEGDE/PAAm DN hydrogel had great prospect as rapid soft tissue repairing materials.

Hydrogels toughened by biominerals providing energy-dissipative sacrificial bonds.
Kazuki Fukao, Kazuki Tanaka, Ryuji Kiyama, Takayuki Nonoyama, Jian Ping Gong
Journal of materials chemistry. B, 2020年05月15日, ［査読有り］, ［責任著者］, ［国際誌］
英語, Inspired by bone tissues, we mineralized low crystalline hydroxyapatite (HAp) particles in double network (DN) hydrogels, and we observed that the HAp minerals toughen the gels. The contribution of dissipated energy from HAp minerals was over 500% higher than that from the polymer during tensile deformation. We elucidated that the amorphous parts in the HAp minerals break at deformation, acting as energy-dissipative sacrificial bonds. This result implies that not only brittle polymer networks but also minerals can provide sacrificial bonds to toughen soft materials.

Meet the phase-separation polymeric gel　　　　　　　　　　　　　　　
Takayuki Nonoyama, Jian Ping Gong
The Innovation Platform, 1, 73, 74, 2020年03月, ［招待有り］
英語, 研究論文（学術雑誌）

Surface charge dominated protein absorption on hydrogels.
Honglei Guo, Yuto Uehara, Takahiro Matsuda, Ryuji Kiyama, Long Li, Jamil Ahmed, Yoshinori Katsuyama, Takayuki Nonoyama, Takayuki Kurokawa
Soft matter, 16, 7, 1897, 1907, 2020年01月29日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Soft tissue engineering requires antifouling materials that are biocompatible and mechanically flexible. Conventional hydrogels containing more than 70 wt% water are thus promising antifouling material candidates. However, some hydrogels are difficult to apply in internal body organs because of undesirable protein absorption on their surfaces. Due to the lack of an effective method for observing the true charge densities of hydrogels, the reason why electrostatic interactions dominate protein absorption behavior remains unclear. In this work, we adopt the microelectrode technique (MET) to study the electrical potentials of hydrogels with negative, positive, and neutral potentials and demonstrate the protein absorption behaviors on those hydrogels. The results show that MET is an effective method to obtain the surface charge densities of various hydrogels. Furthermore, the amounts of absorbed proteins on the gels were quantified with respect to the charge densities of the hydrogels. The results indicate that electrostatic absorption is quantitatively dominated by a combination of hydrogel charge density and overall protein charge. Based on the knowledge obtained in this work, the effects of hydrogel surface charges on protein absorption can be better understood. Thus, the results are expected to promote the application of hydrogels in tissue engineering.

Instant Thermal Switching from Soft Hydrogel to Rigid Plastics Inspired by Thermophile Proteins
Nonoyama, T., Lee, Y.W., Ota, K., Fujioka, K., Hong, W., Gong, J.P.
Advanced Materials, 32, 4, e1905878, 2020年, ［査読有り］, ［筆頭著者, 責任著者］
研究論文（学術雑誌）

Erratum: Preparation of Tough Double- and Triple-Network Supermacroporous Hydrogels through Repeated Cryogelation (Chem. Mater. (2020) 32:19 (8576−8586) DOI: 10.1021/acs.chemmater.0c02911)
Sedla?{\'i}k, T., Nonoyama, T., Guo, H., Kiyama, R., Nakajima, T., Takeda, Y., Kurokawa, T., Gong, J.P.
Chemistry of Materials, 32, 24, 10737, 10737, 2020年
研究論文（学術雑誌）

Robust hydrogel–bioceramics composite and its osteoconductive properties
Takayuki Nonoyama
Polymer Journal, 2020年, ［査読有り］, ［招待有り］, ［筆頭著者, 責任著者］
© 2020, The Society of Polymer Science, Japan. Due to the soft and wet characteristics of hydrogels that acquire high mechanical strength by toughening strategies, tough and robust hydrogels are attractive as next-generation structural biomaterials, especially for the substitution of soft connective tissues such as cartilage, tendons, and ligaments. Firm fixation of the gels to bone in vivo is an indispensable technology in clinical applications. However, since the surface of the hydrogel is very watery, current medical adhesives cannot fix the gels at all. In this review, first, the double network (DN) strategy, a universal method to toughen hydrogels, is presented. Second, by combining hydroxyapatite (HAp) of a main bony inorganic component with a high-strength DN gel, a biocompatible adhesion method accompanied by spontaneous osteogenesis penetration into the gel matrix is introduced. In addition, the HAp-gel composite can be used as a simplified model of bone tissues because of their similarity in terms of components. Third, HAp formation spatially confined by the polymer network of gel is shown as a model of the earliest stage of biomineralization in vivo. These studies on biomineral–hydrogel composites have great potential to contribute not only basic research on osteogenesis mechanisms but also clinical applications of tough hydrogels.

Effect of Relative Strength of Two Networks on the Internal Fracture Process of Double Network Hydrogels As Revealed by in Situ Small-Angle X-ray Scattering
Kazuki Fukao, Tasuku Nakajima, Takayuki Nonoyama, Takayuki Kurokawa, Takahiko Kawai, Jian Ping Gong
Macromolecules, 2020年, ［査読有り］
研究論文（学術雑誌）, Copyright © 2020 American Chemical Society. Double network hydrogels (DN gels) exhibit extraordinarily high strength and toughness by interplay of the two contrasting networks: the rigid, brittle network serves as a sacrificial bond that fractures at a relatively low strain, while the soft, stretchable network serves as hidden length that sustains stress by large extension afterward. The internal fracture process of the brittle network strongly depends on the relative strength of the two networks. In this study, we study the internal fracturing process of typical DN gels that show yielding or necking under uniaxial stretching using in situ small-angle X-ray scattering. Two samples consisting of the same brittle first network from poly(2-acrylamido-2-methylpropanesulfonic acid) but stretchable second network from poly(N,N-dimethylacrylamide) of different concentrations were adopted. We found that (1) the brittle network shows nonaffine deformation even far below the yield strain by local fracture; (2) for the sample of low second network concentration, significant strain amplification occurs around the submicrometer-scale voids (defects) preexisting in the brittle network, which induces the fracture percolation of brittle network from voids to show the necking phenomenon; and (3) the strain amplification at voids is suppressed in the sample of high second network concentration, and fracture of brittle network occurs dispersedly, showing yielding without necking.

Effect of Structure Heterogeneity on Mechanical Performance of Physical Polyampholytes Hydrogels
Cui Kunpeng, Ye Ya Nan, Sun Tao Lin, Chen Liang, Li Xueyu, Kurokawa Takayuki, Nakajima Tasuku, Nonoyama Takayuki, Gong Jian Ping
MACROMOLECULES, 52, 19, 7369, 7378, AMER CHEMICAL SOC, 2019年10月08日, ［査読有り］
英語, 研究論文（学術雑誌）, Recent studies reported a multiscale structure in tough and self-healing hydrogels containing physical associations. For example, a type of tough and self-healing hydrogel from charge-balanced polyampholytes (PA) has a mesoscale bicontinuous double network structure with structural length around 400 nm. This mesoscale network structure plays an essential role in the multistep rupture process, which leads to the high toughness of PA hydrogels. In this work, by using an osmotic stress method, we symmetrically studied how the relative strength of soft and hard networks and the strength of ionic bonds influence the property of PA gels. We found that increasing osmotic stress of the bath solution triggers the structure transition from bicontinuous double network structure to a homogeneous structure, which drives the concurrently opaque-transparent transition in optical property and viscoelastic-glassy transition in mechanical behavior. The gels around the structural transition point were found to possess both high toughness (fracture energy of 7200 J m(-2)) and high stiffness (Young's modulus of 12.9 MPa), which is a synergy of soft network and hard network of the bicontinuous structure. Our work not only provides an approach to tune the structure and property of physical hydrogels through tuning physical association but also gives a demo to investigate their relationships, yet another step forward gives inspiration to design a new type of tough and self-healing materials around the structural transition point.

Tough double network elastomers reinforced by the amorphous cellulose network
Murai, J., Nakajima, T., Matsuda, T., Tsunoda, K., Nonoyama, T., Kurokawa, T., Gong, J.P.
Polymer, 178, 2019年09月12日, ［査読有り］
研究論文（学術雑誌）

Tough Triblock Copolymer Hydrogels with Different Micromorphologies for Medical and Sensory Materials
Zhang Hui Jie, Luo Feng, Ye Yanan, Sun Tao Lin, Nonoyama Takayuki, Kurokawa Takayuki, Nakajima Tasuku
ACS APPLIED POLYMER MATERIALS, 1, 8, 1948, 1953, AMER CHEMICAL SOC, 2019年08月, ［査読有り］
英語, 研究論文（学術雑誌）, Tough triblock copolymer hydrogels with microstructures of sphere, cylinder, and laminae were constructed using a newly developed "drying and swelling" method without changing the chemical structures of their monomeric units. These tough triblock copolymer hydrogels commonly showed high fracture stress of similar to 10 MPa but exhibited varied elastic moduli depending on their microstructures. Furthermore, the constructed laminar gel formed pH-sensitive photonic gel at the base conditions, providing the gel application with potential as a sensor. Given their high toughness, biocompatibility, and tunable modulus, this study helps expand the potential application of amphiphilic block copolymer hydrogels for medical and industrial use.

Osteochondral Autograft Transplantation Technique Augmented by an Ultrapurified Alginate Gel Enhances Osteochondral Repair in a Rabbit Model.
Ryosuke Hishimura, Tomohiro Onodera, Kazutoshi Hontani, Rikiya Baba, Kentaro Homan, Shinji Matsubara, Zenta Joutoku, WooYoung Kim, Takayuki Nonoyama, Takayuki Kurokawa, Jian Ping Gong, Norimasa Iwasaki
The American journal of sports medicine, 47, 2, 468, 478, 2019年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: One of the most important limitations of osteochondral autograft transplantation (OAT) is the adverse effect on donor sites in the knee. To decrease the number and/or size of osteochondral defects, we devised a method with biomaterial implantation after OAT. HYPOTHESIS: OAT augmented by ultrapurified alginate (UPAL) gel enhances cartilage repair capacity. STUDY DESIGN: Controlled laboratory study. METHODS: Seventy-five osteochondral defects in rabbits were divided into 3 groups: osteochondral defects with OAT alone, defects with OAT augmented by UPAL gel (combined group), and defects without intervention as controls. Macroscopic and histological evaluations of the reparative tissues were performed at 4 and 12 weeks postoperatively. Histological evaluation of graft cartilage degradation was also performed. To evaluate the effects of UPAL gel on graft healing, repaired bone volumes and osseointegration of the graft were evaluated. Collagen orientation and the mechanical properties of the reparative tissue and graft cartilage were also evaluated qualitatively. RESULTS: The macroscopic and histological evaluations of the combined group were significantly superior to the other groups at 12 weeks postoperatively. Regarding degenerative change of the graft, the histological scores of the combined group were significantly higher than those of the OAT-alone group. The values of repaired subchondral bone volumes and osseointegration of the graft were almost identical in both groups. Collagen orientation and the mechanical properties of the reparative tissue and graft cartilage were significantly better in the combined group than in the other groups. CONCLUSION: Administration of UPAL gel in OAT enhanced cartilage repair and protected graft cartilage without inhibiting subchondral bone repair and graft survival. CLINICAL RELEVANCE: OAT augmented by UPAL gel decreases the number and/or size of osteochondral grafts, minimizing the risk of donor site morbidity. This combination technique has the potential to improve clinical outcomes and expand the surgical indications for OAT.

Tough Particle-Based Double Network Hydrogels for Functional Solid Surface Coatings
Takahashi, R., Shimano, K., Okazaki, H., Kurokawa, T., Nakajima, T., Nonoyama, T., King, D.R., Gong, J.P.
Advanced Materials Interfaces, 5, 23, 2018年12月07日, ［査読有り］
研究論文（学術雑誌）

An acellular bioresorbable ultra-purified alginate gel promotes intervertebral disc repair: A preclinical proof-of-concept study.
Takeru Tsujimoto, Hideki Sudo, Masahiro Todoh, Katsuhisa Yamada, Koji Iwasaki, Takashi Ohnishi, Naoki Hirohama, Takayuki Nonoyama, Daisuke Ukeba, Katsuro Ura, Yoichi M Ito, Norimasa Iwasaki
EBioMedicine, 37, 521, 534, 2018年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The current surgical procedure of choice for lumbar intervertebral disc (IVD) herniation is discectomy. However, defects within IVD produced upon discectomy may impair tissue healing and predispose patients to subsequent IVD degeneration. This study aimed to investigate whether the use of an acellular bioresorbable ultra-purified alginate (UPAL) gel implantation system is safe and effective as a reparative therapeutic strategy after lumbar discectomy. METHODS: Human IVD cells were cultured in a three-dimensional system in UPAL gel. In addition, lumbar spines of sheep were used for mechanical analysis. Finally, the gel was implanted into IVD after discectomy in rabbits and sheep in vivo. FINDINGS: The UPAL gel was biocompatible with human IVD cells and promoted extracellular matrix production after discectomy, demonstrating sufficient biomechanical characteristics without material protrusion. INTERPRETATION: The present results indicate the safety and efficacy of UPAL gels in a large animal model and suggest that these gels represent a novel therapeutic strategy after discectomy in cases of lumbar IVD herniation. FUND: Grant-in-Aid for the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan Agency for Medical Research and Development, and the Mochida Pharmaceutical Co., Ltd.

Micro patterning of hydroxyapatite by soft lithography on hydrogels for selective osteoconduction.
Kiyama R, Nonoyama T, Wada S, Semba S, Kitamura N, Nakajima T, Kurokawa T, Yasuda K, Tanaka S, Gong JP
Acta biomaterialia, 81, 60, 69, 2018年10月, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Mechanically robust hydrogels are promising biomaterials as artificial supportive tissue. These applications require selective and robust bonding of the hydrogels to living tissue. Recently, we achieved strong in vivo bone bonding of a tough double network (DN) hydrogel, a potential material for use as artificial cartilage and tendon, by hybridizing osteoconductive hydroxyapatite (HAp) in the gel surface layer. In this work, we report micro patterning of HAp at the surface of the DN hydrogel for selective osteoconduction. Utilizing the dissolution of HAp in an acidic environment, the soft lithography technique using an acid gel stamp was adopted to form a high-resolution HAp pattern on the gel. The HAp-patterned gel showed well-regulated migration and adhesion of cells in vitro. Moreover, the HAp-patterned gel showed selective and robust bonding to the rabbit bone tissue in vivo. This HAp soft lithography technique allows for simple and quick preparation of tailor-made osteoconductive hydrogels and can be applied to other hydrogels for selective bone bonding. STATEMENT OF SIGNIFICANCE: Hydrogels, preserving large amount of water, have been studied for next-generation artificial soft tissues. However, fixation of hydrogels to living tissue was unsolved issue for clinical application. Recently, we achieved robust bonding of a tough double network gel to bone in vivo by coating of osteoconductive hydroxyapatite in the gel surface layer. For further progress for practical use, we report the micro patterning of HAp at the surface of the DN hydrogel by using soft lithography technique, to perform selective bonding to only objective area without unnecessary coalescence. The HAp lithography technique is simple, quick and non-toxic method to prepare tailor-made osteoconductive hydrogels and has universality of species of hydrogels.

Tough and Self-Recoverable Thin Hydrogel Membranes for Biological Applications
Ye Ya Nan, Frauenlob Martin, Wang Lei, Tsuda Masumi, Sun Tao Lin, Cui Kunpeng, Takahashi Riku, Zhang Hui Jie, Nakajima Tasuku, Nonoyama Takayuki, Kurokawa Takayuki, Tanaka Shinya, Gong Jian Ping
ADVANCED FUNCTIONAL MATERIALS, 28, 31, WILEY-V C H VERLAG GMBH, 2018年08月01日, ［査読有り］
英語, 研究論文（学術雑誌）, Tough and self-recoverable hydrogel membranes with micrometer-scale thickness are promising for biomedical applications, which, however, rarely be realized due to the intrinsic brittleness of hydrogels. In this work, for the first time, by combing noncovalent DN strategy and spin-coating method, we successfully fabricated thin (thickness: 5-100 mu m), yet tough (work of extension at fracture: 10(5)-10(7) J m(-3)) and 100% self-recoverable hydrogel membranes with high water content (62-97 wt%) in large size (approximate to 100 cm(2)). Amphiphilic triblock copolymers, which form physical gels by self-assembly, were used for the first network. Linear polymers that physically associate with the hydrophilic midblocks of the first network, were chosen for the second network. The inter-network associations serve as reversible sacrificial bonds that impart toughness and self-recovery properties on the hydrogel membranes. The excellent mechanical properties of these obtained tough and thin gel membranes are comparable, or even superior to many biological membranes. The in vitro and in vivo tests show that these hydrogel membranes are biocompatible, and postoperative nonadhesive to neighboring organs. The excellent mechanical and biocompatible properties make these thin hydrogel membranes potentially suitable for use as biological or postoperative antiadhesive membranes.

