Faculty Profiles - IGAWA Kazuyo

Papers - IGAWA Kazuyo

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The Early Response After Radiation Therapy on Three-Dimensional Oral Cancer Model Using Patient-Derived Cancer-Associated Fibroblasts

Izumi Yamamoto, Kazuyo Igawa, Natsuko Kondo, Yoshinori Sakurai, Atsushi Fujimura, Kiyofumi Takabatake, Peng Huang, Hiroyuki Michiue, Soichiro Ibaragi, Kenji Izumi

International Journal of Translational Medicine 5 ( 1 ) 12 - 12 2025.3

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

Background/Objectives: Cancer-associated fibroblasts (CAFs), which are an important component of the tumor microenvironment, have been reported to have an adverse effect on conventional radiotherapy. This study aims to elucidate the effects of CAFs in boron neutron capture therapy (BNCT) using a three-dimensional (3D) oral cancer model. Methods: Three-dimensional cancer models were fabricated using patient-derived CAFs or patient-derived normal oral fibroblasts (NOFs) and a human oral squamous cell carcinoma cell line. Each 3D cancer model was performed with either a conventional X-ray treatment or BNCT and additionally analyzed histomorphologically. Results: The 3D oral cancer-CAFs model demonstrated a greater depth of cancer cell invasion than the 3D oral cancer-NOFs model. Radiation therapy for the 3D oral cancer models indicated a trend for decreasing cancer cell invasion and cell number with dose dependence in both X-ray and BNCT. In comparison with X-rays, BNCT showed a consistent increase in the number of NOFs and a significant reduction in the number of CAFs. Conclusions: BNCT for the 3D oral cancer model was shown to be effective against cancer cells and CAFs but not against NOFs, indicating its usefulness as a minimally invasive treatment for advanced cancer. Furthermore, it is indicated that the 3D oral cancer-CAFs model is a valuable tool to evaluate cancer treatment and research, particularly in high-grade malignant tumors with invasion.

DOI： 10.3390/ijtm5010012

Development and Characterization of a Three-Dimensional Organotypic In Vitro Oral Cancer Model with Four Co-Cultured Cell Types, Including Patient-Derived Cancer-Associated Fibroblasts. International journal

Yuka Aizawa, Kenta Haga, Nagako Yoshiba, Witsanu Yortchan, Sho Takada, Rintaro Tanaka, Eriko Naito, Tatsuya Abé, Satoshi Maruyama, Manabu Yamazaki, Jun-Ichi Tanuma, Kazuyo Igawa, Kei Tomihara, Shinsaku Togo, Kenji Izumi

Biomedicines 12 ( 10 ) 2024.10

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

Background/Objectives: Cancer organoids have emerged as a valuable tool of three-dimensional (3D) cell cultures to investigate tumor heterogeneity and predict tumor behavior and treatment response. We developed a 3D organotypic culture model of oral squamous cell carcinoma (OSCC) to recapitulate the tumor-stromal interface by co-culturing four cell types, including patient-derived cancer-associated fibroblasts (PD-CAFs). Methods: A stainless-steel ring was used twice to create the horizontal positioning of the cancer stroma (adjoining normal oral mucosa connective tissue) and the OSCC layer (surrounding normal oral mucosa epithelial layer). Combined with a structured bi-layered model of the epithelial component and the underlying stroma, this protocol enabled us to construct four distinct portions mimicking the oral cancer tissue arising in the oral mucosa. Results: In this model, α-smooth muscle actin-positive PD-CAFs were localized in close proximity to the OSCC layer, suggesting a crosstalk between them. Furthermore, a linear laminin-γ2 expression was lacking at the interface between the OSCC layer and the underlying stromal layer, indicating the loss of the basement membrane-like structure. Conclusions: Since the specific 3D architecture and polarity mimicking oral cancer in vivo provides a more accurate milieu of the tumor microenvironment (TME), it could be crucial in elucidating oral cancer TME.

DOI： 10.3390/biomedicines12102373

Overcoming immunotherapy resistance and inducing abscopal effects with boron neutron <scp>immunotherapy</scp> (B‐<scp>NIT</scp>) Reviewed

Takuya Fujimoto, Osamu Yamasaki, Noriyuki Kanehira, Hirokazu Matsushita, Yoshinori Sakurai, Naoya Kenmotsu, Ryo Mizuta, Natsuko Kondo, Takushi Takata, Mizuki Kitamatsu, Kazuyo Igawa, Atsushi Fujimura, Yoshihiro Otani, Makoto Shirakawa, Kunitoshi Shigeyasu, Fuminori Teraishi, Yosuke Togashi, Minoru Suzuki, Toshiyoshi Fujiwara, Hiroyuki Michiue

Cancer Science 2024.8

Publishing type：Research paper (scientific journal) Publisher：Wiley

Abstract

Immune checkpoint inhibitors (ICIs) are effective against many advanced malignancies. However, many patients are nonresponders to immunotherapy, and overcoming this resistance to treatment is important. Boron neutron capture therapy (BNCT) is a local chemoradiation therapy with the combination of boron drugs that accumulate selectively in cancer and the neutron irradiation of the cancer site. Here, we report the first boron neutron immunotherapy (B‐NIT), combining BNCT and ICI immunotherapy, which was performed on a radioresistant and immunotherapy‐resistant advanced‐stage B16F10 melanoma mouse model. The BNCT group showed localized tumor suppression, but the anti‐PD‐1 antibody immunotherapy group did not show tumor suppression. Only the B‐NIT group showed strong tumor growth inhibition at both BNCT‐treated and shielded distant sites. Intratumoral CD8+ T‐cell infiltration and serum high mobility group box 1 (HMGB1) levels were higher in the B‐NIT group. Analysis of CD8⁺ T cells in tumor‐infiltrating lymphocytes (TILs) showed that CD62L‐ CD44⁺ effector memory T cells and CD69⁺ early‐activated T cells were predominantly increased in the B‐NIT group. Administration of CD8‐depleting mAb to the B‐NIT group completely suppressed the augmented therapeutic effects. This indicated that B‐NIT has a potent immune‐induced abscopal effect, directly destroying tumors with BNCT, inducing antigen‐spreading effects, and protecting normal tissue. B‐NIT, immunotherapy combined with BNCT, is the first treatment to overcome immunotherapy resistance in malignant melanoma. In the future, as its therapeutic efficacy is demonstrated not only in melanoma but also in other immunotherapy‐resistant malignancies, B‐NIT can become a new treatment candidate for advanced‐stage cancers.

DOI： 10.1111/cas.16298

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

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

Hadron therapy in radiation oncology and why BNCT is a paradigm shift Reviewed

Wolfgang A. G. Sauerwein, Kazuyo Igawa, Joël Herault, Piero Fossati, Saverio Altieri, Raymond L. Moss, Andrea Wittig

Health and Technology 2024.5

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

Abstract

Purpose

Hadrons, i.e. particles that are heavier than electrons, are playing an increasingly important role in radiation oncology. Due to the high investment costs for the necessary infrastructure, this option is only available in specialized centers.

