Updated on 2024/10/07

写真a

 
IZUMI Kenji
 
Organization
Academic Assembly Institute of Medicine and Dentistry SHIGAKU KEIRETU Professor
Graduate School of Medical and Dental Sciences Oral Life Science Oral Biological Science Professor
Title
Professor
Contact information
メールアドレス
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The Best Research Achievement in Research Career

Degree

  • 博士(歯学) ( 1992.3   新潟大学 )

Research Interests

  • 組織工学

  • Oral and Maxillotacial Surgery

  • Tissue Engineering

Research Areas

  • Life Science / Regenerative dentistry and dental engineering

  • Life Science / Prosthodontics

Research History (researchmap)

  • 株式会社CollaWind   代表取締役CEO

    2023.6

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    Country:Japan

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  • Niigata University   Graduate School of Medical and Dental Sciences   Professor

    2013.6

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  • Niigata University   Graduate School of Medical and Dental Sciences   Associate Professor

    2009.1 - 2013.5

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  • ミシガン大学   歯学部   Research Scientist/Clinical Assistant Professor

    2005.3 - 2008.12

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  • ミシガン大学   歯学部口腔外科学   Visiting Professor

    2002.7 - 2005.2

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  • Niigata University   Graduate School of Medical and Dental Sciences   Assistant Professor

    2001.4 - 2005.2

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  • ミシガン大学   歯学部口腔外科学   Visiting Professor

    1997.5 - 1999.2

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  • University of Michigan, visiting professor

    1997 - 1999

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  • Niigata University   Faculty of Dentistry   Research Assistant

    1992.7 - 2001.3

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  • Niigata University   Faculty of Dentistry

    1992.4 - 1992.6

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Research History

  • Niigata University   Graduate School of Medical and Dental Sciences Oral Life Science Oral Biological Science   Professor

    2013.6

  • Niigata University   Graduate School of Medical and Dental Sciences Oral Life Science Oral Biological Science   Associate Professor

    2009.1 - 2013.5

  • Niigata University   Faculty of Dentistry School of Dentistry   Associate Professor

    2009.1 - 2013.5

Education

  • Niigata University   Graduate School, Division of Dental Research

    - 1992

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  • Niigata University   歯学研究科   口腔外科学

    - 1992

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    Country: Japan

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  • Niigata University   Faculty of Dentistry

    - 1988

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  • Niigata University   Faculty of Dentistry   School of Dentistry

    - 1988

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    Country: Japan

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Professional Memberships

 

Papers

  • The effects of carbon-ion beam irradiation on three-dimensional in vitro models of normal oral mucosa and oral cancer: development of a novel tool to evaluate cancer therapy Reviewed

    Eriko Naito, Kazuyo Igawa, Sho Takada, Kenta Haga, Witsanu Yortchan, Orakarn Suebsamarn, Ryota Kobayashi, Manabu Yamazaki, Jun-ichi Tanuma, Tsuyoshi Hamano, Takashi Shimokawa, Kei Tomihara, Kenji Izumi

    In Vitro Cellular & Developmental Biology - Animal   2024.8

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

    DOI: 10.1007/s11626-024-00958-4

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    Other Link: https://link.springer.com/article/10.1007/s11626-024-00958-4/fulltext.html

  • Radiation evaluation assay using a human three-dimensional oral cancer model for clinical radiation therapy. Reviewed

    Lucie Sercombe, Kazuyo Igawa, Kenji Izumi

    Talanta Open   9   100297 - 100297   2024.8

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    Authorship:Last author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    DOI: 10.1016/j.talo.2024.100297

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  • Recent trends and perspectives in reconstruction and regeneration of intra/extra-oral wounds using tissue-engineered oral mucosa equivalents Reviewed

    Kenji Izumi, Witsanu Yortchan, Yuka Aizawa, Ryota Kobayashi, Emi Hoshikawa, Yiwei Ling, Ayako Suzuki

    Japanese Dental Science Review   59 ( DEC )   365 - 374   2023.12

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    DOI: 10.1016/j.jdsr.2023.10.002

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  • Development of a lip vermilion epithelium reconstruction model using keratinocytes from skin and oral mucosa Reviewed

    Eri Kobayashi, Yiwei Ling, Ryota Kobayashi, Emi Hoshikawa, Eriko Itai, Osamu Sakata, Shujiro Okuda, Eiji Naru, Kenji Izumi

    Histochemistry and Cell Biology   160 ( 4 )   349 - 359   2023.10

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

    DOI: 10.1007/s00418-023-02206-4

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    Other Link: https://link.springer.com/article/10.1007/s00418-023-02206-4/fulltext.html

  • The EGF/EGFR axis and its downstream signaling pathways regulate the motility and proliferation of cultured oral keratinocytes. Reviewed International journal

    Ryota Kobayashi, Emi Hoshikawa, Taisuke Saito, Orakarn Suebsamarn, Eriko Naito, Ayako Suzuki, Seiichiro Ishihara, Hisashi Haga, Kei Tomihara, Kenji Izumi

    FEBS open bio   13 ( 8 )   1469 - 1484   2023.5

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    We previously reported that the cell and colony motion of oral keratinocytes are correlated with proliferative capacity, and speculated that this may be a specific index for monitoring cell quality. However, how cell motility and proliferation are regulated by signaling pathways remains unelucidated. Here, we found that the regulation of cell motility and proliferative capacity of oral keratinocytes can be attributed to the epidermal growth factor/epidermal growth factor receptor (EGF/EGFR) axis. The EGFR downstream cascade involving the Src/PI3K/Akt/mTOR signaling pathway showed a major effect on cell motility and proliferative capacity in oral keratinocytes. Furthermore, both EGFR and Src attenuated E-cadherin expression. Taken together, these findings provide a potential basis for future quality control of cells for therapeutic use.

    DOI: 10.1002/2211-5463.13653

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  • Development of the Follow-Up Human 3D Oral Cancer Model in Cancer Treatment Invited Reviewed

    Kazuyo Igawa, Kenji Izumi, Yoshinori Sakurai

    BioTech   12 ( 2 )   35 - 35   2023.5

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

    As function preservation cancer therapy, targeted radiation therapies have been developed for the quality of life of cancer patients. However, preclinical animal studies evaluating the safety and efficacy of targeted radiation therapy is challenging from the viewpoints of animal welfare and animal protection, as well as the management of animal in radiation-controlled areas under the regulations. We fabricated the human 3D oral cancer model that considers the time axis of the follow up in cancer treatment. Therefore, in this study, the 3D model with human oral cancer cells and normal oral fibroblasts was treated based on clinical protocol. After cancer treatment, the histological findings of the 3D oral cancer model indicated the clinical correlation between tumor response and surrounding normal tissue. This 3D model has potential as a tool for preclinical studies alternative to animal studies.

    DOI: 10.3390/biotech12020035

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  • Cholesterol Is a Regulator of CAV1 Localization and Cell Migration in Oral Squamous Cell Carcinoma Reviewed

    Nyein Nyein Chan, Manabu Yamazaki, Satoshi Maruyama, Tatsuya Abé, Kenta Haga, Masami Kawaharada, Kenji Izumi, Tadaharu Kobayashi, Jun-ichi Tanuma

    International Journal of Molecular Sciences   24 ( 7 )   6035   2023.3

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

    DOI: 10.3390/ijms24076035

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  • In-process monitoring of a tissue-engineered oral mucosa fabricated on a micropatterned collagen scaffold: use of optical coherence tomography for quality control Reviewed International journal

    O. Suebsamarn, Y. Kamimura, A. Suzuki, Y. Kodama, R. Mizuno, Y. Osawa, T. Komatsu, T. Sato, K. Haga, R. Kobayashi, E. Naito, M. Kida, K. Kishimoto, J. Mizuno, H. Hayasaki, K. Izumi

    Heliyon   8 ( 11 )   e11468 - e11468   2022.11

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    BACKGROUND: We previously reported a novel technique for fabricating dermo-epidermal junction (DEJ)-like micropatterned collagen scaffolds to manufacture an ex vivo produced oral mucosa equivalent (EVPOME) for clinical translation; however, more biomimetic micropatterns are required to promote oral keratinocyte-based tissue engineering/regenerative medicine. In addition, in-process monitoring for quality control of tissue-engineered products is key to successful clinical outcomes. However, evaluating three-dimensional tissue-engineered constructs such as EVPOME is challenging. This study aimed to update our technique to fabricate a more biomimetic DEJ structure of oral mucosa and to investigate the efficacy of optical coherence tomography (OCT) in combination with deep learning for non-invasive EVPOME monitoring. METHODS: A picosecond laser-textured microstructure mimicking DEJ on stainless steel was used as a negative mould to fabricate the micropatterned collagen scaffold. During EVPOME manufacturing, OCT was applied twice to monitor the EVPOME and evaluate its epithelial thickness. FINDINGS: Our moulding system resulted in successful micropattern replication on the curved collagen scaffold. OCT imaging visualised the epithelial layer and the underlying micropatterned scaffold in EVPOME, enabling to non-invasively detect specific defects not found before the histological examination. Additionally, a gradual increase in epithelial thickness was observed over time. CONCLUSION: These findings demonstrate the feasibility of using a stainless-steel negative mould to create a more biomimetic micropattern on collagen scaffolds and the potential of OCT imaging for quality control in oral keratinocyte-based tissue engineering/regenerative medicine.

    DOI: 10.1016/j.heliyon.2022.e11468

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  • Fabrication of Micropatterned Fish Scale Collagen Scaffold Using Microelectromechanical Systems Technologies for Oral Mucosa Tissue Engineering Reviewed

    Kazuma Kishimoto, Keito Miwa, Ayako Suzuki, Isamu Yamaguchi, Yoshihiro Kodama, Orakarn Suebsamarn, Shuichi Shoji, Kenji Izumi, Jun Mizuno

    Transactions of The Japan Institute of Electronics Packaging   15   E21 - 008   2022.7

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Japan Institute of Electronics Packaging  

    In this study, we developed a novel tissue-engineered oral mucosa with micropatterned fish scale collagen as a biomaterial scaffold. Marine collagen derived from the fish scale is considered to have a significant potential of becoming an alternative transplant material for mucosa regeneration due to its vast resources and minimal risk of transmitting infectious diseases. Eight different types of Grid-Rectangular (GR) negative patterns were manufactured using microelectromechanical systems technologies to evaluate size dependency in collagen replication and epithelial cell layer formation. Among the obtained histological images of the tissue-engineered oral mucosa, the height, width, and channel width of 100 μm showed the most successful formation of the epithelial layer and the most similar structure of oral mucosa <i>in vivo</i>. This study not only established a technique for fabricating a novel biomimetic scaffold but also made an extended approach to structural optimization for mold fabrication. We believe this study will be a crucial step for structural optimization in the future and will have a positive impact on the field of tissue regeneration.

    DOI: 10.5104/jiepeng.15.e21-008-1

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  • Analysis of setting expansion pressure on dental calcium sulfate hemihydrate using universal testing machine Reviewed

    41   162 - 172   2022.3

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    DOI: 10.18939/jsdmd.41.2_162

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  • Detection of Potential Markers for Lip Vermilion Epithelium in Japanese Macaques Based on the Results of Gene Expression Profile Reviewed

    Hiroko Kato, Yiwei Ling, Emi Hoshikawa, Ayako Suzuki, Kenta Haga, Eriko Naito, Atsushi Uenoyama, Shujiro Okuda, Kenji Izumi

    Anatomia   1 ( 1 )   3 - 13   2022.1

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    Authorship:Corresponding author   Publishing type:Research paper (scientific journal)   Publisher:MDPI AG  

    Development of effective in vitro human lip models, specific to the vermilion epithelium, has not progressed as much as that of skin and oral mucosa/gingiva models in vitro. Our histologic examination demonstrated that a Japanese macaque (male, 7 years and 9 months old) had vermilion in the lip distinct from adjacent skin and oral mucosa, resembling histological characteristics of the human lip. Therefore, in this study, we examined the gene expression profile of the three distinct epithelia (skin/vermilion/oral mucosa) within the lip of a Japanese macaque to explore a single potential marker of human vermilion epithelium. Six pairwise comparisons in the skin/vermilion/oral mucosa epithelium in vitro and in vivo revealed 69 differentially up-regulated genes in vermilion epithelium in vivo, in which a few unique genes were highly expressed when compared with both skin and oral mucosa epithelium in vivo using clustering analysis. However, we could not detect a single marker specific to vermilion epithelium supported by the gene expression profile of a Japanese macaque. Instead, the pair of keratin 10 and small proline-rich protein 3 resulted in a potential marker of vermilion epithelium in the human lip (female, 53-year-old) via a double-immunostaining technique. Nonetheless, our result may provide further clues leading to other potential markers of the vermilion epithelium.

    DOI: 10.3390/anatomia1010002

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  • Laminin Isoforms in Human Dental Pulp: Lymphatic Vessels Express Laminin-332, and Schwann Cell-Associated Laminin-211 Modulates CD163 Expression of M2-like Macrophages. Reviewed International journal

    Nagako Yoshiba, Naoki Edanami, Naoto Ohkura, Tomoki Maekawa, Naoki Takahashi, Takahiro Tsuzuno, Takeyasu Maeda, Koichi Tabeta, Kenji Izumi, Yuichiro Noiri, Kunihiko Yoshiba

    ImmunoHorizons   5 ( 12 )   1008 - 1020   2021.12

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

    Laminin, a basement membrane heterotrimeric glycoprotein composed of α/β/γ subunits, has important tissue-specific functions in the control of cellular behavior. Our recent study showed the colocalization of CD163+ M2-like macrophages with Schwann cells in human dental pulp, leading us to hypothesize that the laminin isoform of Schwann cells is associated with CD163 expression. The present study investigated the distribution of laminin isoforms in human dental pulp and the underlying mechanisms that affect macrophage phenotypes. Immunofluorescence analysis indicated that blood vessels were exclusively positive for laminin α4 and α5, whereas laminin α2 was associated with Schwann cells. Unexpectedly, laminin α3/laminin-332 (α3β3γ2) was detected on lymphatic vessels. In intact and carious teeth, CD163+ cells were associated with laminin α2, whereas CD206 single-positive cells were present inside, outside, and along blood vessels. In vitro incubation of THP-1 macrophages in plates coated with laminin-211/511 or its functionally analogous E8 fragments of α-chain (E8-α) indicated that cell shapes differed between macrophages grown on laminin-211/E8-α2 and macrophages grown on laminin-511/E8-α5. Laminin-211/E8-α2-coated plates upregulated CD163 expression, compared with laminin-511/E8-α5-coated plates. Integrin α3- and integrin α6-neutralizing Abs altered the shape of THP-1 macrophages and upregulated mRNA levels of CD206 and CD163 in macrophages grown on laminin-511; the neutralizing Abs did not affect macrophages grown on laminin-211. These findings suggest that laminin isoforms differentially regulate macrophage behavior via distinct integrin-laminin affinities. Of note, laminin-332 is expressed by pulpal lymphatic vessels, the existence of which has been debated; laminin-211 might have a role in maintaining CD163 expression on macrophages.

    DOI: 10.4049/immunohorizons.2100110

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  • Cells/colony motion of oral keratinocytes determined by non-invasive and quantitative measurement using optical flow predicts epithelial regenerative capacity Reviewed

    Emi Hoshikawa, Taisuke Sato, Kenta Haga, Ayako Suzuki, Ryota Kobayashi, Koichi Tabeta, Kenji Izumi

    Scientific Reports   11 ( 1 )   2021.12

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    Authorship:Corresponding author   Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media {LLC}  

    <title>Abstract</title>Cells/colony motion determined by non-invasive, quantitative measurements using the optical flow (OF) algorithm can indicate the oral keratinocyte proliferative capacity in early-phase primary cultures. This study aimed to determine a threshold for the cells/colony motion index to detect substandard cell populations in a subsequent subculture before manufacturing a tissue-engineered oral mucosa graft and to investigate the correlation with the epithelial regenerative capacity. The distinctive proliferating pattern of first-passage [passage 1 (p1)] cells reveals the motion of p1 cells/colonies, which can be measured in a non-invasive, quantitative manner using OF with fewer full-screen imaging analyses and cell segmentations. Our results demonstrate that the motion index lower than 40 μm/h reflects cellular damages by experimental metabolic challenges although this value shall only apply in case of our culture system. Nonetheless, the motion index can be used as the threshold to determine the quality of cultured cells while it may be affected by any different culture conditions. Because the p1 cells/colony motion index is correlated with epithelial regenerative capacity, it is a reliable index for quality control of oral keratinocytes.

    DOI: 10.1038/s41598-021-89073-y

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    Other Link: http://www.nature.com/articles/s41598-021-89073-y

  • Crosstalk between oral squamous cell carcinoma cells and cancer-associated fibroblasts via the TGF-β/SOX9 axis in cancer progression Reviewed

    Kenta Haga, Manabu Yamazaki, Satoshi Maruyama, Masami Kawaharada, Ayako Suzuki, Emi Hoshikawa, Nyein Nyein Chan, Akinori Funayama, Toshihiko Mikami, Tadaharu Kobayashi, Kenji Izumi, Jun-ichi Tanuma

    Translational Oncology   14 ( 12 )   101236 - 101236   2021.12

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    Authorship:Corresponding author   Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    DOI: 10.1016/j.tranon.2021.101236

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  • Isolation and Culture of Primary Oral Keratinocytes from the Adult Mouse Palate. Reviewed International journal

    Yen Xuan Ngo, Kenta Haga, Ayako Suzuki, Hiroko Kato, Hiromi Yanagisawa, Kenji Izumi, Aiko Sada

    Journal of visualized experiments : JoVE   ( 175 )   2021.9

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    For years, most studies involving keratinocytes have been conducted using human and mouse skin epidermal keratinocytes. Recently, oral keratinocytes have attracted attention because of their unique function and characteristics. They maintain the homeostasis of the oral epithelium and serve as resources for applications in regenerative therapies. However, in vitro studies that use oral primary keratinocytes from adult mice have been limited due to the lack of an efficient and well-established culture protocol. Here, oral primary keratinocytes were isolated from the palate tissues of adult mice and cultured in a commercial low-calcium medium supplemented with a chelexed-serum. Under these conditions, keratinocytes were maintained in a proliferative or stem cell-like state, and their differentiation was inhibited even after increased passages. Marker expression analysis showed that the cultured oral keratinocytes expressed the basal cell markers p63, K14, and α6-integrin and were negative for the differentiation marker K13 and the fibroblast marker PDGFRα. This method produced viable and culturable cells suitable for downstream applications in the study of oral epithelial stem cell functions in vitro.

    DOI: 10.3791/62820

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  • The human vermilion surface contains a rich amount of cholesterol sulfate than the skin. Reviewed International journal

    Md Al Mamun, Ariful Islam, Md Mahmudul Hasan, A S M Waliullah, Zinat Tamannaa, Do Huu Chi, Tomohito Sato, Tomoaki Kahyo, Kenji Kikushima, Yutaka Takahashi, Eiji Naru, Osamu Sakata, Mutsumi Yamanoi, Eri Kobayashi, Kenji Izumi, Tetsuya Honda, Yoshiki Tokura, Mitsutoshi Setou

    Journal of dermatological science   103 ( 3 )   143 - 150   2021.7

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    BACKGROUND: The vermilion of the human lip presents characteristic features and undergoes aging faster than the skin. Therefore, knowledge of the vermilion surface-specific functional molecules is important to understand lip aging and formulate lip care products. Previously, we analyzed the free fatty acids distributions and showed that docosahexaenoic acid highly accumulated in the vermilion's epithelium than in the skin. OBJECTIVE: We aimed to explore the functional molecules other than the free fatty acids on the vermilion's surface. METHODS: Human lip tissues from children and tape-stripped samples from smooth and rough lips of adults were measured by desorption electrospray ionization-mass spectrometry imaging (DESI-MSI). RESULTS: DESI-MSI of children's lip sections revealed a major distribution of five phospholipid species in the viable layer, but not in the superficial area, of both the vermilion and the skin than that in the underlying tissue. Interestingly, a remarkably higher distribution of cholesterol sulfate was observed in the vermilion's superficial area compared to that in the skin in all subjects under this study. Furthermore, theDESI-MSI of tape-stripped lip sample showed an overall higher accumulation of cholesterol sulfate in the stratum corneum of the rough lip than that in the smooth lips showed an overall higher accumulation of cholesterol sulfate in the stratum corneum of the rough lips than that in the smooth lips. CONCLUSION: Our study concluded that cholesterol sulfate has a characteristic distribution to the vermilion's surface and showed an association with the roughness of the lip.

    DOI: 10.1016/j.jdermsci.2021.07.008

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  • HEATR1, a novel interactor of Pontin/Reptin, stabilizes Pontin/Reptin and promotes cell proliferation of oral squamous cell carcinoma Reviewed

    Akihiko Nakamura, Yoshito Kakihara, Akinori Funayama, Kenta Haga, Toshihiko Mikami, Daiki Kobayashi, Yutaka Yoshida, Kenji Izumi, Tadaharu Kobayashi, Makio Saeki

    Biochemical and Biophysical Research Communications   557   294 - 301   2021.6

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    DOI: 10.1016/j.bbrc.2021.04.021

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  • Perivascular Hedgehog responsive cells play a critical role in peripheral nerve regeneration via controlling angiogenesis Reviewed International journal

    Yurie Yamada, Jun Nihara, Supaluk Trakanant, Takehisa Kudo, Kenji Seo, Izumi Iida, Kenji Izumi, Masayuki Kurose, Yutaka Shimomura, Miho Terunuma, Takeyasu Maeda, Atsushi Ohazama

    Neuroscience Research   173   62 - 70   2021.6

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    Hh signaling has been shown to be activated in intact and injured peripheral nerve. However, the role of Hh signaling in peripheral nerve is not fully understood. In the present study, we observed that Hh signaling responsive cells [Gli1(+) cells] in both the perineurium and endoneurium. In the endoneurium, Gli1(+) cells were classified as blood vessel associated or non-associated. After injury, Gli1(+) cells around blood vessels mainly proliferated to then accumulate into the injury site along with endothelial cells. Hh signaling activity was retained in Gli1(+) cells during nerve regeneration. To understand the role of Hedgehog signaling in Gli1(+) cells during nerve regeneration, we examined mice with Gli1(+) cells-specific inactivation of Hh signaling (Smo cKO). After injury, Smo cKO mice showed significantly reduced numbers of accumulated Gli1(+) cells along with disorganized vascularization at an early stage of nerve regeneration, which subsequently led to an abnormal extension of the axon. Thus, Hh signaling in Gli1(+) cells appears to be involved in nerve regeneration through controlling new blood vessel formation at an early stage.

    DOI: 10.1016/j.neures.2021.06.003

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  • Identification and characterization of R2TP in the development of oral squamous cell carcinoma Reviewed

    Tetsuo Kiguchi, Yoshito Kakihara, Manabu Yamazaki, Kouji Katsura, Kenji Izumi, Jun-ichi Tanuma, Takashi Saku, Ritsuo Takagi, Makio Saeki

    Biochemical and Biophysical Research Communications   548   161 - 166   2021.4

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    DOI: 10.1016/j.bbrc.2021.02.074

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  • Effect of pre-coating with methyl methacrylate containing UV photoinitiators on the bond strength of poly(ether ether ketone).

    Seigo Okawa, Yujin Aoyagi, Tatsuya Kimura, Kenji Izumi

    Dental materials journal   40 ( 2 )   519 - 524   2021.3

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    This study investigates the effect of pre-coating with methyl methacrylate (MMA) containing ultraviolet (UV) photoinitiators on the bond strength of poly(ether ether ketone) (PEEK). Cylindrical PEEK blocks were irradiated with 365 nm UV light for 5-20 s after they were coated with MMA containing 0.4-3.0 wt% UV photoinitiators: [1-phenyl-1,2-propanedione (PPD)], [diphenyl(2,4,6-trimethylbenzoyl) (TMDPO)], and [phenyl bis(2,4,6-trimethylbenzoyl) phosphine oxide (BTMPO)]. Pre-coated PEEKs were bonded to PEEK blocks with a MMA-based adhesive resin. The shear bond strength was measured using a universal testing machine. Secondary electron images were captured to observe failure surfaces. The data were analyzed with one- and two-way ANOVA and Tukey's post hoc tests (p<0.05). The highest bond strength (20.7±5.1 MPa) was observed for pre-coating with MMA containing 0.4 wt% BTMPO, for 20 s of UV irradiation. Cohesive failure of the adhesive resin was observed. The use of this pre-coating led to improved bonding performance of PEEK.

    DOI: 10.4012/dmj.2020-068

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  • Metabolomic Alteration of Oral Keratinocytes and Fibroblasts in Hypoxia Reviewed

    Hiroko Kato, Masahiro Sugimoto, Ayame Enomoto, Miku Kaneko, Yuko Hara, Naoaki Saito, Aki Shiomi, Hisashi Ohnuki, Kenji Izumi

    Journal of Clinical Medicine   10 ( 6 )   1156 - 1156   2021.3

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    Authorship:Corresponding author   Publishing type:Research paper (scientific journal)   Publisher:{MDPI} {AG}  

    The oxygen concentration in normal human tissue under physiologic conditions is lower than the atmospheric oxygen concentration. The more hypoxic condition has been observed in the cells with wound healing and cancer. Somatic stem cells reside in a hypoxic microenvironment in vivo and prefer hypoxic culture conditions in vitro. Oral mucosa contains tissue-specific stem cells, which is an excellent tissue source for regenerative medicine. For clinical usage, maintaining the stem cell in cultured cells is important. We previously reported that hypoxic culture conditions maintained primary oral keratinocytes in an undifferentiated and quiescent state and enhanced their clonogenicity. However, the metabolic mechanism of these cells is unclear. Stem cell biological and pathological findings have shown that metabolic reprogramming is important in hypoxic culture conditions, but there has been no report on oral mucosal keratinocytes and fibroblasts. Herein, we conducted metabolomic analyses of oral mucosal keratinocytes and fibroblasts under hypoxic conditions. Hypoxic oral keratinocytes and fibroblasts showed a drastic change of metabolite concentrations in urea cycle metabolites and polyamine pathways. The changes of metabolic profiles in glycolysis and the pentose phosphate pathway under hypoxic conditions in the oral keratinocytes were consistent with those of other somatic stem cells. The metabolic profiles in oral fibroblasts showed only little changes in any pathway under hypoxia except for a significant increase in the antioxidant 2-oxoglutaric acid. This report firstly provides the holistic changes of various metabolic pathways of hypoxic cultured oral keratinocytes and fibroblasts.

