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青木 薫  アオキ カオル

教員組織学術研究院(保健学系)電話番号0263-37-3545
教育組織医学部 保健学科 応用理学療法学FAX番号
職名准教授メールアドレスkin29men@shinshu-u.ac.jp
住所〒390-8621 長野県松本市旭3-1-1ホームページURL

更新日:2022/11/26

プロフィール

研究分野
生体材料学
生体医工学
整形外科学
キーワード:骨軟部腫瘍
所属学会
所属学会
中部日本整形外科・災害外科学会
日本リハビリテーション医学会
日本整形外科学会
学歴
出身大学院
2008 , 信州大学

取得学位
博士(医学) , 信州大学(日本)

免許・資格等
20140401 , がん治療認定医
20080330 , 整形外科専門医
20010502 , 医師

研究活動業績

研究業績(著書・
発表論文等)
書籍等出版物
カーボンナノチューブ・グラフェンの応用研究最前線, 280
エヌ・ティー・エス 2016(Sep. 16)
Author:青木 薫、齋藤直人、樽田誠一、荻原伸英、西村直之
Abstract:カーボンナノチューブ・グラフェンの応用研究最前線 エヌ・ティー・エス


論文
Future Prospects for Clinical Applications of Nanocarbons Focusing on Carbon Nanotubes.
Advanced science (Weinheim, Baden-Wurttemberg, Germany),9(24):e2201214 2022(Aug.)
Author:Naoto Saito; Hisao Haniu; Kaoru Aoki; Naoyuki Nishimura; Takeshi Uemura
Abstract:Over the past 15 years, numerous studies have been conducted on the use of nanocarbons as biomaterials towards such applications as drug delivery systems, cancer therapy, and regenerative medicine. However, the clinical use of nanocarbons remains elusive, primarily due to short- and long-term safety concerns. It is essential that the biosafety of each therapeutic modality be demonstrated in logical and well-conducted experiments. Accordingly, the fundamental techniques for assessing nanocarbon biomaterial safety have become more advanced. Optimal controls are being established, nanocarbon dispersal techniques are being refined, the array of biokinetic evaluation methods has increased, and carcinogenicity examinations under strict conditions have been developed. The medical implementation of nanocarbons as a biomaterial is in sight. With a particular focus on carbon nanotubes, these perspectives aim to summarize the contributions to date on nanocarbon applications and biosafety, introduce the recent achievements in evaluation techniques, and clarify the future prospects and systematic introduction of carbon nanomaterials for clinical use through practical yet sophisticated assessment methods.


Influence of the adductor compartment resection on muscle strength and postoperative function in soft-tissue sarcoma of the thigh.
Japanese journal of clinical oncology,52(4):370-374 2022(Apr. 06)
Author:Atsushi Tanaka; Masanori Okamoto; Munehisa Kito; Yasuo Yoshimura; Kaoru Aoki; Shuichiro Suzuki; Akira Takazawa; Yukiko Komatsu; Takaaki Ishida; Jun Takahashi
Abstract:OBJECTIVE: To predict the muscle strength and postoperative function for soft-tissue sarcoma arising from the adductor compartment of the thigh. METHODS: Between 2003 and 2019, 17 cases that underwent resection of the adductor muscle group (adductor longus, adductor magnus, adductor brevis, gracilis and pectineus) for soft-tissue sarcoma in the adductor compartment of the thigh were included. The muscle strength was measured with an isokinetic dynamometer for the knee joint and with a hand-held dynamometer for the hip joint (ratio of affected to unaffected side). The Musculoskeletal Tumor Society score, Toronto Extremity Salvage Score, European Quality of Life-5 Dimensions and maximum walking speed were used to assess postoperative function and examine correlations with muscle strength. RESULTS: In 13 cases that underwent an isolated resection of the adductor compartment, reduced adduction strength correlated with increased number of resected muscles in the adductor muscle group (P < 0.001). Postoperative function was maintained, showing no correlations with adduction strength. In four cases that underwent combined resections of other compartments, a decrease was observed in adduction strength as well as the muscle strength of other resected muscles, in addition to a decline in postoperative function. In the 4 or 5 adductor muscle resection group, the comparison between isolated and combined resection revealed comparable results for adduction strength but a significant decrease in postoperative function for the combined resection group. CONCLUSIONS: Postoperative function can be preserved for isolated adductor compartment resection. Combined resections of multiple muscles in other compartments and most adductor muscles may result in decreased postoperative function.