A Facile Method to Fabricate Anisotropic Hydrogels with Perfectly Aligned Hierarchical Fibrous Structures
Md. Tariful Islam Mredha, Yun Zhou Guo, Takayuki Nonoyama, Tasuku Nakajima, Takayuki Kurokawa, Jian Ping Gong
Advanced Materials, 30, 9, Wiley-VCH Verlag, 2018年03月01日, ［査読有り］
英語, 研究論文（学術雑誌）, Natural structural materials (such as tendons and ligaments) are comprised of multiscale hierarchical architectures, with dimensions ranging from nano- to macroscale, which are difficult to mimic synthetically. Here a bioinspired, facile method to fabricate anisotropic hydrogels with perfectly aligned multiscale hierarchical fibrous structures similar to those of tendons and ligaments is reported. The method includes drying a diluted physical hydrogel in air by confining its length direction. During this process, sufficiently high tensile stress is built along the length direction to align the polymer chains and multiscale fibrous structures (from nano- to submicro- to microscale) are spontaneously formed in the bulk material, which are well-retained in the reswollen gel. The method is useful for relatively rigid polymers (such as alginate and cellulose), which are susceptible to mechanical signal. By controlling the drying with or without prestretching, the degree of alignment, size of superstructures, and the strength of supramolecular interactions can be tuned, which sensitively influence the strength and toughness of the hydrogels. The mechanical properties are comparable with those of natural ligaments. This study provides a general strategy for designing hydrogels with highly ordered hierarchical structures, which opens routes for the development of many functional biomimetic materials for biomedical applications.

Tough and variable-band-gap photonic hydrogel displaying programmable angle-dependent colors
Md. Anamul Haque, Kei Mito, Takayuki Kurokawa, Tasuku Nakajima, Takayuki Nonoyama, Muhammad Ilyas, Jian Ping Gong
ACS Omega, 3, 1, 55, 62, American Chemical Society, 2018年, ［査読有り］
英語, 研究論文（学術雑誌）, One-dimensional photonic crystals or multilayer films produce colors that change depending on viewing and light illumination angles because of the periodic refractive index variation in alternating layers that satisfy Bragg’s law. Recently, we have developed multilayered photonic hydrogels of two distinct bulk geometries that possess an alternating structure of a rigid polymeric lamellar bilayer and a ductile polyacrylamide (PAAm) matrix. In this paper, we focus on fabrication of composite gels with variable photonic band gaps by controlling the PAAm layer thickness. We report programmable angle-dependent and angle-independent structural colors produced by composite hydrogels, which is achieved by varying bulk and internal geometries. In the sheet geometry, where the lamellae are aligned parallel to the sheet surface, the photonic gel sheet exhibits strong angle-dependent colors. On the other hand, when lamellae are coaxially aligned in a cylindrical geometry, the gel rod exhibits an angle-independent color, in sharp contrast with the gel sheet. Rocking curves have been constructed to justify the diverse angle-dependent behavior of various geometries. Despite varying the bulk geometry, the tunable photonic gels exhibit strong mechanical performances and toughness. The distinct angle dependence of these tough photonic materials with variable band gaps could benefit light modulation in displays and sensor technologies.

Anisotropic Growth of Hydroxyapatite in Stretched Double Network Hydrogel
Kazuki Fukao, Takayuki Nonoyama, Ryuji Kiyama, Kazuya Furusawa, Takayuki Kurokawa, Tasuku Nakajima, Jian Ping Gong
ACS Nano, 11, 12, 12103, 12110, American Chemical Society, 2017年12月26日, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌）, Bone tissues possess excellent mechanical properties such as compatibility between strength and flexibility and load bearing owing to the hybridization of organic/inorganic matters with anisotropic structure. To synthetically mimic such an anisotropic structure of natural organic/inorganic hybrid materials, we carried out hydroxyapatite (HAp) mineralization in stretched tough double network (DN) hydrogels. Anisotropic mineralization of HAp took place in stretched hydrogels, as revealed by high brightness synchrotron X-ray scattering and transmission electron microscopic observation. The c-axis of mineralized HAp aligned along the stretching direction, and the orientation degree S calculated from scattering profiles increased with increasing in the elongation ratio λ of the DN gel, and S at λ = 4 became comparable to that of rabbit tibial bones. The morphology of HAp polycrystal gradually changed from spherical to unidirectional rod-like shape with increased elongation ratio. A possible mechanism for the anisotropic mineralization is proposed, which would be one of the keys to develop mechanically anisotropic organic/inorganic hybrid materials.

Water-Triggered Ductile-Brittle Transition of Anisotropic Lamellar Hydrogels and Effect of Confinement on Polymer Dynamics
Muhammad Ilyas, Md. Anamul Haque, Youfeng Yue, Takayuki Kurokawa, Tasuku Nakajima, Takayuki Nonoyama, Jian Ping Gong
MACROMOLECULES, 50, 20, 8169, 8177, AMER CHEMICAL SOC, 2017年10月, ［査読有り］
英語, 研究論文（学術雑誌）, We study the effect of dehydration On the structure and mechanical properties of anisotropic lamellar hydrogels, consisting of alternative stacking of several thousands of nanoscale rigid bilayers from amphiphilic poly(dodecyl glyceryl itaconate) (PDGI) and submicroscale soft hydrogel layers from hydrophilic polyacrylamide (PAAm) networks. We found that the layered microstructure is well preserved with dehydration, and a ductile-brittle transition occurs at the critical water-content. This, transition is related to the rubbery-glassy transition of the PAAm layers, which occurs at 58 wt % water content and is much higher than 26 wt% of bulk PAAm hydrogels. Such specific behavior of the lamellar hydrogels indicates that the dynamics of the submicroscale PAAm hydrated layer intercalated between the rigid bilayers are very different from its bulk state.

Supramolecular hydrogels with multi-cylindrical lamellar bilayers: Swelling-induced contraction and anisotropic molecular diffusion
Kei Mito, Md. Anamul Haque, Tasuku Nakajima, Maki Uchiumi, Takayuki Kurokawa, Takayuki Nonoyama, Jian Ping Gong
POLYMER, 128, 373, 378, ELSEVIER SCI LTD, 2017年10月, ［査読有り］
英語, 研究論文（学術雑誌）, Novel, supramolecular, anisotropic hydrogels (called MC-PDGI gels) are presented in this study. These MC-PDGI gels consist of multi-cylindrical lipid bilayers aligned in a uniaxial manner and embedded in a soft hydrogel matrix. The bilayers and the hydrogel interact weakly due to hydrogen bonding. These MC-PDGI gels swell after exposure to water, which causes their volume and diameter to increase while simultaneously causing their length to decrease. This anisotropic swelling-induced contraction behavior is the result of competition between the isotropic elasticity of the hydrogel matrix and the interfacial tension of the lipid bilayers. Moreover, the MC-PDGI gels exhibit unique quasi one-dimensional diffusion behavior owing to the difficulty of molecular penetration through the multi-layered lipid bilayers. These materials would be useful for prolonged drug release or as an actuator. (C) 2017 Elsevier Ltd. All rights reserved.

Anisotropic tough double network hydrogel from fish collagen and its spontaneous in vivo bonding to bone.
Mredha MTI, Kitamura N, Nonoyama T, Wada S, Goto K, Zhang X, Nakajima T, Kurokawa T, Takagi Y, Yasuda K, Gong JP
Biomaterials, 132, 85, 95, ELSEVIER SCI LTD, 2017年07月, ［査読有り］
英語, 研究論文（学術雑誌）, Soft supporting tissues in the human body, such as cartilages and ligaments, are tough materials and firmly fixed to bones. These soft tissues, once injured, cannot regenerate spontaneously in vivo. Developing tough and biocompatible hydrogels as artificial soft supporting tissues would substantially improve outcomes after soft tissue injury. Collagen is the main rigid component in soft connective tissues which is organized in various hierarchical arrays. We have successfully developed a novel class of collagen fibril-based tough hydrogels based on the double network (DN) concept using swim bladder collagen (SBC) extracted from Bester sturgeon fish. The DN hydrogels, SBC/PDMAAm, are composed of physically/chemically crosslinked anisotropic SBC fibril as the first network and neutral, biocompatible poly(N,N'-dimethylacrylamide) (PDMAAm) as the second network. The anisotropic structure of SBC fibril network, which is well retained in the DN hydrogels, is formed by free injection method, taking advantage of the excellent fibrillogenesis capacity of SBC. The denaturation temperature of collagen is improved in the DN hydrogels. These DN gels possess anisotropic swelling behavior, exhibit excellent mechanical properties comparable to natural cartilage. The 4 weeks implantation of the gels in the osteochondral defect of rabbit knee also shows excellent biomechanical performance in vivo. Furthermore, the hydroxyapatite (HAp) coated DN gels, HAp/SBC/PDMAAm gels, strongly bond to bone after 4 weeks. This new class of collagen-based hybrid DN gels, as soft and elastic ceramics, having good biomechanical performance and strong bonding ability with bone would expand the choice for designing next generation orthopedic implants such as artificial cartilage, bone defect repair material in the load bearing region of the body. (C) 2017 Elsevier Ltd. All rights reserved.

Energy-Dissipative Matrices Enable Synergistic Toughening in Fiber Reinforced Soft Composites
Yiwan Huang, Daniel R. King, Tao Lin Sun, Takayuki Nonoyama, Takayuki Kurokawa, Tasuku Nakajima, Jian Ping Gong
ADVANCED FUNCTIONAL MATERIALS, 27, 9, 1605350, WILEY-V C H VERLAG GMBH, 2017年03月, ［査読有り］
英語, 研究論文（学術雑誌）, Tough hydrogels have shown strong potential as structural biomaterials. These hydrogels alone, however, possess limited mechanical properties (such as low modulus) when compared to some load-bearing tissues, e.g., ligaments and tendons. Developing both strong and tough soft materials is still a challenge. To overcome this obstacle, a new material design strategy has been recently introduced by combining tough hydrogels with woven fiber fabric to create fiber reinforced soft composites (FRSCs). The new FRSCs exhibit extremely high toughness and tensile properties, far superior to those of the neat components, indicating a synergistic effect. Here, focus is on understanding the role of energy dissipation of the soft matrix in the synergistic toughening of FRSCs. By selecting a range of soft matrix materials, from tough hydrogels to weak hydrogels and even a commercially available elastomer, the toughness of the matrix is determined to play a critical role in achieving extremely tough FRSCs. This work provides a good guide toward the universal design of soft composites with extraordinary fracture resistance capacity.

Double Networkゲルをマトリックスとした骨組織類似構造の創製　　　　　　　　　　　　　　　
深尾 一城, 野々山 貴行, 黒川 孝幸, 中島 祐, きょう 剣萍
日本バイオマテリアル学会大会予稿集, シンポジウム2016, 237, 237, 日本バイオマテリアル学会, 2016年11月
日本語

Hydroxyapatite-coated double network hydrogel directly bondable to the bone: Biological and biomechanical evaluations of the bonding property in an osteochondral defect
Susumu Wada, Nobuto Kitamura, Takayuki Nonoyama, Ryuji Kiyama, Takayuki Kurokawa, Jian Ping Gong, Kazunori Yasuda
ACTA BIOMATERIALIA, 44, 125, 134, ELSEVIER SCI LTD, 2016年10月, ［査読有り］
英語, 研究論文（学術雑誌）, We have developed a novel hydroxyapatite (HAp)-coated double-network (DN) hydrogel (HAp/DN gel). The purpose of this study was to determine details of the cell and tissue responses around the implanted HAp/DN gel and to determine how quickly and strongly the HAp/DN gel bonds to the bone in a rabbit osteochondral defect model. Immature osteoid tissue was formed in the space between the HAp/DN gel and the bone at 2 weeks, and the osteoid tissue was mineralized at 4 weeks. The push-out load of the HAp/DN gel averaged 37.54 N and 42.15 N at 4 and 12 weeks, respectively, while the push-out load of the DN gel averaged less than 5 N. The bonding area of the HAp/DN gel to the bone was above 80% by 4 weeks, and above 90% at 12 weeks. This study demonstrated that the HAp/DN gel enhanced osseointegration at an early stage after implantation. The presence of nanoscale structures in addition to osseointegration of HAp promoted osteoblast adhesion onto the surface of the HAp/DN gel. The HAp/DN gel has the potential to improve the implant-tissue interface in next-generation orthopaedic implants such as artificial cartilage.
Statement of Significance
Recent studies have reported the development of various hydrogels that are sufficiently tough for application as soft supporting tissues. However, fixation of hydrogels on bone surfaces with appropriate strength is a great challenge. We have developed a novel, tough hydrogel hybridizing hydroxyapatite (HAp/DN gel), which is directly bondable to the bone. The present study demonstrated that the HAp/DN gel enhanced osseointegration in the early stage after implantation. The presence of nanoscale structures in addition to the osseointegration ability of hydroxyapatite promoted osteoblast adhesion onto the surface of the HAp/DN gel. The HAp/DN gel has the potential to improve the implant-tissue interface in next-generation orthopaedic implants such as artificial cartilage. (C) 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Fundamental biomaterial properties of tough glycosaminoglycan-containing double network hydrogels newly developed using the molecular stent method
Kotaro Higa, Nobuto Kitamura, Takayuki Kurokawa, Keiko Goto, Susumu Wada, Takayuki Nonoyama, Fuminori Kanaya, Kazuyuki Sugahara, Jian Ping Gong, Kazunori Yasuda
ACTA BIOMATERIALIA, 43, 38, 49, ELSEVIER SCI LTD, 2016年10月, ［査読有り］
英語, 研究論文（学術雑誌）, The purpose of this study was to clarify fundamental mechanical properties and biological responses of the sodium hyaluronate-containing double network (HA-DN) gel and chondroitin sulfate-containing double network (CS-DN) gel, which were newly developed using the molecular stent method. This study discovered the following facts. First, these hydrogels had high mechanical performance comparable to the native cartilage tissue, and the mechanical properties were not affected by immersion in the saline solution for 12 weeks. Secondly, the mechanical properties of the CS-DN gel were not significantly reduced at 12 weeks in vivo, while the mechanical properties of the HA-DN gel were significantly deteriorated at 6 weeks. Thirdly, the degree of inflammation around the HA-DN gel was the same as that around the negative control. The CS-DN gel showed a mild but significant foreign body reaction, which was significantly greater than the negative control and less than the positive control at 1 week, while the inflammation was reduced to the same level as the negative control at 4 and 6 weeks. Fourthly, these gels induced differentiation of the ATDC5 cells into chondrocytes in the culture with the insulin free maintenance medium. These findings suggest that these tough hydrogels are potential biomaterials for future application to therapeutic implants such as artificial cartilage.
Statement of Significance
The present study reported fundamental biomaterial properties of the sodium hyaluronate-containing double network (HA-DN) gel and chondroitin sulfate-containing double network (CS-DN) gel, which were newly developed using the molecular stent method. Both the HA- and CS-DN gels had high mechanical properties comparable to the cartilage tissue and showed the ability to induce chondrogenic differentiation of ATDC5 cells in vitro. They are potential biomaterials that may meet the requirements of artificial cartilage concerning the material properties. Further, these DN gels can be also applied to the implantable inducer for cell-free cartilage regeneration therapy. (C) 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

ハイドロキシアパタイト複合化PAMPS/PDMAAmダブルネットワークゲル人工軟骨の関節内におけるin vivo骨接着性評価
和田 進, 北村 信人, 野々山 貴行, 木山 竜二, 仙葉 愼吾, 小野寺 純, 横田 正司, 後藤 佳子, 比嘉 浩太郎, 黒川 孝幸, Gong Jian Ping, 安田 和則
日本整形外科学会雑誌, 90, 8, S1598, S1598, (公社)日本整形外科学会, 2016年08月
日本語

Creep Behavior and Delayed Fracture of Tough Polyampholyte Hydrogels by Tensile Test
Sadia Nazneen Karobi, Tao Lin Sun, Takayuki Kurokawa, Feng Luo, Tasuku Nakajima, Takayuki Nonoyama, Jian Ping Gong
MACROMOLECULES, 49, 15, 5630, 5636, AMER CHEMICAL SOC, 2016年08月, ［査読有り］
英語, 研究論文（学術雑誌）, Polyampholyte (PA) hydrogels are a new class of tough and selfhealing supramolecular hydrogels that have a potential as load-bearing soft materials. Studying on the creep behavior of these hydrogels and understanding the molecular mechanism are important for prediction of lifetime of the materials. In the present work, we study the creep rupture dynamics of the PA hydrogels with and without chemical cross-linking, in a certain observation time window. We have found that above some critical loading stress both physical and lightly chemically cross-linked hydrogels undergo creep rupture while moderately chemically cross-linked hydrogel resists creep flow. To elucidate the molecular mechanism, we have further compared the creep behaviors of the physical and lightly chemically cross-linked samples. The creep rate of the samples decreases with the creep time, following a power law relation, regardless of the loading stress variation. The fracture time of both of these hydrogels exponentially decreases with the increase of the loading stress, following the same master curve at high loading stress region, while the behavior of the two samples becomes different in the low loading stress region. We have explained the delayed fracture dynamics at high loading stress region in terms of a relatively weak strong bond rupture mechanism.