    DOI: 10.3390/jcm10061156

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  • Fabrication of Micropatterned Fish Scale Collagen Scaffold Using Soft Lithography for Oral Mucosa Tissue Engineering

    Kazuma Kishimoto, Keito Miwa, Ayako Suzuki, Isamu Yamaguchi, Yoshihiro Kodama, Orakarn Suebsamarn, Shuichi Shoji, Kenji Izumi, Jun Mizuno

    2021 INTERNATIONAL CONFERENCE ON ELECTRONICS PACKAGING (ICEP 2021)   25 - 26   2021

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    Language:English   Publishing type:Research paper (international conference proceedings)   Publisher:IEEE  

    Fish-derived collagen is considered a promising material for oral mucosa tissue engineering because it is free from risk of transmissible infectious diseases. We developed a novel fish scale collagen scaffold with micropatterns on which oral keratinocytes are cultured to create a tissue-engineered oral mucosa. Anisotropic and isotropic etching were used to fabricate negative patterns on the Si substrate and soft lithography was used to translate the patterns to PDMS and fish scale collagen. The histological evaluation of the tissue-engineered oral mucosa confirmed the successful formation of the epithelial layer mimicking oral mucosa in vivo. This study suggests that our novel approach for fabricating biomimetic scaffold is promising and will make a huge contribution to the field of oral mucosa regeneration.

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  • Manufacturing micropatterned collagen scaffolds with chemical-crosslinking for development of biomimetic tissue-engineered oral mucosa Reviewed

    Ayako Suzuki, Yoshihiro Kodama, Keito Miwa, Kazuma Kishimoto, Emi Hoshikawa, Kenta Haga, Taisuke Sato, Jun Mizuno, Kenji Izumi

    Scientific Reports   10 ( 1 )   22192 - 22192   2020.12

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    <title>Abstract</title>The junction between the epithelium and the underlying connective tissue undulates, constituting of rete ridges, which lack currently available soft tissue constructs. In this study, using a micro electro mechanical systems process and soft lithography, fifteen negative molds, with different dimensions and aspect ratios in grid- and pillar-type configurations, were designed and fabricated to create three-dimensional micropatterns and replicated onto fish-scale type I collagen scaffolds treated with chemical crosslinking. Image analyses showed the micropatterns were well-transferred onto the scaffold surfaces, showing the versatility of our manufacturing system. With the help of rheological test, the collagen scaffold manufactured in this study was confirmed to be an ideal gel and have visco-elastic features. As compared with our previous study, its mechanical and handling properties were improved by chemical cross-linking, which is beneficial for grafting and suturing into the complex structures of oral cavity. Histologic evaluation of a tissue-engineered oral mucosa showed the topographical microstructures of grid-type were well-preserved, rather than pillar-type, a well-stratified epithelial layer was regenerated on all scaffolds and the epithelial rete ridge-like structure was developed. As this three-dimensional microstructure is valuable for maintaining epithelial integrity, our micropatterned collagen scaffolds can be used not only intraorally but extraorally as a graft material for human use.

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  • Higher Accumulation of Docosahexaenoic Acid in the Vermilion of the Human Lip than in the Skin Reviewed International journal

    Md. Al Mamun, Shumpei Sato, Eiji Naru, Osamu Sakata, Emi Hoshikawa, Ayako Suzuki, Ariful Islam, Tomoaki Kahyo, Tomohito Sato, Takashi K. Ito, Makoto Horikawa, Reimu Fukui, Kenji Izumi, Mitsutoshi Setou

    International Journal of Molecular Sciences   21 ( 8 )   2020.4

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    The vermilion of the human lip is a unique facial area because of certain distinguishing features from the adjacent tissues such as the white lip (skin) and oral mucosa. However, the distinction in terms of molecular distribution between the vermilion and skin has remained unexplored. Therefore, we aimed to map the human lip by mass spectrometry imaging to gain understanding of the free fatty acid distribution in the vermilion. The lip specimens trimmed off during cheiloplasty were analyzed using desorption electrospray ionization-mass spectrometry imaging. Distributions of two monounsaturated fatty acids and three polyunsaturated fatty acids were observed in the human lip tissue: palmitoleic acid (POA) and oleic acid (OA) and linoleic acid (LA), arachidonic acid (AA), and docosahexaenoic acid (DHA), respectively. Although POA, OA, LA, and AA were differentially distributed across the vermilion and skin, DHA showed a higher accumulation in the epithelium of the vermilion compared to that in the skin. Our results clearly demonstrated the difference in fatty acid distributions between the vermilion and skin. The highly abundant DHA in the epithelium of the vermilion may have an antioxidant role and may thus protect the lip from aging. Our findings can provide a novel strategy for treating lip disorders.

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  • Development of microstructured fish scale collagen scaffolds to manufacture a tissue-engineered oral mucosa equivalent Reviewed International journal

    Kenji Izumi

    Journal of Biomaterials Science, Polymer Edition   31 ( 5 )   578 - 600   2020.1

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    The present study aimed to develop a more biomimetic tissue-engineered oral mucosa equivalent comprising 1% type I tilapia scale collagen scaffold having microstructures mimicking the dermal-epidermal junction of oral mucosa and oral keratinocytes as graft materials for human use. We designed four micropattern prototypes mimicking the dermal-epidermal junction. Using a semiconductor process and soft lithography, negative molds were fabricated to develop microstructures using both polydimethylsiloxane and silicon substrates. Micropattern configurations of dermal-epidermal junctions manufactured from fish collagen consisting of a fibril network using our micropatterning system were well preserved, although the internal fibril network of the pillar pattern was sparse. Mixing 1% chondroitin sulfate with the collagen matrix minimized tissue-engineered oral mucosa equivalent contraction. Histologic examinations showed a flattening of the vertical dimensions of all microstructures and expansion of their pitches, indicating changes in the originally designed configurations. Nonetheless, histologic examinations revealed that a fully differentiated and stratified epithelial layer was developed on all scaffolds, suggesting that the microstructured fish scale collagen scaffolds have potential in the manufacturing of tissue-engineered oral mucosa equivalents for clinical use; however, enhancement of the mechanical properties of micropatterns is required. Our micropatterning technology can also apply to the development of oral mucosa in vitro models.

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  • Noninvasive measurement of cell/colony motion using image analysis methods to evaluate the proliferative capacity of oral keratinocytes as a tool for quality control in regenerative medicine Reviewed

    Emi Hoshikawa, Taisuke Sato, Yoshitaka Kimori, Ayako Suzuki, Kenta Haga, Hiroko Kato, Koichi Tabeta, Daisuke Nanba, Kenji Izumi

    Journal of Tissue Engineering   10   204173141988152 - 204173141988152   2019.1

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    Image-based cell/colony analyses offer promising solutions to compensate for the lack of quality control (QC) tools for noninvasive monitoring of cultured cells, a regulatory challenge in regenerative medicine. Here, the feasibility of two image analysis algorithms, optical flow and normalised cross-correlation, to noninvasively measure cell/colony motion in human primary oral keratinocytes for screening the proliferative capacity of cells in the early phases of cell culture were examined. We applied our software to movies converted from 96 consecutive time-lapse phase-contrast images of an oral keratinocyte culture. After segmenting the growing colonies, two indices were calculated based on each algorithm. The correlation between each index of the colonies and their proliferative capacity was evaluated. The software was able to assess cell/colony motion noninvasively, and each index reflected the observed cell kinetics. A positive linear correlation was found between cell/colony motion and proliferative capacity, indicating that both algorithms are potential tools for QC.

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  • Tissue Engineered Oral Mucosa Reviewed

    Izumi, K., Kato, H., Feinberg, S.E.

    Stem Cell Biology and Tissue Engineering in Dental Sciences   53   721 - 731   2015

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    Oral mucosa primarily acts as a barrier against the external harmful environments. Loss of its barrier function due to diseases or injury will cause significant dysfunction within the oral cavity. Surgeons are frequently confronted with finding an acceptable source of autologous grafts for reconstruction of oral mucosa defects. Thus, there is a need to overcome these shortcomings of limited supply and donor site morbidity in the current surgical management/reconstruction of oral mucosa defects. Tissue engineering/regenerative medicine is an interdisciplinary field of developmental biology, life sciences, and engineering efforts that attempts to address challenges in the clinical arena. The understanding of the growth and functions of cells, the principles and methods of engineering, and the signals regulating cellular responses drives the fabrication of matrices and the design of tissue assembly to generate tissue-engineered products for in vivo and in vitro applications. Progress has been made over the years in the development of tissue-engineered substitutes that mimic human oral mucosa, either to be used as grafts for the replacement of mucosa defects, or for the in vitro oral mucosa models while tissue engineering of oral mucosa is still in its infancy. An increased understanding of stem cells, scaffolding, and signaling with extracellular matrix interactions will make its future possible. This chapter gives a comprehensive overview of the developments and future prospects of tissue-engineered constructs as oral mucosa substitutes for tissue repair and regeneration.

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  • Hypoxia induces an undifferentiated phenotype of oral keratinocytes in vitro Reviewed

    Kato, H., Izumi, K., Uenoyama, A., Shiomi, A., Kuo, S., Feinberg, S.E.

    Cells Tissues Organs   199 ( 5-6 )   393 - 404   2014

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    The aim of this study was to determine the effects of hypoxia on the proliferating potential and phenotype of primary human oral keratinocytes cultured at ambient oxygen tension (20%) or at different levels of hypoxia (2 and 0.5% O-2). The effects of oxygen tensions on cellular metabolic activity, cell proliferation, clonogenicity and proliferation heterogeneity were measured. Cell cycle profiles were analyzed by a fluorescent-activated cell sorter, and p21(WAF1/CIP1) expression in the G(0)/G(1) phase was also concomitantly quantitated. The expression levels of cell cycle regulatory proteins were examined by immunoblotting, and the cellular senescence was assessed by senescence-associated beta-galactosidase staining. Basal and suprabasal keratinocyte phenotypes were determined by the expression levels of 14-3-3 sigma, p75(NTR) and alpha 6 integrin. Despite having a lower metabolism, the proliferation rate and clonogenic potential were remarkably enhanced in hypoxic cells. The significantly higher percentage of cells in the G(0)/G(1) phase under hypoxia and the expression patterns of cell cycle regulatory proteins in hypoxic cells were indicative of a state of cell cycle arrest in hypoxia. Furthermore, a decrease in the expression of p21(WAF1/CIP1) and p16(INK4A) and fewer beta-galactosidase-positive cells suggested a quiescent phenotype rather than a senescent one in hypoxic cells. Compared with normoxic cells, the differential expression patterns of keratinocyte phenotypic markers suggest that hypoxic cells that generate minimal reactive oxygen species, suppress the mammalian target of rapamycin activity and express hypoxia-inducible factor-1 alpha favor a basal cell phenotype. Thus, regardless of the predisposition to the state of cell cycle arrest, hypoxic conditions can maintain oral keratinocytes in vitro in an undifferentiated and quiescent state. (C) 2015 S. Karger AG, Basel

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  • Intraoral Grafting of Tissue-Engineered Human Oral Mucosa Reviewed

    Kenji Izumi, Rodrigo F. Neiva, Stephen E. Feinberg

    INTERNATIONAL JOURNAL OF ORAL & MAXILLOFACIAL IMPLANTS   28 ( 5 )   E295 - E303   2013.9

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    Purpose: The primary objective of this study was to evaluate the safety of a tissue-engineered human ex vivo-produced oral mucosa equivalent (EVPOME) in intraoral grafting procedures. The secondary objective was to assess the efficacy of the grafted EVPOME in producing a keratinized mucosal surface epithelium. Materials and Methods: Five patients who met the inclusion criteria of having one mucogingival defect or a lack of keratinized gingiva on a nonmolar tooth, along with radiographic evidence of sufficient interdental bone height, were recruited as subjects to increase the width of keratinized gingiva at the defect site. A punch biopsy specimen of the hard palate was taken to acquire oral keratinocytes, which were expanded, seeded, and cultured on an acellular dermal matrix for fabrication of an EVPOME. EVPOME grafts were applied directly over an intact periosteal bed and secured in place. At baseline (biopsy specimen retrieval) and at 7, 14, 30, 90, and 180 days postsurgery, Plaque Index and Gingival Index were recorded for each subject. In addition, probing depths, keratinized gingival width, and keratinized gingival thickness were recorded at baseline, 30, 90, and 180 days. Results: No complications or adverse reactions to EVPOME were observed in any subjects during the study. The mean gain in keratinized gingival width was 3 mm (range, 3 to 4 mm). The mean gain in keratinized gingival thickness was 1 mm (range, 1 to 2 mm). No significant changes in probing depths were observed. Conclusion: Based on these findings, it can be concluded that EVPOME is safe for intraoral use and has the ability to augment keratinized tissue around teeth. Future clinical trials are needed to further explore this potential.

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  • コンピュータシステム活用法としての戦略的情報システムの事例

    金谷 貢, 青柳 裕仁, 高 昇将, 三井田 慶斗, 泉 健次

    日本歯科医学会連合雑誌   2   58 - 63   2023.12

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    アメリカ合衆国(米国)には1980年当時,123社の航空会社があり,アメリカン航空(American Airlines,AA)はその中で中位クラスであったが,クランドール(Robert L. Crandall)が考え出した戦略的情報システム(Strategic Information System,SIS)により業績が上がり,他社を次々に淘汰した。AAのSISに気づいて戦略的に手を打ったユナイテッド航空とデルタ航空は生き残り,目先の戦術に追われた他社はことごとく倒産した。結局,米国の航空会社は3社系列にまで統合された。また,アメリカン・ホスピタル・サプライは独自の情報システムを用い,米国に2,000店あった医薬品医療機器流通業者を40店にまで淘汰した。このようにコンピュータシステムを戦略的に活用したSISの事例が研究された結果,事業を成功に導くには,好印象を持たれるように人の心に訴えることが重要だと考えられるようになった。(著者抄録)

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  • 臨床の視点から脱細胞化組織に期待すること Reviewed

    寺師 浩人, 榊原 俊介, 泉 健次

    人工臓器   52 ( 2 )   S - 18   2023.10

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  • Distinct differences in hypoxic responses between human oral mucosa and skin fibroblasts in a 3D collagen matrix Reviewed International journal

    Kenji Izumi

    In Vitro Cellular & Developmental Biology - Animal   56 ( 6 )   452 - 479   2020.6

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    The differences between oral mucosa and skin wound healing involving hypoxic responses of fibroblasts are poorly elucidated. In this study, we aimed to study the different hypoxic responses between oral and skin fibroblasts embedded in a three-dimensional (3D) collagen matrix to address the early stage of wound healing. Primary oral mucosa fibroblasts (OMFs) obtained from the retromolar area and skin fibroblasts (SFs) obtained from the abdomen were cultured in the 3D 'floating model' under either 21%, 5% or 1% O2 for 2 days. Cell viability under hypoxia was higher in the OMFs than in the SFs. Collagen gel contraction was suppressed under hypoxic conditions in both fibroblasts, consistent with the reduction of alpha smooth muscle actin expression, except for SFs under 1% O2. Subsequently, their gene expression profiles between 21 and 1% O2 concentrations were compared via microarray technology, and the expression profiles of the extracellular matrix (ECM)-associated proteins, including matrix metalloproteinases and collagens, were evaluated. The OMFs were more susceptible to 1% O2, and more of their genes were downregulated than the SFs'. Although the production and expression levels of ECM-associated proteins in both fibroblasts diminished under hypoxia, those levels in OMFs were significantly higher than those in SFs. In the case of single origin OMFs and SFs, our findings suggest that OMFs possess a higher baseline production capacity of several ECM-associated proteins than SFs, except type III collagen. The intrinsic hypoxic responses of OMFs may be attributed to a more favourable wound healing in oral mucosa.

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  • Periodontal Ligament Cell Sheets and RGD-Modified Chitosan Improved Regeneration in the Horizontal Periodontal Defect Model Reviewed

    Kenji Izumi

    European Journal of Dentistry   2020.5

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    <jats:title>Abstract</jats:title><jats:p>
    Objective The aim of this study was to examine the potential of periodontal ligament (PDL) cells sheet and arginine-glycyl-aspartic acid (RGD)-modified chitosan scaffold for periodontal tissue regeneration in horizontal periodontal defect model.</jats:p><jats:p>
    Materials and Methods PDL cell cytotoxicity was tested with 3–[4,5- dimethylthiazol-2yl]–2,5-diphenyl-2H-tetrazolium bromide assay. Cell migration toward the chitosan-based materials was analyzed with trans-well migration assay. Horizontal periodontal defect model was created in four maxillary and mandibular lateral incisors of Macaque nemestrina. Following periodontal therapy, the sites were transplanted with various regenerative materials: (1) chitosan, (2) RGD-modified chitosan, (3) PDL cell sheet with chitosan, (4) PDL cell sheet with RGD-modified chitosan. The periodontal tissue regeneration was evaluated clinically and radiographically. Gingival crevicular fluids were collected each week to evaluate cementum protein-1 (CEMP-1) expression with enzyme-linked immunosorbent assay, while the biopsies were retrieved after 4 weeks for histological and microcomputed tomography evaluation.</jats:p><jats:p>
    Statistical Analysis Data was statistically analyzed using GraphPad Prism 6 for MacOS X. Normality was tested using the Shapiro–Wilk normality test. The Kruskal–Wallis test was used to compare the groups. Significance was accepted when p &lt; 0.05.</jats:p><jats:p>
    Results Clinical examination revealed more epithelial attachment was formed in the group with PDL cell sheet with RGD-modified chitosan. Similarly, digital subtraction radiography analysis showed higher gray scale, an indication of higher alveolar bone density surrounded the transplanted area, as well as higher CEMP-1 protein expression in this group. The incorporation of RGD peptide to chitosan scaffold in the group with or without PDL cells sheet reduced the distance of cement–enamel junction to the alveolar bone crest; hence, more periodontal tissue formed.</jats:p><jats:p>
    Conclusions Horizontal periodontal defect model could be successfully created in M. nemestrina model. Combination of PDL cell sheet and RGD-modified chitosan resulted in the higher potential for periodontal tissue regeneration. The results of this study highlight the PDL cell sheet and RGD-modified chitosan as a promising approach for future clinical use in periodontal regeneration.</jats:p>

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  • Rac1-dependent phagocytosis of apoptotic cells by oral squamous cell carcinoma cells: A possible driving force for tumor progression Reviewed International journal

    Kenji Izumi

    Experimental Cell Research   392 ( 1 )   112013 - 112013   2020.4

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    Apoptotic cell death frequently occurs in human cancer tissues including oral squamous cell carcinoma (SCC), wherein apoptotic tumor cells are phagocytosed not only by macrophages but also by neighboring tumor cells. We previously reported that the engulfment of apoptotic SCC cells by neighboring SCC cells frequently occurs at the invading front. Therefore, we hypothesized that the phagocytosis of these apoptotic cells by tumor cells contributes to disease progression. Herein, using cultured oral SCC cells, we aimed to confirm whether tumor cells actually phagocytose apoptotic cells and to examine whether cellular activities are regulated by the phagocytosis of apoptotic cells. Co-culture experiments showed that living cells could ingest apoptotic cells into phagolysosomes. NSC23766, an inhibitor of Rac1, which is a key regulator of phagocytic cup formation in professional phagocytes, dramatically suppressed the phagocytosis of apoptotic cells by living cells. Additionally, cell migration and the secretion of DKK1, a tumor-promoting protein, were enhanced by co-culture with apoptotic cells, whereas NSC23766 inhibited these effects. These results show that tumor cells can actively phagocytose apoptotic neighbors in a Rac1-dependent manner and that such activity increases their migration. The regulation of apoptotic cell phagocytosis thus represents new directions for therapeutic intervention for oral cancer.

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  • ROCK inhibitors enhance bone healing by promoting osteoclastic and osteoblastic differentiation Reviewed International journal

    Kenji Izumi

    Biochemical and Biophysical Research Communications   526 ( 3 )   547 - 552   2020.3

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    Osteoclast and osteoblast are essential for proper bone development and remodeling as well as recovery of bone fracture. In this study, we seek chemical compounds that enhance turnover of bone metabolism for promoting bone healing. First, we screen a chemical library which includes 378 compounds by using murine pre-osteoclastic RAW264.7 cells to identify compounds that promote osteoclastic differentiation. We find that two ROCK (Rho-associated coiled-coil kinase) inhibitors, HA-1077 (Fasudil) and Y-27632, enhance osteoclastogenesis. Subsequently, we identify that these two compounds also increase osteoblastic differentiation of MC3T3-E1 cells. Finally, our in vivo experiment shows that the local administration of ROCK inhibitors accelerate the bone healing of the rat calvarial defect.

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  • Biological reaction control using topography regulation of nanostructured titanium. Reviewed International journal

    Kenji Izumi

    Scientific reports   10 ( 1 )   2438 - 2438   2020.2

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    The micro- and nanosize surface topography of dental implants has been shown to affect the growth of surrounding cells. In this study, standardized and controlled periodic nanopatterns were fabricated with nanosized surface roughness on titanium substrates, and their influence on bone marrow stromal cells investigated. Cell proliferation assays revealed that the bare substrate with a 1.7 nm surface roughness has lower hydrophilicity but higher proliferation ability than that with a 0.6 nm surface roughness. Further, with the latter substrate, directional cell growth was observed for line and groove patterns with a width of 100 nm and a height of 50 or 100 nm, but not for those with a height of 10 or 25 nm. With the smooth substrate, time-lapse microscopic analyses showed that more than 80% of the bone marrow cells on the line and groove pattern with a height of 100 nm grew and divided along the lines. As the nanosized grain structure controls the cell proliferation rate and the nanosized line and groove structure (50-100 nm) controls cell migration, division, and growth orientation, these standardized nanosized titanium structures can be used to elucidate the mechanisms by which surface topography regulates tissue responses to biomaterials.

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  • M2 Phenotype Macrophages Colocalize with Schwann Cells in Human Dental Pulp Reviewed

    N. Yoshiba, N. Edanami, N. Ohkura, T. Maekawa, N. Takahashi, A. Tohma, K. Izumi, T. Maeda, A. Hosoya, H. Nakamura, K. Tabeta, Y. Noiri, K. Yoshiba

    Journal of Dental Research   99 ( 3 )   329 - 338   2020.1

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    Macrophages are immune cells with high plasticity that perform many functions related to tissue injury and repair. They are generally categorized as 2 functional phenotypes: M1 (proinflammatory) and M2 (anti-inflammatory and prohealing). To investigate the role of macrophages in human dental pulp, we examined the localization and distributional alterations of macrophages in healthy dental pulp as well as during the reparative process of pulp capping with mineral trioxide aggregate (MTA) and in cariously inflamed pulp of adult human teeth. We also quantified the populations of M1/M2 macrophages in healthy dental pulp by flow cytometric analysis. CD68<sup>+</sup>CD86<sup>+</sup>cells (M1 phenotype) and CD68<sup>+</sup>CD163<sup>+</sup>cells (M2 phenotype) were 2.11% ± 0.50% and 44.99% ± 2.22%, respectively, of 2.96% ± 0.41% CD68<sup>+</sup>cells (pan-macrophages) in whole healthy dental pulp. Interestingly, M2 phenotype macrophages were associated with Schwann cells in healthy pulp, during mineralized bridge formation, and in pulp with carious infections in vivo. Furthermore, the M2 macrophages associated with Schwann cells expressed brain-derived neurotrophic factor (BDNF) under all in vivo conditions. Moreover, we found that plasma cells expressed BDNF. Coculture of Schwann cells isolated from human dental pulp and human monocytic cell line THP-1 showed that Schwann cells induced M2 phenotypic polarization of THP-1 cell-derived macrophages. The THP-1 macrophages that maintained contact with Schwann cells were stimulated, leading to elongation of their cell shape and expression of M2 phenotype marker CD163 in cocultures. In summary, we revealed the spatiotemporal localization of macrophages and potent induction of the M2 phenotype by Schwann cells in human dental pulp. M2 macrophages protect neural elements, whereas M1 cells promote neuronal destruction. Therefore, suppressing the neurodestructive M1 phenotype and maintaining the neuroprotective M2 phenotype of macrophages by Schwann cells may be critical for development of effective treatment strategies to maintain the viability of highly innervated dental pulp.

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  • Evaluation of a Newly Designed Microperforated Pure Titanium Membrane for Guided Bone Regeneration. Reviewed

    Kenji Izumi

    The International journal of oral & maxillofacial implants   34 ( 2 )   411 - 422   2019.3

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    PURPOSE:This study aimed to evaluate the safety and efficacy of newly designed, laser-perforated pure titanium membranes for guided bone regeneration and to compare them with an existing product, the FRIOS BoneShield (FBS). MATERIALS AND METHODS:Acute-type lateral ridge defects were bilaterally created in the mandibles of 13 dogs (two defects per animal). The defects were randomly divided into three groups and were reconstructed with particulate autologous bone (PAB) in combination with three different titanium membranes: (1) F001M0 (prototype without a frame), (2) F001M1 (prototype with a frame), and (3) FBS as a standard membrane. All animals were observed periodically and sacrificed 26 or 27 weeks postoperatively. At 26 weeks, approximately half of the dogs in each group underwent membrane removal to examine the postoperative condition of the titanium membranes. The samples were dissected and processed for radiographic, histologic, and histomorphometric analyses. RESULTS:Membrane exposure was not found in the F001M0 or F001M1 groups, and their membranes were removed easily without adhesion to the surrounding tissue. Regenerated bone tissue volume was largest in the F001M1 group, followed by the F001M0 and FBS groups. A significant difference was observed only between the F001M1 and FBS groups (P = .047). In contrast, bone mineral density was similar among the three groups. Histologically, a layer of fibrous tissue was present underneath the titanium membrane, overlying the regenerated cortical bone in all the groups. Notably, the tissue was highly vascular in the F001M1 and F001M0 groups compared with the FBS group. In addition, there was little difference in the semiquantitative soft tissue evaluation and histologic findings of bone regeneration among the three groups. The histomorphometric analysis revealed that the regenerated bone area was larger in the F001M1 and F001M0 groups than in the FBS group, and a significant difference was observed only between the F001M1 and FBS groups (P = .045). Calcific osseous area was similar among the three groups. CONCLUSION:The safety and efficacy of both F001M0 and F001M1 were equivalent to or greater than those of FBS, thereby indicating their potential for future clinical applications.

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  • Evaluation of a newly designed microperforated titanium membrane with beta-tricalcium phosphate for guided bone regeneration in dog mandibles Reviewed

    Hasegawa, H., Kaneko, T., Kanno, C., Endo, M., Akimoto, T., Yamazaki, M., Kitabatake, T., Masui, S., Ishihata, H., Izumi, K.