Methods

This article describes some of the physical properties that make hadrons attractive for external beam radiation therapy (EBRT), but also some of the challenges that need to be considered.

Results

The importance of linear energy transfer for biological effects is discussed.

Conclusions

In addition to the use of charged particles, the importance of neutrons for radiotherapy is also highlighted, in particular the properties of boron neutron capture therapy (BNCT), which open up completely new possibilities for the further development of EBRT.

DOI： 10.1007/s12553-024-00848-5

Other Link： https://link.springer.com/article/10.1007/s12553-024-00848-5/fulltext.html

The current status and novel advances of boron neutron capture therapy clinical trials. Reviewed International journal

Tianyun Zhou, Kazuyo Igawa, Tomonari Kasai, Takuya Sadahira, Wei Wang, Tomofumi Watanabe, Kensuke Bekku, Satoshi Katayama, Takehiro Iwata, Tadashi Hanafusa, Abai Xu, Motoo Araki, Hiroyuki Michiue, Peng Huang

American journal of cancer research 14 ( 2 ) 429 - 447 2024

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

Boron neutron capture therapy (BNCT) is a treatment method that focuses on improving the cure rate of patients with cancer who are difficult to treat using traditional clinical methods. By utilizing the high neutron absorption cross-section of boron, material rich in boron inside tumor cells can absorb neutrons and release high-energy ions, thereby destroying tumor cells. Owing to the short range of alpha particles, this method can precisely target tumor cells while minimizing the inflicted damage to the surrounding normal tissues, making it a potentially advantageous method for treating tumors. Globally, institutions have progressed in registered clinical trials of BNCT for multiple body parts. This review summarized the current achievements in registered clinical trials, Investigator-initiated clinical trials, aimed to integrate the latest clinical research literature on BNCT and to shed light on future study directions.

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

Kazuyo Igawa, Kenji Izumi, Yoshinori Sakurai

BioTech 12 ( 2 ) 35 - 35 2023.5

Authorship：Lead author,　Corresponding author 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

Particle and Heavy Ion Transport Code System‐Based Microdosimetry for the Development of Boron Agents for Boron Neutron Capture Therapy Reviewed

Takafumi Shigehira, Tadashi Hanafusa, Kazuyo Igawa, Tomonari Kasai, Shuichi Furuya, Hisakazu Nishimori, Yoshinobu Maeda, Hiroyuki Michiue, Atsushi Fujimura

Advanced Theory and Simulations 2023.4

Gelatin-based cell culture device for construction and X-ray irradiation of a three-dimensional oral cancer model. Reviewed International journal

Tomoka Bessho, Tomoko Takagi, Kazuyo Igawa, Kae Sato

Analytical sciences : the international journal of the Japan Society for Analytical Chemistry 2023.2

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

Bioassays using three-dimensional (3D) tissue models offer several advantages over 2D culture assays because they can reproduce the structure and function of native tissues. In this study, we used our newly designed gelatin device to generate a miniature 3D model of human oral squamous cell carcinoma with stroma and blood vessels. To enable air-liquid interface culture, we conceived a new device structure in which three wells were lined up and separated by a dividing thread; the wells could be connected by removing the dividing thread. Cells were seeded in the center well with the dividing thread to form a multilayer, followed by the supply of media from the side wells after thread removal. Human oral squamous cell carcinoma (HSC-4) cells, human umbilical vein endothelial cells (HUVECs), and normal human dermal fibroblasts (NHDFs) were successfully cocultured, resulting in structures that mimicked 3D-cancer tissues. This 3D-cancer model was subjected to an X-ray sensitivity assay, followed by the evaluation of DNA damage using confocal microscopy and section-scanning electron microscopy.

DOI： 10.1007/s44211-023-00308-6

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, 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

日本口腔科学会雑誌 71 ( 2 ) 61 - 61 2022.7

Prevention and early management of carotid blowout syndrome for patients receiving head and neck salvage boron neutron capture therapy (BNCT). Reviewed International journal

Tien-Li Lan, Feng-Chi Chang, Chun-Wei Wang, Kazuyo Igawa, Szu-Hsien Wu, Wen-Liang Lo, Yi-Wei Chen

Journal of dental sciences 16 ( 3 ) 854 - 860 2021.7

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

BACKGROUND/PURPOSE: The incidence rate of oral and pharyngeal cancers in Taiwan has increased gradually over the past few decades. The standard treatment strategy for oral and pharyngeal cancers includes surgery or radiotherapy, with concurrent chemotherapy in certain types of tumors. Unfortunately, in-field recurrence is sometimes inexorable. Furthermore, re-irradiation of the recurrence site may cause severe complications due to the tolerance of normal tissue to radiation therapy. One fatal complication is carotid blowout syndrome (CBS). Boron neutron capture therapy (BNCT) is a new modality of radiation therapy, which is also mentioned as targeted radiotherapy. It is a feasible treatment that has the potential to spare normal tissue from being damaged by irradiation while simultaneously treating the primary tumor. In this presentation, we will share our experience with BNCT in treating recurrent head and neck cancers, as well as the prevention and management of CBS. MATERIALS AND METHODS: We evaluated 4 patients with head and neck cancers treated by BNCT in Taiwan. All patients had undergone surgery previously and had received postoperative concurrent chemoradiotherapy. RESULTS: The 4 patients in this study were diagnosed with head and neck malignancies. The median follow-up period after the first course of BNCT was 15.1 months. After BNCT, 2 patients developed impending CBS, and 1 of them died. The remaining 3 patients survived until the last date of follow-up. CONCLUSION: Pre-BNCT carotid artery evaluation through computed tomography angiography and early intervention if necessary is crucial when treating patients with recurrent head and neck cancers by BNCT.

DOI： 10.1016/j.jds.2020.12.013

Self-assembling A6K peptide nanotubes as a mercaptoundecahydrododecaborate (BSH) delivery system for boron neutron capture therapy (BNCT). Reviewed International journal

Hiroyuki Michiue, Mizuki Kitamatsu, Asami Fukunaga, Nobushige Tsuboi, Atsushi Fujimura, Hiroaki Matsushita, Kazuyo Igawa, Tomonari Kasai, Natsuko Kondo, Hideki Matsui, Shuichi Furuya

Journal of controlled release : official journal of the Controlled Release Society 330 788 - 796 2021.2

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

Boron neutron capture therapy (BNCT) is a tumor selective therapy, the effectiveness of which depends on sufficient 10B delivery to and accumulation in tumors. In this study, we used self-assembling A6K peptide nanotubes as boron carriers and prepared new boron agents by simple mixing of A6K and BSH. BSH has been used to treat malignant glioma patients in clinical trials and its drug safety and availability have been confirmed; however, its contribution to BNCT efficacy is low. A6K nanotube delivery improved two major limitations of BSH, including absence of intracellular transduction and non-specific drug delivery to tumor tissue. Varying the A6K peptide and BSH mixture ratio produced materials with different morphologies-determined by electron microscopy-and intracellular transduction efficiencies. We investigated the A6K/BSH 1:10 mixture ratio and found high intracellular boron uptake with no toxicity. Microscopy observation showed intracellular localization of A6K/BSH in the perinuclear region and endosome in human glioma cells. The intracellular boron concentration using A6K/BSH was almost 10 times higher than that of BSH. The systematic administration of A6K/BSH via mouse tail vein showed tumor specific accumulation in a mouse brain tumor model with immunohistochemistry and pharmacokinetic study. Neutron irradiation of glioma cells treated with A6K/BSH showed the inhibition of cell proliferation in a colony formation assay. Boron delivery using A6K peptide provides a unique and simple strategy for next generation BNCT drugs.