Double-Network Hydrogels Strongly Bondable to Bones by Spontaneous Osteogenesis Penetration
Takayuki Nonoyama, Susumu Wada, Ryuji Kiyama, Nobuto Kitamura, Md. Tariful Islam Mredha, Xi Zhang, Takayuki Kurokawa, Tasuku Nakajima, Yasuaki Takagi, Kazunori Yasuda, Jian Ping Gong
ADVANCED MATERIALS, 28, 31, 6740, +, WILEY-V C H VERLAG GMBH, 2016年08月, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌）, On implanting hydroxyapatite-mineralized tough hydrogel into osteochondral defects of rabbits, osteogenesis spontaneously penetrates into the gel matrix owing to the semi-permeablility of the hydrogel. The gradient layer (around 40 mu m thick) contributes quite strong bonding of the gel to bone. This is the first success in realizing the robust osteointegration of tough hydrogels, and the method is simple and feasible for practical use.

Molecular Structure and Properties of Click Hydrogels with Controlled Dangling End Defect
Ao-kai Zhang, Jun Ling, Kewen Li, Guo-dong Fu, Tasuku Nakajima, Takayuki Nonoyama, Takayuki Kurokawa, Jian Ping Gong
JOURNAL OF POLYMER SCIENCE PART B-POLYMER PHYSICS, 54, 13, 1227, 1236, WILEY-BLACKWELL, 2016年07月, ［査読有り］
英語, 研究論文（学術雑誌）, In this study, controlled amount of dangling ends is introduced to the two series of poly(ethylene glycol)-based hydrogel networks with three and four crosslinking functionality by using click chemistry. The structure of the gels with regulated defect percentage is confirmed by comparing the results of low-field NMR characterization and Monte Carlo simulation. The mechanical properties of these gels were characterized by tensile stress-strain behaviors of the gels, and the results are analyzed by Gent model and Mooney-Rivlin model. The shear modulus of the swollen gels is found to be dependent on the functionality of the network, and decreases with the defect percentage. Furthermore, the value of shear modulus well obeys the Phantom model for all the gels with varied percentage of the defects. The maximum extension ratio, obtained from the fitting of Gent model, is also found to be dependent on the functionality of the network, and does not change with the defect percentage, except at very high defect percentage. The value of the maximum extension ratio is between that predicted from Phantom model and the Affine model. This indicates that at the large deformation, the fluctuation of the crosslinking points is suppressed for some extend but still exists. Polymer volume fractions at various defect percentages obtained from prediction of Flory-Rehner model are found to be in well agreement with the swelling experiment. All these results indicate that click chemistry is a powerful method to regulate the network structure and mechanical properties of the gels. (C) 2016 Wiley Periodicals, Inc.

Self-Healing Behaviors of Tough Polyampholyte Hydrogels
Abu Bin Ihsan, Tao Lin Sun, Takayuki Kurokawa, Sadia Nazneen Karobi, Tasuku Nakajima, Takayuki Nonoyama, Chanchal Kumar Roy, Feng Luo, Jian Ping Gong
MACROMOLECULES, 49, 11, 4245, 4252, AMER CHEMICAL SOC, 2016年06月, ［査読有り］
英語, 研究論文（学術雑誌）, Recently, polyampolytes have been discovered to form hydrogels that possess high toughness, full resilience, and self-healing between two cut surfaces. The self-healing of this class of hydrogels is based on the re-forming of the multiple Tonic bonds at the fractured surfaces, in which the mobility of the polymer segments and strength of the ionic bonds play an important role. In this work, we study the effects of healing temperature and chemistry of the polyampholyte hydrogels (chemical cross -linker density and chemical structure of the monomers) on the healing kinetics and healing efficiency. The high healing temperature substantially accelerates the self-healing kinetics. Chemical cross-linking reduces the self-healing efficiency. Monomers with more hydrophobic feature give a low self-healing efficiency. For polyampholyte physical hydrogels with a softening temperature below the room temperature, excellent-healing efficiency (similar to 84% on average and maximum 99%) was observed without any external stimuli.- We found a correlation between the self-healing efficiency and the fraction of dynamic bonds in the total bonds for relatively soft samples, which is an evidence that the self healing is due to the re-forming of dynamic bonds.

Tough Physical Double-Network Hydrogels Based on Amphiphilic Triblock Copolymers
Hui Jie Zhang, Tao Lin Sun, Ao Kai Zhang, Yumihiko Ikura, Tasuku Nakajima, Takayuki Nonoyama, Takayuki Kurokawa, Osamu Ito, Hiroyuki Ishitobi, Jian Ping Gong
ADVANCED MATERIALS, 28, 24, 4884, 4890, WILEY-V C H VERLAG GMBH, 2016年06月, ［査読有り］
英語, 研究論文（学術雑誌）, A series of physical double-network hydrogels is synthesized based on an amphiphilic triblock copolymer. The gel, which contains strong hydrophobic domains and sacrificial dynamic bonds of hydrogen bonds, is stiff and tough, and even stiffens in concentrated saline solution. Furthermore, due to its supramolecular structure, the gel features improved self-healing and self-recovery abilities.

Quantitative Observation of Electric Potential Distribution of Brittle Polyelectrolyte Hydrogels Using Microelectrode Technique
Honglei Guo, Takayuki Kurokawa, Masakazu Takahata, Wei Hong, Yoshinori Katsuyama, Feng Luo, Jamil Ahmed, Tasuku Nakajima, Takayuki Nonoyama, Jian Ping Gong
MACROMOLECULES, 49, 8, 3100, 3108, AMER CHEMICAL SOC, 2016年04月, ［査読有り］
英語, 研究論文（学術雑誌）, We report, for the first time, the quantitative measurement of the local electric potential of brittle polyelectrolyte hydrogels using the microelectrode technique (MET). Given the solid-like nature of the hydrogels, the difficulty of applying MET is how to make a good contact of the microelectrode to the hydrogel. Poor local contact substantial underestimates the potential. We observed that, the potential measured decays exponentially with the increase of capillary diameter of the microelectrode. This behavior is related to the capillary wall thickness that determines the contact distance of the electrode probe to the hydrogel. The characteristic decay length in respective to the wall thickness is very close to the local Debye length around the capillary. The latter is much larger than that of the bath solution due to the reverse osmosis effect. By using microelectrodes with a tip wall thickness less than the local Debye length, the Donnan potential of polyelectrolyte gel could be accurately measured. Using a micromanipulator, the inserting process of the microelectrode is precisely controlled, and the depth profile of electric potential in the hydrogels can be measured with a spatial resolution down to similar to 5 nm. From the spatial distribution of potential, the microstructure of hydrogels both in bulk and near the surface, the thickness of ultrathin hydrogels, and the heterogeneous layered structure of composite gels, can be determined accurately. The MET established in this work provides a powerful tool for direct characterization of the spatial distribution of electric potential of hydrogels.

二分子膜を有するゲルの構造転移と機能改変
水戸 京, 中島 祐, 野々山 貴行, 龔 剣萍
高分子論文集, 73, 2, 157, 165, 公益社団法人 高分子学会, 2016年, ［査読有り］
日本語, 研究論文（学術雑誌）, 脂質分子は，水中でラメラ構造やひも状ミセルのようなさまざまな異方的自己集合体を形成する．近年筆者らは，脂質分子の二分子膜を一軸配向させてゲル中に固定し，マクロスケールで異方的な構造および物性を有するヒドロゲルの合成に成功した．本ゲルは，重合性界面活性剤ポリドデシルイタコン酸グリセリル(PDGI)による二分子膜の膜間にポリアクリルアミド(PAAm)ゲルのマトリックスを有しており，異方的な膜構造に由来する膨潤，力学物性，物質拡散などの異方性を示す．ところで，微妙な外部環境の変化で容易に不安定になる自然界の二分子膜を考えると，なぜ，二分子膜はPAAmゲル内に安定なラメラ構造を形成できるのか，というのは興味深い問題である．本報ではゲル内の二分子膜の構造に焦点を当て，その膜構造形成メカニズム，安定化メカニズム，二分子膜への脂質分子の挿入による膜の構造改変などについて系統的に述べる．

Stretching-induced ion complexation in physical polyampholyte hydrogels
Kunpeng Cui, Tao Lin Sun, Takayuki Kurokawa, Tasuku Nakajima, Takayuki Nonoyama, Liang Chen, Jian Ping Gong
SOFT MATTER, 12, 43, 8833, 8840, ROYAL SOC CHEMISTRY, 2016年, ［査読有り］
英語, 研究論文（学術雑誌）, Recently, we have developed a series of charge balanced polyampholyte (PA) physical hydrogels by random copolymerization in water, which show extraordinarily high toughness, self-healing ability and viscoelasticity. The excellent performance of PA hydrogels is ascribed to dynamic ionic bond formation through inter-and intra-chain interactions. The randomness results in ionic bonds of wide strength distribution, the strong bonds, which serve as permanent crosslinking, imparting the elasticity, while the weak bonds reversibly break and re-form, dissipating energy. In this work, we developed a simple physical method, called a pre-stretching method, to promote the performance of PA hydrogels. By imposing a pre-stretching on the sample in the as-prepared state, ion complexation during dialysis is prominently accelerated and the final performance is largely promoted. Further analysis suggests that the strong bond formation induced by pre-stretching is responsible for the change in final performance. Pre-stretching decreases the entropy of the system and increases the chain alignment, resulting in an increased possibility for strong bond formation.

Coupled instabilities of surface crease and bulk bending during fast free swelling of hydrogels
Riku Takahashi, Yumihiko Ikura, Daniel R. King, Takayuki Nonoyama, Tasuku Nakajima, Takayuki Kurokawa, Hirotoshi Kuroda, Yoshihiro Tonegawa, Jian Ping Gong
SOFT MATTER, 12, 23, 5081, 5088, ROYAL SOC CHEMISTRY, 2016年, ［査読有り］
英語, 研究論文（学術雑誌）, Most studies on hydrogel swelling instability have been focused on a constrained boundary condition. In this paper, we studied the mechanical instability of a piece of disc-shaped hydrogel during free swelling. The fast swelling of the gel induces two swelling mismatches; a surface-inner layer mismatch and an annulus-disc mismatch, which lead to the formation of a surface crease pattern and a saddle-like bulk bending, respectively. For the first time, a stripe-like surface crease that is at a right angle on the two surfaces of the gel was observed. This stripe pattern is related to the mechanical coupling of surface instability and bulk bending, which is justified by investigating the swelling-induced surface pattern on thin hydrogel sheets fixed onto a saddle-shaped substrate prior to swelling. A theoretical mechanism based on an energy model was developed to show an anisotropic stripe-like surface crease pattern on a saddle-shaped surface. These results might be helpful to develop novel strategies for controlling crease patterns on soft and wet materials by changing their three-dimensional shape.

Double-network hydrogel and its potential biomedical application: A review
Takayuki Nonoyama, Jian Ping Gong
PROCEEDINGS OF THE INSTITUTION OF MECHANICAL ENGINEERS PART H-JOURNAL OF ENGINEERING IN MEDICINE, 229, 12, 853, 863, SAGE PUBLICATIONS LTD, 2015年12月, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌）, Double-network hydrogels are one of the most promising candidates as artificial soft supporting tissues owing to their excellent mechanical performance, water storage capability, and biocompatibility. A double-network hydrogel consists of two contrasting polymer networks: rigid and brittle first network and soft and ductile second network. To satisfy this double-network requirement, polyelectrolyte and neutral polymer are suitable as the first and the second networks, respectively. Combination of these two networks gives rise to extraordinarily tough double-network hydrogel as a result of substantial internal fracture of the brittle first network at large deformation, which contributes to the energy dissipation. Therefore, the first network serves as the sacrificial bonds to toughen the material. The double-network principle is universal and many kinds of double-network hydrogels composed of various chemical species have been developed. Moreover, a molecular stent technology has been developed to synthesize the double-network hydrogels using neutral polymer network as the brittle first network. The sulfonic double-network hydrogel was found to induce spontaneous hyaline cartilage regeneration in vivo.

Self-Adjustable Adhesion of Polyampholyte Hydrogels
Chanchal Kumar Roy, Hong Lei Guo, Tao Lin Sun, Abu Bin Ihsan, Takayuki Kurokawa, Masakazu Takahata, Takayuki Nonoyama, Tasuku Nakajima, Jian Ping Gong
ADVANCED MATERIALS, 27, 45, 7344, +, WILEY-V C H VERLAG GMBH, 2015年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Developing nonspecific, fast, and strong adhesives that can glue hydrogels and biotissues substantially promotes the application of hydrogels as biomaterials. Inspired by the ubiquitous adhesiveness of bacteria, it is reported that neutral polyampholyte hydrogels, through their self-adjustable surface, can show rapid, strong, and reversible adhesion to charged hydrogels and biological tissues through the Coulombic interaction.

Extremely tough composites from fabric reinforced polyampholyte hydrogels
Daniel R. King, Tao Lin Sun, Yiwan Huang, Takayuki Kurokawa, Takayuki Nonoyama, Alfred J. Crosby, Jian Ping Gong
MATERIALS HORIZONS, 2, 6, 584, 591, ROYAL SOC CHEMISTRY, 2015年11月, ［査読有り］
英語, 研究論文（学術雑誌）, Ligaments are unique wet biological tissues with high tensile modulus and fracture stress, combined with high bending flexibility. Developing synthetic materials with these properties is a significant challenge. Hydrogel composites made from high stiffness fabrics is a strategy to develop such unique materials; however, the ability to produce these materials has proven difficult, since common hydrogels swell in water and interact poorly with solid components, limiting the transfer of force from the fabric to the hydrogel matrix. In this work, for the first time, we successfully produce extraordinarily tough hydrogel composites by strategically selecting a recently developed tough hydrogel that de-swells in water. The new composites, consisting of polyampholyte hydrogels and glass fiber woven fabrics, exhibit extremely high effective toughness (250 000 J m(-2)), high tear strength (similar to 65 N mm(-1)), high tensile modulus (606 MPa), and low bending modulus (4.7 MPa). Even though these composites are composed of water-containing, biocompatible materials, their mechanical properties are comparable to high toughness Kevlar/polyurethane blends and fiber-reinforced polymers. Importantly, the mechanical properties of these composites greatly outperform the properties of either individual component. A mechanism is proposed based on established fabric tearing theory, which will enable the development of a new generation of mechanically robust composites based on fabrics. These results will be important towards developing soft biological prosthetics, and more generally for commercial applications such as tear-resistant gloves and bulletproof vests.

Phase-Separation-Induced Anomalous Stiffening, Toughening, and Self-Healing of Polyacrylamide Gels
Koshiro Sato, Tasuku Nakajima, Toshiyuki Hisamatsu, Takayuki Nonoyama, Takayuki Kurokawa, Jian Ping Gong
ADVANCED MATERIALS, 27, 43, 6990, +, WILEY-V C H VERLAG GMBH, 2015年11月, ［査読有り］
英語, 研究論文（学術雑誌）, Novel, tough, strong, and self-healable polyacrylamide (PAAm) gels are fabricated by inducing an appropriate phase-separation structure using a poor solvent. The phase separation induces a gel-glass-like transition of the PAAm gels, providing the gels an anomalously high modulus (211 MPa), fracture stress (7.13 MPa), and fracture energy (4.16 x 10(4) J m(-2)), while keeping a high solvent content (approximate to 60 vol%).