    International Journal of Oral and Maxillofacial Implants   34 ( 5 )   1132 - 1142   2019

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    PURPOSE:This study evaluated the efficacy of newly designed, laser-perforated pure titanium membranes for guided bone regeneration using beta-tricalcium phosphate (β-TCP), and compared them with the existing membrane. MATERIALS AND METHODS:Bilateral acute lateral ridge defects were created in the mandibles of 12 dogs (four defects per animal), which were then randomly divided into two groups (six dogs each). The twenty-four bone defects in each group were then further divided into five groups. The groups were as follows: (1) F001M0, a prototype membrane without a frame plus β-TCP (n = 5); (2) F001M1, a prototype membrane with a frame plus β-TCP (n = 5); (3) FBS, an existing control membrane plus β-TCP (n = 5); (4) control 1, β-TCP without membrane and with covering flap only (n = 5); and (5) control 2, no treatment (no β-TCP and no membrane) (n = 4). In all groups where β-TCP was used, it was mixed with peripheral blood. The animals were necropsied at 6 or 12 weeks postoperatively (six dogs each), and samples were collected and processed for radiographic, histologic, and histomorphometric analyses. RESULTS:Among the three membrane groups, regenerated tissue and bone volume was greatest in the F001M1 group at both 6 and 12 weeks postoperatively, although differences among groups were not statistically significant. Bone mineral density was similar among the membrane groups. Histologic analysis revealed that immature fibroblasts were present on the laser-perforated portion at 6 weeks, which induced vascularization. In addition, more calcified bone was replaced beneath the prototypes than beneath the FBS membrane at 12 weeks. Histomorphometric analyses revealed that the calcific osseous areas at 12 weeks after surgery were significantly greater in the F001M1 and F001M0 groups than in the FBS group (P = .021, P = .032). Furthermore, the fibrous tissue areas beneath the membrane at 12 weeks postoperatively were significantly smaller in the prototype groups than in the FBS group (P = .02, P = .02). CONCLUSION:The efficacies of both prototype membranes were not inferior to that of the FBS membrane, indicating that they may facilitate bone regeneration and maturation when β-TCP mixed with autologous blood is employed.

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  • Deformation characteristics of cultured single viable cells by squeezing tests Reviewed

    Ishii, H., Ishii, T., Narumi, T., Izumi, K., Ushida, A., Sato, T.

    Nihon Reoroji Gakkaishi   46 ( 4 )   179 - 184   2018

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  • Study on deformation characteristics of single cells by squeezing test

    Haruhiko Ishii, Tatsuji Ishii, Takatsune Narumi, Kenji Izumi, Akiomi Ushida

    Proceedings of The XVIIth International Congress on Rheology, ICR2016   ( 5706 )   2016.8

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  • Effects of C-xylopyranoside derivative on epithelial regeneration in an in vitro 3D oral mucosa model Reviewed

    Uenoyama, A., Kakizaki, I., Shiomi, A., Saito, N., Hara, Y., Saito, T., Ohnuki, H., Kato, H., Takagi, R., Maeda, T., Izumi, K.I.

    Bioscience, Biotechnology and Biochemistry   80 ( 7 )   1344 - 1355   2016

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    Identifying substandard tissue-engineered oral mucosa grafts with a poor epithelium before clinical use is critical to ensure quality assurance/control in regenerative medicine, leading to success of grafting. This study investigated the effects of one of the C-xylopyranoside derivatives, -D-xylopyranoside-n-propane-2-one (XPP), on oral epithelial regeneration. Using a three-dimensional oral mucosa model, we analyzed changes of the epithelial structure, glycosaminoglycan (GAG) synthesis, the expression levels of basement membrane zone markers, and substrates of Akt/mTOR signaling. Compared with the control, 2mM XPP treatment increased the mean and minimal epithelial thickness, and reduced the variation of epithelial thickness. It also stimulated expressions of decorin and syndecan-1 with change of GAG amount and/or composition, and enhanced the expressions of integrin 6, CD44, and Akt/mTOR signaling substrates. These findings suggest that XPP supplementation contributes to consistent epithelial regeneration. Moreover, upregulation of those markers may play a role in increasing the quality of the oral mucosal epithelium.

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  • Cyclic mechanical pressure-loading alters epithelial homeostasis in a three-dimensional in vitro oral mucosa model: Clinical implications for denture-wearers Reviewed

    Shiomi, A., Izumi, K., Uenoyama, A., Saito, T., Saito, N., Ohnuki, H., Kato, H., Kanatani, M., Nomura, S., Egusa, H., Maeda, T.

    Journal of Oral Rehabilitation   42 ( 3 )   192 - 201   2015

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    Denture-wearing affects the quality and quantity of epithelial cells in the underlying healthy oral mucosa. The physiologic mechanisms, however, are poorly understood. This study aimed to compare histologic changes and cellular responses of an epithelial cell layer to cyclic mechanical pressure-loading mimicking denture-wearing using an organotypic culture system to develop a three-dimensional in vitro oral mucosa model (3DOMM). Primary human oral keratinocytes and fibroblasts were serially grown in a monolayer culture, and cell viability was measured under continuous cyclic mechanical pressure (50kPa) for 7days (cycles of 60min on, 20s off to degas and inject air). Upon initiation of an air-liquid interface culture for epithelial stratification, the cyclic pressure, set to the mode above mentioned, was applied to the 3DOMMs for 7days. Paraffin-embedded 3DOMMs were examined histologically and immunohistochemically. In the monolayer culture, the pressure did not affect the viability of oral keratinocytes or fibroblasts. Few histologic changes were observed in the epithelial layer of the control and pressure-loaded 3DOMMs. Immunohistochemical examination, however, revealed a significant decrease in Ki-67 labelling and an increase in filaggrin and involucrin expression in the suprabasal layer of the pressure-loaded 3DOMMs. Pressure-loading attenuated integrin 1 expression and increased matrix metalloproteinase-9 activity. Incomplete deposition of laminin and type IV collagen beneath the basal cells was observed only in the pressure-loaded 3DOMM. Cyclic pressure-loading appeared to disrupt multiple functions of the basal cells in the 3DOMM, resulting in a predisposition towards terminal differentiation. Thus, denture-wearing could compromise oral epithelial homeostasis.

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  • Zoledronic acid impairs re-epithelialization through downregulation of integrin alpha v beta 6 and transforming growth factor beta signalling in a three-dimensional in vitro wound healing model Reviewed

    T. Saito, K. Izumi, A. Shiomi, A. Uenoyama, H. Ohnuki, H. Kato, M. Terada, K. Nozawa-Inoue, Y. Kawano, R. Takagi, T. Maeda

    INTERNATIONAL JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY   43 ( 3 )   373 - 380   2014.3

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    This study examined the negative effects of zoledronic acid on the re-epithelialization of oral mucosa in a three-dimensional in vitro oral mucosa wound healing model. A living oral mucosa equivalent was constructed by seeding a mixture of primary human oral keratinocytes and fibroblasts, at a cell density of 1.5 x 10(5) cm(2) each, onto human cadaver dermis. This was cultured in a submerged condition in 1.2 mM Ca2+ EpiLife for 5 days, and then in an air liquid interface for 14 days. The equivalent was wounded by excising a linear 2-mm-wide epithelial layer on day 8 and subsequently incubated with 10 mu M zoledronic acid for an additional 11 days. Histological and immunohistochemical observations revealed zoledronic acid to significantly suppress the epithelial thickness and Ki-67-labelling index. Zoledronic acid also abolished integrin alpha v beta 6 expression, implying impaired keratinocyte migration. Zoledronic acid did not attenuate the total transforming growth factor beta 1 (TGF-beta 1) production into the supernatant, but down-regulated TGF-beta receptor types I and II expression and Smad3 phosphorylation, as was also confirmed by immunofluorescence microscopy. This study therefore showed zoledronic acid to abrogate integrin alpha v beta 6 expression, cause the down-regulation of TGF-beta/Smad signalling in oral keratinocytes, and impair re-epithelialization, suggesting compromised oral mucosa homeostasis in patients receiving zoledronic acid.

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  • Distinct expression patterns and roles of aldehyde dehydrogenases in normal oral mucosa keratinocytes: differential inhibitory effects of a pharmacological inhibitor and RNAi-mediated knockdown on cellular phenotype and epithelial morphology Reviewed

    Hiroko Kato, Kenji Izumi, Taro Saito, Hisashi Ohnuki, Michiko Terada, Yoshiro Kawano, Kayoko Nozawa-Inoue, Chikara Saito, Takeyasu Maeda

    HISTOCHEMISTRY AND CELL BIOLOGY   139 ( 6 )   847 - 862   2013.6

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    Aldehyde dehydrogenases (ALDHs), enzymes responsible for detoxification and retinoic acid biosynthesis, are considered a potent functional stem cell marker of normal and malignant cells in many tissues. To date, however, there are no available data on ALDH distributions and functions in oral mucosa. This study aims to clarify the levels and types of ALDH expression using immunohistochemistry with accompanying mRNA expression as well as an ALDEFLUOR assay, and to assess phenotypic and histological changes after manipulation of the ALDH activity of oral keratinocytes to increase the potency of a tissue-engineered oral mucosa by a specific ALDH inhibitor, diethylaminobenzaldehyde (DEAB), together with small interfering RNA of ALDH1A3 and ALDH3A1. Results showed the mRNA and cytoplasmic protein expression of ALDH1A3 and ALDH3A1 to be mostly localized in the upper suprabasal layer although no ALDH1A1 immunoreaction was detected throughout the epithelium. Oral keratinocytes with high ALDH activity exhibited a profile of differentiating cells. By pharmacological inhibition, the phenotypic analysis revealed the proliferating cell-population shifting to a more quiescent state compared with untreated cells. Furthermore, a well-structured epithelial layer showing a normal differentiation pattern and a decrease in Ki-67 immunopositive basal cells was developed by DEAB incubation, suggesting a slower turnover rate efficient to maintain undifferentiated cells. Histological findings of a regenerated oral epithelium by ALDH1A3 siRNA were similar to those when treated with DEAB while ALDH3A1 siRNA eradicated the epithelial regenerative capacity. These observations suggest the effects of phenotypic and morphological alterations by DEAB on oral keratinocytes are mainly consequent to the inhibition of ALDH1A3 activity.

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  • Tissue-engineered constructs of human oral mucosa examined by raman spectroscopy Reviewed

    Alexander Khmaladze, Arindam Ganguly, Shiuhyang Kuo, Mekhala Raghavan, Raghu Kainkaryam, Jacqueline H. Cole, Kenji Izumi, Cynthia L. Marcelo, Stephen E. Feinberg, Michael D. Morris

    Tissue Engineering - Part C: Methods   19 ( 4 )   299 - 306   2013.4

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    A noninvasive quality monitoring of tissue-engineered constructs is a required component of any successful tissue-engineering technique. During a 2-week production period, ex vivo produced oral mucosa-equivalent constructs (EVPOMEs) may encounter adverse culturing conditions that might compromise their quality and render them ineffective. We demonstrate the application of near-infrared Raman spectroscopy to in vitro monitoring of EVPOMEs during their manufacturing process, with the ultimate goal of applying this technology in situ to monitor the grafted EVPOMEs. We identify Raman spectroscopic failure indicators for less-than optimal EVPOMEs that are stressed by higher temperature and exposure to higher than normal concentration of calcium ions. Raman spectra of EVPOMEs exposed to thermal and calcium stress showed correlation of the band height ratio of CH2 deformation to phenylalanine ring breathing modes, providing a Raman metric to distinguish between viable and nonviable constructs. We compared these results to histology and glucose consumption measurements, demonstrating that Raman spectroscopy is more sensitive and specific to changes in proteins' secondary structure not visible by H&amp
    E histology. We also exposed the EVPOMEs to rapamycin, a cell growth inhibitor and cell proliferation capacity preserver, and distinguished between EVPOMEs pretreated with 2 nM rapamycin and controls, using the ratio of the Amide III envelope to the phenylalanine band as an indicator. © 2013, Mary Ann Liebert, Inc.

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  • Enrichment of oral mucosa and skin keratinocyte progenitor/stem cells Reviewed

    Kenji Izumi, Cynthia L. Marcelo, Stephen E. Feinberg

    Methods in Molecular Biology   989   293 - 303   2013

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    The isolation of human oral mucosa/skin keratinocytes progenitor/stem cells is clinically important to regenerate epithelial tissues for the treatment of oral mucosa/skin defects. Researchers have attempted to isolate a keratinocyte progenitor/stem cell population using cell markers, rapid adherence to collagen type IV, and other methods. In this regard, one of the specific characteristics of keratinocyte progenitor/stem cells is that these cells have a smaller diameter than differentiated cells. This chapter describes methods used in our laboratory to set up primary human oral mucosa and skin keratinocytes in a chemically defined culture system devoid of animal derived products. We utilized the cells in a FDA-approved human clinical trial that involved the intraoral grafting of an ex vivo produced oral mucosa equivalent to increase keratinized tissue around teeth. We also provide two protocols on how to sort keratinocytes using physical criterion, cell size, using a cell sorter and a serial filtration system. © 2013 Springer Science+Business Media New York.

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  • Construction and characterization of a tissue-engineered oral mucosa equivalent based on a chitosan-fish scale collagen composite Reviewed

    Michiko Terada, Kenji Izumi, Hisashi Ohnuki, Taro Saito, Hiroko Kato, Marie Yamamoto, Yoshiro Kawano, Kayoko Nozawa-Inoue, Haruhiko Kashiwazaki, Toshiyuki Ikoma, Junzo Tanaka, Takeyasu Maeda

    JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS   100B ( 7 )   1792 - 1802   2012.10

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

    This study was designed to (1) assess the in vitro biocompatibility of a chitosancollagen composite scaffold (C3) constructed by blending commercial chitosan and tilapia scale collagen with oral mucosa keratinocytes, (2) histologically and immunohistochemically characterize an ex vivo-produced oral mucosa equivalent constructed using the C3 (EVPOME-C), and (3) compare EVPOME-C with oral mucosa constructs utilizing AlloDerm (R) (EVPOME-A), BioMend (R) Extend (TM) (EVPOME-B), and native oral mucosa. C3 scaffold had a well-developed fibril network and a sufficiently small porosity to prevent keratinocytes from growing inside the scaffold after cell-seeding. The EVPOME oral mucosa constructs were fabricated in a chemically defined culture system. After culture at an air-liquid interface, EVPOME-C and EVPOME-B had multilayered epithelium with keratinization, while EVPOME-A had a more organized stratified epithelium. Ki-67 and p63 immunolabeled cells in the basal layer of all EVPOMEs suggested a regenerative ability. Compared with native oral mucosa, the keratin 15 and 10/13 expression patterns in all EVPOMEs showed a less-organized differentiation pattern. In contrast to the beta 1-integrin and laminin distribution in EVPOME-A and native oral mucosa, the subcellular deposition in EVPOME-C and EVPOME-B indicated that complete basement membrane formation failed. These findings demonstrated that C3 has a potential application for epithelial tissue engineering and provides a new potential therapeutic device for oral mucosa regenerative medicine. (C) 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2012.

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  • Zoledronic acid induces S-phase arrest via a DNA damage response in normal human oral keratinocytes Reviewed

    Hisashi Ohnuki, Kenji Izumi, Michiko Terada, Taro Saito, Hiroko Kato, Akiko Suzuki, Yoshiro Kawano, Kayoko Nozawa-Inoue, Ritsuo Takagi, Takeyasu Maeda

    ARCHIVES OF ORAL BIOLOGY   57 ( 7 )   906 - 917   2012.7

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    Objective: This study aimed to clarify the effects of zoledronic acid (ZOL) on human primary oral mucosal keratinocytes growing in a monolayer culture and on a tissue-engineered oral mucosal construct.
    Design: Changes in the viability and proliferation of oral keratinocytes incubated with ZOL were measured. Following treatment with 10 mu M ZOL, histological examinations and immunohistochemical analyses for Ki-67, Geminin, and phospho-histone (gamma)-H2A.X were performed on tissue-engineered oral mucosa. Cell cycle distribution and the degree of apoptosis were also measured by flow cytometry. Additionally, we measured the expression of cell cycle regulatory proteins as well as phospho-Chk1 and -Chk2.
    Results: ZOL treatment suppressed cell viability and proliferation in a dose-dependent manner. Compared with untreated tissue-engineered oral mucosa, ZOL treatment resulted in a thinner epithelium in which the basal cells appeared less-organised. This is consistent with the observed significant reduction in the Ki-67 labelling index. In contrast, the Geminin labelling index was significantly higher than that in the untreated sample. In spite of the presence of a few apoptotic cells, ZOL induced an arrest in S-phase, which was confirmed by our observed alterations in the expression levels of cyclin A, B1, p27(KIP1), Rb and phospho-Rb. When the proteasome inhibitor MG132 was added to the ZOL-treated cells, we observed a partial restoration of the expression of cyclin A, cyclin B1, and p27(KIP1). Expression of phospho-Chk1 was detected, and a significant increase in the labelling index of gamma-H2A.X was also seen.
    Conclusions: These results indicate that a 10-mu M ZOL treatment induces a DNA damage response in oral keratinocytes that activates the ubiguitin-mediated proteolysis of cell cycle regulators, resulting in cell cycle arrest and repressive effects on cell viability, proliferation, and epithelial turnover. (C) 2011 Elsevier Ltd. All rights reserved.

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  • Raman spectroscopic analysis of human tissue engineered oral mucosa constructs (EVPOME) perturbed by physical and biochemical methods Reviewed

    Alexander Khmaladze, Arindam Ganguly, Mekhala Raghavan, Shiuhyang Kuo, Jacqueline H. Cole, Cynthia L. Marcelo, Stephen E. Feinberg, Kenji Izumi, Michael D. Morris

    Progress in Biomedical Optics and Imaging - Proceedings of SPIE   8219   2012

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    We show the application of near-infrared Raman Spectroscopy to in-vitro monitoring of the viability of tissue constructs (EVPOMEs). During their two week production period EVPOME may encounter thermal, chemical or biochemical stresses that could cause development to cease, rendering the affected constructs useless. We discuss the development of a Raman spectroscopic technique to study EVPOMEs noninvasively, with the ultimate goal of applying it in-vivo. We identify Raman spectroscopic failure indicators for EVPOMEs, which are stressed by temperature, and discuss the implications of varying calcium concentration and pre-treatment of the human keratinocytes with Rapamycin. In particular, Raman spectra show correlation of the peak height ratios of CH 2 deformation to phenylalanine ring breathing, providing a Raman metric to distinguish between viable and nonviable constructs. We also show the results of singular value decomposition analysis, demonstrating the applicability of Raman spectroscopic technique to both distinguish between stressed and non-stressed EVPOME constructs, as well as between EVPOMEs and bare AlloDerm substrates, on which the oral keratinocytes have been cultured. We also discuss complications arising from non-uniform thickness of the AlloDerm® substrate and the cultured constructs, as well as sampling protocols used to detect local stress and other problems that may be encountered in the constructs. © 2012 SPIE.

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  • Raman Spectroscopic Analysis of Human Tissue Engineered Oral Mucosa Constructs (EVPOME) Perturbed by Physical and Biochemical Methods Reviewed

    Alexander Khmaladze, Arindam Ganguly, Mekhala Raghavan, Shiuhyang Kuo, Jacqueline H. Cole, Cynthia L. Marcelo, Stephen E. Feinberg, Kenji Izumi, Michael D. Morris

    BIOMEDICAL VIBRATIONAL SPECTROSCOPY V: ADVANCES IN RESEARCH AND INDUSTRY   8219   2012

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    Language:English   Publishing type:Research paper (international conference proceedings)   Publisher:SPIE-INT SOC OPTICAL ENGINEERING  

    We show the application of near-infrared Raman Spectroscopy to in-vitro monitoring of the viability of tissue constructs (EVPOMEs). During their two week production period EVPOME may encounter thermal, chemical or biochemical stresses that could cause development to cease, rendering the affected constructs useless. We discuss the development of a Raman spectroscopic technique to study EVPOMEs noninvasively, with the ultimate goal of applying it in-vivo. We identify Raman spectroscopic failure indicators for EVPOMEs, which are stressed by temperature, and discuss the implications of varying calcium concentration and pre-treatment of the human keratinocytes with Rapamycin. In particular, Raman spectra show correlation of the peak height ratios of CH2 deformation to phenylalanine ring breathing, providing a Raman metric to distinguish between viable and nonviable constructs. We also show the results of singular value decomposition analysis, demonstrating the applicability of Raman spectroscopic technique to both distinguish between stressed and non-stressed EVPOME constructs, as well as between EVPOMEs and bare AlloDerm (R) substrates, on which the oral keratinocytes have been cultured. We also discuss complications arising from non-uniform thickness of the AlloDerm (R) substrate and the cultured constructs, as well as sampling protocols used to detect local stress and other problems that may be encountered in the constructs.

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  • Tissue Engineering Reviewed

    Miller H. Smith, Kenji Izumi, Stephen E. Feinberg

    Current Therapy in Oral and Maxillofacial Surgery   79 - 91   2012

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    Language:English   Publishing type:Part of collection (book)   Publisher:Elsevier Inc.  

    DOI: 10.1016/B978-1-4160-2527-6.00009-8

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  • COMPARISON OF SCANNING ACOUSTIC MICROSCOPY AND HISTOLOGY IMAGES IN CHARACTERIZING SURFACE IRREGULARITIES AMONG ENGINEERED HUMAN ORAL MUCOSAL TISSUES Reviewed

    Frank Winterroth, Kyle W. Hollman, Shiuhyang Kuo, Kenji Izumi, Stephen E. Feinberg, Scott J. Hollister, J. Brian Fowlkes

    ULTRASOUND IN MEDICINE AND BIOLOGY   37 ( 10 )   1734 - 1742   2011.10

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    Acoustic microscopy was used to monitor an ex vivo produced oral mucosal equivalent (EVPOME) developed on acellular cadaveric dermis (AlloDerm (R)). As seeded cells adhered and grew, they filled in and smoothed out the surface irregularities, followed by the production of a keratinized protective outermost layer. If noninvasive in vitro ultrasonic monitoring of these cellular changes could be developed, then tissue cultivation could be adjusted in-process to account for biologic variations in the development of these stratified cell layers. Cultured keratinocytes (from freshly obtained oral mucosa) were harvested and seeded onto AlloDerm (R) coated with human type IV collagen and cultured 11 days. EVPOMEs were imaged on the 11th day post-seeding using a scanning acoustic microscope (SAM) that consists of a single-element transducer: 61 MHz center frequency, 32 MHz bandwidth, 1.52 f-number. The specimen surface was determined by thresholding the magnitude of the signal at the first axial incidence of a value safely above noise: 20-40 dB above the signal for the water and 2-dimensional (2-D) ultrasonic images were created using confocal image reconstruction. A known area from each micrograph was divided into 12-40 even segments and examined for surface irregularities. These irregularities were quantified and one-way analysis of variance (ANOVA) and linear regression analysis were performed to correlate the surface profiles for both the AlloDerm (R) and EVPOME specimens imaged by SAM. Histology micrographs of the AlloDerm (R) and EVPOME specimens were also prepared and examined for surface irregularities. Unseeded AlloDerm (R) averaged seven to nine surface changes per 400 mu m. The number of changes in surface irregularities decreased to two to three per 400 mu m on the mature EVPOMEs. The numbers of surface irregularities between the unseeded AlloDerm (R) vs. developing EVPOME are similar for both histology and SAM 2-D B-scan images. For the EVPOME 2-D B-scan micrographs produced by SAM, the decrease in surface irregularities is indicative of the stratified epithelium formed by seeded oral keratinocytes; verified in the histology images between the AlloDerm (R) and EVPOME. A near 1: 1 linear correlation shows the similarities between the two imaging modalities. SAM demonstrates its ability to discern the cell development and differentiation occurring on the EVPOME devices. Unlike histology, SAM measurements are noninvasive and can be used to monitor tissue graft development without damaging any cells/tissues. (E-mail: fwinterr@umich.edu) (C) 2011 World Federation for Ultrasound in Medicine & Biology.

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  • Raman spectroscopy monitoring of the cellular activities of a tissue-engineered ex vivo produced oral mucosal equivalent Reviewed

    Wen-Liang Lo, Jian-Yun Lai, Stephen E. Feinberg, Kenji Izumi, Shou-Yen Kao, Che-Shoa Chang, Alan Lin, Huihua Kenny Chiang

    JOURNAL OF RAMAN SPECTROSCOPY   42 ( 2 )   174 - 178   2011.2

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    To ensure quality control and assurance in tissue engineering, noninvasive, real-time and aseptic evaluation of cell-based devices is required before product release. In this study, Raman spectroscopy was applied to monitor the cellular activities of an oral mucosa equivalent (EVPOME) produced ex vivo from cultured autogenous oral keratinocytes and acellular dermis - AlloDerm. Raman spectra showed a positive correlation of the peak area ratio of amide I (1655 cm(-1))/phenylalanine (1004 cm(-1)) with a negative linear regression (R(2) &gt; 0.95) according to the number of cultured days, especially on the 14th and 21st day. This work demonstrates the successful application of Raman spectroscopy for quantitatively monitoring and evaluating the maturity of EVPOME. Copyright (C) 2010 John Wiley & Sons, Ltd.