Points of consideration when performing surgical procedures for proximal femoral bone metastasis.
Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association,27(1):229-234 2022(Jan.)
Author:Atsushi Tanaka; Masanori Okamoto; Munehisa Kito; Yasuo Yoshimura; Kaoru Aoki; Shuichiro Suzuki; Akira Takazawa; Jun Takahashi
Abstract:BACKGROUND: To assess the points of consideration when performing surgical procedures for proximal femoral bone metastasis. METHODS: Fourty patients who underwent surgery for proximal femoral bone metastasis from 2009 to 2019 were included. Prognostic assessments were performed based on the Katagiri scoring system. The low-risk group underwent endoprosthetic replacement (EPR) following resection, while the high-risk group underwent internal fixation (IF). For the intermediate-risk group, one of the surgical procedures was chosen depending on general and local condition. Survival period, walking ability, and treatment failure were evaluated. RESULTS: Sixteen and 24 patients underwent EPR and IF, respectively. Although walking reacquisition rate was 94% (15 of 16 patients) for EPR and 75% (18 of 24 patients) for IF (p = 0.210), the median time to walking was shorter in IF compared to EPR (EPR, 29 days, interquartile range [IQR] 23-40; IF, 14 days, IQR 9-24; p = 0.014). Neither EPR nor IF resulted in treatment failure for those with survival periods of <1 year. The treatment failure rate for those with survival periods of ≥1 year was significantly different between EPR (9%, 1 of 11 patients) and IF (50%, 5 of 10 patients) (p = 0.038). All five patients of treatment failure for IF were renal cancer with no bone formation in the intermediate-risk group. Of the 13 patients who underwent IF for the intermediate-risk group, treatment failure did not occur in 5 patients with bone formation. CONCLUSIONS: Although EPR is a more reliable treatment than IF, patients with life expectancy of <1 year are sufficiently manageable with IF. For the intermediate-risk group, EPR should be selected for cases without expected bone formation, and IF can be considered for cases with expected bone formation due to the risk of treatment failure for IF at ≥ 1 year after surgery.


Biokinetic Evaluation of Contrast Media Loaded Carbon Nanotubes Using a Radiographic Device
TOXICS,9(12) 2021(Dec.)
Author:Mieko Takasaka; Shinsuke Kobayashi; Yuki Usui; Hisao Haniu; Shuji Tsuruoka; Kaoru Aoki; Naoto Saito
Abstract:Considerable progress has been made in various fields of applied research on the use of carbon nanotubes (CNTs). Because CNTs are fibrous nanomaterials, biosafety of CNTs has been discussed. The biokinetic data of CNTs, such as using the radioisotope of carbon and surface labeling of CNTs, have been reported. However, the use of radioisotopes requires a special facility. In addition, there are problems in the surface labeling of CNTs, including changes in surface properties and labels eliminating over time. In order to solve these problems and properly evaluate the biokinetics of CNTs, the authors synthesize peapods with platinum (Pt) encapsulated within the hollow region of Double-Walled CNTs (DWCNTs) and develop a new system to evaluate biokinetics using widely available imaging equipment. In the cell assay, no significant difference is observed with and without Pt in CNTs. In animal studies, radiography of the lungs of rats that inhaled Pt-peapods show the detectability of Pt inside the CNTs. This new method using Pt-peapods enables image evaluation with a standard radiographic imaging device without changing the surface property of the CNTs and is effective for biokinetics evaluation of CNTs.