DOI： 10.1016/j.jconrel.2020.11.001

Scaling parameter of the lethal effect of mammalian cells based on radiation-induced OH radicals: effectiveness of direct action in radiation therapy. Reviewed International journal

Tamon Kusumoto, Ryo Ogawara, Kazuyo Igawa, Kentaro Baba, Teruaki Konishi, Yoshiya Furusawa, Satoshi Kodaira

Journal of radiation research 62 ( 1 ) 86 - 93 2021.1

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

We have been studying the effectiveness of direct action, which induces clustered DNA damage leading to cell killing, relative to indirect action. Here a new criterion Direct Ation-Based Biological Effectiveness (DABBLE) is proposed to understand the contribution of direct action for cell killing induced by C ions. DABBLE is defined as the ratio of direct action to indirect action. To derive this ratio, we describe survival curves of mammalian cells as a function of the number of OH radicals produced 1 ps and 100 ns after irradiation, instead of the absorbed dose. By comparing values on the vertical axis of the survival curves at a certain number of OH radicals produced, we successfully discriminate the contribution of direct action induced by C ions from that of indirect action. DABBLE increases monotonically with increasing linear energy transfer (LET) up to 140 keV/μm and then drops, when the survival curves are described by the number of OH radicals 1 ps after irradiation. The trend of DABBLE is in agreement with that of relative biological effectiveness (RBE) of indirect action. In comparison, the value of DABBLE increases monotonically with LET, when the survival curves are described by the number of OH radicals 100 ns after irradiation. This finding implies that the effectiveness of C ion therapy for cancer depends on the contribution of direct action and we can follow the contribution of direct action over time in the chemical phase.

DOI： 10.1093/jrr/rraa111

The accelerator-based boron neutron capture reaction evaluation system for head and neck cancer. Reviewed International journal

Shou Wang, Kazuyo Igawa, Ryo Ogawara, Mitsuru Suda, Tsuyoshi Hamano, Soichiro Ibaragi, Tadashi Hanafusa, Yasuaki Ichikawa, Akira Sasaki

Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine 165 109271 - 109271 2020.11

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

The purpose of this study is to assess accelerator-based boron neutron capture reaction (BNCR) in human tumor cell lines by colony formation assay and modified high density survival assay (HDS assay). The results of post irradiation survival rate in human oral squamous cell carcinoma and osteosarcoma using both assays were similar. Therefore, HDS assay would be efficient to evaluate BNCR in not only tumor cells but also in normal cells as BNCT screening.

DOI： 10.1016/j.apradiso.2020.109271

In Vitro Studies to Define the Cell-Surface and Intracellular Targets of Polyarginine-Conjugated Sodium Borocaptate as a Potential Delivery Agent for Boron Neutron Capture Therapy. Reviewed International journal

Atsushi Fujimura, Seiji Yasui, Kazuyo Igawa, Ai Ueda, Kaori Watanabe, Tadashi Hanafusa, Yasuaki Ichikawa, Sachiko Yoshihashi, Kazuki Tsuchida, Atsunori Kamiya, Shuichi Furuya

Cells 9 ( 10 ) 2020.9

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

Boron neutron capture therapy (BNCT) requires pharmaceutical innovations and molecular-based evidence of effectiveness to become a standard cancer therapeutic in the future. Recently, in Japan, 4-borono-L-phenylalanine (BPA) was approved as a boron agent for BNCT against head and neck (H&N) cancers. H&N cancer appears to be a suitable target for BPA-BNCT, because the expression levels of L-type amino acid transporter 1 (LAT1), one of the amino acid transporters responsible for BPA uptake, are elevated in most cases of H&N cancer. However, in other types of cancer including malignant brain tumors, LAT1 is not always highly expressed. To expand the possibility of BNCT for these cases, we previously developed poly-arginine peptide (polyR)-conjugated mercaptoundecahydrododecaborate (BSH). PolyR confers the cell membrane permeability and tumor selectivity of BSH. However, the molecular determinants for the properties are not fully understood. In this present study, we have identified the cluster of differentiation 44 (CD44) protein and translational machinery proteins as a major cell surface target and intracellular targets of BSH-polyR, respectively. CD44, also known as a stem cell-associated maker in various types of cancer, is required for the cellular uptake of polyR-conjugated molecules. We showed that BSH-polyR was predominantly delivered to a CD44High cell population of cancer cells. Once delivered, BSH-polyR interacted with the translational machinery components, including the initiation factors, termination factors, and poly(A)-biding protein (PABP). As a proof of principle, we performed BSH-polyR-based BNCT against glioma stem-like cells and revealed that BSH-polyR successfully induced BNCT-dependent cell death specifically in CD44High cells. Bioinformatics analysis indicated that BSH-polyR would be suitable for certain types of malignant tumors. Our results shed light on the biochemical properties of BSH-polyR, which may further contribute to the therapeutic optimization of BSH-BNCT in the future.

DOI： 10.3390/cells9102149

Clinical significance of buccal branches of the facial nerve and their relationship with the emergence of Stensen's duct: An anatomical study on adult Taiwanese cadavers. Reviewed International journal

Chen-Hsi Tsai, Chun-Chan Ting, Szu-Yuan Wu, Jih-Yu Chiu, Hansheng Chen, Kazuyo Igawa, Ting-Hsun Lan, Chun-Ming Chen, Tsuoyoshi Takato, Kazuto Hoshi, Edward Chengchuan Ko

Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery 47 ( 11 ) 1809 - 1818 2019.11