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  • Detection of acid-sensing ion channel 3 (ASIC3) in periodontal Ruffini endings of mouse incisors Reviewed

    Farhana Rahman, Fumiko Harada, Isao Saito, Akiko Suzuki, Yoshiro Kawano, Kenji Izumi, Kayoko Nozawa-Inoue, Takeyasu Maeda

    NEUROSCIENCE LETTERS   488 ( 2 )   173 - 177   2011.1

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    The acid-sensing ion channel 3 (ASIC3), a member of the epithelial sodium channel/degenerin (ENaC/DEG) superfamily, has been reported to participate in acid sensing, mechanosensation, and nociception. However, no information is available regarding the precise localization and function of this molecule in the periodontal ligament, which contains abundant sensory nerves originating from the trigeminal ganglion. The present study examined the expression of ASIC3 in the lingual periodontal ligament of mouse incisors by immunohistochemistry. Furthermore, the expression of ASIC3 in the trigeminal ganglion which innervates the periodontal ligament - was investigated at protein (immunohistochemistry and quantitative analysis) and mRNA levels (RT-PCR technique and in situ hybridization histochemistry). Immunohistochemistry for ASIC3 was able to demonstrate dendritic profiles of the periodontal Ruffini endings in the mouse incisors. No thin fibers terminating as nociceptive free nerve endings exhibited ASIC3 immunoreactivity. Double immunofluorescent staining revealed ASIC3 immunoreaction in the axoplasm but not in the ordinary Schwann cells - including the associated terminal Schwann cells. Observation of the trigeminal ganglia showed variously sized neurons expressing ASIC3 immunoreaction; the most intense immunopositivity was found in the small and medium-sized neurons, as confirmed by in situ hybridization histochemistry using a specific cRNA probe. Quantitative analysis on trigeminal ganglion neurons showed that 38.0% of ASIC3 neurons could be categorized as medium-sized neurons which mediate mechanotransduction. These findings suggest that ASIC3 functions as a molecule for mechanosensation in the periodontal Ruffini endings. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

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  • Intraoral Grafting of Ex Vivo Produced Oral Mucosa Equivalents (EVPOME) Applied to Patients with Cleft Lip and Palate Reviewed

    IIDA Akihiko, YOSHIZAWA Michiko, KOYAMA Takahiro, SAITO Taro, TAKAGI Ritsuo, SAITO Chikara, SAITO Isao, ONO Kazuhiro, IZUMI Kenji

    J.Jpn.Cleft Palate Assoc.   35 ( 3 )   235 - 240   2010.10

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    This report presents the use of &lt;I&gt;ex vivo&lt;/I&gt; produced oral mucosa equivalent (EVPOME) applied to an oral mucosa defect in two patients with cleft lip and palate. Autologous keratinocytes were placed and propagated in a chemically-defined, animal product and a xenogeneic feeder layer free culture system. Cells were then seeded and cultured on an acellular dermal substrate, AlloDerm&lt;sup&gt;&amp;reg;&lt;/sup&gt;, which provides strength, durability, and elasticity to the graft.&lt;br&gt;In case 1, a 20-year-old female underwent closure of the oronasal fistula in the midline of the hard palate using a rotational palatal flap. A circular EVPOME graft (approximately 20 mm in diameter) was grafted onto the bone surface of the donor site of the flap. In case 2, a 16-year-old male underwent vestibuloplasty in the premaxilla region. After trimming, two circular EVPOME grafts were placed over the intact periosteum.&lt;br&gt;The grafts were easily fixed in place to the surrounding scarred mucosa. Although the underlying tissue of the EVPOME graft sutures was scarred, graft adherence was achieved within a week. The successful clinical outcome reported here suggests the efficacy of EVPOME grafts onto a less-vascularized, scarred tissue, and that the use of EVPOME grafts is highly applicable for patients with cleft lip and palate. EVPOME grafting could be extended especially toward pediatric patients with cleft lip and palate for reconstruction of oral mucosa defects by using cryopreserved autologous keratinocytes and by developing a novel material to ensure a steady supply of scaffold instead of the man-made AlloDerm&lt;sup&gt;&amp;reg;&lt;/sup&gt;.

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  • Development of an in vitro model for radiation-induced effects on oral keratinocytes

    Tobita, T., Izumi, K., Feinberg, S.E.

    International Journal of Oral and Maxillofacial Surgery   39 ( 4 )   2010

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  • Isolation of small-sized human epidermal progenitor/stem cells by Gravity Assisted Cell Sorting (GACS) Reviewed

    Yasushi Fujimori, Kenji Izumi, Stephen E. Feinberg, Cynthia L. Marcelo

    JOURNAL OF DERMATOLOGICAL SCIENCE   56 ( 3 )   181 - 187   2009.12

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    Background: Small diameter characterizes epidermal progenitor/stem cells. We have developed Gravity Assisted Cell Sorting (GACS) to simply enrich small-sized epidermal progenitor/stem cells.
    Objective: The cells sorted by GACS were characterized by fluorescence-activated cell sorting analysis, and cultured for up to 7 weeks. The cultured cells were then used for reconstruction of skin equivalent.
    Methods: GACS was performed on primary cultures (primary cell) and passage 6-7 cultures (cultured cell) of keratinocytes. A keratinocyte suspension was sized into two groups: cells trapped by a 20 mu m filter (trapped cells), and cells flowing through both a 20 and 11 mu m filter (non-trapped cells).
    Results: In the primary cell groups, viability of the trapped cells was 62.5 +/- 7.2% compared to 77.0 +/- 3.7% for the non-trapped cells. In the cultured cell groups, viability of the trapped cells was 64.3 +/- 14.9%, compared to the non-trapped cells (93.1 +/- 2.0%). Flow cytometric analysis showed better discrimination by cell size between trapped and non-trapped cells in culture than in the primary cell suspension. Non-trapped cells contained a larger number of cells with high levels of alpha 6 integrin and low levels of CD71 (alpha 6 integrin(bri)CD71(dim),), indicating an enriched progenitor/stem cell population. The difference in these markers between the non-trapped and trapped cells was seen in both the primary and cultured cell groups although this difference was more distinct in cultured cells. Culture of both groups showed that cultures originating from the trapped cells senesced after approximately 15 days while the non-trapped keratinocytes grew for up to 40 days. Manufacture of an epidermis/dermal device (artificial skin) showed that non-trapped cells formed a significantly thicker epithelial layer than the trapped cells, demonstrating the enhanced regenerative capability of the smaller diameter, alpha 6 integrin(bri)CD71(dim) cells separated by GACS.
    Conclusion: These results indicate that GACS is simple and useful technique to enrich for epidermal progenitor/stem cell populations, and is more efficient when used on cells in culture. (C) 2009 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

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  • Pharmacological retention of oral mucosa progenitor/stem cells Reviewed

    K. Izumi, K. Inoki, Y. Fujimori, C. L. Marcelo, S. E. Feinberg

    Journal of Dental Research   88 ( 12 )   1113 - 1118   2009.12

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    Oral mucosa progenitor/stem cells reside as a small-sized cell population that eventually differentiates concurrently with an increase in cell size. Activation of the mammalian target of rapamycin (mTOR) leads to an increase in cell size. We hypothesized that rapamycin, a specific inhibitor of mTOR, will maintain primary human oral keratinocytes as a small-sized, undifferentiated cell population capable of retaining their proliferative capacity. Primary, rapamycin-treated (2 nM, 20 nM) oral keratinocytes showed a diminished cell size that correlated with a higher clonogenicity, a longer-term proliferative potential, and a slower cycling cell population concurrent with decreased expression of a differentiation marker when compared with untreated cells. Only the 2-nM rapamycin-treated oral keratinocytes maintained their ability to regenerate oral mucosa in vitro after 15 weeks of culture. Rapamycin, a Food and Drug Administration-approved drug, may have applicability for use in creating a highly proliferative cell population for use in regenerative medicine.

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  • Constitutive Release of Cytokines by Human Oral Keratinocytes in an Organotypic Culture Reviewed

    Qin Xu, Kenji Izumi, Takayoshi Tobita, Yoshitaka Nakanishi, Stephen E. Feinberg

    JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY   67 ( 6 )   1256 - 1264   2009.6

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    Purpose: The Food and Drug Administration requires an accurate determination of the dose and potency of tissue-engineered or combination products as is required for drugs. This needs to be done as a rapid, quantitative, and noninvasive measurement of biologic function/activity in a way so as not to perturb the tissue-engineered product being developed. The aim of this study was to correlate constitutive release of cytokine(s) from unstimulated cells, at different stages of development, within a 3-dimensional (3D) organotypic ex vivo produced oral mucosa equivalent (EVPOME) to be used for intraoral grafting, with oral keratinocyte cell viability of the EVPOME.
    Materials and Methods: Tissue culture medium was assayed with an enzyme-linked immunosorbent assay from monolayer culture of oral keratinocytes and a 3D EVPOME to determine the constitutive release of interleukin (IL) 1 alpha, IL-6, IL-8, and vascular endothelial growth factor (VEGF). VEGF messenger ribonucleic acid expression by oral keratinocytes within the 3D EVPOME was detected by in situ hybridization at days 4, 7, and 11. The number of viable oral keratinocytes within the EVPOME was extrapolated from VEGF release by use of a modified MTT assay.
    Results: Both VEGF release level and the number of viable cells in the monolayer cultures and 3D EVPOME as measured by MTT assay significantly increased in a time-dependent manner (P &lt; .001, r = 0.743).
    Conclusion: These results suggest that the increasing detectable levels of VEGF associated with the increasing number of Viable cells in the EVPOME may provide a useful noninvasive/nondestructive means of assessing both cellular viability (dose) and biologic function/activity (potency) of a combination cell-based device such as the EVPOME. (C) 2009 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 67:1256-1264, 2009

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  • The expression and production of vascular endothelial growth factor in oral mucosa equivalents Reviewed

    Y. Nakanishi, K. Izumi, M. Yoshizawa, C. Saito, Y. Kawano, T. Maeda

    INTERNATIONAL JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY   36 ( 10 )   928 - 933   2007.10

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    Angiogenesis is anticipated during wound healing. Vascular endothelial growth factor (VEGF) is a potent direct angiogenic factor that stimulates endothelial cell migration and proliferation in vitro and angiogenesis in vivo. Ex vivo produced oral mucosa equivalent (EVPOME) grafts have been reported to promote revascularization in the underlying tissue after grafting. The aim of this study was to evaluating the following: VEGF mRNA and its protein expression in EVPOME grafts, the protein levels in conditioned media produced by EVPOMEs, and the ability of VEGF to stimulate the growth of microvascular endothelial cells. VEGF mRNA expression and immunoreaction were found in basal and suprabasal layers. VEGF secreted by EVPOME was detected throughout the period of manufacture of the grafts, and became elevated for the first week at an air-liquid interface. Both EVPOME-conditioned media and a medium containing 10 ng/mL recombinant human VEGF induced endothelial cell proliferation, while neutralization of VEGF by an antibody blocked cell growth. These results suggest that VEGF secreted by EVPOME grafts might assist initial vascularization after grafting, which is critical to subsequent graft survival.

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  • 癌治療への再生医療の応用 培養複合口腔粘膜(EVPOME)の口腔癌治療への応用 Reviewed

    芳澤 享子, 泉 健次, 飯田 明彦, 鈴木 一郎, 齊藤 力, 高木 律男, 寺師 浩人, 横尾 聡, 古森 孝英, 津野 宏彰, 古田 勲

    再生医療   6 ( 2 )   203 - 208   2007.5

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  • Isolation of human oral keratinocyte progenitor/stem cells

    Izumi, K., Tobita, T., Feinberg, S.E.

    Journal of Dental Research   86 ( 4 )   2007

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    DOI: 10.1177/154405910708600408

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  • Sensing metabolic activity in tissue engineered constructs Reviewed

    Malavika Chandra, Robert H. Wilson, Wen-Liang Lo, Karthik Vishwanath, Kenji Izumi, Stephen E. Feinberg, Mary-Ann Mycek

    DIAGNOSTIC OPTICAL SPECTROSCOPY IN BIOMEDICINE IV   6628   2007

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    Tissue engineered constructs can be employed to graft wounds or replace diseased tissue. Non-invasive methods are required to assess cellular viability in these constructs both pre- and post- implantation into patients. In this study, Monte Carlo simulations and fluorescence experiments were executed on ex vivo produced oral mucosa equivalent (EVPOME) constructs to investigate the fluorescence emitted at 355 nm excitation from these constructs. Both simulations and experiments indicated the need to investigate alternative excitation wavelengths in order to increase the cellular fluorescence from these constructs, while decreasing contributions from extra-cellular fluorophores.

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  • 口腔癌の新しい治療戦略 培養複合口腔粘膜の臨床応用 Reviewed

    寺師 浩人, 泉 健次, 田原 真也, 横尾 聡, 古森 孝英, 芳澤 享子, 鈴木 一郎, 齋藤 力, 飯田 明彦, 高木 律男, 津野 宏彰, 古田 勲

    頭頸部癌   32 ( 3 )   281 - 285   2006.10

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    われわれの開発した培養複合上皮(皮膚、口腔粘膜)は、動物由来蛋白や3T3マウスfeeder layerを使用せずに完全無血清培地でkeratinocyteを培養した移植材料である。培養細胞を無細胞真皮上に播種して作製される培養複合上皮は、文部科学省高度先進医療開発経費Bの支援のもと、口腔粘膜上皮に関して新潟大学、富山大学、神戸大学の三施設合同で臨床応用され、平成14年〜16年の三年間で106症例を数えた。その内52症例が口腔癌もしくはin situであり、結果として90症例で成功し、何らかの理由により16症例で不成功となった。この方法の利点は、異種移植と定義されないこと、理論上将来のプリオン病への危惧がほぼ皆無であること、把持縫合可能な操作性を有すことである。欠点として、無細胞であるが他人の真皮をscaffoldとして使用すること、作製に約一ヵ月を要することである。(著者抄録)

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  • High glucose inhibits human epidermal keratinocyte proliferation for cellular studies on diabetes mellitus Reviewed

    Hiroto Terashi, Kenji Izumi, Mustafa Deveci, Lenore M. Rhodes, Cynthia L. Marcelo

    International Wound Journal   2 ( 4 )   298 - 326   2005.12

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    In order to more clarify the delayed wound healing in diabetes mellitus, we cultured the human epidermal keratinocytes in both 6 mM (control group) and 12 mM glucose (high-glucose group) of 'complete' MCDB 153 medium. Hyperglycaemia slowed the rate of their proliferation and inhibited their DNA synthesis and the production of total proteins. By 1 month after primary seeding in high-glucose group, the cells ceased their proliferation, whereas the cells in control group grew for more than 40 days. Mean population doublings in high-glucose group was 5.27 (vs. 7.25 in control, P = 0.001), and mean population doubling time during 1 month in high glucose group was 5.43 days (vs. 3.65 days in control, P = 0.02). They indicate that prolonged exposure to high glucose decreases the replicative life span of human epidermal keratinocytes in vitro. Furthermore, analysis of fatty acid contents in membrane phospholipids with thin-layer and gas chromatography showed no difference between the cultured keratinocytes in both conditions. Immunocytochemical staining of glucose transporter 1 shows that 28.1% of cells in high-glucose group were almost twice positive of those in control group (13.2%, P = 0.008). The mechanism of the ill effects of high glucose on epidermal keratinocytes is not so far clear, but it indicates the possibility of any direct effect of hyperglycaemia on glucose metabolism without changing lipid metabolism on cell membrane. The high-glucose group presented in this report can be available as an in vitro valuable study model of skin epidermal condition on diabetes mellitus. © Blackwell Publishing Ltd and Medicalhelplines.com Inc 2005.

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  • Development and characterization of a canine oral mucosa equivalent in a serum-free environment

    Song, J., Izumi, K., Lanigan, T., Feinberg, S.E.

    Journal of Biomedical Materials Research - Part A   71 ( 1 )   2004

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  • Development of a tissue-engineered human oral mucosa: From the bench to the bed side Reviewed

    K Izumi, JH Song, SE Feinberg

    CELLS TISSUES ORGANS   176 ( 1-3 )   134 - 152   2004

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    The main objective of this publication is to make the reader aware of the complexity and steps that are necessary to make a Food and Drug Administration (FDA)-approved laboratory produced cell-based device, for use in clinical trials for reconstructive surgery. Most tissue-engineered cell-based devices are considered as 'human somatic cell therapy' and fall under the auspices of the Center of Biologic Evaluation and Research (CBER) and are considered a combination product by the FDA. We have illustrated the algorithm that is necessary to follow an Independent New Drug (IND) application by using our ex vivo produced oral mucosa equivalents (EVPOME), a tissue-engineered oral mucosa, as an example of a cell-based device that needs FDA approval prior to clinical application. By illustrating the experimental approach and presenting resulting data we attempt to explain each step that we address along the way. Copyright (C) 2004 S. Karger AG, Basel.

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  • Malignant fibrous histiocytoma arising in abutting soft tissue after resection of a benign fibrous histiocytoma of the mandible Reviewed

    Kenji Izumi, Jun Cheng, Takeyasu Maeda, Takashi Saku

    Oral Oncology Extra   40 ( 2 )   24 - 28   2004

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    We present a unique case of malignant fibrous histiocytoma (MFH) developing around a masseter muscle close to the surgical margin from which a benign fibrous histiocytoma (BFH) of the mandible was excised 3 years and 10 months earlier. In the interval between the surgical removal of the original BFH and the MFH, several surgical procedures were performed in the related region. Clinical and histopathological evidence showed that this case represented two separate lesions rather than a single disease process. The clinical history suggests that the chronic repair process might have contributed to the tumorigenic factor of a MFH. © 2004 Elsevier Ltd. All rights reserved.

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  • Intraoral grafting of an ex vivo produced oral mucosa equivalent: a preliminary report Reviewed

    K Izumi, SE Feinberg, A Iida, M Yoshizawa

    INTERNATIONAL JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY   32 ( 2 )   188 - 197   2003.4

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    The objective of this study was to assess the efficacy of the use of an ex vivo produced oral mucosa equivalent (EVPOME) for intraoral grafting procedures. Autogenous keratinocytes were harvested from a punch biopsy 4 weeks phor to surgery. placed in a serum-free culture system and seeded onto a human cadaveric dermal equivalent, AlloDerm (R). Thirty patients with either a premalignant or cancerous lesion were triaged into two groups, depending on the stage of disease: Group 1: EVPOME or Group 2: AlloDerm (R), control without an epithelial layer. Clinically, EVPOME grafts were easy to handle and showed excellent compliance on grafting. Both, EVPOME and AlloDerm (R) grafts, showed a 100% take rate, At 6 days post-grafting, the EVPOME clinically showed changes indicating vascular ingrowth and had cytologic evidence of the persistence of grafted cultured keratinocytes on the surface. The EVPOME grafts had enhanced maturation of the underlying submucosal layer associated with rapid epithelial coverage when compared to the AlloDerm (R) grafts at biopsies taken at 28 days post-grafting. In summary, EVPOME appears to be an acceptable oral mucosal substitute for human intraoral grafting procedures and results in a more favorable wound healing response than AlloDerm (R) alone.

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  • Evaluation of transplanted tissue-engineered oral mucosa equivalents in severe combined immunodeficient mice Reviewed

    K Izumi, SE Feinberg, H Terashi, CL Marcelo

    TISSUE ENGINEERING   9 ( 1 )   163 - 174   2003.2

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    The aim of this study was to determine the optimal stage of development at which transplant human ex vivo-produced oral mucosa equivalents (EVPOMEs) in vivo. EVPOMEs were generated in a serum-free culture system, without the use of an irradiated xenogeneic feeder layer, by seeding human oral keratinocytes onto a human cadaveric dermal equivalent, AlloDerm. EVPOMEs were cultured for 4 days submerged and then for 7 or 14 days at an air-liquid interface to initiate stratification before transplantation into SCID mice. AlloDerm, without epithelium, was used as a control. Mice were killed on days 3, 10, and 21 posttransplantation. Epithelium of the transplanted EVPOMEs was evaluated with the differentiation marker keratin 10/13. Dermal microvessel ingrowth was determined by immunohistochemistry with a mouse vascular marker, lectin binding from Triticum vulgaris. The presence and stratification of the epithelium were correlated with revascularization of the underlying dermis. The microvessel density of AlloDerm without epithelium was less than that of EVPOMEs with an epithelial layer. Microvessel density of the dermis varied directly with the degree of epithelial stratification of the EVPOMEs. The EVPOMEs cultured at an air-liquid interface for 7 days had the optimal balance of neoangiogenesis and epithelial differentiation necessary for in vivo grafting.

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  • Two cases of transport distraction osteogenesis for mandibular reconstruction Reviewed

    Kobayashi Tadaharu, Izumi Kenji, Honma Katsuhiko

    Niigata dental journal   32 ( 2 )   87 - 91   2002.12

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    Distraction osteogenesis is a method of increasing bone length, and is now being used in the craniofacial region. The authors report two cases in which segmental mandibular defects were reconstructed by transport distraction osteogenesis and bone transplantation. The patients were a 67-year-old man and a 54-year-old man with squamous cell carcinoma of the lower gingiva and their mandible had been resected from the first molar on the right side to the mandibular angle region on the left side. In the first patient, transport distraction osteogenesis in the mandible was performed at the both sides and low-intensity pulsed ultrasound was used to accelerate bone healing. In the second patient, transport distraction osteogenesis was performed at the right side. Although bone transplants were needed for complete continuity in both cases, segmental mandibular defects were decreased by the regenerated bone. Successful new bone formations in the lengthened areas were recognized by radiographic observation, especially in the old patient used low-intensity pulsed ultrasound. Low-intensity pulsed ultrasound may be effective measures to accelerate bone healing after distraction osteogenesis.骨延長法は、骨そのものを牽引延長することにより骨の増生をはかる方法で、近年顎顔面領域においても広く応用されるようになってきた。今回われわれは、下顎骨欠損に対してトランスポート骨延長と骨移植を組み合わせた下顎骨再建を2症例に施行したので報告する。患者は、67歳と54歳の男性で、ともに下顎歯肉癌の診断にて右側第一大臼歯から左側下顎角部の下顎骨区域切除を施行した。症例1では、両側において骨トランスポート法による下顎骨延長を行い、低出力超音波パルス照射を応用して骨形成の促進を囲った。症例2では、右側において骨トランスポート法による下顎骨延長を行った。両症例とも骨の延長に伴い欠損範囲を縮小し、骨移植を容易にすることができた。特に、低出力超音波パルス照射を応用した症例1では、高齢にも関わらず良好な骨形成が認められ、骨延長における骨形成促進に低出力超音波パルス照射は有用ではないかと思われた。

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  • Clinical Study on Dental Occlusion of Patients with Bone-Grafted Alveolar Clefts Reviewed

    IZUMI Kenji, KOBAYASHI Tadaharu, HONMA Katsuhiko, SHINGAKI Susumu, SAITO Chikara, TERADA Kazuto, ISHII Kazuhiro, MORITA Shuichi, NOMURA Akiko

    Journal of Japanese Cleft Palate Association   27 ( 1 )   58 - 66   2002.4

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    Orthodontic space closure of a cleft in the maxillary arch without prosthetic rehabilitation has been enabled by secondary bone grafting. It is easily achieved when the canine has not fully erupted at the time of bone grafting. However, not a few bone grafting procedures must be performed after the canine has erupted. The aim of this research was to investigate the outcome of dental occlusion in patients with bone-grafted alveolar clefts. Subjects were 88 patients who underwent secondary bone grafting, in our department, from 1987 to 1998, and they were divided into two groups, of the canine not fully erupted, and fully erupted, at the time of surgery. The numbers of the various types of clefts are as follows: 28cases of cleft of the lip and alveolus (unilateral,26; bilateral,2); 60 cases of cleft of the lip and palate (unilateral,52; bilateral,8). Of the total of 99 clefts,51 were in the group of the canine not fully erupted, and 48 were in that of fully erupted. Dental occlusion was classified into nine categories as follows: orthodontic space closure with the canine or the lateral incisor (C), space closure with restoration of the dwarf lateral incisor (Cr), bridgework (B), partial denture (D), autotransplantation of a tooth (T), application of an implant (I), no prosthetic treatment (N), unknown (U), and under orthodontic treatment or observation (O). In the group of the canine not fully erupted, the outcome of dental occlusion was as follows: C,28; Cr,2; B,1; T,1; N,1; U,2, and 0,16 cases. In the group of the canine fully erupted, the outcome of dental occlusion was as follows C,22; Cr,1; B,14; D,1; T,3; I,1; N,2; U,2, and 0,2 cases. According to the types of clefts, the major dental occlusion in patients with unilateral and bilateral cleft lip and alveolus and unilateral cleft lip and palate, was C, while it was B for bilateral cleft lip and palate. Non-prosthetic space closure (categories C, Cr, T, I) was accomplished in 61% of cleft sites in which the canine was not fully erupted at surgery, and in 52% of cleft sites in which the canine was fully erupted at surgery. Orthodontic space closure without prosthetic rehabilitation was the major procedure in both groups. In particular, in the not fully eruption group, the prospect that cases of category Oare likely to move into category C will result in the achievement of space closure in 92% of cleft sites, sustaining the clinical significance of bone grafting before the canine eruption. Bridgework was the second major procedure in the canine fully eruption group, as well as in bilateral cleft lip and palate patients. Desirably, a primary goal in the canine fully eruption group is also achieving orthodontic closure of the cleft space, or the application of tooth autotransplantation and dental implant to bone-grafted alveolar clefts, without prosthetic rehabilitation.

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  • Skin and oral mucosal substitutes Reviewed

    Kenji Izumi, Stephen E. Feinberg

    Oral and Maxillofacial Surgery Clinics of North America   14 ( 1 )   61 - 71   2002

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    To date, successfully developed EVPOMEs in a serum-free culture system without a feeder layer are the most acceptable and promising oral mucosal substitutes for human intraoral grafting because of minimal risk of foreign contaminants, easy handling and stitching, subsequent rapid revascularization into dermal component after transplantation, and contribution to favorable open wound closure without functional compromise, although several types of oral mucosal substitutes described in this article have been used in patients.

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  • Myoepithelioma of the submandibular gland: Report of a case Reviewed

    YOSHIZAWA Michiko, SHIBATA Keiko, TAKADA Masahito, IZUMI Kenji, SHINGAKI Susumu, TAIRA Shuzou

    Journal of Oral Surgery Society of Japan   46 ( 11 )   677 - 679   2000.11

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    A rare case of myoepithelioma originating from the submandibular gland is reported. A 28-yearold woman was referred for treatment of an asymptomatic mass in the left submandibular region. On clinical examination, a 30×15mm hard, mobile, non-tender mass was noted. Ultrasonography and computed tomography demonstrated a large, well-demarcated mass that was not distinct from the submandibular gland. The tumor was removed surgically in March 1998. Histopathologically, the tumor consisted of both spindle-shaped cells and plasmacytoid cells with proliferation of many vessels in the stroma. The neoplastic cells expressed S-100 protein, DF-3, and EMA immunohistochemically. The histopathological diagnosis was myoepithelioma. There was no evidence of recurrence 2 years postoperatively.

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  • A case of sublingual ranula in a neonate Reviewed

    CHUUJOH Tomoe, IZUMI Kenji, SHINGAKI Susumu, NAKAJIMA Tamio, HAYASHI Takafumi, SUZUKI Makoto

    Journal of Oral Surgery Society of Japan   46 ( 9 )   536 - 538   2000.9

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    A case of ranula in a neonate is reported. A 2-month-old infant was found to have a small swelling in the floor of the mouth at birth. Initial examination revealed a fluctuant, translucent swelling with protrusion from the mouth. The lesion arose in the left side of the mouth floor. A computed tomographic examination confirmed the presence of a cystic lesion, un associated with the sublingual gland. The clinical diagnosis was a sublingual ranula. Although marsupialization was performed three times, the swelling recurred and returned to its original size soon after treatment. Three months later, extirpation of the cyst and the sublingual gland was performed. The postoperative course was uncomplicated, with no signs of recurrence for 6 months. The histological diagnosis was mucous retension cyst. To prevent recurrence, extirpation of the sublingual gland was effective, even in an infant.