バイオミネラリゼーションにより複合化したハイドロキシアパタイトコーティングPAMPS/PDMAAmダブルネットワークゲルの骨接着性の評価
和田 進, 北村 信人, 野々山 貴行, 木山 竜二, 仙葉 愼吾, 比嘉 浩太郎, 黒川 孝幸, Gong Jian Ping, 安田 和則
日本整形外科学会雑誌, 89, 8, S1585, S1585, (公社)日本整形外科学会, 2015年09月
日本語

Friction of Zwitterionic Hydrogel by Dynamic Polymer Adsorption
Jamil Ahmed, Tetsurou Yamamoto, Honglei Guo, Takayuki Kurokawa, Takayuki Nonoyama, Tasuku Nakajima, Jian Ping Gong
MACROMOLECULES, 48, 15, 5394, 5401, AMER CHEMICAL SOC, 2015年08月, ［査読有り］
英語, 研究論文（学術雑誌）, A simplified model describing the sliding friction of hydrogel on solid surface by dynamic adsorption of the polymer chains is proposed on the basis of polymer adsorption-repulsion theory. This dynamic adsorption model is used to analyze the friction results of zwitterionic hydrogels sliding over glass substrates with different substrate wettability, hydrogel swelling degree, ionic strength, and pH of bath solution. The adsorption time tau(b) of polymer strands is found to decrease with the increase in sliding velocity or the Weissenberg number as a result of stretching. The adsorption time tau(0)(b), and the adsorption energy U-ads at stress-free condition, which are characteristic for each friction system, are also estimated. Roughly, a master curve is observed for the normalized adsorption lifetime tau(b)/tau(0)(b) and the Weissenberg number, with less dependence on the adsorption energy and the bulk properties of the gels in the observed experimental conditions. Thus, the dynamic adsorption model successfully correlates the frictional behavior of hydrogels with the adsorption dynamics of polymer strands, which gives insight into the molecular design of hydrogels with predefined frictional properties for biomedical applications.

Swim bladder collagen forms hydrogel with macroscopic superstructure by diffusion induced fast gelation
Md. Tariful Islam Mredha, Xi Zhang, Takayuki Nonoyama, Tasuku Nakajima, Takayuki Kurokawa, Yasuaki Takagid, Jian Ping Gong
JOURNAL OF MATERIALS CHEMISTRY B, 3, 39, 7658, 7666, ROYAL SOC CHEMISTRY, 2015年, ［査読有り］
英語, 研究論文（学術雑誌）, Marine collagen has been attracting attention as a medical material in recent times due to the low risk of pathogen infection compared to animal collagen. Type I collagen extracted from the swim bladder of Bester sturgeon fish has excellent characteristics such as high denaturation temperature, high solubility, low viscosity and an extremely fast rate to form large bundle of fibers under certain conditions. These specific characteristics of swim bladder collagen (SBC) permit us to create stable, disk shaped hydrogels with concentric orientation of collagen fibers by the controlled diffusion of neutral buffer through collagen solution at room temperature. However, traditionally used animal collagens, e.g. calf skin collagen (CSC) and porcine skin collagen (PSC), could not form any stable and oriented structure by this method. The mechanism of the superstructure formation of SBC by a diffusion induced gelation process has been explored. The fast fibrillogenesis rate of SBC causes a quick squeezing out of the solvent from the gel phase to the sol phase during gelation, which builds an internal stress at the gel-sol interface. The tensile stress induces the collagen molecules of the gel phase to align along the gel-sol interface direction to give this concentric ring-shaped orientation pattern. On the other hand, the slow fibrillogenesis rate of animal collagens due to the high viscosity of the solution does not favor the ordered structure formation. The denaturation temperature of SBC increases significantly from 31 degrees C to 43 degrees C after gelation, whereas that of CSC and PSC were found to increase a little. Rheology experiment shows that the SBC gel has storage modulus larger than 15 kPa. The SBC hydrogels with thermal and mechanical stability have potential as bio-materials for tissue engineering applications.

Control superstructure of rigid polyelectrolytes in oppositely charged hydrogels via programmed internal stress
Riku Takahashi, Zi Liang Wu, Md Arifuzzaman, Takayuki Nonoyama, Tasuku Nakajima, Takayuki Kurokawa, Jian Ping Gong
NATURE COMMUNICATIONS, 5, 4490, NATURE PUBLISHING GROUP, 2014年08月, ［査読有り］
英語, 研究論文（学術雑誌）, Biomacromolecules usually form complex superstructures in natural biotissues, such as different alignments of collagen fibres in articular cartilages, for multifunctionalities. Inspired by nature, there are efforts towards developing multiscale ordered structures in hydrogels (recognized as one of the best candidates of soft biotissues). However, creating complex superstructures in gels are hardly realized because of the absence of effective approaches to control the localized molecular orientation. Here we introduce a method to create various superstructures of rigid polyanions in polycationic hydrogels. The control of localized orientation of rigid molecules, which are sensitive to the internal stress field of the gel, is achieved by tuning the swelling mismatch between masked and unmasked regions of the photolithographic patterned gel. Furthermore, we develop a double network structure to toughen the hydrogels with programmed superstructures, which deform reversibly under large strain. This work presents a promising pathway to develop superstructures in hydrogels and should shed light on designing biomimetic materials with intricate molecular alignments.

Mechano-actuated ultrafast full-colour switching in layered photonic hydrogels
Youfeng Yue, Takayuki Kurokawa, Md Anamul Haque, Tasuku Nakajima, Takayuki Nonoyama, Xufeng Li, Itsuro Kajiwara, Jian Ping Gong
NATURE COMMUNICATIONS, 5, 4659, NATURE PUBLISHING GROUP, 2014年08月, ［査読有り］
英語, 研究論文（学術雑誌）, Photonic crystals with tunability in the visible region are of great interest for controlling light diffraction. Mechanochromic photonic materials are periodically structured soft materials designed with a photonic stop-band that can be tuned by mechanical forces to reflect specific colours. Soft photonic materials with broad colour tunability and fast colour switching are invaluable for application. Here we report a novel mechano-actuated, soft photonic hydrogel that has an ultrafast-response time, full-colour tunable range, high spatial resolution and can be actuated by a very small compressive stress. In addition, the material has excellent mechanical stability and the colour can be reversibly switched at high frequency more than 10,000 times without degradation. This material can be used in optical devices, such as full-colour display and sensors to visualize the time evolution of complicated stress/strain fields, for example, generated during the motion of biological cells.

Double network hydrogels from polyzwitterions: high mechanical strength and excellent anti-biofouling properties
Haiyan Yin, Taigo Akasaki, Tao Lin Sun, Tasuku Nakajima, Takayuki Kurokawa, Takayuki Nonoyama, Toshio Taira, Yoshiyuki Saruwatari, Jian Ping Gong
JOURNAL OF MATERIALS CHEMISTRY B, 1, 30, 3685, 3693, ROYAL SOC CHEMISTRY, 2013年, ［査読有り］
英語, 研究論文（学術雑誌）, Polyzwitterionic materials, which have both cationic and anionic groups in the polymeric repeat unit, show excellent anti-biofouling properties and are drawing more attention in the biomedical field. In this study, we have successfully synthesized novel single network hydrogels and double network (DN) hydrogels from the zwitterionic monomer, N-(carboxymethyl)-N,N-dimethyl-2-(methacryloyloxy) ethanaminium, inner salt (CDME). The polyCDME (PCDME) single network hydrogel behaves like a hydrophilic neutral hydrogel and its properties are not sensitive to temperature, pH, or ionic strength over a wide range. DN hydrogels using the poly(2-acrylamido-2-methylpropanesulfonic) (PAMPS) as the first network and PCDME as the second network, having a Young's modulus of 0.2-0.9 MPa, possess excellent mechanical strength (fracture stress: 1.2-1.4 MPa, fracture strain: 2.2-6.0 mm/mm) and toughness (work of extension at fracture: 0.9-2.4 MJ m(-3)) depending on the composition ratio of PCDME to PAMPS. The strength and toughness of the optimized PAMPS/PCDME DN is comparable to the normal PAMPS/PAAm DN hydrogels that use poly(acrylamide) (PAAm) as the second network. By macrophage adhesion test, both the PCDME hydrogels and the PAMPS/PCDME DN hydrogels have shown excellent anti-biofouling properties. These results demonstrate that the PCDME-based DN hydrogels have high potential as a novel soft and wet biomaterial.

Arrangement techniques of proteins and cells using amorphous calcium phosphate nanofiber scaffolds
Takayuki Nonoyama, Takatoshi Kinoshita, Masahiro Higuchi, Kenji Nagata, Masayoshi Tanaka, Mari Kamada, Kimiyasu Sato, Katsuya Kato
APPLIED SURFACE SCIENCE, 262, 8, 12, ELSEVIER SCIENCE BV, 2012年12月, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌）, We demonstrate arrangement techniques of proteins and cells using an amorphous calcium phosphate (ACP) nanofiber scaffold. It is well known that protein andosteoblastic cell are preferably adsorbed onto ACP surface. The ACP nanofiber scaffold was prepared by calcium phosphate mineralization on a polypeptide monolayer-coated mica substrate, and ACP nanofibers were oriented unidirectionaly. In a protein system, the ACP nanofiber scaffold was soaked in a fluorescein isothiocyanate conjugated immunoglobulin G (IgG-FITC) aqueous solution. From fluorescence microscopic measurement, the adsorbed IgG-FITC was highly confined and arranged on the ACP nanofiber. In a cell system, a mouse osteoblast-like cell (MC3T3-E1) behavior on the ACP nanofiber scaffold was observed. The cell was elongated unidirectionaly, and its cytoskeletal shape showed high aspect ratio. These results are clearly different from an ACP bulk template or bare mica substrate, and the arrangement technique enable to fabricate a fine-tuned biomaterial template. Crown Copyright (c) 2011 Published by Elsevier B.V. All rights reserved.

Structural Formation Ability of Peptide Secondary Structure on Silica Biomineralization
Tatsuya Kuno, Takayuki Nonoyama, Kiyoshi Hirao, Katsuya Kato
CHEMISTRY LETTERS, 41, 11, 1547, 1549, CHEMICAL SOC JAPAN, 2012年11月, ［査読有り］
英語, 研究論文（学術雑誌）, To investigate the influence of the secondary structure of peptide on silica biomineralization, alpha-helix and beta-sheet conformational peptides were synthesized and applied as catalyst in silica biomineralization.

TiO2 Synthesis Inspired by Biomineralization: Control of Morphology, Crystal Phase, and Light-Use Efficiency in a Single Process
Takayuki Nonoyama, Takatoshi Kinoshita, Masahiro Higuchi, Kenji Nagata, Masayoshi Tanaka, Kimiyasu Sato, Katsuya Kato
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 134, 21, 8841, 8847, AMER CHEMICAL SOC, 2012年05月, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌）, Hydroxyapatite is mineralized along the long axis of collagen fiber during osteogenesis. Mimicking such biomineralization has great potential to control inorganic structures and is fast becoming an important next-generation inorganic synthesis method. Inorganic matter synthesized by biomineralization can have beautiful and functional structures that cannot be created artificially. In this study, we applied biomineralization to the synthesis of the only photocatalyst in practical use today, titanium dioxide (TiO2). The photocatalytic activity of TiO2 mainly relates to three properties: morphology, crystal phase, and light-use efficiency. To optimize TiO2 morphology, we used a simple sequential peptide as an organic template. TiO2 mineralized by a beta-sheet peptide nanofiber template forms fiber-like shapes that are not observed for mineralization by peptides in the shape of random coils. To optimize TiO2 crystal phase, we mineralized TiO2 with the template at 400 degrees C to transform it into the rutile phase and at 700 degrees C to transform it into a mixed phase of anatase and rutile. To optimize light-use efficiency, we introduced nitrogen atoms of the peptide into the TiO2 structure as doped elemental material during sintering. Thus, this biomineralization method enables control of inorganic morphology, crystal phase, and light-use efficiency in a single process.

Enzyme structure and catalytic properties affected by the surface functional groups of mesoporous silica
Kazuki Murai, Takayuki Nonoyama, Takao Saito, Katsuya Kato
CATALYSIS SCIENCE & TECHNOLOGY, 2, 2, 310, 315, ROYAL SOC CHEMISTRY, 2012年, ［査読有り］
英語, 研究論文（学術雑誌）, The enzyme subtilisin from Bacillus licheniformis (4.1 nm x 7.8 nm x 3.7 nm) was easily immobilized onto a mesoporous silica (MPS) surface by a direct one-step method and the amount of subtilisin immobilized on each functionalized MPS surface was similar (approximately 0.30 mg of enzyme/ mg of MPS support). The catalytic performance (hydrolytic activity and enantioselectivity) of the immobilized subtilisin was found to depend on the properties of the organofunctional group on the MPS surface. In particular, the hydrolytic activity of enzyme immobilized on ethyl-group-modified MPS increased relative to the behavior of free subtilisin (relative activity 143%). The activity of subtilisin immobilized on the modified MPS was improved by facilitation of contact between enzyme and hydrophobic substrate by increase in hydrophobicity with an immobilized carrier. On the other hand, the enantioselectivity of subtilisin immobilized on 3-mercaptopropyl-group-modified MPS significantly decreased (enantioselectivity of 2.6 compared to 4.3 for free subtilisin). This decrease in enantioselectivity indicated that the mercapto group on the MPS surface was changed in the secondary structure of enzyme by interacting between enzyme and immobilized support. The denaturation temperature of subtilisin immobilized on no-substituted MPS increased (65 degrees C compared with 57 degrees C for free subtilisin). The denaturation temperature of immobilized subtilisin was dependent on the absorbed fraction of thermal energy by functional groups on the MPS surface.

Calcium phosphate biomineralization in peptide hydrogels for injectable bone-filling materials
Takayuki Nonoyama, Hokuto Ogasawara, Masayoshi Tanaka, Masahiro Higuchi, Takatoshi Kinoshita
SOFT MATTER, 8, 45, 11531, 11536, ROYAL SOC CHEMISTRY, 2012年, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌）, We performed amorphous calcium phosphate (ACP) and hydroxyapatite (HAp) mineralization in peptide hydrogels for the formation of a novel bone-filling material. We prepared two kinds of beta-sheet peptides, (LE)(8) and (VEVSVKVS)(2), respectively, using hydrophilic glutamic acid (E), serine (S) and lysine (K), and hydrophobic leucine (L) and valine (V). Both peptides hierarchically self-assembled as nanofibers and formed hydrogels in the presence of calcium ions. The formation of the hydrogel was due to the ionic cross-linkage between carboxyl groups in the glutamic acid side chains of the peptide nanofibers and the calcium ion. (LE)(8) formed a clear hydrogel above a calcium ion concentration of 4.0 x 10(-3) M and the hydrogel collapsed at 1.0 x 10(-2) M, owing to excess ionic cross-linkage. On the other hand, (VEVSVKVS)(2) containing two glutamic acid residues per molecule retained the hydrogel structure at a higher concentration of calcium ions in the hydrogel where the (LE)(8) hydrogel collapsed. The viscoelastic property of both peptide hydrogels was increased by increasing the calcium ion concentration, showing adequate strength as a bone-filling material. When phosphate ion was added into the (LE)(8) hydrogel containing calcium ion, ACP was mineralized along the peptide nanofiber in the hydrogel under neutral pH. The (VEVSVKVS)(2) hydrogel, on the other hand, produced HAp under basic pH. In addition, the peptide hydrogel smoothly recovered its original moduli just after the shear deformation of the hydrogel. It was also clarified that calcium ions are not only a source of mineralization but also induce an increase in the mechanical strength of the hydrogels as a reinforcing agent. It was shown, moreover, that the crystallinity of the HAp was slightly dependent on the modulus of the peptide hydrogels. Therefore, it may be said that peptide hydrogels are applicable for tailor-made injectable bone-filling materials.

Influence of the Charge Relay Effect on the Silanol Condensation Reaction as a Model for Silica Biomineralization
Tatsuya Kuno, Takayuki Nonoyama, Kiyoshi Hirao, Katsuya Kato
LANGMUIR, 27, 21, 13154, 13158, AMER CHEMICAL SOC, 2011年11月, ［査読有り］
英語, 研究論文（学術雑誌）, The catalytic effect of various sequential peptides for silica biomineralization has been studied. In peptide sequence design, lysine (K) and histidine (H) were selected as the standard amino acids and aspartic acid (D) was selected to promote the charge relay effects, such as in the enzyme active site. Therefore, homopolypeptides (K(10) and H(10)), block poly-peptides (K(5)D(5) and H(5)D(5)), and alternate polypeptides [ (KD)(5) and (HD)(5)] were designed, and the dehydration reaction ability of trimethylethoxysilane was investigated as a quantitative model of silica mineralization. The catalytic activity per basic residue of alternate polypeptide was the highest because of the charge relay effects at the surface of the peptide. In silica mineralization using tetraethoxysilane, spherical silica particles were obtained, and their size is related to the catalytic activities of the peptides in the model systems. From these results, the effect of the functional group combination by the peptide sequence design enables the control of the efficiency of mineralization and preparation of specific inorganic materials.