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

OBJECTIVE: This observational study on adult Taiwanese cadavers focused mainly on the intersection of buccal branches of the facial nerve with Stensen's duct, using the emergence of Stensen's duct as the reference landmark. MATERIALS AND METHODS: Thirty-five cadaveric hemifaces were included in our research. Samples with facial defects due to tumor, trauma, or surgery were all excluded. Buccal branches of the facial nerve were identified according to the Gray's Anatomy 40th edition definition. The distance was measured from the intersection to the emergence of Stensen's duct, running from the anterior border of the parotid gland. RESULTS: In the 35 hemifaces, the number of buccal branch/Stensen's duct intersections ranged from 1 to 5 (average 2.49 ± 1.15). Two-point intersections accounted for 37% (13 hemifaces) of the sample, forming the largest group. Samples of facial nerve buccal branches were divided into four types: Type 1, with two buccal branches, accounted for 37.15% (13/35); Type 2, with three buccal branches, made up 48.59% (17/35) of our samples - the biggest group (Type 2-a was the most frequent pattern among our samples, with two superior buccal branches and one inferior buccal branch, accounting for 34.31% of our samples); Type 3, with four buccal branches, accounted for only 5.7%. Three cases of double Stensen's duct were classified as Type 4, though this is supposed to be a very rare anatomical variation. With Type 2a, the most frequent pattern among our specimens, the distance from the emergence of the Stensen's duct to the emergence point of the first superior buccal branch along the anterior border of the parotid gland was 9.58 ± 5.68 mm. The distance from the emergence point to the emergence of the inferior buccal branch along the anterior border of the parotid gland was 11.03 ± 5.38 mm. The distance (D1) from Stensen's duct to the emergence of the first superiorly located buccal branch of the group Type 2-a was statistically different from the distance (D1) of the other groups (p = 0.02). No direct anastomoses or communicating fibers between upper and lower buccal branches were noted in 11 hemifaces (31%). CONCLUSION: The distribution of buccal branches was described using the emergence of Stensen's duct as a reference landmark. According to our observations, the relationship between the buccal branches and Stensen's duct was much more complicated than described in previous studies. This was the first study to investigate the complete distribution of buccal branches of the facial nerve emerging from the anterior of the parotid gland, and their relative locations and branching numbers.

DOI： 10.1016/j.jcms.2018.12.018

Development of thermal neutron moderator for testing boron agents for Boron Neutron Capture Therapy (BNCT) Reviewed

Ichikawa, G., Tsuchida, K., Kiyanagi, Y., Ishikawa, A., Hirata, Y., Yoshihashi, S., Watanabe, K., Uritani, A., Hamano, T., Ogawara, R., Suda, M., Igawa, K.

JOURNAL OF INSTRUMENTATION 14 2019.6

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：IOP PUBLISHING LTD

We developed a thermal neutron source for performance tests of boron agents for Boron Neutron Capture Therapy (BNCT) at Neutron exposure Accelerator System for Biological Effect Experiments (NASBEE) in National Institute of Radiological Sciences, Japan. The thermal neutron flux at the experimental position was measured to be 2.18 x 10(8) n/cm(2)/s, the cadmium ratio was 9.21, and gamma ray dose ratewas 2.11 Gy/h. The neutron dose ratewas estimated to be 2.96 Gy/h. These values indicate that the neutron source can be applicable for tests of boron agents although application range is limited. An example of irradiation experiment is described.

DOI： 10.1088/1748-0221/14/06/T06010

A Case of Giant Pilomatrix Carcinoma

井川和代, 北原正樹

日本形成外科学会会誌 37 ( 7 ) 393 - 398 2017

ホウ素中性子捕捉療法（BNCT)

井川和代, 瀬戸?一

クインテッセンス別冊 138 - 146 2015

粒子線・ホウ素中性子捕捉療法

井川和代, 瀬戸?一

標準口腔外科学第4版 ( 18 ) 509 - 513 2015

Comparison of the long-term effects on rabbit bone defects between Tetrabone and β-tricalcium phosphate granules implantation. Reviewed

Sungjin Choi, I-Li Liu, Kenichi Yamamoto, Muneki Honnami, Shinsuke Ohba, Ryosuke Echigo, Takamasa Sakai, Kazuyo Igawa, Shigeki Suzuki, Ryouhei Nishimura, Ung-Il Chung, Nobuo Sasaki, Manabu Mochizuki

Journal of artificial organs : the official journal of the Japanese Society for Artificial Organs 17 ( 4 ) 344 - 51 2014.12

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

Tetrabone is a newly developed granular artificial bone. The 1-mm Tetrabone has a four-legged structure. In this study, the long-term effect of implanting Tetrabone or β-TCP granules in rabbit femoral cylindrical defects was evaluated. The rabbits were euthanized at 4, 13, and 26 weeks after implantation. Micro-CT was conducted to evaluate the residual material volume and the non-osseous tissue volume. New bone tissue areas were measured by histological analysis. Micro-CT imaging showed that the residual material volume in the β-TCP group had decreased significantly at 4 weeks after implantation (P < 0.05) and that the β-TCP granules had nearly disappeared at 26 weeks after implantation. In the Tetrabone group, it did not significantly change until 13 weeks after implantation; it then continued to decrease slightly until 26 weeks after implantation. The non-osseous volume increased in the β-TCP group, whereas that of the Tetrabone group decreased (P < 0.05). Histological examination showed that the new bone areas were significantly greater in the Tetrabone group than in the β-TCP group at 13 and 26 weeks. In conclusion, resorption of β-TCP granules occurs before sufficient bone formation, thereby allowing non-osseous tissue invasion. Tetrabone resorption progressed slowly while the new bone tissues were formed, thus allowing better healing. Tetrabone showed better osteoconductivity, whereas the β-TCP granules lost their function over a long duration. These results may be caused by the differences in the absorption rate of the granules, intergranular pore structure, and crystallinity of each granule.

DOI： 10.1007/s10047-014-0778-9

Molecular and structural patterns of bone regeneration in surgically created defects containing bone substitutes. Reviewed International journal

Ibrahim Elgali, Kazuyo Igawa, Anders Palmquist, Maria Lennerås, Wei Xia, Sungjin Choi, Ung-Il Chung, Omar Omar, Peter Thomsen

Biomaterials 35 ( 10 ) 3229 - 42 2014.3

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

Several biomaterials have been introduced for bone augmentation. However, information is lacking about the mechanisms of bone regeneration and/or integration of these materials in the recipient bone. This study aimed to determine the molecular and structural events in bone defects after augmentation with synthetic tetrapod-shaped calcium phosphate (Tetrabone; TetraB) compared with natural deproteinized bovine bone (DBB). Defects were created in the epiphyses of rat femurs and filled with TetraB or DBB or left empty (Sham). After 3, 6, 14 and 28 d, samples were harvested for histology, histomorphometry, ultrastructure and gene expression analyses. At 3 d, higher expressions of bone formation (ALP and OC) and remodeling (CatK) genes were detected in TetraB compared with DBB and Sham. Downregulation of bone remodeling genes (TRAP and CatK) was detected in DBB as compared to Sham after 14 d. Histomorphometry at 6 and 14 d demonstrated greater bone contact with the granules in TetraB. At 28 d, a larger bone area per defect was found in TetraB. The present experiments show that a synthetic substitute, consisting of α-tricalcium and octacalcium phosphates, induces early osteogenic and osteoclastic activities and promotes bone formation in trabecular bone defects.