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  • Human stratified squamous epithelia differ in cellular fatty acid composition Reviewed

    H Terashi, K Izumi, LM Rhodes, CL Marcelo

    JOURNAL OF DERMATOLOGICAL SCIENCE   24 ( 1 )   14 - 24   2000.9

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    The phospholipid component of the cellular membrane is crucial to the structure and function of cells. Basal cells from three epithelial tissues, adult human skin epidermis, oral mucosa, and hair follicles, grow rapidly in serum- and lipid-free medium. Analysis of phospholipid extracts from the above three types of stratified squamous epithelium in both in vivo and in vitro was done to relate fatty acid cell composition to cell function. The fatty acid composition of hair follicles in vivo was analyzed in plucked scalp hairs, and those of skin epidermis and oral mucosa in vivo were analyzed after separating the tissue into suprabasal and basal layers. The fatty acid composition of the in vivo cells from hair follicles shows a partial essential fatty acid (EFA)-deficient state. There was no significant difference between the skill epidermis and the oral mucosa in the fatty acid composition of the in vivo cells from each basal layer. However, in the suprabasal layers, the percent of linoleic acid (18:2) from the skin epidermis was higher than that from the oral mucosa. This study shows that total fatty acid composition in cell membranes of stratified squamous epithelium varies with their keratinization pattern. When cultured, the three types of rapidly growing keratinocytes showed the same essential fatty acid deficient pattern in the membrane phospholipids. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.

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  • Relationship between recipient condition and periodontal healing of autotransplanted teeth Reviewed

    HAMAMOTO Yoshioki, HAMAMOTO Naoki, IZUMI Kenji, KOBAYASHI Tadaharu, NAKAJIMA Tamio, MOHRI Tamaki, HANADA Kouji

    Japanese Journal of Oral and Maxillofacial Surgery   43 ( 10 )   733 - 738   1997.10

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    The relationship between recipient condition and the period required for periodontal healing of autotransplanted teeth was studied. The period for periodontal healing was evaluated on the basis of regeneration of the periodontal space and lamina dura on dental radiographs. Age, sex, site of transplantation, period after tooth extraction at the recipient site, and the timing of occlusal function were the recipient factors examined. The mean periods required for regeneration of the periodontal space and lamina dura were 3.7 months and 7.6 months, respectively. Regeneration of the periodontal space was not influenced by any recipient factor, whereas regeneration of lamina dura was associated with the period after tooth extraction, site of transplantation, and timing of occlusal function. It was suggested that regeneration of the lamina dura may not totally depend on that of the periodontal space.

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  • Complications During Operation for Jaw Deformities. Reviewed

    SUZUKI KIMIHIRO, IZUMI KENJI, HONMA KATSUHIKO, KOBAYASHI TADAHARU, NAKAJIMA TAMIO

    The Japanese Journal of Jaw Deformities   7 ( 2 )   141 - 146   1997.10

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:THE JAPANESE SOCIETY FOR JAW DEFORMITIES  

    Unfavorable fractures and blood vessel injuries encountered during 196 operations on 185 patients who underwent surgical correction of jaw deformities were studied to analyze the causes. There were 12 unfavorable fractures (6.1%) and 9 blood vessel injuries (4.6%). All complications occurred in two-jaw surgery and sagittal splitting ramus osteotomy (SSRO). Blood loss and operation time were significantly higher in cases with complications than in those without complication in SSRO.<BR>SSRO. With the exception of one case, all fractures were encountered during SSRO. Most of them were minor fractures occurring along the osteotomy line, but relatively large segments of the proximal segment were fractured in 3 cases, 2 of which were not repositioned. Blood vessel injury of the descending palatine artery was encountered in 2 cases of Le Fort I osteotomy. In SSRO, injuries of the inferior alveolar artery, facial artery, and unidentified artery occurred in 3, 1, and 3 cases, respectively. Ligation of the arteries was required to stop bleeding in 2 cases, whereas in the other cases, bleeding was controlled by packing of gauze or oxidized regenerated cellulose.<BR>Insufficient bony cut, forcible splitting, and careless handling of surgical instruments were the main causes of the complications. It is thought that the complications can be avoided by precise analysis of structures at the operation site by computed tomography, sufficient bony cut, and careful handling of surgical instruments.

    DOI: 10.5927/jjjd1991.7.141

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  • Unilateral Temporomandibular Joint Ankylosis: Report of a Case. Reviewed

    KOBAYASHI TADAHARU, HONMA KATSUHIKO, IZUMI KENJI, SUZUKI KIMIHIRO, NAKAJIMA TAMIO, HANADA KOOJI

    The Japanese Journal of Jaw Deformities   7 ( 1 )   57 - 62   1997

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    A case of unilateral ankylosis of the temporomandibular joint, which caused micrognathia with facial asymmetry, was reported. A 3-year-old female visited our department because of facial asymmetry She was placed on conservative therapy using a functional appliance to improve facial asymmetry and occlusal relationship. Because of mandibular trismus, condylectomy was performed at the age of 13 years 10 months. Interincisal distance increased to 38mm, but micrognathia with facial asymmetry remained. Therefore, Le Fort I osteotomy combined with extraoral vertical ramus osteotomy on the affected side and sagittal split ramus osteotomy on the opposite side was performed at the age of 16 years 10 months. In addition, augmentation genioplasty with a porous hydroxyapatite block was performed at the age of 17 years 6 months. Four years later, the patient was satisfied with recovery of jaw opening and improvement in facial appearance.

    DOI: 10.5927/jjjd1991.7.57

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  • 顎関節症患者の臨床統計的観察 Reviewed

    岡田朋子, 濱本宣興, 小林正治, 本間克彦, 泉健次, 高田佳之, 中島民雄

    日顎誌   1996.9

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  • Relationship between root canal filling and periodontal healing of autotransplanted teeth Reviewed

    HAMAMOTO Yoshioki, KOBAYASHI Yutaka, HAMAMOTO Naoki, IZUMI Kenji, KOBAYASHI Tadaharu, NAKAJIMA Tamio, MOHRI Tamaki, HANADA Kooji

    Japanese Journal of Oral and Maxillofacial Surgery   42 ( 7 )   684 - 689   1996.7

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    The relationship between root canal filling and the periodontal healing of autotransplantated teeth was studied clinically and radiographically in 21 autotransplanted teeth with complete root formation that were followed up for more than 6 months. The teeth were classified into three types according to the status of root canal filling immediately after transplantation: type A) teeth with root canal (s) wide enough to be detected on radiographs and root canal filling (s) to the apex (es); type B) teeth having incomplete root canal filling (s) because of narrow root canal (s); and type C) teeth having root canal (s) detectable on radiographs but with incomplete filling (s). The periodontal healing was examined more than 6 months postoperatively. Ten teeth classified as type A had no clinical symptoms and showed regeneration of the periodontium on radiographs. Eight teeth classified as type B had no clinical symptoms but the periodontal spaces were indistinct in 5 teeth. No clinical symptoms were associated with 2 of 3 teeth classified as type C, but the periodontal spaces were not clearly seen in the apical regions. The presence of apical lesions and inflammatory resorption of the root was observed on radiographs of the other tooth. These findings suggest that periodontal healing is associated with the width of the root canal and the status of root canal filling.

    DOI: 10.5794/jjoms.42.684

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  • Tooth autotransplantation and periodontal damage Reviewed

    Y Hamamoto, K Izumi, T Kobayashi, T Nakajima

    3RD ASIAN CONGRESS ON ORAL AND MAXILLOFACIAL SURGERY   561 - 565   1996

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    Language:English   Publishing type:Research paper (international conference proceedings)   Publisher:MONDUZZI EDITORE  

    The effect of damage to the periodontium on the outcome of tooth transplantation was studied by examining the relationship of macroscopic condition of the root surface to the clinical course in 27 human autotransplanted teeth. The macroscopic conditions were classified into the areas with A) remnants of periodontal tissue, B) cementum exposure, and C) cementum loss. The macroscopic evaluation was confirmed to be well correlated with the histological findings or 10 healthy teeth. Most of the root surfaces of autotransplanted teeth consisted of the areas with cementum exposure and attachment of periodontal tissue in varying proportions. These teeth showed normal periodontal healing both clinically and radiographically. Replacement resorption in the area of cementum loss was observed in one tooth. The results were consistent with those of previous reports which showed that cementum is important for normal periodontal healing.

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  • Nerve terminals immunoreactive to neurofilament protein (NFP) in the periodontal ligament of rat molars. Reviewed

    N. Kamasaki, T. Maeda, K. Izumi, Y. Kozawa

    Jap. J Oral Biol.   34 ( 2 )   239 - 243   1992

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    DOI: 10.2330/joralbiosci1965.34.239

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  • Responses of neural elements in the experimentally induced carcinoma of the hamster tongue: An immunohistochemical study using antibodies to neurofilament protein(NFP) and glia-specific S-100 protein.:An immunohistochemical study using antibodies to neurofilament protein (NFP) and glia-specific S-100 protein Reviewed

    IZUMI Kenji, MAEDA Takeyasu

    Journal of Oral Surgery Society of Japan   38 ( 6 )   896 - 904   1992

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    Authorship:Lead author   Language:Japanese   Publisher:Japanese Society of Oral and Maxillofacial Surgeons  

    Innervation of carcinomas induced by application of 9, 10-dimethy1-1, 2-benzanthracene (DMBA) was investigated in the hamster tongue by using immunohistochemistry concerning neurofilament protein (NFP) and glia specific S-100 protein.<BR>The tumor induced by application of DMBA was a well-differentiated squamous cell carcinoma having cord-like invasion of the underlying fibrcus tissue and muscle layer.<BR>The characteristic feature of the innervation was the extreme scarcity of NFP-and S-100 pro tein-immunopositive neural elements recognized in the stroma and around blood vessels of the carcinomas.<BR>A few NFP-positive neural elements which were observed in the carcinoma invading zone were very fine and also found not to bear any relation to blood vesseles nor tumor nests.<BR>Unlike calcitonin gene-related peptide-positive nerves, a dense distribution of S-100 protein-positive neural elements characteristic of arterioles in the surrounding muscle layer was also not seen around arterioles abundant in the carcinoma invading zone.<BR>The results indicate a high pain threshold and the absence of autoregulatory mechanism in the blood vessels of the carcinoma tissue.

    DOI: 10.5794/jjoms.38.896

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    Other Link: http://search.jamas.or.jp/link/ui/1993109170

  • <b>CORRECTION:</b> Calcitonin gene-related peptide-immunoreactive nerves in carcinoma experimentally induced in the hamster tongue, Biomedical Research 12 (6) 377-390

    IZUMI K., MAEDA T., NAKAJIMA T.

    Biomed. Res.   13 ( 1 )   85 - 85   1992

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    In Fig. 8 in the above article (page 387), some specified lines should have been printed in red, but printed in black due to an editorial error. On this page, the figure is correctly printed as was intended by the authors.

    DOI: 10.2220/biomedres.13.85

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  • CALCITONIN GENE-RELATED PEPTIDE-IMMUNOREACTIVE NERVES IN CARCINOMA EXPERIMENTALLY INDUCED &lt;/b&gt;&lt;b&gt;IN THE HAMSTER TONGUE &lt;/b&gt; Reviewed

    KENJI IZUMI, TAKEYASU MAEDA, TAMIO NAKAJIMA

    Biomedical Research   12 ( 6 )   377 - 390   1991

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    DOI: 10.2220/biomedres.12.377

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Books

  • オルガノイド研究 : 培養・作製、活用、臨床応用

    谷口, 英樹( Role: Joint author ,  第4章疾患モデルの開発 第4節ヒト三次元培養口腔がんモデルの開発)

    エヌ・ティー・エス  2024.8  ( ISBN:9784860438739

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    Total pages:iv, xiii, 405, ixp   Language:Japanese

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  • スタンダード歯科理工学第8版 : 生体材料と歯科材料

    新谷, 明一, 中嶌, 裕, 宮崎, 隆, 米山, 隆之, 石川, 邦夫, 赤坂, 司( Role: Joint author ,  第4章生体材料の安全性と適合性)

    学建書院  2024.3  ( ISBN:9784762466144

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  • 口腔組織・発生学

    前田, 健康, 網塚, 憲生, 中村, 浩彰(第9章口腔の軟組織 VI 臨床的考察 1口腔粘膜)

    医歯薬出版  2024.1  ( ISBN:9784263456767

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  • 口腔粘膜組織再生医療:歯科再生医学

    泉 健次( Role: Joint author ,  第4章、第5項)

    医歯薬出版  2019.4 

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  • スタンダード歯科理工学第7版

    泉 健次( Role: Joint author ,  第4章 生体材料の安全性と適合性)

    学建書院  2019.3 

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  • Tissue engineering:Operative oral and maxillofacial surgery

    Smith MH, Izumi K, Feinberg SE( Role: Joint author ,  Chapter 2-11)

    CRC Press, Abingdon, UK  2016 

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  • 口腔の軟組織 臨床的考察:口腔組織・発生学

    泉 健次( Role: Joint author ,  第9章)

    医歯薬出版  2015 

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  • 培養口腔粘膜作成技術と製品評価, 『再生医療事業の課題解決のための手引書』

    加藤寛子, 泉 健次( Role: Joint author ,  第6部2章2節5項)

    技術情報協会  2013 

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  • Skin Stem Cells

    Izumi K, Marcelo CM, Feinberg SE( Role: Joint author ,  Chapter 23)

    Humana Press  2013 

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  • 口腔粘膜の再生医療:再生医療叢書

    泉 健次( Role: Joint author ,  第8巻 歯学系)

    朝倉書店  2012 

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  • Tissue engineering. Current therapy in oral and maxillofacial surgery

    Smith MH, Izumi K, Feinberg SE( Role: Joint author ,  Chapter 9)

    Elsevier Saunders  2012 

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  • Skin and oral mucosal substitutes

    W.B. SAUNDERS.  2001 

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  • Electron microscopic atlas of oral disease

    Nagasue Shoten  1998 

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  • Athas of electron microscope of oral disease

    1996 

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MISC

  • 口腔癌と口腔粘膜に対する重粒子線照射の影響に関する3次元in vitroモデルを用いた研究

    泉健次, 内藤絵里子, 内藤絵里子, 井川和代, 羽賀健太, 小林亮太, 小林亮太, 齋藤夕子, 山崎学, 田沼順一, 冨原圭

    日本口腔科学会学術集会プログラム・抄録集   77th   2023

  • 正常口腔粘膜細胞と口腔癌細胞を用いた3次元in vitroモデル作製法とその応用

    内藤絵里子, 小林亮太, 小林亮太, 羽賀健太, 羽賀健太, 齊藤夕子, 山崎学, 田沼順一, 井川和代, 冨原圭, 泉健次

    日本口腔科学会学術集会プログラム・抄録集   76th   2022

  • ヒト培養口腔粘膜上皮角化細胞の運動/増殖能を制御/調節する分子基盤の解明

    小林亮太, 小林亮太, SUEBSAMARN Orakarn, WITSANU Yortchan, 相澤有香, 相澤有香, 内藤絵里子, 内藤絵里子, 干川絵美, 干川絵美, 鈴木絢子, 冨原圭, 泉健次

    新潟歯学会雑誌   52 ( 2 )   2022

  • 口腔癌および口腔粘膜3次元in vitroモデルに対する重粒子線照射の影響に関する研究-異種放射線治療評価の標準化システムの構築-

    内藤絵里子, 内藤絵里子, 高田翔, 羽賀健太, SUEBSAMARN Orakarn, WITSANU Yortchan, 小林亮太, 小林亮太, 鈴木絢子, 山崎学, 田沼順一, 冨原圭, 泉健次

    新潟歯学会雑誌   52 ( 2 )   2022

  • 細胞品質評価ツールとして口腔粘膜角化細胞に対する非侵襲的運動能測定の有用性に関する検討

    小林亮太, 小林亮太, 干川絵美, 佐藤大祐, ORAKARN Suebsamarn, 内藤絵里子, 内藤絵里子, 鈴木絢子, 冨原圭, 冨原圭, 泉健次

    口腔組織培養学会誌   31 ( 1 )   2022

  • 画像解析による口腔ケラチノサイトの細胞増殖能の非侵襲的評価

    干川絵美, 干川絵美, 佐藤大祐, 鈴木絢子, 羽賀健太, 羽賀健太, 多部田康一, 泉健次

    新潟歯学会雑誌   50 ( 2 )   2020

  • マイクロパターン化した魚うろこコラーゲン足場材を用いた培養口腔粘膜の開発

    鈴木絢子, 鈴木絢子, 加藤寛子, 干川絵美, 羽賀健太, 塩見晶, 上野山敦士, 兒玉泰洋, 河上貴宏, 三輪慶人, 桑江博之, 塩澤茉由子, 水野潤, 齋藤一誠, 早崎治明, 泉健次

    日本再生医療学会総会(Web)   18th   2019

  • 細胞品質管理に向けた画像解析による口腔ケラチノサイトの非侵襲的,定量的運動能評価の試み

    干川絵美, 干川絵美, 木森義隆, 佐藤大祐, 加藤寛子, 鈴木絢子, 羽賀健太, 難波大輔, 多部田康一, 泉健次

    日本再生医療学会総会(Web)   18th   2019

  • ヒト歯髄においてシュワン細胞はマクロファージをM2型へ転換する

    吉羽永子, 大倉直人, 前川知樹, 泉健次, 細矢明宏, 中村浩彰, 前田健康, 野杁由一郎, 吉羽邦彦

    Journal of Oral Biosciences Supplement (Web)   2019   2019

  • 魚のうろこコラーゲンを足場に利用した培養口腔粘膜の開発

    鈴木絢子, 鈴木絢子, 加藤寛子, 加藤寛子, 干川絵美, 塩見晶, 上野山敦士, 河上貴宏, 兒玉泰洋, 齋藤一誠, 早崎治明, 泉健次

    日本再生医療学会総会(Web)   17th   2018

  • ROCK阻害剤の骨代謝および矯正学的歯の移動への影響

    中田 樹里, 柿原 嘉人, 秋葉 陽介, 江口 香里, 丹原 惇, 大倉 麻里子, 加藤 寛子, 泉 健次, 佐伯 万騎男, 齋藤 功

    新潟歯学会雑誌   47 ( 2 )   120 - 120   2017.12

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  • うろこコラーゲンを使用した培養口腔粘膜の開発

    鈴木絢子, 鈴木絢子, 加藤寛子, 加藤寛子, 干川絵美, 塩見晶, 河上貴宏, 兒玉泰洋, 齋藤一誠, 早崎治明, 泉健次

    日本バイオマテリアル学会大会予稿集(Web)   39th   97 (WEB ONLY) - 97   2017.11

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  • ホーム、スイートホーム -口腔粘膜ティッシュエンジニアリングの展望ー Invited Reviewed

    泉 健次

    新潟歯学会雑誌   47 ( 1 )   1 - 10   2017.6

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  • コラーゲンゲル内で3次元培養したヒト口腔粘膜線維芽細胞の低酸素応答

    原 夕子, 加藤 寛子, 塩見 晶, 高木 律男, 泉 健次

    新潟歯学会雑誌   46 ( 2 )   114 - 114   2016.12

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  • ラット間葉系細胞の多面的骨誘導能に対する低酸素処理の効果に関する検討

    齋藤直朗, 齋藤直朗, 齋藤直朗, 泉健次, 秋葉陽介, 加藤寛子, 加藤寛子, 原夕子, 小島拓, 芳澤享子, 小林正治, 大峡淳, 前田健康, 前田健康

    新潟歯学会雑誌   45 ( 2 )   106 - 106   2015.12

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  • P-43 Surface characteristics of PEEK by SiC polishing : Comparison of polishing characteristics of restorative resins for CAD/CAM

    Okawa S, Taka N, Kanatani M, Izumi K

    The journal of the Japanese Society for Dental Materials and Devices   34 ( 5 )   387 - 387   2015.9

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    The aim of this study was to characterize the surface properties of PEEK and CAD/CAM resins, CAM-A and CAM-B, by SiC polishing. Two way polishing unit was used with a waterproof P#1200-SiC paper. Mean wear rate was calculated based on the polishing pressure and sliding distance. The surface properties were analyzed with AFM. The mean wear rate of PEEK, CAM-A and CAM-B was about 0.5, 1.9 and 0.5 mm^3/Nm, respectively. The surface roughness (Ra) of these specimens was around 0.51, 0.29 and 0.23 μm, respectively. These results indicated that PEEK can be used as a material for CAD/CAM resin.

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  • 低酸素環境が培養ヒト正常口腔粘膜上皮細胞に及ぼす影響

    加藤寛子, 泉健次, 原夕子, 塩見晶, 上野山敦士, 前田健康

    組織培養研究   34 ( 1 )   34 - 34   2015.3

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  • P-27 Application of hexagonal boron nitride for gold alloy casting in air

    Kanatani M, Okawa S, Izumi K, Kimura I

    The journal of the Japanese Society for Dental Materials and Devices   34 ( 2 )   98 - 98   2015.3

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    The present study examined the feasibility of hexagonal boron nitride (hBN) as a wax pattern coating material for gold alloy casting in air. After wax patterns were coated with hBN, they were outer-invested with a gypsum-bonded investment. The thin specimens made of the gold alloy, 0.55 mm in thickness, were cast in air. The color of the cast surface by using hBN was rusty red. The X-ray diffractometer analysis revealed that copper oxide produced on the hBN cast surface was the only Cu_2O, and CuO produced on the control was not detected. This means that hBN remarkably inhibited the oxidation during casting. Thus, the use of hBN could be effective in hardness of the cast surface.

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  • C配糖体が口腔粘膜上皮角化細胞と線維芽細胞から成る3次元口腔粘膜モデルに及ぼす影響の検討

    上野山敦士, 泉健次, 塩見晶, 齋藤直朗, 原夕子, 齋藤太郎, 大貫尚志, 加藤寛子, 安島久雄, 高木律男, 前田健康

    新潟歯学会雑誌   44 ( 2 )   127 - 127   2014.12

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  • Hypoxia Induces Undifferentiated Phenotype of Oral Keratinocytes In Vitro

    H. Kato, K. Izumi, A. Shiomi, A. Uenoyama, S. Kuo, S. Feinberg, T. Maeda

    TISSUE ENGINEERING PART A   20   S17 - S17   2014.12

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  • P-34 Preparation of organo-mineral complexes by electrolysis : Adhesion characteristic of mineral particles on metal plate

    Okawa S, Kanatani M, Izumi K

    The journal of the Japanese Society for Dental Materials and Devices   33 ( 5 )   420 - 420   2014.9

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    The aim of this study was to characterize the adhesion of mineral particles to a metal (titanium) plate by electrolysis. MMA including a conductive monomer and zircon powder treated with stearic acid was used as an electrolyte. Titanium and carbon plates were used as electrodes. Twenty volts DC were applied between the electrodes for 3,600 s. EPMA revealed the adhesion of zircon particles to the metal surface. In addition, S, O elements were concurrently detected on and around the particles. Since both elements were derived from the conductive monomer, the present study indicated the formation of an organic material including conductive monomer on the metal surface preceded the adhesion of zircon particles.

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  • P-34 Effects of water droplets adhering on a mechanical spatulator with vacuum and hand spatula on water-powder ratio and compressive strength of dental stone

    Kanatani M, Okawa S, Izumi K, Kimura I

    The journal of the Japanese Society for Dental Materials and Devices   33 ( 2 )   143 - 143   2014.3

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    The water-powder ratio (W/P ratio) affects compressive strength of dental stone. In this study, we investigated the effects of water droplets adhering on a mechanical spatulator with vacuum and hand spatula on W/P ratio. The amount of water droplets was measured using an electronic balance. The compressive strength of dental stone was calculated based on the loaded weight. The total amount of water droplets adhering onto spatulator (volume; 250 and 500 mL) and a hand spatula were 0.90 mL (SD 0.10) and 1.33 mL (SD 0.12), respectively. The compressive strength of the dental stone were 10.23 kg/mm^2 (SD 0.27) and 6.89 kg/mm^2 (SD 1.31) at W/P ratio 0.20 and 0.23, respectively. Thus, the total amount of water droplets adhering on those instruments should be taken into consideration when mixing dental stone.

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  • C配糖体が培養口腔粘膜上皮角化細胞に及ぼす影響の検討

    上野山敦士, 泉健次, 塩見晶, 齋藤直朗, 齋藤太郎, 大貫尚志, 加藤寛子, 寺田(中石)典子, 河野芳朗, 野澤(井上, 佳世子, 高木律男, 前田健康

    再生医療   13   234   2014.1

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  • P-19 A study of strategy beneficial for patients by utilizing title system of Japanese society for dental materials and devices

    Kanatani M, Okawa S, Yamaga Y, Kaneko H, Izumi K

    The journal of the Japanese Society for Dental Materials and Devices   32 ( 5 )   353 - 353   2013.9

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    Japanese society for dental materials and devices has title system of Dental Materials Adviser (DMA) and Dental Materials Senior Adviser (DMSA), which are titles about dental materials and devices. Dentists use dental materials and devices in their clinics. Therefore, it appears to be beneficial for patients that dentists take DMA and DMSA. In this study, we explored the strategy beneficial for patients by utilizing this title system. Since Japan dental association (JDA) is the largest association of dentists including general practitioners, we will be able to inform dentists of our title system by using the advertising media in the JDA. If the JDA agreed with our plan, the number of DMA and DMSA would increase dramatically. Consequently, our strategy would result in the benefit for thousands of patients.

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  • P-62 Preparation and characterization of organo-mineral complex by electrolysis

    Okawa S, Kaneko H, Yamaga Y, Kanatani M, Izumi K

    The journal of the Japanese Society for Dental Materials and Devices   32 ( 5 )   412 - 412   2013.9

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    The aim of this study was to prepare organo-mineral complex by electrolysis and to characterize it. MMA including conductive monomer and oxide with a stearic acid treatment was used as an electrolyte. Titanium and stainless substrate were used as electrodes. Twenty volts DC were applied between the electrode and Pt counter electrode in the electrolyte for 3,600 s. FTIR results confirmed the preparation material to be a PMMA. Mineral particles were well dispersed on the PMMA matrix according to the EPMA results. The mineral particle size was the order of submicron by AFM image. Consequently, the organo-mineral complex was easily prepared by the electrolysis.