Antitumor Effect of Sclerostin against Osteosarcoma
Cancers,13(23):6015-6015 2021(Nov. 29)
Author:Hirokazu Ideta; Kazushige Yoshida; Masanori Okamoto; Jun Sasaki; Munehisa Kito; Kaoru Aoki; Yasuo Yoshimura; Shuichiro Suzuki; Atsushi Tanaka; Akira Takazawa; Hisao Haniu; Takeshi Uemura; Takashi Takizawa; Atsushi Sobajima; Takayuki Kamanaka; Jun Takahashi; Hiroyuki Kato; Naoto Saito
Abstract:Various risk factors and causative genes of osteosarcoma have been reported in the literature; however, its etiology remains largely unknown. Bone formation is a shared phenomenon in all types of osteosarcomas, and sclerostin is an extracellular soluble factor secreted by osteocytes that prevents bone formation by inhibiting the Wnt signaling pathway. We aimed to investigate the antitumor effect of sclerostin against osteosarcoma. Osteosarcoma model mice were prepared by transplantation into the dorsal region of C3H/He and BALB/c-nu/nu mice using osteosarcoma cell lines LM8 (murine) and 143B (human), respectively. Cell proliferations were evaluated by using alamarBlue and scratch assays. The migratory ability of the cells was evaluated using a migration assay. Sclerostin was injected intraperitoneally for 7 days to examine the suppression of tumor size and extension of survival. The administration of sclerostin to osteosarcoma cells significantly inhibited the growth and migratory ability of osteosarcoma cells. Kaplan–Meier curves and survival data demonstrated that sclerostin significantly inhibited tumor growth and improved survival. Sclerostin suppressed the proliferative capacity and migratory ability of osteosarcoma cells. Osteosarcoma model mice inhibited tumor growth and prolonged survival periods by the administration of sclerostin. The effect of existing anticancer drugs such as doxorubicin should be investigated for future clinical applications.


Carbon nanohorn-bisphosphonate複合体の材料学的評価および細胞応答性評価
日本整形外科学会雑誌,95(8):S1834-S1834 2021(Aug.)
Author:上田 勝也; 岡本 正則; 鎌仲 貴之; 三村 哲彦; 出田 宏和; 青木 薫; 湯田坂 雅子; 中村 真紀; 羽二生 久夫; 齋藤 直人


改良型チタンファイバープレートの骨伝導能の評価
日本整形外科学会雑誌,95(8):S1752-S1752 2021(Aug.)
Author:三村 哲彦; 滝沢 崇; 中山 昇; 羽二生 久夫; 青木 薫; 岡本 正則; 鎌仲 貴之; 出田 宏和; 高橋 淳; 齋藤 直人


リン酸化処理PEEKの家兎大腿骨への埋め込み試験
日本整形外科学会雑誌,95(8):S1559-S1559 2021(Aug.)
Author:青木 薫; 岡本 正則; 鎌仲 貴之; 三村 哲彦; 出田 宏和; 高橋 淳; 沖原 巧; 森山 茂章; 西村 直之; 上田 勝也; 齋藤 直人


カーボンファイバーを用いた癌転移骨の治療
日本整形外科学会雑誌,95(2):S127-S127 2021(Mar.)
Author:鎌仲 貴之; 出田 宏和; 傍島 淳; 吉田 和薫; 滝沢 崇; 岡本 正則; 青木 薫; 金 隆岩; 羽二生 久夫; 高橋 淳; 加藤 博之; 齋藤 直人