Ordered nanopattern arrangement of gold nanoparticles on β-sheet peptide templates through nucleobase pairing.
Nonoyama T, Tanaka M, Inai Y, Higuchi M, Kinoshita T
ACS nano, 5, 8, 6174, 6183, AMER CHEMICAL SOC, 2011年08月, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌）, We have demonstrated a unique method for rational arrangement of gold (Au) nanoparticles on a beta-sheet peptide template through nucleobase pairing. For the template, the 16-mer peptide 1 was synthesized, which is based on an alternating amphiphilic sequence of Asp-Leu. Here Leu at the sixth position Is replaced by thymine-modified Lys, and a polyethylene glycol chain is introduced to the C-terminus. The surface of Au nanoparticles was modified with, the complementary adenyl group. Peptide 1 formed a stable beta-sheet monolayer at the air/water interface Under an appropriate surface pressure. The monolayer film transferred onto a mica surface by the Langmuir-Blodgett method showed a linearly striped pattern with 6.1 nm average stripe width and 6 nm average interval between stripes, derived from beta-sheet assembly. The adenine-bound Au nanoparticles were successfully Immobilized on the thymine-bound template through a complementary adenine-thymine hydrogen bonding pair. Interestingly; linear, assembly. mixtures of. the Au nanoparticles were observed, thus being successfully reproduced by the original striped pattern of the template of 1. Our method might readily fabricate Au materials with our desirable 2D pattern through fine-tuning of beta-sheet sequence and nucleobase position.

Multistep Growth Mechanism of Calcium Phosphate in the Earliest Stage of Morphology-Controlled Biomineralization
Takayuki Nonoyama, Takatoshi Kinoshita, Masahiro Higuchi, Kenji Nagata, Masayoshi Tanaka, Kimiyasu Sato, Katsuya Kato
LANGMUIR, 27, 11, 7077, 7083, AMER CHEMICAL SOC, 2011年06月, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌）, We studied the effect of surface-functional-group position on precipitate morphology in the earliest stage of calcium phosphate biomineralization and determined the detailed mechanism of precipitation starting from nucleation to precipitate growth. The biomineralization template was a beta-sheet peptide scaffold prepared by adsorption with carboxyl groups arranged at strict 7 angstrom intervals. Phosphate was then introduced. Within 10 s, highly ordered embryos of calcium phosphate were formed and confined by a peptide nanofiber pattern. They repeatedly nucleated and dissolved, with the larger embryos absorbing the smaller ones in a clear demonstration of an Ostwald-ripening-like phenomenon, then aggregated in a line pattern, and finally formed highly ordered nanofibers of amorphous calcium phosphate. This multistep growth process constitutes the earliest stage of biomineralization.

Morphology control of calcium phosphate by mineralization on the beta-sheet peptide template
Takayuki Nonoyama, Masayoshi Tanaka, Takatoshi Kinoshita, Fukue Nagata, Kimiyasu Sato, Katsuya Kato
CHEMICAL COMMUNICATIONS, 46, 37, 6983, 6985, ROYAL SOC CHEMISTRY, 2010年10月, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌）, To investigate the influence of the spatial placement of the organic functional groups in mineralization, an amphiphilic peptide assembled monolayer with strictly arrayed carboxyl groups was applied to a mineralization system of calcium phosphate.

人工軟骨を目指した高強度ハイドロゲルーリン酸カルシウムの複合化および骨との接着
野々山貴行, 木山竜二, 深尾一城, 安田和則, 黒川孝幸, 龔剣萍, Ceramics Japan = セラミックス : bulletin of the Ceramic Society of Japan, 55, 3, 166, 170, 2020年03月, ［筆頭著者］
日本セラミックス協会, 日本語, 記事・総説・解説・論説等（学術雑誌）

骨軟骨欠損に対する骨髄穿刺濃縮細胞と高純度アルギン酸ゲル併用移植の検討
XU Liang, 瓜田淳, 小野寺智洋, 菱村亮介, 野々山貴行, 濱崎雅成, 宮崎拓自, LIANG Dawei, 宝満健太郎, GONG Jian Ping, 岩崎倫政, 日本軟骨代謝学会プログラム・抄録集, 33rd, 2020年

家兎半月板部分欠損モデルにおける高純度硬化性アルギン酸ゲル移植の半月板修復に与える効果
金佑泳, 小野寺智洋, 近藤英司, 野々山貴行, 馬場力哉, 上徳善太, 宝満健太郎, 菱村亮介, 岩崎倫政, 整形外科バイオマテリアル研究会プログラム・抄録集, 38th, 38, 2018年11月
日本語

高強度・高靭性ダブルネットワークゲルの開発とソフト人工軟骨への応用 (特集 生体適合性高分子材料の開発)
野々山 貴行, 龔 剣萍, 安田 和則, 機能材料, 38, 5, 51, 59, 2018年05月
シーエムシー出版, 日本語

異方性二層ハイブリッドゲル:作製および水誘起ゴム-ガラス転移
ILYAS Muhammad, HAQUE Md Anamul, YUE Youfeng, KUROKAWA Takayuki, NAKAJIMA Tasuku, NONOYAMA Takayuki, GONG Jian Ping, 高分子学会予稿集(CD-ROM), 67, 2, 2018年

骨形成に再利用される合成HAp系インプラントの同位体顕微鏡観察
野々山貴行, 鈴木裕貴, 木山竜二, WANG Lei, 津田真寿美, 安田和則, 田中伸哉, 永田康祐, 藤田龍介, 坂本直哉, 圦本尚義, GONG Jian Ping, 日本セラミックス協会秋季シンポジウム講演予稿集(CD-ROM), 31st, 2018年

関節軟骨の再生医療 高純度硬化性アルギン酸ゲル移植は家兎半月板部分欠損モデルにおいて半月板修復を促進する
金 佑泳, 近藤 英司, 小野寺 智洋, 野々山 貴行, 馬場 力哉, 本谷 和俊, 上徳 善太, 松原 新史, 宝満 健太郎, 菱村 亮介, Terkawi Muhamad, 岩崎 倫政, 日本整形外科学会雑誌, 91, 8, S1468, S1468, 2017年08月
(公社)日本整形外科学会, 日本語

ダブルネットワークゲル(DNゲル)の軟骨応用に向けた検討
野々山 貴行, 中島 祐, 黒川 孝幸, 北村 信人, 安田 和則, 龔 剣萍, Fine ceramics report, 35, 4, 148, 152, 2017年
日本ファインセラミックス協会, 日本語

異方性層状ヒドロゲルの水誘起延性-脆性遷移
ILYAS Muhammad, HAQUE Md Anamul, YUE Youfeng, KUROKAWA Takayuki, NAKAJIMA Tasuku, NONOYAMA Takayuki, GONG Jian Ping, 高分子学会予稿集(CD-ROM), 66, 2, 2017年

傾斜構造による骨と直接結合する高靱性ハイドロゲル
野々山貴行, 和田進, 木山竜二, 北村信人, 北村信人, 安田和則, きょう剣萍, きょう剣萍, 日本バイオマテリアル学会シンポジウム予稿集, 2016, 230, 230, 2016年11月21日
日本バイオマテリアル学会, 日本語

軟骨基質高分子を複合化したダブルネットワークゲルの生体材料特性評価 軟骨再生誘導材料としての可能性
比嘉 浩太郎, 北村 信人, 後藤 佳子, 黒川 孝幸, 和田 進, 野々山 貴行, Gong Jian Ping, 金谷 文則, 安田 和則, 日本整形外科学会雑誌, 90, 8, S1726, S1726, 2016年08月
(公社)日本整形外科学会, 日本語

抗菌性ゲルのスクリーニング
柴田優輝, 黒川孝幸, 野々山貴行, 中島祐, 相沢智康, きょう剣萍, 高分子学会北海道支部研究発表会講演要旨集, 49th, 6, 2015年
日本語

DNゲルの強靱性に対する数理的考察
井倉弓彦, 中島祐, 野々山貴行, 黒川孝幸, GONG Jian Ping, 長山雅晴, 高分子学会予稿集(CD-ROM), 63, 1, ROMBUNNO.2PD046, 2014年05月09日
日本語

軟骨再生ハイドロゲルと骨組織の接着を目指した高靱性DNゲル表面におけるHApのバイオミネラリゼーション
木山竜二, 野々山貴行, 黒川孝幸, 中島祐, GONG Jian Ping, 日本セラミックス協会年会講演予稿集(CD-ROM), 2014, ROMBUNNO.1P141, 2014年03月07日
日本語

高強度ハイドロゲルとバイオセラミックスの融合:ソフトセラミックスの創製
野々山貴行, 木山竜二, 黒川孝幸, 中島祐, GONG Jian Ping, 日本セラミックス協会年会講演予稿集(CD-ROM), 2014, ROMBUNNO.1J24, 2014年03月07日
日本語

ゲルの異方的膨潤が誘起する液晶性高分子の超構造形成
高橋陸, 中島祐, 黒川孝幸, 野々山貴行, グン剣萍, 化学系学協会北海道支部冬季研究発表会講演要旨集(CD-ROM), 2014, ROMBUNNO.P38, 2014年01月28日
日本語

バイオミネラルの”新たな輝き” 生体分子テンプレート上での生物鉱化反応
加藤且也, 野々山貴行, 木下隆俊, 化学, 66, 8, 66, 67, 2011年08月01日
日本語

生物模倣技術と新材料・新製品開発への応用
田崎裕人, 文部科学省
技術情報協会, 2014年07月, 4861045363, 702

セラミックスを犠牲結合部位としたハイドロゲルの高靭性化
田中香月, 野々山貴行, 深尾一城, 木山竜二, GONG Jian Ping
高分子ゲル研究討論会講演要旨集, 2019年01月09日, 日本語

骨再生を促す高靭性ゲルの同位体顕微鏡法による進展評価
鈴木裕貴, 野々山貴行, 野々山貴行, WANG Lei, WANG Lei, 津田真寿美, 津田真寿美, 木山竜二, 安田和則, 安田和則, GONG Jian Ping, GONG Jian Ping
高分子ゲル研究討論会講演要旨集, 2019年01月09日, 日本語

家兎半月板部分欠損モデルにおける高純度硬化性アルギン酸ゲル移植の半月板修復に与える効果
金佑泳, 小野寺智洋, 近藤英司, 野々山貴行, 馬場力哉, 上徳善太, 宝満健太郎, 菱村亮介, 岩崎倫政
整形外科バイオマテリアル研究会プログラム・抄録集, 2018年11月, 日本語

温度依存性がない物理ゲルの創製
藤岡慶伍, 野々山貴行, 野々山貴行, GUO Honglei, GUO Honglei, GUO Hui, GUO Hui, 中島祐, 中島祐, 黒川孝幸, 黒川孝幸, GONG Jian Ping, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2018年08月29日, 日本語

新規高分子鎖ナノスケール直接観察法を用いたハイドロゲル表面構造解析
木山竜二, 野々山貴行, 野々山貴行, 中島祐, 中島祐, 黒川孝幸, 黒川孝幸, GONG Jian Ping, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2018年08月29日, 日本語

弾性率超転移を示す可逆的温度応答性ハイドロゲルの創製
野々山貴行, 野々山貴行, LEE Yong Woo, 太田玖美, 藤岡慶伍, GONG Jian Ping, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2018年08月29日, 日本語

DNゲルのヒステリシス解析による単一高分子鎖の挙動抽出
高橋由葵子, 松田昂大, 中島祐, 中島祐, 印出井努, 印出井努, 野々山貴行, 野々山貴行, 黒川孝幸, 黒川孝幸, GONG Jian Ping, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2018年08月29日, 日本語

同位体顕微鏡法による高靭性ゲルへの骨再生進展の評価
鈴木裕貴, 野々山貴行, 野々山貴行, WANG Lei, WANG Lei, 津田真寿美, 津田真寿美, 木山竜二, 安田和則, 安田和則, GONG Jian Ping, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2018年08月29日, 日本語

巨視的な犠牲結合を有するソフト複合材料の高靭性化
奥村剛士, 高橋陸, KING Daniel R, KING Daniel R, 中島祐, 中島祐, 野々山貴行, 野々山貴行, 黒川孝幸, 黒川孝幸, GONG Jian Ping, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2018年08月29日, 日本語

企業訪問の取り組みと高分子未来塾
野々山貴行
高分子学会予稿集(CD-ROM), 2018年08月29日, 日本語

一軸延伸過程におけるダブルネットワークゲルのin‐situ小角X線散乱
深尾一城, 野々山貴行, 中島祐, 黒川孝幸, 河井貴彦, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2018年08月29日, 日本語

機械刺激が誘起するDNゲルの自己強靭化
難波遼, 松田昂大, 中島祐, 中島祐, 野々山貴行, 野々山貴行, 黒川孝幸, 黒川孝幸, GONG Jian Ping, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2018年08月29日, 日本語

ダブルネットワーク原理をマクロスケールに拡張した複合材料の創製及び物性制御
奥村剛士, 高橋陸, KING Daniel R, KING Daniel R, 中島祐, 中島祐, 野々山貴行, 野々山貴行, 黒川孝幸, 黒川孝幸, GONG Jian Ping, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2018年05月08日, 日本語

X線散乱法によるDouble Networkゲルの延伸過程における内部構造の評価
深尾一城, 野々山貴行, 野々山貴行, 中島祐, 中島祐, 黒川孝幸, 黒川孝幸, GONG Jian Ping, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2018年05月08日, 日本語

無機粒子複合化によるハイドロゲル高分子鎖の新規直接観察法の開発
木山竜二, 野々山貴行, 中島祐, 黒川孝幸, GONG Jian Ping
日本セラミックス協会年会講演予稿集(CD-ROM), 2018年03月01日, 日本語

伸長下高強度ハイドロゲル内におけるハイドロキシアパタイトの異方的結晶成長
深尾一城, 野々山貴行, 古澤和也, 黒川孝幸, 中島祐, GONG Jian Ping
日本セラミックス協会年会講演予稿集(CD-ROM), 2018年03月01日, 日本語

巨視的なダブルネットワーク構造を有する複合材料の創製及び物性評価
奥村剛士, 高橋陸, 黒川孝幸, 黒川孝幸, KING Daniel R, KING Daniel R, 中島祐, 中島祐, 孫桃林, 孫桃林, 野々山貴行, 野々山貴行, きょう剣萍, きょう剣萍
高分子学会北海道支部研究発表会講演要旨集, 2018年01月15日, 日本語

バイオセラミックスを犠牲結合としたハイドロゲルの高靭化
田中香月, 野々山貴行, 野々山貴行, 木山竜二, 深尾一城, 黒川孝幸, 黒川孝幸, きょう剣萍, きょう剣萍
高分子学会北海道支部研究発表会講演要旨集, 2018年01月15日, 日本語

メカノケミカル重合反応による自己強靭化DNゲルの創製
難波遼, 松田昂大, 中島祐, 中島祐, 野々山貴行, 野々山貴行, 黒川孝幸, 黒川孝幸, きょう剣萍, きょう剣萍
高分子学会北海道支部研究発表会講演要旨集, 2018年01月15日, 日本語

体積相転移の無いLCSTと可逆的熱硬化能を有する新規ハイドロゲルの創製
李永祐, 野々山貴行, 野々山貴行, 中島祐, 中島祐, 黒川孝幸, 黒川孝幸, きょう剣萍, きょう剣萍
高分子学会北海道支部研究発表会講演要旨集, 2018年01月15日, 日本語

ずり流動場での二重膜ハイブリッドゲルの合成とその異方構造解析
井上あかね, MD.ANAMUL Haque, 黒川孝幸, 黒川孝幸, 中島祐, 中島祐, 野々山貴行, 野々山貴行, きょう剣萍, きょう剣萍
高分子学会北海道支部研究発表会講演要旨集, 2018年01月15日, 日本語

高温で高強度・高靭性化するアイソコリック相分離ゲルの創製
野々山貴行, 野々山貴行, 太田玖美, LEE Yong Woo, 藤岡慶伍, 黒川孝幸, 黒川孝幸, GONG Jian Ping, GONG Jian Ping
高分子ゲル研究討論会講演要旨集, 2018年01月04日, 日本語