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  • P-57 Contact corrosion of Ag-Pd-Cu-Au alloys with different Cu content : Analysis of corroded surface by XPS

    Kaneko H, Okawa S, Kanatani M, Ito K, Yamaga Y, Nomura S, Izumi K

    The journal of the Japanese Society for Dental Materials and Devices   32 ( 5 )   407 - 407   2013.9

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    The aim of this study was to investigate the effect on corrosion products due to difference in Cu content. We prepared three kinds of Ag-Pd-Cu-Au alloys with difference Cu content. After casting in 10 × 20 × 1 mm^3, the contacted casting plates were immersed in corrosion solution for 8 weeks at 37℃. After immersed, we analyzed alloy surface by XPS. In spite of Cu content, a peak derived from PdO was confirmed in Pd3d XPS spectra of all specimens.

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  • 培養口腔粘膜上皮細胞における細胞分化とTASCCに関する検討

    泉健次, 加藤寛子, 大貫尚志, 齋藤太郎, 塩見晶, 上野山敦士, 寺田典子, 河野芳朗, 野澤(井上, 佳世子, 前田健康

    日本解剖学会総会・全国学術集会講演プログラム・抄録集   118th   144   2013

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  • 3D口腔粘膜モデルを用いたビスフォスフォネート製剤が創閉鎖に及ぼす影響の組織学的・免疫組織化学的検討

    齋藤太郎, 泉健次, 上野山敦士, 塩見晶, 大貫尚志, 加藤寛子, 寺田典子, 河野芳朗, 野澤(井上, 佳世子, 高木律男, 前田健康

    新潟歯学会雑誌   42 ( 2 )   142 - 143   2012.12

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  • Histological and immunohistological analyses of epithelial regeneration and wound healing affected by Bisphosphonates (BPs) using a living oral mucosa equivalent model

    T. Saito, K. Izumi, A. Shiomi, H. Ohnuki, H. Kato, M. Terada, Y. Kawano, K. Nozawa-Inoue, R. Takagi, T. Maeda

    JOURNAL OF INVESTIGATIVE DERMATOLOGY   132   S135 - S135   2012.5

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  • 1219 Elongating and Collapsing process of single cells Squeezed

    ISHII Tatsuji, NARUMII Takatsune, IZUMI Kenji, SHIOMI Aki

    2012 ( 49 )   121901 - 121902   2012.3

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  • ゾレドロン酸がヒト口腔粘膜上皮細胞に及ぼす影響に関する研究

    大貫尚志, 泉健次, 加藤寛子, 齋藤太郎, 寺田典子, 河野芳郎, 野澤(井上, 佳世子, 高木律男, 前田健康

    新潟歯学会雑誌   41 ( 2 )   119 - 120   2011.12

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  • ALDH活性の薬理学的操作が口腔粘膜角化細胞形質と上皮組織に及ぼす影響の検討

    加藤寛子, 泉健次, 大貫尚志, 齋藤太郎, 寺田典子, 河野芳朗, 野澤(井上, 佳世子, 齊藤力, 前田健康

    新潟歯学会雑誌   41 ( 2 )   128   2011.12

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  • ラット顎関節滑膜におけるデスミン陽性B型表層細胞

    野澤(井上, 佳世子, 鈴木晶子, 真柄仁, 河野芳朗, 寺田典子, 泉健次, 前田健康

    J Oral Biosci   53 ( Supplement )   162 - 162   2011.9

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  • キトサンおよびウロココラーゲンを足場とした培養複合口腔粘膜の組織学的検討

    寺田典子, 泉健次, 加藤寛子, 大貫尚志, 齋藤太郎, 前田健康, 山本麻里絵, 生駒俊之, 田中順三

    再生医療   10   170   2011.2

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  • 顎関節関節円板の発達におけるネスチンとGFAPの局在変化

    鈴木晶子, 野澤(井上, 佳世子, 真柄仁, 河野芳朗, 寺田典子, 泉健次, 前田健康

    解剖学雑誌   85 ( Supplement )   133   2010.3

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  • An anti-aging pill : Rp) Rapamycin 2T 2x1 M und A; G 15 J, start taking at age of 60

    Izumi Kenji

    39 ( 2 )   183 - 184   2009.12

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  • 歯胚中間層における67kD laminin receptor(67LR)の発現:星状網における血管網形成との相関

    河野芳朗, 木下(河野)承子, 鈴木晶子, 野澤(井上, 佳世子, 泉健次, 前田健康

    J Oral Biosci   51 ( Supplement )   73   2009.8

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  • 口腔粘膜の再建における培養複合口腔粘膜(EVPOME)の応用

    芳澤 享子, 泉 健次, 飯田 明彦, 小山 貴寛, 中西 義崇, 鈴木 一郎, 齊藤 力, 高木 律男

    新潟県医師会報   ( 702 )   8 - 10   2008.9

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  • 培養複合口腔粘膜による口腔粘膜再建の臨床的評価

    芳澤 享子, 泉 健次, 飯田 明彦, 鈴木 一郎, 齊藤 力, 高木 律男, 寺師 浩人, 横尾 聡, 古森 孝英, 津野 宏彰, 古田 勲

    日本口腔外科学会雑誌   50 ( 13 )   953 - 954   2004.12

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  • 口腔前庭拡張術(付着歯肉形成術)に培養複合口腔粘膜を使用した4例の臨床的検討

    飯田 明彦, 泉 健次, 高木 律男, 芳澤 享子, 鈴木 一郎, 齊藤 力

    日本口腔粘膜学会雑誌   8 ( 2 )   99 - 100   2002.12

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  • 智歯の移植に関する臨床的検討

    川上 美貴, 芳澤 享子, 小林 正治, 泉 健次, 齋藤 力, 安島 久雄, 小野 和宏, 高木 律男

    日本口腔科学会雑誌   51 ( 6 )   514 - 515   2002.11

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  • The Culture Methods of Epidermal Keratinocytes and Oral Mucosa Keratinocytes and Development of Their Epithelial Sheets Using a Fetal Calf Serum-Free Medium

    TERASHI Hiroto, IZUMI Kenji, FEINBERG Stephen E., MARCELO Cynthia L.

    22 ( 1 )   1 - 5   2002.1

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  • 顎裂骨移植部における永久歯咬合再建に関する臨床的検討

    泉 健次, 小林 正治, 本間 克彦, 新垣 晋

    日本口蓋裂学会雑誌   26 ( 2 )   236 - 236   2001.4

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  • A progressive mandibular radio lucency

    ORAL SURG ORAL MED ORAL PATHOL ORAL RADIOL ENDOD   2001

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  • Expression of glucose transporter 1 in epithelial layer of human oral mucosa equivalent

    IZUMI Kenji, TERASHI Hiroto, YOSHIZAWA Michiko, MARCELO Cynthia L., FEINBERG Stephen E.

    Japanese Journal of Oral and Maxillofacial Surgery   47 ( 5 )   289 - 292   2001

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    Recent studies have revealed that glucose transporter 1 (GLUT 1) expression can be detected in basal layer cells of skin. Expression levels of GLUT 1 are thought to be regulated by glucose transport activity within cells. Glucose metabolism in the epithelial layers may affect keratinocyte differentiation. We studied the localization of GLUT 1 expression in the epithelial layers of oral mucosa equivalents, grown in a defined serum-free culture medium without a feeder layer. The oral mucosa produced in this system is minimally exposed to potential foreign contaminants and is thus more acceptable for use in humans. Samples of native human gingiva and oral mucosa equivalents on days 4, 11, and 18 were fixed in 4% paraformaldehyde, embedded in paraffin, and cut into 5-micrometer-thick sections. For immunohistochemical studies, sections were stained by the ABC method using polyclonal antibodies to rabbit GLUT-1. Well-stratified, differentiated epithelial layers in day 18 oral mucosa equivalents had a similar keratinization pattern to that of native tissue. GLUT 1 was expressed in both the basal cell layer and suprabasal cell layer of oral mucosa epithelium, but not in the superficial layer. Immunoreactivity for GLUT-1 was detected in all epithelial layers of oral mucosa equivalents, except for the superficial layer of day 18 equivalents. In conclusion, keratinocytes of all layers of oral mucosa equivalents were in a highly active metabolic state and showed increased glycolysis, suggesting active proliferative and a less differentiated state as comnared with the basal and na.ra.ba.sa.1 cell lavers of native tissue.

    DOI: 10.5794/jjoms.47.289

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  • Expression of glucose transporter 1 (GLUT1) in the epithelial layer of an ex vivo produced human oral mucosa equivalent

    IZUMI Kenji, TERASHI Hiroto, YOSHIZAWA Michiko, MARCELO Cynthia L., FEINBERG Stephen E.

    Journal of Oral Surgery Society of Japan   47 ( 5 )   289 - 292   2001

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    Recent studies have revealed that glucose transporter 1 (GLUT 1) expression can be detected in basal layer cells of skin. Expression levels of GLUT 1 are thought to be regulated by glucose transport activity within cells. Glucose metabolism in the epithelial layers may affect keratinocyte differentiation. We studied the localization of GLUT 1 expression in the epithelial layers of oral mucosa equivalents, grown in a defined serum-free culture medium without a feeder layer. The oral mucosa produced in this system is minimally exposed to potential foreign contaminants and is thus more acceptable for use in humans. Samples of native human gingiva and oral mucosa equivalents on days 4, 11, and 18 were fixed in 4% paraformaldehyde, embedded in paraffin, and cut into 5-micrometer-thick sections. For immunohistochemical studies, sections were stained by the ABC method using polyclonal antibodies to rabbit GLUT-1. Well-stratified, differentiated epithelial layers in day 18 oral mucosa equivalents had a similar keratinization pattern to that of native tissue. GLUT 1 was expressed in both the basal cell layer and suprabasal cell layer of oral mucosa epithelium, but not in the superficial layer. Immunoreactivity for GLUT-1 was detected in all epithelial layers of oral mucosa equivalents, except for the superficial layer of day 18 equivalents. In conclusion, keratinocytes of all layers of oral mucosa equivalents were in a highly active metabolic state and showed increased glycolysis, suggesting active proliferative and a less differentiated state as comnared with the basal and na.ra.ba.sa.1 cell lavers of native tissue.

    DOI: 10.5794/jjoms.47.289

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  • Development and characterization of a tissue-engineered human oral mucosa equivalent produced in a serum-free culture system

    K Izumi, H Terashi, CL Marcelo, SE Feinberg

    JOURNAL OF DENTAL RESEARCH   79 ( 3 )   798 - 805   2000.3

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    A problem maxillofacial surgeons face is a lack of sufficient autogenous oral mucosa for reconstruction of the oral cavity. Split-thickness or oral mucosa grafts require more than one surgical procedure and can result in donor site morbidity. Skin has disadvantages of adnexal structures and a different keratinization pattern than oral mucosa. In this study, we successfully assembled, ex vivo, a human oral mucosa equivalent, consisting of epidermal and dermal components, in a defined, essential-fatty-acid-deficient, serum-free culture medium without a feeder layer, that could be used for intra-oral grafting in humans. Autogenous oral keratinocytes were seeded onto a cadaveric dermis, AlloDerm(TM). The oral mucosa equivalent was cultured at an air-liquid interface for 2 wks. The resulting equivalent had a well-stratified parakeratinized epithelial layer similar to native oral keratinized mucosa. Expression of differentiation markers, filaggrin and cytokeratin 10/13, suggested a premature keratinized state. The presence of proliferation markers, proliferating cell nuclear antigen (PCNA) and Ki-67, suggested a state of hyperproliferation. Fatty acid composition of the equivalent was similar to that of in vitro cultured oral keratinocytes but differed from the that of in vivo native tissue, showing a lower content of 18:2 and 20:4, and a higher content of 16:1 and 18:1 fatty acids, respectively. The keratinocytes of the equivalent appeared to be in a more active and proliferative state than native keratinized mucosa. The dynamic nature of the cell population on the oral mucosa equivalent may be beneficial for intra-oral grafting procedures and for transfection of the keratinocytes.

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  • Clinical Application of oral mucosa equivalent-Intraoral grafting of human cultured oral mucosa composite-

    THE. QUINTESSENCE   20 ( 6 )   1057 - 1064   2000

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  • -培養複合口腔粘膜の口腔内移植-培養粘膜の臨床応用

    クインテッセンス社   20 ( 6 )   1057 - 1064   2000

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  • Ex vivo production of a composite human oral mucosa equivalent in aserum-free culture system without a feeder layer

    Kenji Izumi, Hiroto Terashi

    Niigata dental journal   29 ( 2 )   63 - 64   1999.12

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  • Polypoid mass of the gingiva

    K Izumi, T Nakajima, T Maeda, T Irie, M Murata, T Saku

    ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY AND ENDODONTICS   88 ( 2 )   117 - 121   1999.8

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  • Ex vivo development of a composite human oral mucosal equivalent

    K Izumi, G Takacs, H Terashi, SE Feinberg

    JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY   57 ( 5 )   571 - 577   1999.5

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    Purpose: The aim of this study was the ex vivo development of a composite oral mucosal equivalent composed of a continuous stratified layer of human oral keratinocytes grown on a cadaveric human dermal matrix in a defined medium without a feeder layer.
    Materials and Methods: Enzymatically dissociated human oral keratinocytes from keratinized oral mucosa were cultured, submerged in a serum-free, low-calcium (0.15 mmol/L) supplemented medium, and expanded through several passages. Once a sufficient population of keratinocytes was reached, they were seeded on 1-cm(2) pieces of AlloDerm (LifeCell Co, Woodlands, TX), an acellular nonimmunogenic cadaveric human dermis, at cell densities of 2.5 x 10(4), 5.0 x 10(4), 1.25 x 10(5), or 2.5 x 10(5). The oral keratinocyte-AlloDerm composites were cultured while submerged in a high-calcium (1.8 mmol/L) medium for 4 days. After 4 days, the composites were raised to an air-liquid interface. Samples of the composites were taken for histologic examination at 4, 11, and 18 days postseeding of the keratinocytes on the AlloDerm.
    Results: At day 4, only the seeded cell density of 2.5 x 10(5) cells/cm(2) formed a continuous monolayer on the AlloDerm. At day 11, a continuous stratified epithelium was seen, and at day 18 a well-differentiated, confluent parakeratotic epithelial layer was developed at cell densities of 5.0 x 10(4), 1.25 x 10(5), and 2.5 x 10(5) cells/cm(2).
    Conclusion: With the method used, it was possible to successfully develop an ex vivo composite oral mucosal equivalent that consisted of a stratified epidermis on a dermal matrix.

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  • Development of oral mucosa equivalent ina serum-free culture system without afeedor layer

    Niigata Dental Journal   29 ( 2 )   187 - 188   1999

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  • よりクリーンな培養複合口腔粘膜の開発

    新潟歯学会雑誌   29 ( 2 )   187 - 188   1999

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  • Temporomandibular joint symptoms and disc displacement in patients with mandibular prognathism

    T. Kobayashi, K. Honma, K. Izumi, T. Hayashi, S. Shingaki, T. Nakajima

    British Journal of Oral and Maxillofacial Surgery   37 ( 6 )   455 - 458   1999

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    Our objective was to find out the incidence of signs and symptoms of temporomandibular joint (TMJ) and disc displacement in patients with mandibular prognathism. Fifty-one patients were examined clinically and by axial computed tomography (CT). The incidence of TMJ signs and symptoms was 6/25 (24) in patients with simple mandibular prognathism and 12/26 (46) in patients with mandibular prognathism and asymmetry. No discs were displaced in patients with simple mandibular prognathism, but 15 (58) of the patients with mandibular prognathism and asymmetry had displaced discs. There was no association between signs and symptoms of TMJ and disc displacement. Patients with mild protrusion and severe asymmetry of the mandible had a high incidence of disc displacement, which interestingly was on the deviated side in 14 of the 15 patients affected. We conclude that skeletal morphology may have a role in the development of TMJ disorders but the mechanism is obscure.

    DOI: 10.1054/bjom.1999.0016

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  • Clinical study of surgically treated temporomandibular joint ankylosis

    IZUMI Kenji, KOBAYASHI Tadaharu, HAMAMOTO Yoshioki, NOMURA Tsutomu, YOKOBAYASHI Toshio, NAKAJIMA Tamio

    Japanese Journal of Oral and Maxillofacial Surgery   45 ( 4 )   296 - 298   1999

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    Seventeen patients with 23 surgically treated ankylotic temporomandibular joints were studied clinically. Including 2 patients with recurrence, high operations, low operations, and gap surgery were performed on 12, 8, and 6 joints, respectively, in patients 6 to 60 years of age. Joints were reconstructed by costochondral grafts and artificial joints in 3 patients (4 joints). Interpositional materials were used in 7 joints in 5 patients. With the exception of 3 patients who underwent joint reconstruction, all patients started postoperative mouth opening exercises within a week after surgery. The maximum mouth opening increased by 6 to 30 mm 4 months to 7 years 9 months postoperatively. The average postoperative maximum mouth opening was greater in patients younger than 16 years of age than in those older than 20 years of age, and there was no re-ankylosis in the former group. Intermaxillary fixation was maintained for 3 weeks postoperatively in the patients who un-derwent reconstruction. Postoperative open bite was encountered in 5 patients. Open bite was controlled by mouth closing exercises, the use of a chin cap and class II elastics, and occlusal adjustment by prosthetic devices. In conclusion, surgical treatment of ankylotic joints should be performed as early as possible in young patients.

    DOI: 10.5794/jjoms.45.296

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  • A clinical study of surgically treated temporomandibular joint ankylosis

    IZUMI Kenji, KOBAYASHI Tadaharu, HAMAMOTO Yoshioki, NOMURA Tsutomu, YOKOBAYASHI Toshio, NAKAJIMA Tamio

    Japanese Journal of Oral and Maxillofacial Surgery   45 ( 4 )   296 - 298   1999

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    Seventeen patients with 23 surgically treated ankylotic temporomandibular joints were studied clinically. Including 2 patients with recurrence, high operations, low operations, and gap surgery were performed on 12, 8, and 6 joints, respectively, in patients 6 to 60 years of age. Joints were reconstructed by costochondral grafts and artificial joints in 3 patients (4 joints). Interpositional materials were used in 7 joints in 5 patients. With the exception of 3 patients who underwent joint reconstruction, all patients started postoperative mouth opening exercises within a week after surgery. The maximum mouth opening increased by 6 to 30 mm 4 months to 7 years 9 months postoperatively. The average postoperative maximum mouth opening was greater in patients younger than 16 years of age than in those older than 20 years of age, and there was no re-ankylosis in the former group. Intermaxillary fixation was maintained for 3 weeks postoperatively in the patients who un-derwent reconstruction. Postoperative open bite was encountered in 5 patients. Open bite was controlled by mouth closing exercises, the use of a chin cap and class II elastics, and occlusal adjustment by prosthetic devices. In conclusion, surgical treatment of ankylotic joints should be performed as early as possible in young patients.

    DOI: 10.5794/jjoms.45.296

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  • Evaluation of ex vivo produced oral mucosa equivalent gratis transplanted to SCID mice

    Journal of Oral and Maxillofacial Surgery   57 ( 81Supple4 )   30   1999

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  • Adenosquamous carcinoma of the tongue - Report of a case with histochemical, immunohistochemical, and ultrastructural study and review of the literature

    K Izumi, T Nakajima, T Maeda, J Cheng, T Saku

    ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY AND ENDODONTICS   85 ( 2 )   178 - 184   1998.2

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    A rare case of oral adenosquamous carcinoma in a 78-year-old woman is reported. The tumor occurred in her tongue and metastasized to the submandibular and cervical lymph node;. Histologically, the tumor showed invasive growth involving the submucosal and muscle lavers. Its solid carcinomatous nests exhibited ductal differentiation in the deeper aspects and squamous differentiation toward the surface. Histochemical examination revealed an accumulation of acid mucopolysaccharide in the ductal luminal and the ductal cells were immunohistochemically positive for carcinoembryonic antigen, epithelial membrane antigen, cancer antigen 15-3 and Ulex europaeus agglutinin I. Ultrastructurally, tonotibrils, desmosomes and numerous cytoplasmic processes were common features of the tumor cells. In addition, true glandular structures and pseudocysts were seen in areas. Clinical features of 13 adenosquamous carcinomas in the literature were analyzed.

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  • Immunohistochemical characterization of composite human oral mucosal equivalent

    Journal of Oral and Maxillofacial Surgery   56 ( 4(補冊) )   99   1998

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  • Development of human composite oral mucosal grafts.

    G Takacs, K Izumi, LM Rhodes, SE Feinberg

    JOURNAL OF DENTAL RESEARCH   77   194 - 194   1998

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  • 3) 上顎歯肉部に発生した腺癌の1例(I. 一般演題, 第51回新潟癌治療研究会演題)

    泉 健次, 野村 努, 河野 正己, 村田 雅史, 朔 敬

    新潟医学会雑誌   110 ( 3 )   120 - 120   1996.3

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    Language:Japanese   Publisher:新潟医学会  

    CiNii Article

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  • 肋骨付き軟骨による下顎頭再建術後のCT上の変化について,症例報告

    アジア口腔外科学会雑誌   8 ( 2 )   171   1996

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  • Computed tomographic study on postoperative changes of reconstructed mandibular condyle following costochondral graft Report of case

    Asian Journal of oral and maxillofacial Surgery   8 ( 2 )   171   1996

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  • PRIMARY LEIOMYOSARCOMA OF THE MAXILLA WITH REGIONAL LYMPH-NODE METASTASIS - REPORT OF A CASE AND REVIEW OF THE LITERATURE

    K IZUMI, T MAEDA, J CHENG, T SAKU

    ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY AND ENDODONTICS   80 ( 3 )   310 - 319   1995.9

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    Language:English   Publisher:MOSBY-YEAR BOOK INC  

    A rare case of oral leiomyosarcoma diagnosed with the aid of immunohistochemical and electron microscopic examinations together with a review of the literature are reported. The patient was a 70-year-old Japanese man. The primary tumor involved the maxillary gingiva and bone and metastasized to the cervical lymph nodes. On histologic examination the tumor showed invasive growth into the maxillary bone. It was composed of interlacing fascicles of spindle-shaped cells with eosinophilic cytoplasm and elongated, blunt-ended nuclei. The tumor formed extensive metastatic foci in the cervical lymph nodes. On immunohistochemical examination most of the tumor cells were positive for desmin, smooth muscle-specific actin, and myosin. The ultrastructural characteristics of the tumor cells were abundant microfilaments, pinocytotic vesicles, and basement membrane formation. The findings were indicative of a tumor demonstrating myogenic differentiation. A review of the literature during the past 50 years disclosed a total of 60 oral leiomyosarcomas, including our case.

    Web of Science

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  • 5)超高齢口腔癌患者の臨床的検討(I. 一般演題, 第50回新潟癌治療研究会)

    棟方 隆一, 泉 健次, 中島 民雄, 朔 敬

    新潟医学会雑誌   109 ( 6 )   299 - 299   1995.6

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    Other Link: http://hdl.handle.net/10191/42442

  • Ultrastructural and immunocytochemical characterization of a gingival neurofibroma.

    Asian Journal of oral and maxillofacial surgery   1995

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  • Responses of neural elements in the experimentally induced carcinoma of the hamster tongue

    Japanese Journal of Oral Maxillofacial Surgery   38 ( 6 )   1992

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  • 実験的ハムスター舌癌組織における神経線維の動態

    日本口腔外科学会雑誌   38 ( 6 )   1992

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Presentations

  • Current and Future Research Topics on Tissue Engineering of Oral Mucosa-

    泉 健次

    The International Collaborative Symposium on Development of Human Resources in Practical Oral Health and Treatment  2019.2 

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    Presentation type:Oral presentation (keynote)  

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  • Oral & Maxillofacial Tissue Enigineering and Reconstruction - Oral Mucosa -

    泉 健次

    The Internartional Conference on Dental Science & Training 2018 “Future Trends in Dentistry”  2018.12 

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    Presentation type:Oral presentation (invited, special)  

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  • Clinical Applications of Oral Keratinocytes: Bench to Bedside, then back to the Bench Invited

    泉 健次

    35th Annual Scientific Meeting@The University of Hong Kong  2017.12 

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  • Tissue Engineering of Oral Mucosa Invited

    泉 健次

    Gadyah Mada University Faculty Meeting  2017.8 

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  • うろこコラーゲンを足場とする培養口腔粘膜作成 Invited

    泉 健次

    日本バイオマテリアル学会シンポジウム2016  2016.11 

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  • A novel approach to identify oral keratinocyte stem cells Invited

    泉 健次

    39th annual scientific meeting of association for dental sciences of the republic of china39th annual scientific meeting of association for dental sciences of the republic of china  2016.9 

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  • 口腔粘膜上皮幹細胞の単離・同定に向けたアプローチ Invited

    泉 健次

    第121回日本解剖学会総会  2016.3 

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  • 3D In Vitro Models As Alternatives to Animal Testng Invited

    泉 健次

    International Symposium on Development of Human Resources in Practical Oral Health and Treatment.  2016.1 

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  • 培養口腔粘膜の臨床応用 Invited

    泉 健次

    日本セラミック協会第28回秋季シンポジウム  2015.9 

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Industrial property rights

  • 解析方法、解析装置及びプログラム

    泉 健次, 小林 亮太, 飯田 佑輔, 三沼 蓮

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    Applicant:新潟大学

    Application no:特願2024-066110  Date applied:2024.4

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  • 立体細胞培養体および立体細胞培養体の製造方法

    泉健次, 羽賀健太, 相澤有香, 高田翔

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    Applicant:新潟大学

    Application no:特願2024-040964  Date applied:2024.3

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  • ヒト4次元治療経過観察モデル

    井川和代, 泉健次

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    Applicant:岡山大学、新潟大学

    Application no:特願2022-118584  Date applied:2022.7

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  • 転写用鋳型、転写用鋳型の製造方法及び医療基材の製造方法

    泉健次

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    Applicant:新潟大学、小松精機工作所、早稲田大学

    Application no:特願2022-051501  Date applied:2022.3

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  • 口腔粘膜上皮細胞培養用の架橋線維化コラーゲンゲル

    泉 健次, 鈴木絢子, 三輪慶人, 桑江博之, 水野潤, 兒玉泰洋, 山口 勇

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    Application no:特願2018-242505  Date applied:2018.12

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  • 細胞の品質評価方法、品質評価システム及び品質評価プログラム

    泉 健次, 干川絵美, 佐藤大祐, 木森義隆

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    Application no:特願2018-149488  Date applied:2018.8

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  • 線維化コラーゲンゲル作製用鋳型材料

    泉 健次, 三輪慶人, 桑江博之, 水野潤, 児玉泰洋, 山口勇

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    Application no:特願2018-145182  Date applied:2018.8

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  • 細胞培養方法及び培養組織

    泉 健次, 加藤 寛子, 前田 竜, 河上 貴宏, 山口 勇

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    Applicant:国立大学法人 新潟大学, 多木化学株式会社

    Application no:特願2016-031777  Date applied:2016.2

    Announcement no:特開2017-147951  Date announced:2017.8

    Patent/Registration no:特許6758616  Date registered:2020.9 

    Rights holder:国立大学法人 新潟大学, 多木化学株式会社

    J-GLOBAL

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Works

  • ヒト培養口腔粘膜の臨床応用

    1999

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  • Clinical application of oral mucosa equivalent

    1999

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Awards

  • a Top Scholar Life time "Oral Mucosa" ranking #20

    2024.7   ScholarGPS  

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Research Projects

  • 画像イメージングを応用した角膜移植用培養口腔粘膜上皮細胞シートの品質評価法の開発

    Grant number:24K15822

    2024.4 - 2027.3

    System name:科学研究費助成事業

    Research category:基盤研究(C)

    Awarding organization:日本学術振興会

    小林 亮太

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    Grant amount:\4680000 ( Direct Cost: \3600000 、 Indirect Cost:\1080000 )

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  • 画像イメージングを応用した角膜移植用培養口腔粘膜上皮細胞シートの品質評価法の開発

    Grant number:24K15822

    2024.4 - 2027.3

    System name:科学研究費助成事業

    Research category:基盤研究(C)

    Awarding organization:日本学術振興会

    小林 亮太

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    Grant amount:\4680000 ( Direct Cost: \3600000 、 Indirect Cost:\1080000 )

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  • 細胞運動能を指標とする間葉系幹細胞の非破壊品質評価法の規格化

    Grant number:24K03319

    2024.4 - 2027.3

    System name:科学研究費助成事業

    Research category:基盤研究(B)

    Awarding organization:日本学術振興会

    泉 健次

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    Grant amount:\18590000 ( Direct Cost: \14300000 、 Indirect Cost:\4290000 )

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  • 血管網を有する口腔がん三次元培養モデルを用いた治療効果評価法の検証

    Grant number:23K11918

    2023.4 - 2026.3

    System name:科学研究費助成事業

    Research category:基盤研究(C)

    Awarding organization:日本学術振興会

    井川 和代, 佐藤 香枝, 泉 健次

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    Grant amount:\4680000 ( Direct Cost: \3600000 、 Indirect Cost:\1080000 )

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  • 口腔粘膜上皮細胞と線維芽細胞から成る2層性自家培養口腔粘膜の開発

    Grant number:22K10016

    2022.4 - 2025.3

    System name:科学研究費助成事業

    Research category:基盤研究(C)

    Awarding organization:日本学術振興会

    齋藤 夕子, 水野 潤, 泉 健次

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    Grant amount:\4160000 ( Direct Cost: \3200000 、 Indirect Cost:\960000 )

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  • エクオールは口腔乾燥症,味覚障害,舌痛症の新たな治療法となりうるか?