Distal femoral impaction bone grafting in revision for tumor endoprosthesis.
The Knee,29:42-48 2021(Mar.)
Author:Munehisa Kito; Masanori Okamoto; Kaoru Aoki; Atsushi Tanaka; Yukiko Komatsu; Shuichiro Suzuki; Akira Takazawa; Yasuo Yoshimura; Jun Takahashi
Abstract:BACKGROUND: Reconstruction using tumor endoprosthesis has been widely used in cases with large bone defects caused by bone and soft tissue tumor resection of the distal femur which extend into the knee joint. However, reconstruction failure can lead to major problems in the long term. We have been performing impaction bone grafting with allogeneic cancellous bone during revision surgery for tumor endoprosthesis of the distal femur to compensate for the thinness and fragility of the remaining femur. The aim of this study is to examine the surgical method, problems, and clinical outcomes of revision surgery with impaction bone grafting. METHODS: Three patients who underwent revision surgery for tumor endoprosthesis using impaction bone grafting at our institution with more than 2 years of follow-up were included. RESULTS: Union between the graft and host bone were achieved in all cases. The mean time to radiographic union was 1.0 year (0.6-1.5 years). Although intraoperative penetration to the anterior cortex of the distal femur occurred in 2 cases, there were no postoperative fractures. There were no failures of tumor endoprosthesis at final observation. CONCLUSION: Good short-term results were observed in 3 patients who underwent revision tumor endoprosthesis with impaction bone grafting following a bone and soft tissue tumor resection of the distal femur. The method was considered to be a useful treatment option. Impaction bone grafting is an established surgical option that can be applied to revision surgery for tumor endoprosthesis.


Isolated lymphatic vessel lumen perfusion system for assessing nanomaterial movements and nanomaterial-induced responses in lymphatic vessels
NANO TODAY,36 2021(Feb.)
Author:Chika Kuroda; Kumiko Ajima; Katsuya Ueda; Atsushi Sobajima; Kazushige Yoshida; Takayuki Kamanaka; Jun Sasaki; Haruka Ishida; Hisao Haniu; Masanori Okamoto; Kaoru Aoki; Hiroyuki Kato; Naoto Saito
Abstract:Nanomaterials have recently been investigated extensively for a wide variety of biological applications, including drug delivery, bioimaging, and regenerative medicine. However, they have found little clinical use because of the lack of an established method for assessing their safety in living organisms. In particular, much remains unknown about the biokinetics of nanomaterials. Nanomaterials may be administered intravenously and reach various tissues via the bloodstream or injected directly into subcutaneous tissue or lesions such as tumors. These nanomaterials are known to enter lymphatic vessels, migrate to the lymph system, and accumulate in lymph nodes. To clarify their biokinetics, therefore, importance should be placed on elucidating their interactions with lymphatic vessels. However, little is known about their movements in, and influence on, the lymphatic vessels. In this study, we developed and assessed the isolated lymphatic vessel lumen perfusion system to allow us to visually and quantitatively elucidate the interactions between nanomaterials and lymphatic vessels, and thereby the biosafety of nanomaterials. The vessel is removed from a living rat and studied in vitro. This perfusion system, compared to in vivo examinations, allows higher-resolution, more detailed examination of the movement of nanomaterials and the lymphatic vessel's reaction to this movement. In addition, the new system also enables both quantitative and histological assessment of a single lymphatic vessel's physiological reaction to nanomaterials. Use of this system to provide essential information about nanomaterial biokinetics is expected to contribute significantly to the development of a wide variety of biological applications of nanomaterials. (C) 2020 Elsevier Ltd. All rights reserved.


Ibandronate-Loaded Carbon Nanohorns Fabricated Using Calcium Phosphates as Mediators and Their Effects on Macrophages and Osteoclasts
ACS Applied Materials & Interfaces,13(3):3701-3712 2021(Jan. 27)
Author:Maki Nakamura; Katsuya Ueda; Yumiko Yamamoto; Kaoru Aoki; Minfang Zhang; Naoto Saito; Masako Yudasaka