ハイドロゲルのナノスケールネットワーク構造の直接観察
木山竜二, 野々山貴行, 野々山貴行, 中島祐, 中島祐, 黒川孝幸, 黒川孝幸, GONG Jian Ping, GONG Jian Ping
高分子ゲル研究討論会講演要旨集, 2018年01月04日, 日本語

半剛直性高分子を用いた強靭・異方的ダブルネットワークゲルの創製
猪飼拓真, 高橋陸, キング ダニエル, キング ダニエル, 中島祐, 中島祐, 野々山貴行, 野々山貴行, 黒川孝幸, 黒川孝幸, グン剣萍, グン剣萍
化学系学協会北海道支部冬季研究発表会(Web), 2018年, 日本語

ハイドロゲルの潤滑におけるリンクル表面形状の効果
黒川孝幸, 野々山貴行, 中島祐, GONG J. P, 小池智, 平井悠司, 大園拓哉
レオロジー討論会講演要旨集, 2017年10月17日, 日本語

破断誘起ラジカル重合による自己強靭化DNゲルの創製
難波遼, 松田昂大, 中島祐, 中島祐, 野々山貴行, 野々山貴行, 黒川孝幸, 黒川孝幸, GONG Jian Ping, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2017年09月06日, 日本語

巨視的な二重網目構造を有する高強度・高靱性複合材料の創製及び制御
奥村剛士, 高橋陸, KING Daniel R, KING Daniel R, 中島祐, 中島祐, SUN Taolin, SUN Taolin, 野々山貴行, 野々山貴行, 黒川孝幸, 黒川孝幸, GONG Jian Ping, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2017年09月06日, 日本語

生体分子イオン液体をベースとする生体分子イオンゲルの創製
村井一喜, 楜澤和也, 大塚渓斗, 野々山貴行, 松本睦良
高分子学会予稿集(CD-ROM), 2017年09月06日, 日本語

多彩な構造色を有する二分子膜ゲルの構造精密制御と配向分析
井上あかね, ANAMUL Haque Md, 黒川孝幸, 黒川孝幸, 中島祐, 中島祐, 野々山貴行, 野々山貴行, GONG Jian Ping, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2017年09月06日, 日本語

ポーラス構造を有する強靭な高分子電解質複合体ゲルの創製と機能発現
村川航平, SUN Taolin, SUN Taolin, KING Daniel R, KING Daniel R, 野々山貴行, 野々山貴行, 中島祐, 中島祐, 黒川孝幸, 黒川孝幸, GONG Jian Ping, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2017年09月06日, 日本語

高純度硬化性アルギン酸ゲル移植は家兎半月板部分欠損モデルにおいて半月板修復を促進する
KIM W.Y, 近藤英司, 小野寺智洋, 野々山貴行, 馬場力哉, 本谷和俊, 上徳善太, 松原新史, 宝満健太郎, 菱村亮介, TERKAWI Muhamad, 岩崎倫政
日本整形外科学会雑誌, 2017年08月31日, 日本語

ダブルネットワーク原理をマクロスケールに拡張した新規複合材料の創製
奥村剛士, 高橋陸, KING Daniel R, KING Daniel R, 中島祐, 中島祐, SUN Taolin, SUN Taolin, 野々山貴行, 野々山貴行, 黒川孝幸, 黒川孝幸, GONG Jian Ping, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2017年05月15日, 日本語

低融点合金を用いた機能性ハイドロゲル複合材料の創製
高橋陸, DANIEL King, DANIEL King, 孫桃林, 孫桃林, 野々山貴行, 野々山貴行, 中島祐, 中島祐, 黒川孝幸, 黒川孝幸, GONG Jian Ping, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2017年05月15日, 日本語

高温で高強度・高靱性化するアイソコリックハイドロゲルの創製
野々山貴行, 野々山貴行, 太田玖美, LEE Yong Woo, 中島祐, 中島祐, 黒川孝幸, 黒川孝幸, GONG Jian Ping, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2017年05月15日, 日本語

人工腱を目指した強配向・高強度生体高分子ゲルの創製
中島祐, 中島祐, MREDHA Md.Tariful Islam, 黒川孝幸, 黒川孝幸, 野々山貴行, 野々山貴行, GONG Jian Ping, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2017年05月15日, 日本語

生体分子のみを構成イオン種とするイオン液体の創成とイオン構造が液体特性に与える影響
村井一喜, 楜澤和也, 大塚渓斗, 野々山貴行, 松本睦良
高分子学会予稿集(CD-ROM), 2017年05月15日, 日本語

自己修復性を有する高温で強靭化する新規アイソコリックゲルの創製
LEE Yong Woo, 野々山貴行, 野々山貴行, 中島祐, 中島祐, 黒川孝幸, 黒川孝幸, GONG Jian Ping, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2017年05月15日, 日本語

電荷を有する微粒子ゲルの潤滑機構
福田泰紀, 黒川孝幸, 黒川孝幸, KING Daniel R, KING Daniel R, 中島祐, 中島祐, 野々山貴行, 野々山貴行, SUN Taolin, SUN Taolin, GONG Jian Ping, GONG Jian Ping
高分子ゲル研究討論会講演要旨集, 2017年01月06日, 日本語

ポーラス構造を有するポリイオンコンプレックスゲルとその機能発現
村川航平, SUN Taolin, SUN Taolin, KING Daniel R, KING Daniel R, 野々山貴行, 野々山貴行, 中島祐, 中島祐, 黒川孝幸, 黒川孝幸, GONG Jian Ping, GONG Jian Ping
高分子ゲル研究討論会講演要旨集, 2017年01月06日, 日本語

破断誘起ラジカル重合による劣化部位修復性DNゲルの創製
難波遼, 松田昂大, 中島祐, 中島祐, 野々山貴行, 野々山貴行, 黒川孝幸, 黒川孝幸, GONG Jian Ping, GONG Jian Ping
高分子ゲル研究討論会講演要旨集, 2017年01月06日, 日本語

破断誘起ラジカル重合による劣化部位修復性DNゲルの創製
難波遼, 松田昂大, 中島祐, 中島祐, 野々山貴行, 野々山貴行, 黒川孝幸, 黒川孝幸, きょう剣萍, きょう剣萍
高分子学会北海道支部研究発表会講演要旨集, 2017年, 日本語

二分子膜からなるマルチシリンダーゲルの創製及び異方的挙動の解析
水戸京, 李旭峰, HAQUE Md. Anamul, 黒川孝幸, 黒川孝幸, 中島祐, 中島祐, 野々山貴行, 野々山貴行, きょう剣萍, きょう剣萍
高分子学会北海道支部研究発表会講演要旨集, 2017年, 日本語

マクロスケールの二重網目構造を有する高強度・高靭性複合材料の創成及び制御
奥村剛士, 高橋陸, 黒川孝幸, 黒川孝幸, KING Daniel R, KING Daniel R, 中島祐, 中島祐, 孫桃林, 孫桃林, 野々山貴行, 野々山貴行, きょう剣萍, きょう剣萍
高分子学会北海道支部研究発表会講演要旨集, 2017年, 日本語

チタン属イオン架橋を用いた強靭な異方性ハイドロゲルの創製
猪飼拓真, 高橋陸, キング ダニエル, キング ダニエル, 中島祐, 中島祐, 野々山貴行, 野々山貴行, 黒川孝幸, 黒川孝幸, きょう剣萍, きょう剣萍
高分子学会北海道支部研究発表会講演要旨集, 2017年, 日本語

ポーラス構造を有するポリイオンコンプレックスゲルとその機能発現
村川航平, 孫桃林, 孫桃林, KING ダニエル R, KING ダニエル R, 野々山貴行, 野々山貴行, 中島祐, 中島祐, 黒川孝幸, 黒川孝幸, きょう剣萍, きょう剣萍
高分子学会北海道支部研究発表会講演要旨集, 2017年, 日本語

粘性エネルギーロスを示さないDouble Networkエラストマーの創製
尾崎雄平, 中島祐, 中島祐, 野々山貴行, 野々山貴行, 黒川孝幸, 黒川孝幸, きょう剣萍, きょう剣萍
高分子学会北海道支部研究発表会講演要旨集, 2017年, 日本語

ネットワークの異方性が誘起するバイオミネラルの配向制御
深尾一城, 野々山貴行, 野々山貴行, 古澤和也, 古澤和也, 黒川孝幸, 黒川孝幸, 中島祐, 中島祐, きょう剣萍, きょう剣萍
高分子学会北海道支部研究発表会講演要旨集, 2017年, 日本語

電荷を有する微粒子ゲルの摩擦低減効果
福田泰紀, 黒川孝幸, 黒川孝幸, キング ダニエル, キング ダニエル, 中島祐, 中島祐, 野々山貴行, 野々山貴行, 孫桃林, 孫桃林, きょう剣萍, きょう剣萍
高分子学会北海道支部研究発表会講演要旨集, 2017年, 日本語

高温で強靭化する新規アイソコリックハイドロゲルの創製
太田玖美, 野々山貴行, 野々山貴行, 中島祐, 中島祐, 黒川孝幸, 黒川孝幸, きょう剣萍, きょう剣萍
高分子学会北海道支部研究発表会講演要旨集, 2017年, 日本語

セラミックスを犠牲結合部位としたハイドロゲルの高靱性化
田中香月, 野々山貴行, 野々山貴行, 中島祐, 中島祐, 黒川孝幸, 黒川孝幸, きょう剣萍, きょう剣萍
高分子学会北海道支部研究発表会講演要旨集, 2017年, 日本語

Double Networkゲルをマトリックスとした骨組織類似構造の創製
深尾一城, 野々山貴行, 野々山貴行, 黒川孝幸, 黒川孝幸, 中島祐, 中島祐, きょう剣萍, きょう剣萍
日本バイオマテリアル学会シンポジウム予稿集, 2016年11月21日, 日本語

傾斜構造による骨と直接結合する高靱性ハイドロゲル
野々山貴行, 和田進, 木山竜二, 北村信人, 北村信人, 安田和則, きょう剣萍, きょう剣萍
日本バイオマテリアル学会シンポジウム予稿集, 2016年11月21日, 日本語

ハイドロキシアパタイト複合化PAMPS/PDMAAmダブルネットワークゲル人工軟骨の関節内におけるin vivo骨接着性評価
和田進, 北村信人, 野々山貴行, 木山竜二, 仙葉愼吾, 小野寺純, 横田正司, 後藤佳子, 比嘉浩太郎, 黒川孝幸, PING Gong Jian, 安田和則
日本整形外科学会雑誌, 2016年08月31日, 日本語

軟骨基質高分子を複合化したダブルネットワークゲルの生体材料特性評価:軟骨再生誘導材料としての可能性
比嘉浩太郎, 北村信人, 後藤佳子, 黒川孝幸, 和田進, 野々山貴行, PING Gong Jian, 金谷文則, 安田和則
日本整形外科学会雑誌, 2016年08月31日, 日本語

高強度ハイドロゲル中でのハイドロキシアパタイトの異方的結晶成長
深尾一城, 野々山貴行, 黒川孝幸, 中島祐, GONG Jian Ping
日本セラミックス協会秋季シンポジウム講演予稿集(CD-ROM), 2016年08月29日, 日本語

軟骨再生DNゲルの骨接着に向けた表面選択的HApパターニング
木山竜二, 野々山貴行, 中島祐, 黒川孝幸, GONG JianPing
日本セラミックス協会秋季シンポジウム講演予稿集(CD-ROM), 2016年08月29日, 日本語

骨と直接結合するタフハイドロゲル
野々山貴行, 野々山貴行, 和田進, 木山竜二, 北村信人, 北村信人, 黒川孝幸, 黒川孝幸, 中島祐, 中島祐, 安田和則, GONG Jian Ping, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2016年08月24日, 日本語

低融点合金を用いた機能性コンポジットゲルの創製
高橋陸, DANIEL King, DANIEL King, 野々山貴行, 野々山貴行, 中島祐, 中島祐, 黒川孝幸, 黒川孝幸, GONG Jian Ping, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2016年08月24日, 日本語

遷移金属イオン架橋による強靭なハイドロゲルの創製
猪飼拓真, 高橋陸, KING Daniel R, 中島祐, 野々山貴行, 黒川孝幸, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2016年08月24日, 日本語

生体分子のみから構成される新規イオン液体およびイオンゲルの創成
大塚渓斗, 村井一喜, 野々山貴行, 松本睦良
高分子学会予稿集(CD-ROM), 2016年08月24日, 日本語

粘性によるエネルギーロスを示さない強靭エラストマーの創製
尾崎雄平, 中島祐, 中島祐, 野々山貴行, 野々山貴行, 黒川孝幸, 黒川孝幸, CONG Jian Ping, CONG Jian Ping
高分子学会予稿集(CD-ROM), 2016年08月24日, 日本語

Diffusion perturbation induced superstructure formation in biopolymer hydrogels
MREDHA Md. Tariful Islam, ZHANG Xi, NONOYAMA Takayuki, NAKAJIMA Tasuku, KUROKAWA Takayuki, HAQUE Md. Anamul, TAKAGI Yasuaki, GONG Jian Ping
高分子ゲル研究討論会講演要旨集, 2016年01月08日, 英語

半剛直性高分子電解質と金属多価イオンを用いた高強度ゲルの創製および配向の制御
猪飼拓真, 高橋陸, 中島祐, 野々山貴行, 黒川孝幸, GONG Jian Ping
高分子ゲル研究討論会講演要旨集, 2016年01月08日, 日本語

微粒子ゲルの摩擦低減効果
福田泰紀, 黒川孝幸, 中島祐, 野々山貴行, GONG Jian Ping
高分子ゲル研究討論会講演要旨集, 2016年01月08日, 日本語

Slow Relaxation Dynamics of Tough and Self-healing Polyampholyte Hydrogels
KAROBI Sadia Nazneen, SUN Tao Lin, KUROKAWA Takayuki, LUO Feng, NAKAJIMA Tasuku, NONOYAMA Takayuki, GONG Jian Ping
レオロジー討論会講演要旨集, 2015年09月23日, 英語

バイオミネラリゼーションにより複合化したハイドロキシアパタイトコーティングPAMPS/PDMAAmダブルネットワークゲルの骨接着性の評価
和田進, 北村信人, 野々山貴行, 木山竜二, 仙葉愼吾, 比嘉浩太郎, 黒川孝幸, GONG Jian Ping, 安田和則
日本整形外科学会雑誌, 2015年09月10日, 日本語

Tough physical double network hydrogels based on amphiphilic tri-block copolymer
ZHANG Huijie, SUN Tao Lin, IKURA Yumihiko, ZHANG Aokai, LI Xufeng, NAKAJIMA Tasuku, NONOYAMA Takayuki, KURUKAWA Takayuki, ITO Osamu, ISHITOBI Hiroyuki, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2015年08月25日, 英語

Precise Control of Gel Structures and Properties with Dangling End Defect
ZHANG Aokai, NAKAJIMA Tasuku, KUROKAWA Takayuki, NONOYAMA Takayuki, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2015年08月25日, 英語

The counter-ion condensation behavior of polyelectrolyte gels as studied by microelectrode technique (MET)
GUO Honglei, KUROKAWA Takayuki, TAKAHATA Masakazu, KATSUYAMA Yoshinori, LUO Feng, AHMED Jamil, NAKAJIMA Tasuku, NONOYAMA Takayuki, GONG JianPing
高分子学会予稿集(CD-ROM), 2015年08月25日, 英語

Polyampholyte hydrogels; smart, soft and wet adhesive
ROY Chanchal Kumar, GUO Hong Lei, IHSAN Abu Bin, SUN Tao Lin, NONOYAMA Takayuki, NAKAJIMA Tasuku, KUROKAWA Takayuki, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2015年08月25日, 英語

Diffusion induced superstructure formation in swim bladder collagen　　　　　　　　　　　　　　　
MREDHA Md. Tariful Islam, ZHANG Xi, NONOYAMA Takayuki, NAKAJIMA Tasuku, KUROKAWA Takayuki, TAKAGI Yasuaki, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2015年05月12日, 英語

銀コーティングを用いた伸縮可能導電性ハイドロゲルの創製　　　　　　　　　　　　　　　
高橋陸, 中島祐, 野々山貴行, 黒川孝幸, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2015年05月12日, 日本語

セルロースを犠牲結合とする高靱性・自己修復性エラストマーの創製　　　　　　　　　　　　　　　
村井城治, 中島祐, 野々山貴行, 黒川孝幸, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2015年05月12日, 日本語