    Grant number:22K10310

    2022.4 - 2025.3

    System name:科学研究費助成事業

    Research category:基盤研究(C)

    Awarding organization:日本学術振興会

    伊藤 加代子, 井上 誠, 高松 潔, 船山 さおり, 本川 佳子, 泉 健次, 濃野 要

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    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

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  • 細胞を安定培養させる魚うろこコラーゲン足場材製造のPoC実証

    Grant number:22100082-0

    2022.4 - 2022.9

    System name:NEDO Entrepreneurs Program(NEP)助成金

    Awarding organization:NEDO

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  • 死細胞貪食による口腔がん細胞活性化:脂質クオリティが果たす役割を探る

    Grant number:21K09856

    2021.4 - 2024.3

    System name:科学研究費助成事業

    Research category:基盤研究(C)

    Awarding organization:日本学術振興会

    山崎 学, 阿部 達也, 丸山 智, 冨原 圭, 泉 健次, 田沼 順一

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    Grant amount:\4160000 ( Direct Cost: \3200000 、 Indirect Cost:\960000 )

    がん細胞は正常細胞とは異なる脂質代謝を有し、近年、がんにおける脂質クオリティ(脂質組成)の重要性が明らかになりつつある。本研究課題では、「死細胞貪食を起点としたがん細胞活性化の機序に、死細胞由来脂質によってもたらされる脂質クオリティ変化が関与する」という仮説のもと、(1)がん細胞のおける死細胞由来脂質の局在変化を追跡し、(2)貪食後に生じるがん細胞の脂質クオリティを解析することで、(3)細胞増殖・遊走・浸潤能に関わる分子機構との接点を明らかにすることを目的としている。今年度は、以下の疑問を解決すべく検討をおこなった。
    1) ネクローシス細胞は生活がん細胞に貪食されるのか?: 口腔扁平上皮癌由来培養細胞株を脂質親和性色素PKH26にて標識後、凍結融解によって誘導したネクローシス細胞を、同種の生活がん細胞と共培養した。共焦点レーザー顕微鏡解析の結果、PKH26陽性を示す死細胞断片は生活がん細胞の細胞質内に認められた。これより、ネクローシス細胞は生活がん細胞によって貪食されることが示された。
    2) 細胞内コレステロール変化は細胞機能を変化させるのか?: これまでの検討により、ネクローシス細胞と共培養した際、生活がん細胞内にコレステロールが蓄積される可能性が推測された。そこでまず、細胞内コレステロールレベル変化による細胞の機能変化を検索した。コレステロール-MCD複合体の添加により、細胞内コレステロールを上昇させると、細胞形態は多辺形から扇状へと変化し、細胞遊走能が亢進することが示された。

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  • 規格化ナノ構造チタンによる接着蛋白質を介した組織形成制御可能な生体材料開発

    Grant number:21K09976

    2021.4 - 2024.3

    System name:科学研究費助成事業

    Research category:基盤研究(C)

    Awarding organization:日本学術振興会

    秋葉 陽介, 魚島 勝美, 照沼 美穂, 水野 潤, 泉 健次

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    Grant amount:\4160000 ( Direct Cost: \3200000 、 Indirect Cost:\960000 )

    デンタルインプラントにおいては、オッセオインテグレーションと呼ばれるチタンと骨の結合が認められる。インプラントの成功基準の一つにオッセオインテグレーションの確立、成立が上げられている。臨床的には、デンタルインプラント表面をエッチングやサンドブラストによって粗造化することによって、骨芽細胞の接着、分化、骨形成を促進することができるとされている。しかし、チタン表面の粗造化がどのような構造因子と、それを認識し得る、細胞のどのような機能で細胞分化を促進するのか、といった詳細なメカニズムについては、十分な理解が進んでしない。これまでの研究において、粗造化されたチタンにおける、骨骨芽細胞の分化促進機構を検証する際に使用されていた、研磨による平滑な無構造チタンとされているチタンにおいても、電子顕微鏡下では、研磨に伴う研磨痕が多く観察され、細胞、タンパク質レベルでは無構造ではなく極めて粗造な構造が認識されていると考えられる。しかし、チタンに規格化され、制御された構造をナノレベルで形成することは、技術的に困難である。これまでの研究においては、数百ナノメートルの非規格化構造や規格化構造であっても数マイクロのサイズでしか構造形成は実現できていない。本研究においては、表面粗さ数ナノメートルの無構造チタン基板を基本に、構造因子に影響されないチタン特異的接着タンパク質群を同定し、さらに粗面構造における接着タンパク質群を同定し、構造因子による骨芽細胞接着分化促進因子を同定するものである。規格化ナノ構造チタンにおいては規格化線状ナノ構造を形成したチタン基板上での細胞挙動、組織形成制御を確認するために、骨髄由来細胞を播種培養し、ナノ構造によって細胞活動が制御され得ることを確認済みである。また、無構造チタン基板上において、接着タンパク質群の回収及び解析を実施している。

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  • 上皮幹細胞コンパートメントを規定する分子機構と生物学的意義の解明

    Grant number:20H03266

    2020.4 - 2024.3

    System name:科学研究費助成事業

    Research category:基盤研究(B)

    Awarding organization:日本学術振興会

    佐田 亜衣子, 柳沢 裕美, 泉 健次, 水野 秀信

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    Grant amount:\17550000 ( Direct Cost: \13500000 、 Indirect Cost:\4050000 )

    皮膚の上皮組織は高度に区画化されており、毛包間表皮、毛包、皮脂腺を生み出す幹細胞が、異なる領域で固有の機能を果たしている。さらに我々は、均一だと考えられてきた表皮基底層の中に、分裂頻度の異なる2種類の独立した幹細胞集団が、規則的なパターンを持って、領域特異的に局在することを明らかにしてきた(Sada et al., Nat Cell Biol 2016)。しかし、なぜ異なる幹細胞集団が上皮組織の中で領域化しているのか、その意義や形成過程、制御機構は不明である。
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    本研究は、皮膚などの上皮組織に存在する不均一な幹細胞集団の領域化に着目し、制御メカニズムを組織―細胞―分子レベルで解明することを目的に実施した。本年度は、アロダームやマイクロパターンゲル培養の条件検討およびマーカーを用いた染色を行った。またマウス口腔ケラチノサイトの新たな培養法を確立し、筆頭著者として論文発表した。上皮幹細胞の領域化を担う因子として細胞外マトリクスfibulin-7の解析を行った。In vivoの解析は、ノックアウトマウスの表現型解析、RNAseqデータ解析を中心に行った。また、fibulin-7が結合すると想定される候補タンパク質を同定し、固相結合アッセイ法により、fibulin-7との相互作用を確認するとともに、若齢、高齢、Fbln7ノックアウトマウス組織を用いた局在解析を行った。

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  • 足場材の硬さの違いを利用した上皮角化・非角化様式解明と培養口腔粘膜作成法への応用

    Grant number:20H03870

    2020.4 - 2023.3

    System name:科学研究費助成事業 基盤研究(B)

    Research category:基盤研究(B)

    Awarding organization:日本学術振興会

    泉 健次

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    Grant amount:\17680000 ( Direct Cost: \13600000 、 Indirect Cost:\4080000 )

    今年度は、コロナの影響で魚うろこコラーゲンの入手がままならず、既製品の魚うろこコラーゲンであるセルキャンパスしか手に入らなかったため、コラーゲンゲルの足場材の硬さをランダムに変えての培養口腔粘膜作成はできなかった。その分、セルキャンパスを用いて、コントロールの硬い培養皿面、同表面でカルシウム濃度をあげた分化培地、および、いわゆるコラーゲンゲルの軟性面で培養したケラチノサイトに対し、運動能解析と外注によるマイクロアレイ解析による網羅的遺伝子発現分析(現在までに2サンプル解析終了し、現在もう2サンプル培養しており、外注予定)を実施し、結果がでたら新たに分担者に加わっていただいた凌先生にヒートマップとクラスター図を作成してもらい、ビッグデータ解析をお願いする。
    細胞運動能解析では驚いたことに、コラーゲンゲル上の細胞運動能が、硬い培養皿面での細胞運動能より上回っていた。これは、いわゆる癌細胞のメカノバイオロジーと真逆の現象である。さらに、運動能が高いにも関わらず、ケラチノサイトの分化マーカー遺伝子発現が更新していることが示唆され、申請者の以前の基盤B研究で報告した結果とも相反するデータを得ており、今後考察を加え、メカニズム解明したい。また、コロナの影響で、研究分担者のいる北海道大学にAFMを用いた細胞の硬さ検索ができなかった。

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  • 加速器中性子源を用いたBNCT組織線量分布評価体系の確立

    Grant number:20K12714

    2020.4 - 2023.3

    System name:科学研究費助成事業

    Research category:基盤研究(C)

    Awarding organization:日本学術振興会

    井川 和代, 小川原 亮, 泉 健次, 楠本 多聞

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    Grant amount:\4420000 ( Direct Cost: \3400000 、 Indirect Cost:\1020000 )


    頭頸部がんに対するホウ素中性子捕捉療法(BNCT)は世界で初めて2001年に日本で行われ、治療効果のみならず治療後の高いQOLが注目、世界初の加速器を用いたBNCTの保険診療が2020年から日本で開始、世界で需要が高まっている。BNCTにおいて、ホウ素ががんに取り込まれること、熱中性子ががんに届くことが成功の鍵となる。そこで、ホウ素の種類や濃度により同じ放射線量でも治療効果が異なるBNCTにおいて、ホウ素濃度とホウ素分布が識別可能なホウ素集積性BNCT検査システムを構築し、世界のどこにいてもBNCTの適応可否を判断できることを目指す。
    今年度は、頭頸部扁平上皮がん細胞株と患者由来の線維芽細胞を用いて三次元口腔がんモデルを作製し、三次元モデルの素材であるゲルのみ、線維芽細胞モデル、扁平上皮がん細胞と線維芽細胞の口腔がんモデルにおいて各々ホウ素濃度とホウ素分布の測定と解析を行った。ホウ素はBNCTの臨床で用いられている4-ボロノフェニルアラニン(BPA)を使用し、ホウ素濃度は誘導結合プラズマ質量分析装置により測定した。また、BPAは癌細胞特異的に発現する抗ヒトL型アミノ酸トランスポーター(LAT-1)を介して細胞内に取り込まれることから、ホウ素分布は各モデルのパラフィン標本におけるLAT-1の発現により解析した。口腔がんモデルのホウ素濃度は線維芽細胞モデルと比較して2倍程度の取り込みがあった。また、LAT-1の発現においては、線維芽細胞モデル内でも多少の発現を認めるもののがん細胞においてほぼ100%の発現を認めた。以上の結果より三次元口腔がんモデルを用いてホウ素の集積性を確認できた。さらに、ホウ素集積性とBNCTの効果を解析することでホウ素集積性BNCT検査システムを構築し、加速器中性子源を用いたBNCT組織内線量分布の評価体系を確立する

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  • 運動能指標による骨分化能を識別するヒト間葉系幹細胞の非破壊的品質評価管理法の開発

    Grant number:20K09991

    2020.4 - 2023.3

    System name:科学研究費助成事業

    Research category:基盤研究(C)

    Awarding organization:日本学術振興会

    塩見 晶, 佐藤 大祐, 泉 健次

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    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

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  • 生理機能亢進細胞混合移植とレドックス制御による長期骨量維持可能な骨増生法開発

    Grant number:20K10051

    2020.4 - 2023.3

    System name:科学研究費助成事業

    Research category:基盤研究(C)

    Awarding organization:日本学術振興会

    秋葉 奈美, 魚島 勝美, 秋葉 陽介, 泉 健次

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    Grant amount:\4420000 ( Direct Cost: \3400000 、 Indirect Cost:\1020000 )

    既存の骨増生法は骨形成促進可能だが、増生後の予期せぬ骨量減少による不確実性が臨床上の課題となっており、確実に骨量維持可能な骨増生法の構築が望まれている。骨折治癒などの生理的骨形成では骨量減少が認めらない。生理的骨形成には骨形成以外に宿主細胞誘導、血管新生、成長因子放出と複数の生理機能活性が必要である。骨増生法において生理的骨形成を模倣しようとしても、単一処理によって必要な生理機能全てを活性化するのは不可能と考えられている。また細胞移植において、移植後の酸化ストレスによるアポトーシスや機能不全が報告されており、酸化還元制御(レドックス制御)により移植細胞を長期生存、機能させることが可能となる。本研究では、骨増生に必要な複数の生理機能を各々あらかじめ亢進させた細胞の混和移植とレドックス制御による移植細胞の長期生存に着目し、骨増生促進と長期骨量維持を達成可能な新規骨増生法の開発を目的とする。課題Ⅰ移植細胞の可視化による識別と機能解析(1)移植細胞識別可能なラット頭蓋骨欠損修復モデル作製(2)骨形成部位における移植細胞の機能の検索、課題Ⅱ:生理機能活性処理による機能亢進の確認、(1)移植に使用予定の骨髄由来細胞を以下に示す条件で機能亢進する。(2)生理機能亢進細能解析、課題Ⅲ:宿主由来細胞への機能亢進細胞の影響検討、課題Ⅳ:生理機能亢進細胞混和移植による骨形成促進の確認、課題Ⅴ:レドックス制御による移植細胞長期生存確認、課題Ⅳ:垂直的骨増生と骨量長期維持の確認。

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  • 培養口腔粘膜作成用マイクロパターン化魚コラーゲン足場材の開発

    2020.4 - 2021.3

    System name:橋渡し研究戦略的推進プログラム

    Research category:革新的医療技術創出に関するシーズA

    Awarding organization:北海道大学病院 臨床研究開発センター

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    Authorship:Principal investigator 

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  • Analysis of the function of cancer-associated fibroblasts (CAFs) in the invasion of oral cancer.

    Grant number:19K10329

    2019.4 - 2022.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

    Funayama Akinori

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    Grant amount:\4160000 ( Direct Cost: \3200000 、 Indirect Cost:\960000 )

    Cancer-associated fibroblasts (CAFs) have important roles in promoting cancer development and progression. This study developed three-dimensional (3D) in vitro models co-cultured with oral squamous cell carcinoma (OSCC) cells and CAFs to examine CAF-mediated cancer migration and invasion. Moreover, we performed an immunohistochemical analysis of alpha-smooth muscle actin and SOX9 expression in surgical specimens from 65 OSCC patients. The results indicated that CAFs promote cancer migration and invasion in migration assays and 3D in vitro models. The invading OSCC cells exhibited significant SOX9 expression. TGF-β1 signaling inhibition reduced SOX9 expression and cancer invasion. In surgical specimens, the presence of CAFs was correlated with SOX9 expression in the invasive cancer nests and had a significant impact on regional recurrence. These findings demonstrate that CAFs promote cancer migration and invasion via the TGF-β/SOX9 axis.

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  • Biological reaction control using topography regulation of nanostructured titanium

    Grant number:18K09679

    2018.4 - 2021.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

    AKIBA YOSUKE

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    Grant amount:\4550000 ( Direct Cost: \3500000 、 Indirect Cost:\1050000 )

    In this study, we fabricated standardized and controlled periodic nanopatterns with nanosized surface roughness on titanium substrates and investigated their influence on bone marrow stromal cells. Cell proliferation assays revealed that the bare substrate with a 1.7 nm surface roughness showed lower hydrophilicity but higher proliferation ability than that with a 0.6 nm surface roughness. Further, with the latter substrate, directional cell growth was observed for line and groove patterns with a width of 100 nm and a height of 50 or 100 nm, but not for those with heights of 10 or 25 nm. With the smooth substrate, time-lapse microscopic analyses showed that more than 80% of the bone marrow cells on the line and groove pattern with a height of 100 nm grew and divided along the lines. As the nanosized grain structure controls the cell proliferation rate and the nanosized line and groove structure controls cell migration, division, and growth orientation.

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  • Elucidation of fate path and regulatory factors of periodontal ligament tissue stem cells

    Grant number:18H02989

    2018.4 - 2021.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (B)

    Awarding organization:Japan Society for the Promotion of Science

    Masaru Kaku

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    Grant amount:\17420000 ( Direct Cost: \13400000 、 Indirect Cost:\4020000 )

    The periodontal ligament (PDL) plays a vital role in oral function and has a multi-layered structure in which cell groups with contradictory characteristics of calcification / non-calcification are stacked. However, the details of the cells constituting each layer are still unclear. An accurate and integrated understanding of the PDL’s multilayer structure, especially the reproduction of the non-mineralized region characteristic of the PDL, will be fundamental for enabling PDL regeneration in natural teeth and the development of the dental implant with PDL. In this study, we used cell proliferation / metabolic activity as an index to clarify the fate and differentiation of PDL tissue stem cells and some of the regulatory mechanisms.

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  • Challenges to development of "bioregenerative therapy"

    Grant number:17H06278

    2017.6 - 2020.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Challenging Research (Pioneering)

    Awarding organization:Japan Society for the Promotion of Science

    Ohazama Atsushi

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    Grant amount:\25870000 ( Direct Cost: \19900000 、 Indirect Cost:\5970000 )

    In recent years, stem cells have been discovered in many adult tissues. The presence of stem cells has also been reported in many adult craniofacial region. The aim of this study is to induce tooth using these adult stem cells. We identified the molecular mechanism of controlling stem cells presented in the paratal rugae. Furthermore, we succeeded in inducing signals of tooth formation using stem cells of the palatal rugae.

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  • Drug discovery for xerostomia treatment targeting oral mucosal epithelium-minor salivary gland units

    Grant number:17K12044

    2017.4 - 2022.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

    Kato Hiroko

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    Grant amount:\4550000 ( Direct Cost: \3500000 、 Indirect Cost:\1050000 )

    Salivary secretion is enhanced by parasympathetically derived acetylcholine binding to muscarinic receptors. Currently, the indication of drugs for xerostomia is limited to specific cases such as Sjogren's syndrome and xerostomia after radiotherapy, however, an effective treatment with a broad indication is needed to reduce the risk of infections and other diseases caused by xerostomia. We hypothesized that the oral mucosal epithelial tissue contains a non-neurogenic cholinergic acetylcholine-producing system that is independent of neural tissue, and that acetylcholine secreted by the epithelial cells promotes salivary gland secretion of minor salivary glands.

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  • Development of Simultaneous Regeneration Treatment for Tooth and Periodontal Tissue -Possibility of Tooth Germ Transplantation-

    Grant number:17K11923

    2017.4 - 2020.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

    Yoshizawa Michiko

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    Grant amount:\4550000 ( Direct Cost: \3500000 、 Indirect Cost:\1050000 )

    In this study, we explored the potential of alveolar bone regeneration at the time of tooth transplantation using an animal model. Mononuclear cells (MNCs) were collected from the bone marrow. The molar of 3-week-old mice and β-tricalcium phosphate (β-TCP) were combined and transplanted with or without MNCs into thigh muscle of syngeneic mice. Tooth alone was transplanted as a control. After 4 weeks, the transplants were harvested and analyzed. Newly formed bone was observed on the lateral wall of the root in the experimental group, while less bone formation was observed in the control group. Bone Volume was significantly larger in β-TCP group than that of the control group. Earlier maturation of trabecular bone in MNC+β-TCP group than control group. Regeneration of collagen fibers were noted in all groups, which exhibited periostin. This study showed the accelerated alveolar bone and periodontal tissue regeneration when the tooth transplantation was performed with β-TCP.

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  • Study for elucidating indiction mechanism of stem cells by manipulation molecule

    Grant number:17H01601

    2017.4 - 2020.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (A)

    Awarding organization:Japan Society for the Promotion of Science

    Ohazama Atsushi

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    Grant amount:\43030000 ( Direct Cost: \33100000 、 Indirect Cost:\9930000 )

    Regenerative therapy requires induction of stem cells to target cells. However, regulatory mechanism inducing target tissue-forming cells from stem cells should be elucidated for that purpose. Organ development is achieved by the differentiation of stem cells. We identified molecular mechanism of regulating stem cells in the tongue and palate development. Moreover, we found that Ofd1 (primary cilia protein) in mesenchymal cells control differentiation of tongue-forming cells during tongue development, suggesting the possibility that the primary cilia indirectly regulate stem cell differentiation.

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  • Bone regeneration with priming cell cocktail transplantation

    Grant number:17K11743

    2017.4 - 2020.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

    Nami Akiba

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    Grant amount:\4680000 ( Direct Cost: \3600000 、 Indirect Cost:\1080000 )

    Osteogenic differentiation treatment, cell recruitment differentiation treatment and blood vessel differentiation treatment could affected to untreated cell in the co-culture conditions.

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  • 細胞運動能を指標とした再生医療向け非侵襲的口腔粘膜上皮細胞評価システムの開発

    2017 - 2019

    System name:基盤研究(B)

    Awarding organization:日本学術振興会

    泉 健次, 医歯学系

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    Authorship:Principal investigator  Grant type:Competitive

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  • Development and application of the trace elements and micro structure analyses of tissue specimens using the quantum beams

    Grant number:16H02688

    2016.4 - 2020.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (A)

    Awarding organization:Japan Society for the Promotion of Science

    UO Motohiro

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    Grant amount:\47190000 ( Direct Cost: \36300000 、 Indirect Cost:\10890000 )

    In this study, the conventional quantitative analysis of the trace elements was combined with the elemental distribution, chemical state, and micro structural analyses using the synchrotron X-ray and focused charged particle beams. Using those combined analyses, the characteristic elemental accumulations in the lesional hard and soft tissues were observed and the relations between the accumulated elements and lesions were suggested. The absorption behavior of the tooth for ions which released from the functional dental materials and ion doping agents was estimated with above methods. The chemical state and local structure of absorbed ions in tooth were also estimated. The obtained information was applied for the development of ion releasing endodontic materials.

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  • Verification of the effect of a novel therapy against BRONJ using local application of bone-marrow derived mesenchymal stem cells

    Grant number:16K20562

    2016.4 - 2019.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Young Scientists (B)

    Awarding organization:Japan Society for the Promotion of Science

    Saito Taro, Izumi Kenji

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    Grant amount:\4030000 ( Direct Cost: \3100000 、 Indirect Cost:\930000 )

    This study aimed to validate the effect of a novel therapy against BRONJ using local application of bone-marrow derived mesenchymal stem cells (BMMSC) for future clinical applications into human. The BMMSCs were seeded into a few biodegradable scaffolds, and the BMMSCs repopulated in these constructs were planned to transplant into the extraction socket of the BRONJ animal model using rat to examine the therapeutic effects by histopathological study. However, this study failed because the animal model was not able to establish and one of the scaffolds were not obtained. Nonetheless, this study confirmed the efficacy of the “priming of bone regeneration” using HDACi and hypoxic culture to enhance the BMMSC functions for developing tissue-engineered constructs.

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  • Investigation of Bone Marrow-derived Stem Cells in Periodontal Ligament

    Grant number:26293407

    2014.4 - 2018.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (B)

    Awarding organization:Japan Society for the Promotion of Science

    KAKU Masaru

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    Grant amount:\16640000 ( Direct Cost: \12800000 、 Indirect Cost:\3840000 )

    The periodontal ligament (PDL) plays important roles in tooth function. The PDL harbors a remarkable reserve of multipotent stem cells, which maintain various types of cells. However, the sources of these stem cells, other than their developmental origin, are not well understood. In the present study, to elucidate the recruitment of bone marrow (BM)-derived stem cells in the PDL, green fluorescent protein (GFP)-expressing BM-derived cells were transplanted into the femoral BM of immunodeficient rats. Four weeks after cell transplantation, GFP-positive cells were detected in the PDL. To evaluate the functional significance of these BM-derived cells to the PDL, tooth replantation was performed. Seven days after tooth replantation, the number of GFP-positive cells significantly increased in PDL. These results indicate that the stem cells and their progeny in PDL are not only derived from their developmental origin but are also supplied from the BM via the blood as the need arises.