DOI： 10.1016/j.biomaterials.2013.12.084

放射線治療装置-最新こそ最良説検証多視点から示すがん治療への期待加速器を用いたホウ素中性子捕捉療法システム民間病院への導入と期待

菊池泰裕, 吉本高志, 渡邉一夫, 瀬戸皖一, 晴山雅人, 今井茂樹, 井川和代

月刊新医療 41 ( 12 ) 53 - 57 2014

Language：Japanese Publisher：(株)エムイー振興協会

ホウ素中性子捕捉療法(BNCT)は、腫瘍に集積するホウ素薬剤を患者に投与した後に中性子線を腫瘍に照射する。腫瘍内に集積したホウ素が中性子を捕捉してヘリウム原子核とリチウム原子核に分裂し、これらの粒子が粒子線として腫瘍内部から狭い範囲に照射される。原子炉でないと施行できなかった本治療を一般病院で利用できるように開発、治験が進められている。BNCTは、治療困難な悪性腫瘍の予後改善に寄与することが期待される。(著者抄録)

Changes in bone regeneration by trehalose coating and basic fibroblast growth factor after implantation of tailor-made bone implants in dogs. Reviewed

Sungjin Choi, Jongil Lee, Kazuyo Igawa, I-Li Liu, Muneki Honnami, Shigeki Suzuki, Ryohei Nishimura, Ung-Il Chung, Nobuo Sasaki, Manabu Mochizuki

The Journal of veterinary medical science 75 ( 6 ) 721 - 6 2013

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

In this study, we aimed to determine the effect of trehalose coating and the optimal dose of basic fibroblast growth factor (bFGF), an osteoinductive protein, loaded onto tailor-made bone implants for implant-induced bone formation in vivo. We fabricated tailor-made α-tricalcium phosphate bone implants (11 mm diameter with 2 parallel cylindrical holes). bFGF 0, 1, 10, 100 or 200 μg/implant was incorporated into implants with and without a trehalose coating, and these were subsequently implanted into dogs to correct temporal bone defects of the same size and shape. Four weeks after implantation, we analyzed the bone implants and surrounding tissues by using micro-computed tomography imaging and histological analyses, as well as gross evaluation. No significant difference in new bone formation was observed between implants with and without a trehalose coating at any of the bFGF doses. Bone implants with 100 and 200 μg bFGF showed significantly more new bone formation at the implant site and within the cylindrical holes of the implants than those without bFGF (P<0.05). However, heterotopic bone formation on the skull near the implant was observed in the group that received 200 μg bFGF. These results suggest that 100 μg bFGF is the optimal dose for this implant in dogs, and that the trehalose coating may not be necessary in vivo, probably due to the presence of blood proteins and electrolytes at the implant site.

DOI： 10.1292/jvms.12-0244

Development and evaluation of tetrapod-shaped granular artificial bones. Reviewed International journal

Sungjin Choi, I-li Liu, Kenichi Yamamoto, Kazuyo Igawa, Manabu Mochizuki, Takamasa Sakai, Ryosuke Echigo, Muneki Honnami, Shigeki Suzuki, Ung-il Chung, Nobuo Sasaki

Acta biomaterialia 8 ( 6 ) 2340 - 7 2012.7

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

We have developed a novel form of granular artificial bone "Tetrabones" with a homogeneous tetrapod shape and uniform size. Tetrabones are four armed structures that accumulate to form the intergranular pores that allow invasion of cells and blood vessels. In this study we evaluated the physicochemical characteristics of Tetrabones in vitro, and compared their biological and biomechanical properties in vivo to those of conventional β-tricalcium phosphate (β-TCP) granule artificial bone. Both the rupture strength and elastic modulus of Tetrabone particles were higher than those of β-TCP granules in vitro. The connectivity of intergranular pores 100, 300, and 400 μm in size were higher in Tetrabones than in the β-TCP granules. Tetrabones showed similar osteoconductivity and biomechanical stiffness to β-TCP at 2 months after implantation in an in vivo study of canine bone defects. These results suggest that Tetrabones may be a good bone graft material in bone reconstruction.

DOI： 10.1016/j.actbio.2012.02.019

Three-dimensional shape control of implant devices Reviewed

Ung-Il Chung, Hideto Saijoh, Kazuyo Igawa, Yuki Kanno, Yoshiyuki Mori, Tsuyoshi Takato

Handbook of Intelligent Scaffolds for Tissue Engineering and Regenerative Medicine 579 - 588 2012.1

Language：English Publishing type：Part of collection (book) Publisher：Pan Stanford Publishing Pte. Ltd.

The performance of the scaffolds holds a key to the realization of tissue engineering/regenerative medicine in clinical settings. We have focused on the vital role of the dimensional compatibility of the scaffolds. By controlling the three-dimensional (3D) shape of the scaffolds, we have significantly improved the performance of the artificial bones, which have good dimensional compatibility, resultant reduction in the operation time and corresponding invasiveness, and resultant speedy union with the host bone tissues. We conclude that 3D shape control is vital to the performance of the scaffolds.We propose that it is worth considering at least once to attempt to control the 3D shape of the scaffold by optimizing the design and fabrication method, before using expensive and highrisk growth factors and cells. © 2012 Pan Stanford Publishing Pte. Ltd. All rights reserved.

DOI： 10.4032/9789814267861

Effect of trehalose coating on basic fibroblast growth factor release from tailor-made bone implants. Reviewed

Sungjin Choi, Jongil Lee, Kazuyo Igawa, Shigeki Suzuki, Manabu Mochizuki, Ryohei Nishimura, Ung-il Chung, Nobuo Sasaki

The Journal of veterinary medical science 73 ( 12 ) 1547 - 52 2011.12

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

Artificial bone implants are often incorporated with osteoinductive factors to facilitate early bone regeneration. Calcium phosphate, the main component in artificial bone implants, strongly binds these factors, and in a few cases, the incorporated proteins are not released from the implant under conditions of physiological pH, thereby leading to reduction in their osteoinductivity. In this study, we coated tailor-made bone implants with trehalose to facilitate the release of basic fibroblast growth factor (bFGF). In an in vitro study, mouse osteoblastic cells were separately cultured for 48 hr in a medium with a untreated implant (T-), trehalose-coated implant (T+), bFGF-incorporated implant (FT-), and bFGF-incorporated implant with trehalose coating (FT+). In the FT+ group, cell viability was significantly higher than that in the other groups (P<0.05). Scanning electron microscopy (SEM) and X-ray diffraction (XRD) revealed that trehalose effectively covered the surface of the artificial bone implant without affecting the crystallinity or the mechanical strength of the artificial bone implant. These results suggest that coating artificial bone implants with trehalose could limit the binding of bFGF to calcium phosphate.