骨組織との接着を目指したDNゲル表面のHApパターニング　　　　　　　　　　　　　　　
木山竜二, 野々山貴行, 黒川孝幸, 中島祐, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2015年05月12日, 日本語

Tough and Self-healing Polyampholyte Hydrogels-Similarity with Glassy Polymers　　　　　　　　　　　　　　　
IHSAN Abu Bin, SUN Tao Lin, NONOYAMA Takayuki, NAKAJIMA Tasuku, KUROKAWA Takayuki, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2015年05月12日, 英語

Abnormal elastic behaviour of poly(2-ureidoethyl methacrylate) physical hydrogels　　　　　　　　　　　　　　　
SUN Taolin, NONOYAMA Takayuki, SARUWATARI Yoshiyuki, LUO Feng, KUROKAWA Takayuki, NAKAJIMA Tasuku, IHSAN Abu Bin, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2015年05月12日, 英語

Tough hydrogels with H-bonds as reversible sacrificial bonds　　　　　　　　　　　　　　　
SUN Taolin, NONOYAMA Takayuki, SARUWATARI Yoshiyuki, LUO Feng, KUROKAWA Takayuki, NAKAJIMA Tasuku, IHSAN Abu Bin, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2015年05月12日, 英語

ダブルネットワークゲルの降伏メカニズムの解明　　　　　　　　　　　　　　　
松田昂大, 中島祐, 黒川孝幸, 野々山貴行, 酒井崇匡, CHUNG Ung‐il, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2015年05月12日, 日本語

Bioadhesion Using Polyampholyte Hydrogel　　　　　　　　　　　　　　　
ROY Chanchal Kumar, IHSAN Abu Bin, SUN Tao Lin, NONOYAMA Takayuki, NAKAJIMA Tasuku, KUROKAWA Takayuki, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2015年05月12日, 英語

軟骨再生DNハイドロゲルの骨組織への接着を目指した表面選択的HApパターニング　　　　　　　　　　　　　　　
木山竜二, 野々山貴行, 黒川孝幸, 中島祐, GONG Jian Ping
日本セラミックス協会年会講演予稿集(CD-ROM), 2015年03月06日, 日本語

DNハイドロゲルの大変形下におけるHApのミネラリゼーション　　　　　　　　　　　　　　　
深尾一城, 野々山貴行, 黒川孝幸, 中島祐, GONG Jian Ping
日本セラミックス協会年会講演予稿集(CD-ROM), 2015年03月06日, 日本語

ハイドロゲルの摩擦と潤滑に及ぼす表面溝形状の効果　　　　　　　　　　　　　　　
小池智, 大園拓哉, 野々山貴行, 中島祐, 黒川孝幸, GONG Jian Ping
高分子ゲル研究討論会講演要旨集, 2015年01月09日, 日本語

軟骨再生ハイドロゲルと骨組織の接着を目指した高靱性ハイドロゲル表面におけるHApのバイオミネラリゼーション　　　　　　　　　　　　　　　
木山竜二, 野々山貴行, 黒川孝幸, 中島祐, GONG Jian Ping
高分子ゲル研究討論会講演要旨集, 2015年01月09日, 日本語

マルチシリンダー構造をもつ二分子膜ゲルの機能発現　　　　　　　　　　　　　　　
水戸京, 黒川孝幸, 中島祐, 野々山貴行, GONG Jian Ping
高分子ゲル研究討論会講演要旨集, 2015年01月09日, 日本語

セルロースを犠牲結合とする高靱性・自己回復性ソフトマテリアルの創製　　　　　　　　　　　　　　　
村井城治, 中島祐, 野々山貴行, 黒川孝幸, きょう剣萍
高分子学会北海道支部研究発表会講演要旨集, 2015年, 日本語

力学的刺激が誘起するDNゲル内部の溶液化学反応　　　　　　　　　　　　　　　
松田昂大, 中島祐, 黒川孝幸, 野々山貴行, きょう剣萍
高分子学会北海道支部研究発表会講演要旨集, 2015年, 日本語

Solvent induced photonic on/off swithing in lamellar bilayer hydrogel　　　　　　　　　　　　　　　
ILYAS Muhammad, KUROKAWA Takayuki, NAKAJIMA Tasuku, NONOYAMA Takayuki, GONG JianPing
高分子学会北海道支部研究発表会講演要旨集, 2015年, 英語

海水を給水源としたゲル上の植物成長システムの開発　　　　　　　　　　　　　　　
大竹俊亮, 黒川孝幸, 中島祐, 野々山貴行, 三輪京子, きょう剣萍
高分子学会北海道支部研究発表会講演要旨集, 2015年, 日本語

両性電解質高分子を用いた繊維状高靱性ゲルの創製　　　　　　　　　　　　　　　
星野顕一, 岡田真典, 孫桃林, 野々山貴行, 中島祐, 黒川孝幸, きょう剣萍
高分子学会北海道支部研究発表会講演要旨集, 2015年, 日本語

抗菌性ゲルのスクリーニング　　　　　　　　　　　　　　　
柴田優輝, 黒川孝幸, 野々山貴行, 中島祐, 相沢智康, きょう剣萍
高分子学会北海道支部研究発表会講演要旨集, 2015年, 日本語

Two-step polymerization: a novel method for preparing polymer-supported lipid bilayer hydrogel　　　　　　　　　　　　　　　
LI Xu Feng, NAKAJIMA Tasuku, NONOYAMA Takayuki, KUROKAWA Takayuki, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2014年09月03日, 英語

ダブルネットワークゲルの高分子鎖内部破断の化学的証明　　　　　　　　　　　　　　　
松田昂大, 中島祐, 黒川孝幸, 野々山貴行, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2014年09月03日, 日本語

Tough and Self-healing Hydrogels from Polyampholytes Based on Reversible Sacrificial Bonds　　　　　　　　　　　　　　　
IHSAN Abu Bin, SUN Tao Lin, NONOYAMA Takayuki, NAKAJIMA Tasuku, KUROKAWA Takayuki, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2014年09月03日, 英語

結合性骨形成を目指したHApコート高強度DNハイドロゲル最表面の構造評価　　　　　　　　　　　　　　　
野々山貴行, 木山竜二, 中島祐, 黒川孝幸, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2014年09月03日, 日本語

Tough and Self-healing Hydrogels from Polyampholytes: Play with Reversible Sacrificial Bonds　　　　　　　　　　　　　　　
IHSAN Abu Bin, SUN Tao Lin, NONOYAMA Takayuki, NAKAJIMA Tasuku, KUROKAWA Takayuki, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2014年05月09日, 英語

DNゲルの強靱性に対する数理的考察　　　　　　　　　　　　　　　
井倉弓彦, 中島祐, 野々山貴行, 黒川孝幸, GONG Jian Ping, 長山雅晴
高分子学会予稿集(CD-ROM), 2014年05月09日, 日本語

Robust Adhesion of Tough DN Hydrogels on Rough Solid Substrates by 'Graft Gelation'　　　　　　　　　　　　　　　
OKAZAKI Haruka, NAKAJIMA Tasuku, NONOYAMA Takayuki, KUROKAWA Takayuki, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2014年05月09日, 英語

高強度ハイドロゲルとバイオセラミックスの融合:ソフトセラミックスの創製　　　　　　　　　　　　　　　
野々山貴行, 木山竜二, 黒川孝幸, 中島祐, GONG Jian Ping
日本セラミックス協会年会講演予稿集(CD-ROM), 2014年03月07日, 日本語

軟骨再生ハイドロゲルと骨組織の接着を目指した高靱性DNゲル表面におけるHApのバイオミネラリゼーション　　　　　　　　　　　　　　　
木山竜二, 野々山貴行, 黒川孝幸, 中島祐, GONG Jian Ping
日本セラミックス協会年会講演予稿集(CD-ROM), 2014年03月07日, 日本語

ゲルの異方的膨潤が誘起する液晶性高分子の超構造形成　　　　　　　　　　　　　　　
高橋陸, 中島祐, 黒川孝幸, 野々山貴行, グン剣萍
化学系学協会北海道支部冬季研究発表会講演要旨集(CD-ROM), 2014年01月28日, 日本語

A novel anisotropic and tough hydrogel from swim bladder collagen　　　　　　　　　　　　　　　
MREDHA Md. Tariful Islam, ZHANG Xi, NONOYAMA Takayuki, NAKAJIMA Tasuku, KUROKAWA Takayuki, HAQUE Md. Anamul, TAKAGI Yasuaki, GONG Jian Ping
高分子ゲル研究討論会講演要旨集, 2014年01月15日, 英語

Reversible and Strong Adhesion of Polyampholyte Hydrogel　　　　　　　　　　　　　　　
ROY Chanchal Kumar, ABU BIN IHSAN, SUN Tao Lin, NONOYAMA Takayuki, NAKAJIMA Tasuku, KUROKAWA Takayuki, GONG Jian Ping
高分子ゲル研究討論会講演要旨集, 2014年01月15日, 英語

Tetra‐PEGゲルを第一網目構造に持つDNゲルの物性評価　　　　　　　　　　　　　　　
松田昂大, 中島祐, 黒川孝幸, 野々山貴行, 酒井崇匡, CHUNG Ung‐il, GONG Jian Ping
高分子ゲル研究討論会講演要旨集, 2014年01月15日, 日本語

繊維状高靱性ゲルの創製　　　　　　　　　　　　　　　
星野顕一, SUN Tao Lin, 野々山貴行, 中島祐, 黒川孝幸, GONG Jian Ping
繊維学会予稿集, 2014年, 日本語

Self-healing behavior of tough hydrogel created by dynamic and reversible sacrificial bonds　　　　　　　　　　　　　　　
IHSAN Abu Bin, SUN Tao Lin, NONOYAMA Takayuki, NAKAJIMA Tasuku, KUROKAWA Takayuki, GONG Jian Ping
高分子学会北海道支部研究発表会講演要旨集, 2014年, 英語

Shear Adhesion of Novel Polyampholyte Hydrogel　　　　　　　　　　　　　　　
ROY Chanchal Kumar, OKAZAKI Haruka, IHSAN Abu Bin, SUN Tao Lin, NONOYAMA Takayuki, NAKAJIMA Tasuku, KUROKAWA Takayuki, GONG Jian Ping
高分子学会北海道支部研究発表会講演要旨集, 2014年, 英語

均一な第一網目構造を持つ超高強度DNゲルの一軸伸長変形挙動解析　　　　　　　　　　　　　　　
松田昂大, 中島祐, 黒川孝幸, 野々山貴行, 酒井崇匡, CHUNG Ung‐il, GONG Jian Ping
エラストマー討論会講演要旨集, 2013年12月10日, 日本語

生体硬組織にならう高靱性DNゲル中でのミネラリゼーション　　　　　　　　　　　　　　　
野々山貴行, 木山竜二, 中島祐, 黒川孝幸, GONG Jian Ping
高分子学会予稿集(CD-ROM), 2013年08月28日, 日本語

ペプチドを用いたバイオミネラリゼーションによる無機結晶の成長制御　　　　　　　　　　　　　　　
安藤正幸, 野々山貴行, 木下隆利
高分子学会予稿集(CD-ROM), 2013年05月14日, 日本語

pHマルチレスポンス型ハイドロゲルの創成とDDSへの応用　　　　　　　　　　　　　　　
一井翔, 野々山貴行, 木下隆利
高分子学会予稿集(CD-ROM), 2013年05月14日, 日本語

バイオミネラリゼーションにならう有機・無機界面におけるエピタキシャル性　　　　　　　　　　　　　　　
野々山貴行, 木下隆利, 樋口真弘, 佐藤公泰, 加藤且也
高分子学会予稿集(CD-ROM), 2012年09月05日, 日本語

骨充填剤に応用可能なリン酸カルシウム含有ペプチドゲルの創成　　　　　　　　　　　　　　　
小笠原北斗, 野々山貴行, 木下隆利
高分子学会予稿集(CD-ROM), 2012年09月05日, 日本語

ペプチドの自己組織化を利用した薬物徐放制御システムの開発　　　　　　　　　　　　　　　
村井一喜, 野々山貴行, 樋口真弘, 加藤且也
高分子学会予稿集(CD-ROM), 2012年05月15日, 日本語

バイオミネラリゼーションによるペプチド単分子膜上でのリン酸カルシウムの結晶成長　　　　　　　　　　　　　　　
野々山貴行, 木下隆利, 樋口真弘, 永田謙二, 佐藤公泰, 加藤且也
高分子学会予稿集(CD-ROM), 2012年05月15日, 日本語

バイオミネラリゼーションにならう有機・無機界面におけるエピタキシャルな関係性
野々山貴行, 木下隆利, 樋口真弘, 永田謙二, 佐藤公泰, 加藤且也
日本セラミックス協会年会講演予稿集, 2012年03月19日, 日本語
バイオミネラリゼーションにおいて、どの段階で何が無機物の結晶相やモルフォロジーを決定しているかは、結晶学的にも非常に興味深い。事実、骨形成においてハイドロキシアパタイト(HAp) がコラーゲンファイバーに沿って形成されるように、バイオミネラリゼーションプロセスは無機構造を自在に制御する可能性を秘めている。我々はこれまでに、β-シートペプチド単分子膜上でのリン酸カルシウムのミネラリゼーションを通して有機・無機界面におけるエピタキシャルな関係性を調査してきた。β-シートペプチドはアミノ酸側鎖の官能基が 2 次元平面で規則正しく配列している。 今回はHAp の a 面及び c 面のカルシウム原子の位置に対応するように、カルボキシル基を配置した二種類のペプチドを新規設計し、 リン酸カルシウムのミネラリゼーションにおいて、形成した結晶相や結晶方位と対応するかを検証した。

pH応答ペプチドを利用した薬物除放制御システムの開発　　　　　　　　　　　　　　　
村井一喜, 野々山貴行, 安藤文雄, 加藤且也
日本セラミックス協会東海支部学術研究発表会講演要旨集, 2011年12月03日, 日本語

バイオミネラリゼーションにならうペプチド単分子膜上でのリン酸カルシウムの結晶成長　　　　　　　　　　　　　　　
野々山貴行, 木下隆利, 樋口真弘, 永田謙二, 佐藤公泰, 加藤且也
日本セラミックス協会東海支部学術研究発表会講演要旨集, 2011年12月03日, 日本語

単一シーケンスペプチドを用いたバイオミネラリゼーション挙動の解析　　　　　　　　　　　　　　　
久野達也, 野々山貴行, 平尾喜代司, 加藤且也
日本セラミックス協会東海支部学術研究発表会講演要旨集, 2011年12月03日, 日本語

バイオミネラリゼーションにおけるチャージリレー効果　　　　　　　　　　　　　　　
久野達也, 野々山貴行, 平尾喜代司, 加藤且也
中部化学関係学協会支部連合秋季大会講演予稿集, 2011年11月05日, 日本語

ペプチドテンプレートによる無機物の結晶相及びモルフォロジー制御　　　　　　　　　　　　　　　
野々山貴行, 木下隆利, 樋口真弘, 永田謙二, 佐藤公泰, 加藤且也
中部化学関係学協会支部連合秋季大会講演予稿集, 2011年11月05日, 日本語

表面機能化メソポーラスシリカ上へのスブチリシンの固定化と表面官能基が酵素触媒特性に与える影響　　　　　　　　　　　　　　　
村井一喜, 野々山貴行, 安藤文雄, 加藤且也
高分子学会予稿集(CD-ROM), 2011年09月13日, 日本語

ペプチドゲル中でのミネラリゼーションにおけるリン酸カルシウムの合成　　　　　　　　　　　　　　　
小笠原北斗, 野々山貴行, 木下隆利
高分子学会予稿集(CD-ROM), 2011年09月13日, 日本語

Titanium Dioxide Biomineralization with Peptide Nanofiber　　　　　　　　　　　　　　　
NONOYAMA Takayuki, KINOSHITA Takatoshi, HIGUCHI Masahiro, NAGATA Kenji, SATO Kimiyasu, KATO Katsuya
高分子学会予稿集(CD-ROM), 2011年09月13日, 英語

自己組織化ペプチドを用いたバイオミネラル形成
久野達也, 野々山貴行, 平尾喜代司, 加藤且也
日本セラミックス協会秋季シンポジウム講演予稿集, 2011年09月07日, 日本語
生物が合成し利用するバイオミネラルは、常温常圧の低環境負荷条件で合成され、かつ有機物と複合化することによりナノスケールで制御されている。そのため、このバイオミネラル形成（バイオミネラリゼーション）は近年、省エネと小型化の双方の観点から注目を集めている。このバイオミネラリゼーションの挙動をより深く理解するために、本研究では、二次構造を制御した自己組織化ペプチドを固相合成し、そのペプチドをバイオミネラリゼーションの触媒として利用し、その触媒活性と合成される無機材料の評価を行った。