Multiwall Carbon Nanotube Composites as Artificial Joint Materials.
ACS biomaterials science & engineering,6(12):7032-7040 2020(Dec. 14)
Author:Atsushi Sobajima; Takumi Okihara; Shigeaki Moriyama; Naoyuki Nishimura; Takako Osawa; Kazutaka Miyamae; Hisao Haniu; Kaoru Aoki; Manabu Tanaka; Yuki Usui; Ken-Ichi Sako; Hiroyuki Kato; Naoto Saito
Abstract:Because ultrahigh-molecular-weight polyethylene (UHMWPE) is susceptible to frictional wear when used in sliding members of artificial joints, it is common practice to use cross-linked UHMWPE instead. However, cross-linked UHMWPE has low impact resistance; implant breakage has been reported in some cases. Hence, sliding members of artificial joints pose a major trade-off between wear resistance and impact resistance, which has not been resolved by any UHMWPE. On the other hand, multiwall carbon nanotubes (MWCNTs) are used in industrial products for reinforcement of polymeric materials but not used as biomaterials because of their unclear safety. In the present study, we attempted to solve this trade-off issue by complexing UHMWPE with MWCNTs. In addition, we assessed the safety of these composites for use in sliding members of artificial joints. The results showed the equivalence of MWCNT/UHMWPE composites to cross-linked UHMWPE in terms of wear resistance and to non-cross-linked UHMWPE in terms of impact resistance. In addition, all MWCNT/UHMWPE composites examined complied with the requirements of biosafety testing in accordance with the ISO10993-series specifications for implantable medical devices. Furthermore, because MWCNTs can occur alone in wear dust, MWCNTs in an amount of about 1.5 times that contained in the dust produced from 50 years of wear (in the worst case) were injected into rat knees, which were monitored for 26 weeks. Although mild inflammatory reactions occurred in the joints, the reactions soon became quiescent. In addition, the MWCNTs did not migrate to other organs. Furthermore, MWCNTs did not exhibit carcinogenicity when injected into the knees of mice genetically modified to spontaneously develop cancer. The MWCNT/UHMWPE composite is a new biomaterial expected to be safe for clinical applications in both total hip arthroplasty and total knee arthroplasty as the first sliding member of artificial joints to have both high wear resistance and high impact resistance.


Carbon nanotube-based biomaterials for orthopaedic applications.
Journal of materials chemistry. B,8(40):9227-9238 2020(Oct. 21)
Author:Kaoru Aoki; Nobuhide Ogihara; Manabu Tanaka; Hisao Haniu; Naoto Saito
Abstract:Carbon nanotubes (CNTs) are cylindrical tubular nanomaterials made of carbon with excellent electrical conductivity, thermal conductivity, and mechanical strength. The material is applied to improve performance in various industrial products. CNTs have been widely researched and developed as biomaterials that can offer high function, performance, and durability in orthopedic applications. However, the use of CNTs as biomaterials must be administered with caution, as the fibrous nanomaterial may be carcinogenic due to its similar size and shape to asbestos. In this review article, we examine the potential clinical application of CNTs in orthopedic surgery. We first provide an overview of biocompatibility and carcinogenicity studies of CNTs with a focus on their effects on the bone, joint, and respiratory system. Furthermore, we introduce CNT-based biomaterials for orthopedic applications that have been reported in the literature, including scaffolds for bone and cartilage regeneration, composites that enhance the performance of biomaterials, CNT coatings, and devices for treating musculoskeletal tumors.


Carbon fibers for treatment of cancer metastasis in bone.
RSC advances,10(55):33071-33079 2020(Sep. 07)
Author:Takayuki Kamanaka; Hisao Haniu; Manabu Tanaka; Takashi Takizawa; Kaoru Aoki; Masanori Okamoto; Atsushi Sobajima; Kazushige Yoshida; Hirokazu Ideta; Tetsuhiko Mimura; Haruka Ishida; Katsuya Ueda; Takeshi Uemura; Jin Hee Kim; Yoong Ahm Kim; Hiroyuki Kato; Naoto Saito
Abstract:When cancer metastasizes to bone, the resulting pain and functional disorders due to bone destruction adversely affect the patient's quality of life. We have developed a new cancer metastasis control system consisting of anticancer agents conjugated to carbon fibers (CFs), which are nonbiodegradable, carriers of a wide variety of molecules with extremely high affinity for bone. In the evaluation of cancer suppression effects on Walker 256 cancer cells, cisplatin (CDDP)-conjugated CFs (CF-CDDP) were found to be as effective in cancer suppression as CDDP. In the evaluation of the cancer suppression effects of local injection in the rat model of tibial cancer bone metastasis, similar cancer suppression was noted in the CF-CDDP group and CDDP group; however, blood Pt concentrations were significantly lower in the CF-CDDP group. Experiments with CDDP and CF-CDDP injected into bone actually destroyed by cancer metastases revealed the presence of significantly more newly formed bone tissue with the administration of CF-CDDP. Local administration of CF-CDDP is expected to become the first therapy to suppress cancer growth with low prevalence of adverse reactions, and to repair bone damaged by metastasis.