DOI： 10.1292/jvms.11-0016

Identification of oxytetracycline as a chondrogenic compound using a cell-based screening system. Reviewed

Hironori Hojo, Fumiko Yano, Shinsuke Ohba, Kazuyo Igawa, Keiji Nakajima, Yuske Komiyama, Akinori Kan, Toshiyuki Ikeda, Takayuki Yonezawa, Je-Tae Woo, Tsuyoshi Takato, Kozo Nakamura, Hiroshi Kawaguchi, Ung-il Chung

Journal of bone and mineral metabolism 28 ( 6 ) 627 - 33 2010.11

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

To effectively treat degenerative joint diseases including osteoarthritis (OA), small chemical compounds need to be developed that can potently induce chondrogenic differentiation without promoting terminal differentiation. For this purpose, we screened natural and synthetic compound libraries using a Col2GFP-ATDC5 system and identified oxytetracycline (Oxy) as a chondrogenic compound. Oxy induced cartilaginous matrix synthesis and mRNA expressions of chondrocyte markers in ATDC5 cells. In addition, Oxy suppressed mineralization and mRNA expressions of terminal chondrocyte differentiation markers in ATDC5 cells, primary chondrocytes, and cultured metatarsal bones. Oxy's induction of Col2 mRNA expression was decreased by the addition of Noggin and was increased by the addition of BMP2. Furthermore, Oxy increased mRNA expression of Id1, Bmp2, Bmp4, and Bmp6. These data suggest that Oxy induces chondrogenic differentiation in a BMP-dependent manner and suppresses terminal differentiation. Oxy may be useful for treatment of OA and also for regeneration of cartilage tissue.

DOI： 10.1007/s00774-010-0179-y

Tibial Cancellous Bone Grafting In Jaw Reconstruction-10 Years of Experience in Taiwan

E. C. Ko, M. Y. Chen, C. Chang, I. P. Chang, K. Igawa

XX CONGRESS OF THE EUROPEAN ASSOCIATION OF CRANIO-MAXILLO-FACIAL-SURGERY 57 ( supp ) 179 - 187 2010

Language：English Publishing type：Research paper (international conference proceedings) Publisher：MEDIMOND S R L

The objectives of this article are to describe a modified lateral approach for procuring cancellous bone graft from the proximal tibia. 80 consecutive jaw reconstruction utilizing tibial cancellous bone grafts in 78 patients from March 1998 through March 2008 were reviewed. Patient group consisted of 45 males and 33 females, aged 18 to 76. Unlike the traditional U-shaped trap door incision on the iliotibial tract, our curvilinear incision was made almost parallel to the fibers of that tract. Only mild complications were observed at donor sites. The average procured graft volume was 17.8 ml. We also presented the first case of reconstructing mandibular continuity defects of up to 6 similar to 7 cm lengthwise by tibial cancellous bone grafting. The modified incision on iliotibial tract allowed access to obtain equally good amount of bone volume from lateral aspect of proximal tibia and it rendered wound closure much easier than the procuring techniques described earlier in the literatures.

Temporal and spatial changes in element distribution in bone and cartilage. Reviewed

Kenichi Yamamoto, Kazuyo Igawa, Hiroshi Ueno, Fumiko Yano, Ung-Il Chung, Isao Koshima

Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association 14 ( 2 ) 198 - 203 2009.3

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

BACKGROUND: Bone and cartilage act as reservoirs for a number of elements, and the perturbation of these elements is suggested to contribute to various diseases. Even so, little is known about their respective temporal and spatial distribution. METHODS: Three knee joints of three mice on the first day after birth, three knee joints of 3-week-old mice, and three knee joints of 20-week-old mice were prepared. We performed element mapping in the bone and cartilage of normal mouse knee joints. We measured element distribution in articular cartilage, trabecular bone, cortical bone, joint cartilage, growth plates, and joint cavities using energy dispersive X-ray spectrometry. RESULTS: The analysis revealed the following: (1) The main elements in articular cartilage of 1-day-old mice were Na, O, P, S, and Ca; and those in bone were Na, O, P, S, K, Ca, and Mg. (2) The main elements in the growth plate of 3-week-old mice were Na, N, O, P, S, Cl, K, and Ca; those in joint cartilage were Na, O, P, S, Cl, and K; and those in bone were Na, O, P, Ca, and Mg. (3) The main elements in the growth plate of 20-week-old mice were Na, O, P, S, Cl, K, and Ca; and those in bone were Na, O, P, S, K, Ca, and Mg. After corrections were made for the Na ratios of these elements, we investigated the temporal and spatial changes in the distribution of each element. On the first day after birth, a spatial change was seen in the growth plate cartilage: the more the cartilage matured toward hypertrophy, the more S and Ca it contained. Temporal changes in element distribution in the growth plate cartilage, articular cartilage, and bone were observed. Growth plate cartilage of the older mice contained more S and Ca than that of the younger mice. Bone of the older mice contained more Ca and Mg than that of the younger mice. Spatial changes in element distribution in the cortical bone were also seen; that is, the more the cortical bone matured toward diaphysis, the more Mg and the less S it contained. In contrast, no temporal or spatial changes in element distribution were observed in the joint space. No significant temporal or spatial changes in the distribution of P, Cl, or K were seen. CONCLUSIONS: These results suggest that element mapping may be useful for identifying the age and maturity of different skeletal tissues. In particular, it may help distinguish between immature cartilage and mature cartilage based on the Ca and S contents.

DOI： 10.1007/s00776-008-1315-6

Maxillofacial reconstruction using custom-made artificial bones fabricated by inkjet printing technology. Reviewed

Hideto Saijo, Kazuyo Igawa, Yuki Kanno, Yoshiyuki Mori, Kayoko Kondo, Koutaro Shimizu, Shigeki Suzuki, Daichi Chikazu, Mitsuki Iino, Masahiro Anzai, Nobuo Sasaki, Ung-il Chung, Tsuyoshi Takato

Journal of artificial organs : the official journal of the Japanese Society for Artificial Organs 12 ( 3 ) 200 - 5 2009

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

Ideally, artificial bones should be dimensionally compatible with deformities, and be biodegradable and osteoconductive; however, there are no artificial bones developed to date that satisfy these requirements. We fabricated novel custom-made artificial bones from alpha-tricalcium phosphate powder using an inkjet printer and implanted them in ten patients with maxillofacial deformities. The artificial bones had dimensional compatibility in all the patients. The operation time was reduced due to minimal need for size adjustment and fixing manipulation. The postsurgical computed tomography analysis detected partial union between the artificial bones and host bone tissues. There were no serious adverse reactions. These findings provide support for further clinical studies of the inkjet-printed custom-made artificial bones.