ペプチドファインチューニング単分子膜表面におけるリン酸カルシウムの結晶相とモルフォロジーの制御
野々山貴行, 木下隆利, 樋口真弓, 永田謙二, 佐藤公泰, 加藤且也
日本セラミックス協会秋季シンポジウム講演予稿集, 2011年09月07日, 日本語
有機無機界面において、一方の表面の化学的性質や形状は、他方のそれに大きく影響を与える。つまり表面を高度に設計することで他方の物質を制御できる。今回は、高度に配向秩序化された有機物表面が無機物の結晶相とモルフォロジーに与える影響を調査した。実際にはリン酸カルシウムのミネラリゼーションをシーケンシャルペプチド自己組織化単分子膜上で行いその析出物を透過電子顕微鏡や三次元断層影像法を用いて解析した。今回の基礎的知見は有機無機ハイブリッド材料創成における一つの指針となるかもしれない。

バイオミネラリゼーションにおけるペプチドの官能基と配列の効果
久野達也, 野々山貴行, 平尾喜代司, 加藤且也
日本セラミックス協会年会講演予稿集, 2011年03月16日, 日本語
バイオミネラルと呼ばれる生体の硬組織である骨や歯や貝殻は常温常圧の温和な条件で合成されるにも関わらず、高い機械的特性をもった材料である。この体内でのバイオミネラル形成（バイオミネラリゼーション）においては、タンパク質や脂質や多糖類のような有機マトリックスの表面上の有機官能基が重要である。そこで本研究では、バイオミネラリゼーションにおける有機官能基の効果について検討するため、単一シーケンスのペプチドを合成し、その触媒効果を評価した。また、合成されたシリカの構造特性を評価した。

固相合成人工ペプチドをテンプレートとするバイオミネラリゼーション挙動の解析　　　　　　　　　　　　　　　
久野達也, 野々山貴行, 平尾喜代司, 加藤且也
日本セラミックス協会東海支部学術研究発表会講演要旨集, 2010年12月18日, 日本語

ペプチドスキャフォールドを用いた官能基秩序界面上でのバイオミネラリゼーションによるリン酸カルシウムの結晶形態制御　　　　　　　　　　　　　　　
野々山貴行, 木下隆利, 樋口真弘, 佐藤公泰, 加藤且也
日本セラミックス協会東海支部学術研究発表会講演要旨集, 2010年12月18日, 日本語

Peptide-assisted Preparation of Silica Nano Particles and Their Application for Biomolecule Encapsulation　　　　　　　　　　　　　　　
KATO Katsuya, NISHIDA Masakazu, NONOYAMA Takayuki, KINOSHITA Takatoshi
日本セラミックス協会秋季シンポジウム講演予稿集, 2010年11月14日, 英語

β‐シートペプチドから成る官能基二次元配向膜上でのミネラリゼーションによるリン酸カルシウムの合成　　　　　　　　　　　　　　　
野々山貴行, 田中正剛, 木下隆利, 樋口真弘, 永田夫久江, 佐藤公泰, 加藤且也
中部化学関係学協会支部連合秋季大会講演予稿集, 2010年11月06日, 日本語

官能基秩序配列を有したペプチドスキャフォールド上でのミネラリゼーション制御　　　　　　　　　　　　　　　
野々山貴行, 田中正剛, 木下隆利, 樋口真弘, 永田夫久江, 佐藤公泰, 加藤且也
日本化学会バイオテクノロジー部会シンポジウム講演要旨集, 2010年09月24日, 日本語

官能基秩序配列を有したペプチドスキャフォールド上でのミネラリゼーションによるリン酸カルシウムの合成　　　　　　　　　　　　　　　
野々山貴行, 田中正剛, 木下隆利, 樋口真弘, 永田夫久江, 佐藤公泰, 加藤且也
高分子学会予稿集(CD-ROM), 2010年09月01日, 日本語

ペプチドテンプレート上でのミネラリゼーションによるリン酸カルシウム合成　　　　　　　　　　　　　　　
野々山貴行, 木下隆利, 永田夫久江, 佐藤公泰, 加藤且也
高分子学会予稿集(CD-ROM), 2010年05月11日, 日本語

ペプチドテンプレート上でのミネラリゼーションによるリン酸カルシウム合成　　　　　　　　　　　　　　　
野々山貴行, 木下隆利, 永田夫久江, 佐藤公泰, 加藤且也
日本セラミックス協会年会講演予稿集, 2010年03月22日, 日本語

ペプチドテンプレート上でのミネラリゼーション
野々山 貴行, 永田 夫久江, 佐藤 公泰, 加藤 且也, 木下 隆利
日本セラミックス協会 年会・秋季シンポジウム 講演予稿集, 2010年, 日本語
有機鎖官能基が空間的に厳密に配置されたペプチドテンプレートを用いて、リン酸カルシウムのミネラリゼーションを行った。β-シート型ペプチド(LE)8-PEG70はグルタミン酸(E)とロイシン(L)の交互シークエンスにより設計し浸漬法により単分子膜を調製した。この基板上に酢酸カルシウム水溶液とリン酸水素二アンモニウム水溶液を交互に滴下しリン酸カルシウムを析出させた。AFM測定により、ペプチドによる等間隔のファイバー構造が観察された。溶液濃度Ca 50 mM, P 30 mMのとき、高配向のナノレーン状析出物がSEM測定より確認された。XPS、TEMおよびED測定からリン酸カルシウムの析出物はアモルファスであることが明らかになった。さらに析出の初期段階において析出形態の違いが確認された。

核酸塩基対を利用したβ‐シートペプチド自己組織化膜上への金ナノ粒子の固定化と配列制御　　　　　　　　　　　　　　　
野々山貴行, 樋口真弘, 田中正剛, 木下隆利
高分子学会予稿集(CD-ROM), 2009年09月01日, 日本語

ペプチドファイバーゲルによるアルブミンの認識　　　　　　　　　　　　　　　
野々山貴行, 斎藤愛, 田中正剛, 木下隆利
繊維学会夏季セミナー講演要旨集, 2009年08月27日, 日本語

ペプチド自己組織化ナノファイバー上への金ナノ粒子の選択的固定化　　　　　　　　　　　　　　　
野々山貴行, 樋口真弘, 田中正剛, 木下隆利
繊維学会夏季セミナー講演要旨集, 2009年08月27日, 日本語

相補的水素結合を利用したβ‐シートペプチド自己組織化膜上への金ナノ粒子の固定化　　　　　　　　　　　　　　　
野々山貴行, 田中正剛, 木下隆利
高分子学会予稿集(CD-ROM), 2009年05月12日, 日本語

相補的水素結合を利用したβ‐シートペプチド自己組織化膜上への金ナノ粒子の固定化　　　　　　　　　　　　　　　
野々山貴行, 田中正剛, 木下隆利
高分子学会予稿集(CD-ROM), 2008年09月09日, 日本語

Physics　　　　　　　　　　　　　　　
Hokkaido university

物理学I　　　　　　　　　　　　　　　
北海道大学

低エントロピー高分子網目材料の設計と機能創出
科学研究費助成事業 国際共同研究加速基金(国際先導研究)
2022年12月20日 - 2029年03月31日
グン 剣萍, Li Xiang, 野々山 貴行, 中島 祐
日本学術振興会, 国際共同研究加速基金(国際先導研究), 北海道大学, 22K21342

メタボリック材料システム：代謝に範を得た破壊と再形成による材料成長
科学研究費助成事業 基盤研究(S)
2022年04月27日 - 2027年03月31日
グン 剣萍, 中島 祐, 印出井 努, 野々山 貴行
日本学術振興会, 基盤研究(S), 北海道大学, 22H04968

工業リグニンの構造－物性相関の解明と高機能材料化技術の創出　　　　　　　　　　　　　　　
ALCA-Next
2023年11月 - 2027年03月
鈴木 栞, 野々山 貴行, 徳永 有希
国立研究開発法人 科学技術振興機構, 北海道大学, JPMJAN23C3

生物に習う高温でガラス化する高分子材料の創製とその学理解明　　　　　　　　　　　　　　　
2020年度創発的研究支援事業
2021年04月 - 2027年03月
国立研究開発法人科学技術振興機構, 北海道大学, 研究代表者

極限相分離構造形成とそれに伴う昇温過程におけるゴム－ガラス転移現象の学理解明
科学研究費助成事業 基盤研究(B)
2021年04月01日 - 2026年03月31日
野々山 貴行
日本学術振興会, 基盤研究(B), 北海道大学, 21H01990

力学トレーニングによる「自己進化」する材料の構築原理の確立
科学研究費助成事業 基盤研究(A)
2022年04月01日 - 2025年03月31日
グン 剣萍, 印出井 努, 野々山 貴行, キング ダニエル, 中島 祐
日本学術振興会, 基盤研究(A), 北海道大学, 22H00327

高強度ポーラスゲルによる３次元がん組織モデル創出とがん幹細胞標的新規治療法の開発
科学研究費助成事業 基盤研究(B)
2021年04月01日 - 2024年03月31日
津田 真寿美, 野々山 貴行, 田中 伸哉
がんの再発は、がん治療に耐性を示すがん幹細胞が生き残ることによって起きる。がんの根絶には、がん組織におけるがん幹細胞の誕生・生存機構の解明が必須であるが、がん幹細胞が微量なことに加えて、従来のポリスチレンdish上でのがん細胞単独培養法は生体内のがん組織環境と大きく乖離しており、真の解明に至っていない。研究代表者らは、近年、高強度ダブルネットワークゲル（DNゲル）上にがん細胞を播種すると、24時間以内に迅速にがん幹細胞が誘導されるリプログラミング（初期化）現象を見出した（Nat. Biomed. Eng., 2021）。当該技術を基盤として、本研究ではがん組織におけるがん幹細胞の誕生・生存機序の解明を目指す。
令和3年度は、高頻度に再発を引き起こす肉腫の生体内環境を模倣するために、高強度DNゲルの作製技術と多孔質ゲルを得る凍結重合法を組み合わせて、高強度多孔質（ポーラス）ゲルを作製した。ポーラスゲルは、1st モノマーにアニオン性高分子NaAMPSを用い、2ndモノマーに中性高分子AAmを用いた。筋組織を模倣するため、細胞外基質としてフィブロネクチンを吸着後、GFPラベル筋芽細胞を播種し、細胞の接着や長期生存を検討した。AAmの濃度を変えることでポーラスサイズを調整し、さらに細胞の播種方法を改善することにより、ポーラスゲルの深部まで細胞が進展するよう3次元組織モデルを最適化した。このポーラスゲルをマウスの筋肉内に埋植すると、１週間以内に宿主細胞がゲル内に侵入して組織を復元した。一方、氷の成長方向を制御するフリーズキャスティング法を用いた凍結重合法により、筋組織を模倣した高度な配向構造を有するポーラスゲルの創製に成功した。
日本学術振興会, 基盤研究(B), 北海道大学, 21H03802

犠牲結合原理が導く戦略：金属を凌駕するソフト・ハード複合強靭材料の創製と機能開拓
科学研究費助成事業 基盤研究(S)
2017年05月 - 2022年03月
龔剣萍
ハード相を犠牲結合とする複合材料では、プラスチックの三次元格子によるハード相と水中における膨潤能を有するハイドロゲルによるソフト相を用い、ソフト相とハード相のポアソン比ミスマッチが複合材料の膨潤・力学特性に与える影響を解析した。ハイドロゲルは、溶媒に浸漬させると溶媒を取り込んで膨潤（体積変化）する性質を持つ。ハード相にジャングルジム型構造を採用した複合材料を溶媒に浸漬させた場合、そのジャングルジム型構造がソフト相の膨潤に全く追随出来ないため、ソフト相の膨潤に伴ってハード相の構造が崩壊し、弾性率・強度が大きく損なわれる。一方、ハード相に負のポアソン比を持つオーセチック構造を採用した場合、ソフト相の膨潤収縮にハード相が追随可能であるため、複合材料が膨潤または収縮しても構造崩壊が起こらず、優れた力学特性が保たれることが見いだされた。
続いてソフト相を犠牲結合とする複合材料では、ソフト相の局所的大変形による粘弾性効果が、ソフト複合材料を大きく強靭化していることを見出した。複合材料の幅が狭い場合、その亀裂進行は、ソフト相からハード相（繊維）が引き抜かれることに起因するソフト相の破断により生じることが見いだされた。ここで、繊維引き抜きが起こる部位ではソフト相が局所的に高速で大変形し、粘性的なエネルギー散逸が生じることで、材料の引裂エネルギーが極めて高くなると予想された。我々は、この局所的な粘性散逸の効果を表す半経験的な式を導いた。本式に従い、ソフト相単独の機械的特性とハード相の構造因子を最適化することで、粘性散逸の効果を増大させ、本タイプのソフト複合材料の靭性をさらに高めることに成功した。
日本学術振興会, 基盤研究(S), 北海道大学, 競争的資金, 17H06144

ソフトフォトニッククリスタルの創製　　　　　　　　　　　　　　　
新学術領域研究(研究領域提案型)
2017年06月 - 2022年02月
龔剣萍
日本学術振興会, 競争的資金

高温で強靭化するアイソコリックゲルの創製　　　　　　　　　　　　　　　
科学研究費助成事業 挑戦的研究（萌芽）
2017年06月 - 2020年03月
野々山貴行
日本学術振興会, 研究代表者, 競争的資金

犠牲結合原理が導く戦略：金属を凌駕するソフト・ハード複合強靭材料の創製
科学研究費助成事業
2017年04月01日 - 2018年03月31日
グン 剣萍, 黒川 孝幸, 中島 祐, 野々山 貴行, キング ダニエル
本研究では、高靭性ゲルの力学挙動（引張試験で見られる降伏現象、弾性率の低下を伴うヒステリシス現象、および引裂試験で見られる亀裂周辺の降伏領域(内部破壊領域)の形成）の三つの特徴を評価することによって、ゲルの靭性及びその高靭性化機構を解明することを目的とした。研究機関内には、ポリアンフォライトゲル/グラスファイバー織物の複合体について、様々な幅のサンプルを作製して引裂試験を行い、破壊エネルギーと降伏領域の関係を見積もった。サンプルの幅が降伏領域のサイズ（~cm）より小さい場合、複合体の破壊エネルギーはサンプルの幅と正の相関があった。一方、サンプルの幅が降伏領域より大きい場合、複合体の破壊エネルギーはサンプルの幅に依存しなかった。これは、本複合体の異常に高い破壊エネルギーが、亀裂近傍の降伏領域形成によるエネルギー散逸によることを強く示唆する結果である。また、破壊されたサンプルを走査型電子顕微鏡で観察した結果、繊維近傍におけるゲル層の破壊が確認された。ここから、本複合体の変形時には、ゲル-繊維間の応力伝達により、ゲル層の変形と破壊によるエネルギー散逸が高効率で発生し、それが本複合体を高効率にタフ化していることが示唆された。
日本学術振興会, 基盤研究(A), 北海道大学, 17H01222

「犠牲結合原理」の普遍性の証明と多様な犠牲結合による高靭性・高機能ゲルの創製
科学研究費助成事業
2012年05月31日 - 2017年03月31日
グン 剣萍, 黒川 孝幸, 中島 祐, 野々山 貴行, 孫 桃林
本研究では、我々が近年提唱した「壊れやすい結合を柔軟なゲルに導入することで強靭化する」という全く新しい「犠牲結合原理」の実証とそれに伴う強靭な機能性ゲル材料の創製を目的とした。壊れやすい結合として共有結合、イオン結合、疎溶媒結合などをゲルに導入した結果、化学種・犠牲結合種のバリエーションを有する一連の強靭ゲルの合成に成功し、本原理がゲルの強靭化に普遍的に適用できることを明らかにした。また導入した犠牲結合の化学種に応じて自己修復性、異方性、構造色などを強靭ゲルに付与することに成功し、犠牲結合原理が多様な機能性ゲルの強靭化に有効であることを示した。
日本学術振興会, 基盤研究(S), 北海道大学, 24225006

高強度ハイドロゲル中でのリン酸カルシウムのバイオミネラリゼーション　　　　　　　　　　　　　　　
科学研究費助成事業 若手研究B
2014年04月 - 2017年03月
野々山貴行
日本学術振興会, 研究代表者, 競争的資金