Role of Platelet C‐Type Lectin‐Like Receptor 2 in Promoting Lung Metastasis in Osteosarcoma
Journal of Bone and Mineral Research,35(9):1738-1750 2020(Sep.)
Author:Jiro Ichikawa; Takashi Ando; Tomonori Kawasaki; Tomoyuki Sasaki; Toshiaki Shirai; Nagaharu Tsukiji; Yujiro Kimura; Kaoru Aoki; Keiko Hayakawa; Katsue Suzuki‐Inoue; Masao Saitoh; Hirotaka Haro


Hydroxyapatite-polyethylene-polyetheretherketone複合体の材料学的評価および細胞応答性評価
日本整形外科学会雑誌,94(8):S2022-S2022 2020(Sep.)
Author:上田 勝也; 岡本 正則; 鎌仲 貴之; 三村 哲彦; 出田 宏和; 山村 和也; 大久保 雄司; 是津 信行; 後藤 康夫; 青木 薫; 齋藤 直人


A Review of T-Cell Related Therapy for Osteosarcoma
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,21(14) 2020(Jul.)
Author:Kazushige Yoshida; Masanori Okamoto; Kaoru Aoki; Jun Takahashi; Naoto Saito
Abstract:Osteosarcoma is one of the most common primary malignant tumors of bone. The combination of chemotherapy and surgery makes the prognosis better than before, but therapy has not dramatically improved over the last three decades. This is partially because of the lack of a novel specialized drug for osteosarcoma, which is known as a tumor with heterogeneity. On the other hand, immunotherapy has been one of the most widely used strategies for many cancers over the last ten years. The therapies related to T-cell response, such as immune checkpoint inhibitor and chimeric antigen receptor T-cell therapy, are well-known options for some cancers. In this review, we offer the accumulated knowledge of T-cell-related immunotherapy for osteosarcoma, and discuss the future of the therapy.


Cellular Responses of Human Lymphatic Endothelial Cells to Carbon Nanomaterials
NANOMATERIALS,10(7) 2020(Jul.)
Author:Mahoko Sano; Makoto Izumiya; Hisao Haniu; Katsuya Ueda; Kosuke Konishi; Haruka Ishida; Chika Kuroda; Takeshi Uemura; Kaoru Aoki; Yoshikazu Matsuda; Naoto Saito
Abstract:One of the greatest challenges to overcome in the pursuit of the medical application of carbon nanomaterials (CNMs) is safety. Particularly, when considering the use of CNMs in drug delivery systems (DDSs), evaluation of safety at the accumulation site is an essential step. In this study, we evaluated the toxicity of carbon nanohorns (CNHs), which are potential DDSs, using human lymph node endothelial cells that have been reported to accumulate CNMs, as a comparison to fibrous, multi-walled carbon nanotubes (MWCNTs) and particulate carbon black (CB). The effect of different surface characteristics was also evaluated using two types of CNHs (untreated and oxidized). In the fibrous MWCNT, cell growth suppression, as well as expression of inflammatory cytokine genes was observed, as in previous reports. In contrast, no significant toxicity was observed for particulate CB and CNHs, which was different from the report of CB cytotoxicity in vascular endothelial cells. These results show that (1) lymph endothelial cells need to be tested separately from other endothelial cells for safety evaluation of nanomaterials, and (2) the potential of CNHs as DDSs.