DOI： 10.1007/s10047-009-0462-7

Bone regeneration within a tailor-made tricalcium phosphate bone implant with both horizontal and vertical cylindrical holes transplanted into the skull of dogs. Reviewed

Sung-jin Choi, Jong-il Lee, Kazuyo Igawa, Osamaru Sugimori, Shigeki Suzuki, Manabu Mochizuki, Ryouhei Nishimura, Ung-il Chung, Nobuo Sasaki

Journal of artificial organs : the official journal of the Japanese Society for Artificial Organs 12 ( 4 ) 274 - 7 2009

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

A new tailor-made bone implant (TI) with six horizontal cylindrical holes fabricated from alpha-tricalcium phosphate powder, as described in our previous report, was modified to include five additional vertical holes (TI-v) in an attempt to accelerate the bone regeneration through the holes. This TI-v implant and hydroxyapatite implants (HI) as controls were transplanted into experimental skull defects in dogs. Computed tomography (CT) was performed immediately after the surgery and then every 4 weeks. The dogs were killed for histological analysis at 24 weeks of implantation. On CT, bone bridging between the implant and the skull was observed in the TI-v group from 8 weeks of implantation, whereas a clear bone bridge was not formed in the HI group after 24 weeks of implantation. Histological analysis revealed collagen tissues and new bone formation in the horizontal cylindrical holes in most of the TI-v group, whereas mainly connective tissues invaded the porous structures in the HI group. In the Ti-v group, at the middle of the horizontal holes where they crossed the vertical holes, fibrous collagen tissues and muscular tissue filled up the hole and new bone formation seemed to be blocked. However, in the TI-v group more collagen and bone tissues were formed than in the HI group; when compared with the data in our previous report, however, the total volume of regenerated bone in the horizontal cylindrical holes in the TI-v seemed to be less than that in the TI. Thus, the addition of vertical cylindrical holes in the TI-v was not effective in promoting the faster stabilization of the TI-v in the skull of the dog.

DOI： 10.1007/s10047-009-0474-3

Development of high-throughput screening system for osteogenic drugs using a cell-based sensor. Reviewed International journal

Hironori Hojo, Kazuyo Igawa, Shinsuke Ohba, Fumiko Yano, Keiji Nakajima, Yuske Komiyama, Toshiyuki Ikeda, Alexander C Lichtler, Je-Tae Woo, Takayuki Yonezawa, Tsuyoshi Takato, Ung-il Chung

Biochemical and biophysical research communications 376 ( 2 ) 375 - 9 2008.11

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

To effectively treat osteoporosis and other bone-loss disorders, small compounds that potently induce bone formation are needed. The present study initially attempted to establish a monitoring system that could detect osteogenic differentiation easily, precisely, and noninvasively. For this purpose, we established pre-osteoblastic MC3T3E1 cells stably transfected with the GFP reporter gene driven by a 2.3 kb fragment of rat type I collagen promoter (Col1a1GFP-MC3T3E1). Among these cells, we selected a clone that fluoresced upon osteogenic stimulation by BMP2. The GFP fluorescence intensity corresponded well to the intensity of alkaline phosphatase (ALP) staining and to the level of osteocalcin (Oc) mRNA. Using this system, we screened natural and synthetic compound libraries and thus identified an isoflavone derivative, glabrisoflavone (GI). GI induced ALP staining and Oc mRNA in a dose-dependent manner. The Col1a1GFP-MC3T3E1 system may be useful for identifying novel osteogenic drugs.

DOI： 10.1016/j.bbrc.2008.08.167

Tailor-made tricalcium phosphate bone implant directly fabricated by a three-dimensional ink-jet printer.

Igawa K, Mochizuki M, Sugimori O, Shimizu K, Yamazawa K, Kawaguchi H, Nakamura K, Takato T, Nishimura R, Suzuki S, Anzai M, Chung UI, Sasaki N

人工臓器 37 ( 1 ) 14 - 16 2008.6

Development of an osteoblast-based 3D continuous-perfusion microfluidic system for drug screening. International journal

Kihoon Jang, Kae Sato, Kazuyo Igawa, Ung-il Chung, Takehiko Kitamori

Analytical and bioanalytical chemistry 390 ( 3 ) 825 - 32 2008.2

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

In this work, we demonstrated that biological cells could be cultured in a continuous-perfusion glass microchip system for drug screening. We used mouse Col1a1GFP MC-3T3 E1 osteoblastic cells, which have a marker gene system expressing green fluorescent protein (GFP) under the control of osteoblast-specific promoters. With our microchip-based cell culture system, we realized automated long-term monitoring of cells and sampling of the culture supernatant system for osteoblast differentiation assay using a small number of cells. The system successfully monitored cells for 10 days. Under the 3D microchannel condition, shear stress (0.07 dyne/cm(2) at a flow rate of 0.2 microL/min) was applied to the cells and it enhanced the GFP expression and differentiation of the osteoblasts. Analysis of alkaline phosphatase (ALP), which is an enzyme marker of osteoblasts, supported the results of GFP expression. In the case of differentiation medium containing bone morphogenetic protein 2, we found that ALP activity in the culture supernatant was enhanced 10 times in the microchannel compared with the static condition in 48-well dishes. A combined system of a microchip and a cell-based sensor might allow us to monitor osteogenic differentiation easily, precisely, and noninvasively. Our system can be applied in high-throughput drug screening assay for discovering osteogenic compounds.

新時代を拓く化学のキーコンセプトインテリジェント化材料インクジェットプリンターによるインプラントデバイスの高機能化

井川和代, 鄭雄一, 鄭雄一

化学 63 ( 1 ) 2008

[Development of high-performance scaffolds].

Kazuyo Igawa, Ung-il Chung, Yuichi Tei

Nihon rinsho. Japanese journal of clinical medicine 66 ( 5 ) 820 - 823 2008

[Custom-made artificial bones fabricated by an inkjet printing technology].

Kazuyo Igawa, Ung-il Chung, Yuichi Tei

Clinical calcium 18 ( 12 ) 1737 - 1743 2008

Language：Japanese

Although current treatment modalities for bone defects include autograft, allograft, and artificial bone substitutes, they have problems concerning invasiveness, safety, and performance, respectively, calling for development of innovative artificial bones with better handling and mechanical strength, better control of external and internal structures, and better biodegradability and osteo-inductive ability. We propose to fabricate novel high performance artificial bones using 3D inkjet printer based on the image data of bone deformity. Shape precisely fitting to the deformity, internal structure facilitating cell invasion, and good biodegradability are achieved. Bioactive substances can be incorporated by printing in combination with drug delivery system to induce bone regeneration at desired locations. These osteo-inductive artificial bones will help efficiently treat various types of bone deformity in a less invasive and safe manner.