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  • Investigation into the mechanism of oral mucosa regeneration by tissue engineered oral mucosa fabricated with oral mucosal progenitor/stem cells -importance of angiogenesis-

    Grant number:26463059

    2014.4 - 2017.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

    Yoshizawa Michiko, TERASHI HIROTO

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    Grant amount:\4810000 ( Direct Cost: \3700000 、 Indirect Cost:\1110000 )

    We have investigated the application of ex vivo-produced oral mucosa equivalent (EVPOME) and evaluated its ability of oral mucosa regeneration. However, cultivated epithelial cells using the present methods has heterogeneity, consequently, there is a risk that EVPOME possess poor cell growth activity and capability of oral mucosa regeneration. The previous study was to investigate the capability of EVPOME fabricated with small-sized cell population in which oral mucosal progenitor/stem-cells enriched subpopulation present and the change after EVPOME grafting subcutaneously in mice histologically. In the present study, we elucidated the mechanism of oral mucosa regeneration, especially the role of angiogenesis. As a results, EVPOME with small-sized cell population has high activity and capability of oral mucosal regeneration and faster elongation of epithelium is led by angiogenesis.

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  • 14-3-3σシグナルを介した薬理学的増殖スイッチ操作による高機能培養粘膜の開発

    Grant number:26462965

    2014.4 - 2015.3

    System name:科学研究費助成事業

    Research category:基盤研究(C)

    Awarding organization:日本学術振興会

    安島 久雄, 前田 健康, 泉 健次

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    Grant amount:\4940000 ( Direct Cost: \3800000 、 Indirect Cost:\1140000 )

    培養口腔粘膜上皮では14-3-3σタンパクが制御するキャップ依存性mRNA翻訳を行う細胞が少なく、in vivoの口腔粘膜に比べ細胞が分化する傾向が高いため、上皮が厚くならないという仮説を検証すること目的として、本研究では薬理学的に培養口腔粘膜上皮基底層の14-3-3σを抑制、mTORシグナルを活性化し、細胞分化抑制、増殖能亢進により、厚い上皮細胞層を有する培養口腔粘膜を開発することを目標とした。14-3-3σ阻害剤とmTOR活性化剤を用いて、患者から採取した初代培養細胞のキャップ依存性翻訳を薬理的に誘導することによって、14-3-3σとmTORの発現パターン・バランスをin vitroで再現することで、厚い上皮をもつ培養口腔粘膜の作成を目指し、本年度は、培養口腔粘膜上皮細胞で、研究計画にリストアップした試薬の効果検討と至適濃度決定をタンパク分析と細胞化学分析を通して行う予定とした。通常の培養環境においては、細胞増殖と細胞分化を優位にするために、培地中のカルシウム濃度をそれぞれ0.06mMと1.2mMに設定することでコントロールしている。本実験では、14-3-3σ阻害剤として合成ペプチドDifopeinを加え、mTOR活性化剤として、培地中に含まれているアミノ酸であるロイシンを追加して、実験を進めた。その結果、残念ながらタンパク分析と細胞化学分析を通じて、明らかな有意差を得ることに至ることがなかった。このネガティブデータから考察できるのは、本実験で用いたカルシウム濃度は培養口腔粘膜の臨床応用プロトコールで使用している濃度であるが、このカルシウム濃度の影響が圧倒的であるために14-3-3σとmTORシグナルの薬理学的阻害と活性化では、細胞の形質が変わるレベルに至らないことが間接的に証明され、実際に薬理学的効果を検証するにはカルシウム濃度の調整が必要であることが示唆された。

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  • 低酸素発光プローブを利用した培養口腔粘膜作成過程に最適な低酸素ニッチ環境の確立

    2014 - 2017

    System name:基盤研究(B)

    Awarding organization:日本学術振興会

    泉 健次, 医歯学系

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    Authorship:Principal investigator  Grant type:Competitive

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  • 口腔粘膜上皮の免疫特権性を利用した口腔扁平苔癬インビトロモデルと治療法の開発

    2014 - 2016

    System name:挑戦的萌芽研究

    Awarding organization:日本学術振興会

    泉 健次, 医歯学系

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    Authorship:Principal investigator  Grant type:Competitive

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  • Roles of new ion channel involved in the regeneration/development of the periodontal Ruffini endings

    Grant number:23390418

    2011.4 - 2014.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (B)

    Awarding organization:Japan Society for the Promotion of Science

    MAEDA Takeyasu, IZUMI Kenji, INOUE Kayoko, KAWANO Yoshiro, OHZAMA Atsushi, SUZUKI Akiko, HARADA Fumiko, YOSHII Tomoko, IHYO Chika

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    Grant amount:\18850000 ( Direct Cost: \14500000 、 Indirect Cost:\4350000 )

    This study examined the regeneration process of the periodontal Ruffini ending, an essential mecahnoreceptor, based on the changes in the expression pattern of acid-sensing ion channel-3 (ASIC3) at the periodontal ligament and trigeminal ganglion. The findings obtained from the nerve injury model (resection of the inferior alveoar nerve at one side) indicate that this molecule is not direcly involved in the axonal regeneration of the periodontal Ruffini endings but rather in neuron-glial interactions such as control of neuronal activity in the trigeminal ganglion.

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  • エイジレスな培養口腔粘膜上皮の開発・作成

    2011 - 2013

    System name:挑戦的萌芽研究

    Awarding organization:日本学術振興会

    泉 健次, 医歯学系

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    Authorship:Principal investigator  Grant type:Competitive

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  • Development of tissue engineered oral mucosa maintaining higher regenerative potential -application of oral mucosa progenitor/stem cells-

    Grant number:23592982

    2011 - 2013

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

    YOSHIZAWA Michiko, KENJI Izumi, TERASHI Hiroto

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    Grant amount:\5200000 ( Direct Cost: \4000000 、 Indirect Cost:\1200000 )

    We have investigated the application of ex vivo-produced oral mucosa equivalent (EVPOME) and its ability of oral mucosa regeneration. However, cultivated epithelial cells using the present methods has heterogeneity, consequently, there is a risk that EVPOME possess poor cell growth activity and capability of oral mucosa regeneration. The objective of the present study was to investigate the capability of EVPOME fabricated with small-sized cell population in which oral mucosal progenitor/stem-cell-enriched subpopulation present and the change after EVPOME grafting subcutaneously in mice histologically. More Ki-67 positive cells were observed in the epithelial cells of EPOME fabricated by small-sized cell population. Epithelial elongation of EVPOME fabricated by small-sized cell population occurs faster than that of EVPOME using present methods. These findings suggest that EVPOME with small-sized cell population has high activity and capability of oral mucosal regeneration.

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  • The verification of the effects on the epidermal wound healing by the topical application of the mixture of cultured oral keratinocytes and hydrogel.

    Grant number:23592882

    2011 - 2013

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

    AJIMA hisao, MAEDA Takeyasu, IZUMI Kenji

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    Grant amount:\5200000 ( Direct Cost: \4000000 、 Indirect Cost:\1200000 )

    Our long-term goal is to develop the current technology of oral mucosa keratinocyte culture system, and treat wounds by using cultured oral keratinocytes to regenerate epithelial defects. This study aimed to produce the mixture of cultured oral keratinocytes and hydrogel and assess the feasibility and effects on epidermal wound care such as burns and ischemic vicious ulcers. We measured the levels of various cytokines secreted from the mixture by ELISA assay. Based on measurement of the cytokine production, we found VEGF was sufficiently secreted into the culture supernatant although there were remarkable variations among samples. Furthermore, other cytokines also showed more remarkable variations in which some of them were undetectable. Thus, we concluded that these variations should have a negative impact on the in vivo animal study and it would be difficult to obtain the consistent outcomes. As a result, we may need to find a different strategy for cells to produce cytokines.

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  • Examination of signaling pathway specific to oral mucosa wound healing.- Difference between oral mucosa and epidermis -

    Grant number:23659857

    2011 - 2012

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Challenging Exploratory Research

    Awarding organization:Japan Society for the Promotion of Science

    MAEDA Takeyasu, IZUMI Kenji

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    Grant amount:\3640000 ( Direct Cost: \2800000 、 Indirect Cost:\840000 )

    Oral mucosa heals faster than does skin, and scar formation during the wound healing in oral mucosa is also less than that in skin. We attempted to explore these differences between oral keratinocytes and epidermal keratinocytes in vitro by intrinsic cellular, biological characteristics. PI3kinase signaling pathway was activated by using a pharmacological means. Using a scratch assay (in vitro wound healing assay), cell motility and protein expressions related to PI3kinase were examined. Those reagents used in this study did not induce any significant differences.

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  • 再生組織/細胞製品出荷前の非侵襲・リアルタイム検査による品質管理システムの開発

    Grant number:22592180

    2010.4 - 2013.3

    System name:科学研究費助成事業

    Research category:基盤研究(C)

    Awarding organization:日本学術振興会

    飯田 明彦, 泉 健次, 芳澤 享子

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    Grant amount:\4420000 ( Direct Cost: \3400000 、 Indirect Cost:\1020000 )

    本学医歯学総合病院の特色である再生医療プロジェクトの一つに、「培養複合口腔粘膜」移植がある。患者に移植した「製品」である培養複合口腔粘膜の性質は、手術直前に一部「製品」を切除、ホルマリン固定し、HE染色により評価している。この検査方法では移植前のリアルタイム検査が不可能であり、「製品」にもキズがつく。実際、HE染色による評価では同一患者の細胞で全く同様に作製した「製品」でも、組織学的に必ずしも同一のものではないことが明らかになっているが、この方法では移植前に「製品」の性能が把握できない。現在のところ、患者移植前の「製品」のスクリーニングとしては、微生物コンタミネーションの確認および培養液中のグルコース濃度の測定を行い、グルコース消費量の少ない「製品」は、移植に用いない。しかし、単一の検査法だけでは「製品」のモニタリングとして十分とはいえない。本研究の目的は、グルコース消費量に加え、移植前に、「製品」をキズつけず、かつリアルタイムに測定可能な検査法を確立し、"出荷基準"を策定することである。
    本年度は昨年度に続き意図的に43℃で24時間インキュベートし、できの悪い培養粘膜を作製した。この条件で作製した培養粘膜を組織学的に観察すると、重層扁平上皮の形成は確認されたものの、上皮全体が下層のスキャホールドと完全に分離していたものが多かった。この培養粘膜について、従来のグルコース濃度測定に加え、Raman分光光度計干渉装置(spectroscopy)、VEGFおよびLDHレベルの測定を行つている。また、対照として39℃で24時間および41℃で24時間インキュベートした培養粘膜についてもすべての検査を開始し、症例数を蓄積している。

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  • オートファジーの薬学的操作による口腔粘膜前駆/幹細胞の抗老化・維持システムの確立

    2010 - 2012

    System name:基盤研究(B)

    Awarding organization:日本学術振興会

    泉 健次, 医歯学系

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    Authorship:Principal investigator  Grant type:Competitive

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  • 口腔粘膜上皮前駆/幹細胞の分離・同定

    Grant number:21659455

    2009 - 2010

    System name:科学研究費助成事業

    Research category:挑戦的萌芽研究

    Awarding organization:日本学術振興会

    前田 健康, 泉 健次, 鈴木 晶子

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    Grant amount:\3000000 ( Direct Cost: \3000000 )

    22年度は、当初計画していた実験手技をそのまま遂行することはなかったが、口腔粘膜上皮前駆/幹細胞の同定という目的を目指して実験を遂行した。最終的な口腔粘膜幹細胞in vitroモデルの確立という最終目的までには至らなかったものの、着実にそれに向かって近づいている。すなわち、培養口腔粘膜上皮細胞中のALDH陽性細胞は、FACS Ariallを用いて分取後organotypic culture環境下において、接着細胞においても、浮遊細胞においても口腔粘膜の上皮再生能が高いことが示された。さらに、ALDH陽性細胞に関しては、インテグリンα6などの接着因子の発現も検索したが、こちらは予想に反してALDHが陽性ではない細胞群に強く発現していた。また、In vivo組織においてALDH陽性細胞は、歯肉重層扁平上皮の基底細胞層には存在せず、基底細胞より1-2層上部の層に存在した。一方、ALDHの機能はビタミンAとその類似体から、生物学的に活性のあるレチノイン酸の生合成に関わる酵素であることから、レチノイン酸を培養液に加え、培養細胞にALDHを多く発現するように操作することで、培養粘膜の分化再生能が変化することを確認した。In vivoで粘膜上皮幹細胞は基底細胞層に存在するという一般的に受け入れられている定説とは異なる所見が得られたことで、ALDHの発現がピュアな前駆/幹細胞マーカーとして受け入れられる状況には至らないが、上記のin vitroの結果は、口腔粘膜上皮におけるALDH陽性の細胞が"ニッチ"の位置に関してなんらかの役割を果たしている可能性を示唆する所見が得られた。

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  • Elucidation of functional significance of caveola in periodontal mechanoreceptor

    Grant number:20390464

    2008 - 2010

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (B)

    Awarding organization:Japan Society for the Promotion of Science

    MAEDA Takeyasu, IZUMI Kenji, INOUE Kayoko, KAWANO Yoshiro, SUZUKI Akiko

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    Grant amount:\18980000 ( Direct Cost: \14600000 、 Indirect Cost:\4380000 )

    The Ruffini endings, a primary mechanoreceptor in the periodontal ligament, well-develop caveolae in their cell membrane. The present study examined the functional significance of caveolae in the periodontal Ruffini endings. The caveolae were consisted of caveolin-1 with diverse functions. A unique immuno-localization pattern of caveolin-1 and Ca^<2+>-pump suggested caveolae is involved in the quick elimination of intracellular Ca^<2+> which influx into the axon terminals in mechanotransduction.

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  • 無血清培地で作成したヒト培養複合口腔粘膜が移植後創傷治癒に及ぼす影響の研究

    Grant number:12771216

    2000 - 2001

    System name:科学研究費助成事業

    Research category:奨励研究(A)

    Awarding organization:日本学術振興会

    泉 健次

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    Grant amount:\2300000 ( Direct Cost: \2300000 )

    平成12年の秋に新潟大学歯学部の倫理委員会でヒト培養複合口腔粘膜の臨床応用についての認可を得、それ以降平成14年の初めまでに、計19例の培養複合口腔粘膜移植を行った。特筆するべきことは、平成13年の秋より、それまで培地に加えていたウシ下垂体抽出物をブタのそれに代替することに成功し、現在ではいわゆる狂牛病(BSE)感染の危険性の全くない培養システムで運営している。口腔内移植後の培養複合口腔粘膜の創傷治癒はいずれの症例でも非常に良好に進み、副作用等の異常所見は全く観察されていない。移植後創傷治癒の検索には、19例の培養複合口腔粘膜移植群の他に、培養粘膜作成に用いている無細胞性ヒト新鮮屍体真皮であるAlloDerm【○!R】単独移植群も設定し、術後に1回のみ採取が許された創部組織の生検の病理組織像により、結局HE染色のみになってしまったが、この2群間を比較することで予想以上のところまで解明できたと考えている。すなわちいずれの群も基本的に術後は炎症を伴った肉芽組織の像を呈するものの、培養複合粘膜移植群ではAlloDerm【○!R】単独移植群に比して、術後2週ではほとんど組織像に差がなかったが、術後4週では明らかに組織の修復がすみやかに行われ、著明に認められていた炎症性細胞浸潤は減少し器質化が進んでいた。同時に肉眼的観察でも、創の上皮化が明らかに早く完了していた。この結果から、培養口腔粘膜角化細胞から何らかのサイトカインなどが分泌されることで、創傷治癒に効果的な影響を及ぼしていると考察した。この情報は、再生医療の分野で日本が世界に発信できるに十分価値のあるものといえよう。もちろんまだまだ、解明の足りない部分は多く残されているが、それは今後の課題である。

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  • 睡眠時無呼吸症候群の歯科における集学的治療法の確立

    Grant number:08672294

    1996 - 1998

    System name:科学研究費助成事業

    Research category:基盤研究(C)

    Awarding organization:日本学術振興会

    河野 正己, 小林 正治, 染矢 源治, 泉 健次

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    Grant amount:\2000000 ( Direct Cost: \2000000 )

    平成8年度,9年度と同様に睡眠時無呼吸症候群の新規患者を対象に研究を進めた.しかし,平成10年4月に本学附属病院に「いびき外来」が開設され,同年には291名の新患が来院し,その後も月平均30名の新患が来院するため,睡眠ポリグラフの需要が増え研究の遂行に支障を来した.しかし,可能な限りの測定機器を駆使して,PMAとnasal CPAPとの相互関係を検討した.対象は,睡眠ポリグラフの稼働制限が生じたためnasal CPAPの適応となった無呼吸低換気指数が20以上の50症例の内,nasal CPAPのtitrationをマニュアルで行った9例と患者の都合で中止した2例を除いた39例について分析したところ,平均CPAP圧は7.2cmH20であった.この内,PMAを併用しているのは4例で,その平均CPAP圧は6.6cmH20と全例の平均よりも低く,nasal CPAPとPMAとの相乗効果が認められた.さらに,PMAの効果をCPAP圧として換算するとおよそ4cmH20に相当することがわかった.一方,Uvulopalatopharyngoplasty(UPPP)やLaser assisted uvulopalatoplasty(LAUP)という軟口蓋手術を行っている5例の平均CPAP圧は6.9cmH20で,nasal CPAPとの相乗効果は認められなかった.以上から,PMAとnasal CPAPとは積極的に併用しするとCPAP圧を下げたり下顎前突量を軽減したりして,それぞれの治療法のコンプライアンス向上に寄与するが,UPPPやUPPやLAUPといった軟口蓋手術とnasal CPAPとはそれぞれの欠点を補うことができないため,併用は避けるのが賢明であると思われた.今後は,上下顎前方移動術など新しい手術に対してもそれぞれの保存的療法との相互関係を検討する必要があると思われた.

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  • 口腔粘膜のLichenoid Tissue Reaction に関する組織学的研究

    Grant number:06671878

    1994

    System name:科学研究費助成事業

    Research category:一般研究(C)

    Awarding organization:日本学術振興会

    鈴木 一郎, 泉 健次

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    Grant amount:\2000000 ( Direct Cost: \2000000 )

    Lichenoid Tissue Reaction(LTR)という視点から口腔粘膜疾患をながめ、口腔粘膜におけるLTRの意義や口腔粘膜疾患へのかかわりをさぐることを目的で以下の研究をおこなった。Lichen Planus、Leukoplakia、Erythroplakia、正常口腔粘膜の生検標本を材料とし、これらの標本を、免疫組織化学的にリンパ球サブセットや免疫系接着分子(以下、接着分子)の発現をみた。LTRの成立に関係するといわれているT-Cellサブセットおよび接着因子として、CD1,CD3,CD4,CD7,CD8,LFA-1,CD19,CD45RA/RO,CD54に対する抗体を用いて、免疫組織化学染色をおこなった。染色陽性リンパ球数のカウント、その分布を見るために、染色像を顕微鏡よりCCDカメラ画像でパソコンに取り込み、画像処理ソフトにより陽性リンパ球数を粘膜の部位ごとにカウントした。正常粘膜、各種粘膜疾患とも上皮下に浸潤するリンパ球の多くはCD4+,CD45R0+であるが、Lichen PlanusではCD8+やCD45RA+も上皮直下に比較的多く認められた。更にこの上皮直下のリンパ球には、LFA-1の発現もみられた。皮膚と比較して、正常粘膜においてもmemory T cellが多く浸潤しているこは、粘膜が外来刺激に対して、免疫寛容状態となっていることが推察され、Lichen Planusにおいては、naive T cellが接着分子を発現して上皮下に浸潤することで、寛容状態が破綻をきたして、上皮を障害するものと考えられた。皮膚におけるLTRは過剰免疫反応と考えられているが、口腔粘膜では、このような過剰免疫反応によるLTRは存在しないことが推察された。

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  • Morpholohical study on the pathological changes of odontogenic epithelium

    Grant number:05671662

    1993 - 1995

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for General Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

    HAMAMOTO Yoshioki, IZUMI Kenji, SUZUKI Ichirou

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    Grant amount:\2200000 ( Direct Cost: \2200000 )

    [Production of amelogenin by the enamel epithelium of Hertwig's root sheath]
    The enamel epithelium of Hertwig's root sheath formed the epithelial islands, which resembled epithelial rests of Malassez, due to inflammatory stimulation of pulpitis. Parts of the epithelial cells, which were in contact with subsequently formed calcified fissue, showed columnar appearance. Immunohistochemical reactions were positive both in the cells and at the are between the cells and the calcified tissue. The findings suggestedthat the enamel epithelium of Hertwig's root sheath havethe potential of differentiation into ameloblasts.
    [Experimental study on odontogenic tumors induced by local administration of MNU]
    The mixture with the alginate impression material for dental use and MNU was injected on the bone surfaces of left mandibles. The inflammatory reactions were localized around the mixture, which was gradually resolved by macrophages. The odontogenic tumors, which resembled ameloblastoma, were occurred in cervical and bifurcational regions of molars more than 5 months after the injection. The tumors were confirmed to be derived form epithelial rests of Malassez. The incidence of occurrence of the tumors was nearly 100%.
    [Co-culture of human ameloblastoma cells and calcified tissues from teeth]
    The morphological changes of human ameloblastoma cessl in vitro was examined by the co-culture with fragments of teeth . The human ameloblastoma cells in vitro showed mono-layr seat like appearance, but they did not survive more than 1 month. There was no morphological change of the cells in theco-culture with the fragments of teeth within one month. It was suggested that long term survival of the ameloblastoma cells was important for the morphological changes.

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  • Development of human oral mucosa equivalent

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    Grant type:Competitive

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  • The relationship between apoptosis and oral mucosal lesion

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    Grant type:Competitive

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  • Oral mucosal keratinocyte culture and application of oral mucosal reconstruction

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    Grant type:Competitive

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  • The histological Study on the replacement of a collagen material in rabbit TMJ.

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    Grant type:Competitive

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Teaching Experience

  • 「食べる」

    2021
    Institution name:新潟大学

  • 生体組織再生工学特論IA

    2021
    Institution name:新潟大学

  • 生体組織再生工学演習IIB

    2021
    Institution name:新潟大学

  • 人体のしくみ

    2021
    Institution name:新潟大学

  • 生体組織再生工学特論IIA

    2021
    Institution name:新潟大学

  • 生体組織再生工学特論IIB

    2021
    Institution name:新潟大学

  • 生体組織再生工学特論IB

    2021
    Institution name:新潟大学

  • 生体組織再生工学演習IIA

    2021
    Institution name:新潟大学

  • 基礎歯学コースワーク(生体組織再生工学コースワークI)

    2021
    Institution name:新潟大学

  • 基礎歯学コースワーク(生体組織再生工学コースワークII)

    2021
    Institution name:新潟大学

  • 生体組織再生工学演習IA

    2021
    Institution name:新潟大学

  • 生体組織再生工学演習IB

    2021
    Institution name:新潟大学

  • 生体材料学演習IB

    2021
    Institution name:新潟大学

  • 生体材料学特論IIA

    2021
    Institution name:新潟大学

  • 基礎歯学コースワーク(生体材料関係コースワークI)

    2021
    Institution name:新潟大学

  • ネットワーク型先端歯学研究

    2021
    Institution name:新潟大学

  • 生体材料学演習IIB

    2021
    Institution name:新潟大学

  • 基礎歯学コースワーク(生体材料関係コースワークII)

    2021
    Institution name:新潟大学

  • 生体材料学特論IB

    2021
    Institution name:新潟大学

  • 生体材料学特論IIB

    2021
    Institution name:新潟大学

  • 生体材料学演習IIA

    2021
    Institution name:新潟大学

  • 生体材料学特論IA

    2021
    Institution name:新潟大学

  • 生体材料学演習IA

    2021
    Institution name:新潟大学

  • 歯科理工学Ⅱ

    2020
    Institution name:新潟大学

  • 基礎歯学コースワーク(生体材料関係コースワークⅡ)

    2020
    Institution name:新潟大学

  • 生体材料学

    2018
    Institution name:新潟大学

  • 生体理工学

    2018
    Institution name:新潟大学

  • 生体組織再生工学演習ⅡA

    2018
    Institution name:新潟大学

  • 生体組織再生工学特論ⅠA

    2018
    Institution name:新潟大学

  • 生体組織再生工学特論ⅡA

    2018
    Institution name:新潟大学

  • 基礎歯学コースワーク(生体組織再生工学コースワークⅠ)

    2017
    -
    2020
    Institution name:新潟大学

  • 基礎歯学コースワーク(生体組織再生工学コースワークⅡ)

    2017
    -
    2018
    Institution name:新潟大学

  • 生体組織再生工学演習ⅠA

    2017
    -
    2018
    Institution name:新潟大学

  • 生体組織再生工学演習ⅠB

    2017
    Institution name:新潟大学

  • 生体組織再生工学特論ⅡB

    2017
    Institution name:新潟大学

  • 生体組織再生工学演習ⅡB

    2017
    Institution name:新潟大学

  • 「食べる」

    2016
    -
    2020
    Institution name:新潟大学

  • 歯学研究入門

    2016
    -
    2017
    Institution name:新潟大学

  • 早期臨床実習Ⅱ

    2015
    Institution name:新潟大学

  • 歯科理工学Ⅰ

    2014
    Institution name:新潟大学

  • 人体のしくみ

    2010
    -
    2014
    Institution name:新潟大学

  • 口腔組織発生学

    2010
    -
    2013
    Institution name:新潟大学

  • 人体発生学

    2010
    -
    2011
    Institution name:新潟大学

  • 基礎科学演習

    2009
    -
    2016
    Institution name:新潟大学

  • 組織学総論

    2009
    -
    2013
    Institution name:新潟大学

  • 組織学各論

    2009
    -
    2013
    Institution name:新潟大学

  • 感覚器学

    2009
    Institution name:新潟大学

  • 神経解剖学

    2009
    Institution name:新潟大学

  • 形態解析学演習

    2009
    Institution name:新潟大学

  • 基礎歯学コースワーク(ベーシック培養細胞実験コース)

    2009
    Institution name:新潟大学

  • 骨筋学

    2009
    Institution name:新潟大学

  • 脈管内臓学

    2009
    Institution name:新潟大学

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