Applications of Carbon Nanotubes in Bone Regenerative Medicine.
Nanomaterials (Basel, Switzerland),10(4) 2020(Apr. 02)
Author:Manabu Tanaka; Kaoru Aoki; Hisao Haniu; Takayuki Kamanaka; Takashi Takizawa; Atsushi Sobajima; Kazushige Yoshida; Masanori Okamoto; Hiroyuki Kato; Naoto Saito
Abstract:Scaffolds are essential for bone regeneration due to their ability to maintain a sustained release of growth factors and to provide a place where cells that form new bone can enter and proliferate. In recent years, scaffolds made of various materials have been developed and evaluated. Functionally effective scaffolds require excellent cell affinity, chemical properties, mechanical properties, and safety. Carbon nanotubes (CNTs) are fibrous nanoparticles with a nano-size diameter and have excellent strength and chemical stability. In the industrial field, they are used as fillers to improve the performance of materials. Because of their excellent physicochemical properties, CNTs are studied for their promising clinical applications as biomaterials. In this review article, we focused on the results of our research on CNT scaffolds for bone regeneration, introduced the promising properties of scaffolds for bone regeneration, and described the potential of CNT scaffolds.


Leiomyosarcoma of the femur arising from an aneurysmal bone cyst treated seven years before: A case report and literature review
J Orthop Sci,:S0949-2658(20)30074-9 2020(Mar. 28)
Author:Mimura T, Yoshimura Y, Sano K, Araki N, Okamoto M, Kito M, Tanaka A, Suzuki S, Takazawa A, Aoki K.
Abstract:J Orthop Sci


The Use of Electrospun Organic and Carbon Nanofibers in Bone Regeneration
Nanomaterials (Basel),10(3):562 2020(Mar. 20)
Author:Aoki K, Haniu H, Kim YA, Saito N.
Abstract:Nanomaterials (Basel)


Ultrastructure of CIC-DUX4 sarcoma: the first pathological report
ULTRASTRUCTURAL PATHOLOGY,44(2):237-244 2020(Mar.)
Author:Hisashi Tamada; Mikiko Kobayashi; Kenji Sano; Takeshi Uehara; Yuki Matsumoto; Ayako Tateishi; Maki Ohya; Munehisa Kito; Kaoru Aoki; Hiroyuki Kanno
Abstract:CIC-DUX4 sarcoma (CDS) is a recently identified subtype of small round cell sarcoma. Morphologically, CDS partially resembles Ewing sarcoma (ES) and has been classified as "ES-like sarcoma"; however, detailed clinicopathologic and molecular genetic analyses have indicated that CDS is a new independent disease. Many studies have provided light microscopic, immunohistochemical, and genetic information about CDS. However, ultrastructural findings associated with this sarcoma are lacking. The aim of this study was to investigate the ultrastructure of CDS tumors and to compare their features with those of ES. We examined two cytogenetically confirmed CDS cases. We found that, compared to typical ES, CDS presented heterogeneity: in cell density, from tightly packed to loosely unconnected areas; in cell shape, from polygonal to pleomorphic with small processes; and in nuclear shape including round, oval, polygonal, elongated, invaginated, or wrinkled formations. However, abundant glycogen in the cytoplasm and rare cell adhesion apparatus between cells are major similarities between CDS and typical ES. Neuroendocrine granules, which are seen in rare ES cases, could not be identified in these two CDS cases. Although cytogenetic differences can validate a definite diagnosis, ultrastructural features could also provide important information about the differences between CDS and ES.