Clinical application of artificial bone in the maxillofacial region. Reviewed

Hideto Saijo, Ung-il Chung, Kazuyo Igawa, Yoshiyuki Mori, Daichi Chikazu, Mitsuyoshi Iino, Tsuyoshi Takato

Journal of artificial organs : the official journal of the Japanese Society for Artificial Organs 11 ( 4 ) 171 - 6 2008

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

Hard tissue reconstruction is very useful for bony defects of the maxillofacial region. Autogenous bone, allogeneic bone, and artificial bone have been used to reconstruct maxillofacial bone; however, the use of autogenous bone involves high surgical invasiveness because of the need to harvest the bone. The use of allogeneic bone is associated with infections, raises ethical concerns, and is not widely used in Japan. Artificial bone has several advantages, including no need for bone harvesting, excellent biocompatibility, and a relatively easy surgical procedure. Use of artificial bone avoids the much greater invasiveness of harvesting bone, and several types of artificial bone have been developed. Design requirements for artificial bone include surgical manipulability, structural compatibility with the defective area, support properties, and the ability to induce bone regeneration; however, no artificial bone meeting all these requirements has yet been developed. Artificial bone is used in many patients in our medical center, and we have been active in developing the next generation of artificial bone with better properties. In this article, we present a case history and discuss the future development of artificial bone for use in maxillofacial reconstruction.

DOI： 10.1007/s10047-008-0425-4

テトラポッド形状骨補填材 Reviewed

井川和代, 富塚健, 大庭伸介, 小笠原徹, 近津大地, 森良之, 高戸毅, 鄭雄一

日本口腔外科学会雑誌 53 ( Suppl. ) 177 - 177 2007.8

A novel osteogenic helioxanthin-derivative acts in a BMP-dependent manner. Reviewed International journal

Shinsuke Ohba, Keiji Nakajima, Yusuke Komiyama, Fumitaka Kugimiya, Kazuyo Igawa, Keiji Itaka, Toru Moro, Kozo Nakamura, Hiroshi Kawaguchi, Tsuyoshi Takato, Ung-il Chung

Biochemical and biophysical research communications 357 ( 4 ) 854 - 60 2007.6

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

To effectively treat serious bone defects using bone regenerative medicine, there is a need for the development of a small chemical compound that potently induces bone formation. We now report a novel osteogenic helioxanthin-derivative, TH. TH induced osteogenic differentiation in MC3T3-E1 cells, mouse primary osteoblasts, and mouse embryonic stem cells. The combination of TH and bone morphogenetic protein (BMP) 2 induced the mRNA expression of osteoblast marker genes and calcification in primary fibroblasts. The TH induced the mRNA of the inhibitor of DNA-binding 1 (Id-1), and its osteogenic effect was inhibited by Smad6 or Noggin. Furthermore, TH induced the mRNA expression of Bmp4 and Bmp6. These data suggest that TH exerts its potent osteogenic effect in a BMP-dependent manner by enhancing the effects of the existing BMPs and/or increasing the expression of Bmp4 and Bmp6. TH may help establish a more efficient bone regeneration system.

DOI： 10.1016/j.bbrc.2007.03.173

骨形成性シグナル経路の最適化と幹細胞を用いない新規骨再生法の開発 Reviewed

大庭伸介, 矢野文子, 井川和代, 藤原夕子, 小笠原徹, 近津大地, 森良之, 米原啓之, 須佐見隆史, 鄭雄一, 高戸毅

日本口腔科学会雑誌 56 ( 1 ) 112 - 112 2007

新しい医療を築く組織工学顎骨再建

西條英人, CHUNG Ung-il, 井川和代, 井川和代, 高戸毅, 高戸毅

人工臓器(日本人工臓器学会) 36 ( 1 ) 113 - 116 2007

Language：Japanese Publisher：(一社)日本人工臓器学会

頭蓋顎顔面骨における骨再建に対して、より良い人工骨を求めて次世代人工骨の開発に取り組んだ。18歳女。汎発性強皮症に伴う顔面変形を主訴で受診した。顔面は非対称性で、右側の中〜下顔面に陥凹を認めた。術後における脂肪組織の下垂や二次変形、女性における採取部の傷を避けることなどを考慮し、硬組織再建を選択した。すなわち陥凹部にカスタムメイド人工骨を移植することにより硬組織を再建し、顔貌の改善を図った。人工骨の作製には3次元造形モデルを応用した。術後3ヵ月経過した3次元CT画像では人工骨の位置のズレは認めず、顔貌形態についても満足した形態が得られた。さらに、術後6ヵ月経過した現在、大きな合併症を併発することなく経過している。

DOI： 10.11392/jsao1972.36.113

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2007&ichushi_jid=J00706&link_issn=&doc_id=20070717290015&doc_link_id=10.11392%2Fjsao1972.36.113&url=https%3A%2F%2Fdoi.org%2F10.11392%2Fjsao1972.36.113&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Microchip-based osteosis system for rapid drug screening for osteogenesis

Kae Sato, Kazuyo Igawa, Yuki Tanaka, Kiichi Sato, Ung-Il Chung, Takehiko Kitamori

Micro Total Analysis Systems - Proceedings of MicroTAS 2006 Conference: 10th International Conference on Miniaturized Systems for Chemistry and Life Sciences 1008 - 1010 2006

Language：English Publishing type：Research paper (international conference proceedings) Publisher：Japan Academic Association Inc

In the geriatric research field, osteoporosis is the major target of regenerative medicine and osteoblast is known as a key cell to osteoporosis. We developed continuous perfusion microfluidic cell culture system for osteoblast differentiation drug screening assays. © 2006 Society for Chemistry and Micro-Nano Systems.

Mechanism of osteogenic induction by FK506 via BMP/Smad pathways Reviewed

F Kugimiya, F Yano, S Ohba, K Igawa, K Nakamura, H Kawaguchi, UI Chung

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 338 ( 2 ) 872 - 879 2005.12

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

FK506 is an immunosuppressant that exerts effects by binding to FK506-binding protein 12 (FKBP12). Recently, FK506 has also been reported to promote osteogenic differentiation when administered locally or in vitro in combination with bone morphogenetic proteins (BMPs), although the underlying mechanism remains unclarified. The present study initially showed that FK506 alone at a higher concentration (1 mu M) induced osteogenic differentiation of mesenchymal cell lines, which was suppressed by adenoviral introduction of Smad6. FK506 rapidly activates the BMP-dependent Smads in the absence of BMPs, and the activation was blocked by Smad6. Overexpression of FKBP 12, which was reported to block the ligand-independent activation of BMP type I receptor A (BMPRIA), suppressed Smad signaling induced by FK506, but not that induced by BMP2. BMPRIA and FKBP12 bound to each other, and this binding was suppressed by FK506. These data suggest that FK506 promotes osteogenic differentiation by activating BMP receptors through interacting with FKBP12. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2005.10.024

Operation Simulation System Using 3D Models Fabricated by the 3D Printer.

西條英人, 井川和代, 鄭雄一, 米原啓之, 高戸毅

?日本形成外科学会会誌? 54 ( 4 ) 525 - 526 2005.9

老年医学の展望骨・軟骨の再生医療

大庭伸介, 井川和代, 中村耕三, 川口浩, 高戸毅, 鄭雄一

?日本老年医学会雑誌 40 ( 1 ) 264 - 266 2004

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