Biocompatibility and Carcinogenicity of Carbon Nanotubes as Biomaterials
Nanomaterials (Basel),10(2):264 2020(Feb. 04)
Author:Aoki K, Saito N.
Abstract:Nanomaterials (Basel)


Continued growth of locally aggressive fibrous dysplasia of 22 years duration after reaching adulthood: a case report
JOURNAL OF SURGICAL CASE REPORTS,(2) 2020(Feb.)
Author:Yusuke Yamagishi; Masanori Okamoto; Yasuo Yoshimura; Munehisa Kito; Kaoru Aoki; Jun Takahashi
Abstract:Fibrous dysplasia generally stops growing when patients reach adulthood. Locally aggressive fibrous dysplasia is an extremely rare subtype of fibrous dysplasia that is characterized by progressive enlargement after bone maturation, cortical bone destruction and soft tissue invasion but without malignant transformation. At 50 years of age, a tumor was found in the rib of a patient. The tumor gradually enlarged over time and imaging findings suggested a malignant tumor. The case was further complicated by restrictive lung disorder. Biopsies from multiple sites showed no malignant findings, and marginal resection with partial curettage was performed. The final diagnosis was locally aggressive fibrous dysplasia, and the restrictive lung disorder improved postoperatively. The natural history of the disease is also unknown. This is the first report in the literature to describe a case in which a lesion exhibited long-term growth over a period of 22 years after reaching adulthood.


Biodegradable Polymers as Drug Delivery Systems for Bone Regeneration
Pharmaceutics,12(2):95 2020(Jan. 24)
Author:Aoki K, Saito N.
Abstract:Pharmaceutics


Anti-PD-1 antibody decreases tumour-infiltrating regulatory T cells
BMC CANCER,20(1) 2020(Jan.)
Author:Kazushige Yoshida; Masanori Okamoto; Jun Sasaki; Chika Kuroda; Haruka Ishida; Katsuya Ueda; Hirokazu Ideta; Takayuki Kamanaka; Atsushi Sobajima; Takashi Takizawa; Manabu Tanaka; Kaoru Aoki; Takeshi Uemura; Hiroyuki Kato; Hisao Haniu; Naoto Saito
Abstract:Background There are many types of therapies for cancer. In these days, immunotherapies, especially immune checkpoint inhibitors, are focused on. Though many types of immune checkpoint inhibitors are there, the difference of effect and its mechanism are unclear. Some reports suggest the response rate of anti-PD-1 antibody is superior to that of anti-PD-L1 antibody and could potentially produce different mechanisms of action. On the other hand, Treg also express PD-1; however, their relationship remains unclear. Methods In this study, we used osteosarcoma cell lines in vitro and osteosarcoma mouse model in vivo. In vitro, we analyzed the effect of IFN gamma for expression of PD-L1 on the surface of cell lines by flowcytometry. In vivo, murine osteosarcoma cell line LM8 was subcutaneously transplanted into the dorsum of mice. Mouse anti-PD-1 antibody was intraperitoneally administered. we analysed the effect for survival of anti-PD-1 antibody and proportion of T cells in the tumour by flowcytometry. Results We discovered that IFN gamma increased PD-L1 expression on the surface of osteosarcoma cell lines. In assessing the relationship between anti-PD-1 antibody and Treg, we discovered the administration of anti-PD-1 antibody suppresses increases in tumour volume and prolongs overall survival time. In the tumour microenvironment, we found that the administration of anti-PD-1 antibody decreased Treg within the tumour and increased tumour-infiltrating lymphocytes. Conclusions Here we clarify for the first time an additional mechanism of anti-tumour effect-as exerted by anti-PD-1 antibody decreasing Treg- we anticipate that our findings will lead to the development of new methods for cancer treatment.


Risk factor for wound complications following wide resection of soft tissue sarcoma in the adductor compartment of the thigh
Jpn J Clin Oncol,49(10):932-937 2019(Oct. 01)
Author:Kito M, Ae K, Koyanagi H, Gokita T, Furuoka H, Okamoto M, Tanaka A, Suzuki S, Takazawa A, Aoki K, Yoshimura Y.
Abstract:Jpn J Clin Oncol


Successful treatment of adult pleomorphic rhabdomyosarcoma with bone invasion in the lower leg by chemotherapy and biological reconstruction: A case report
JOURNAL OF ORTHOPAEDIC SCIENCE,24(5):930-935 2019(Sep.)
Author:Atsushi Tanaka; Yasuo Yoshimura; Takashige Momose; Ken'ichi Isobe; Kaoru Aoki; Munehisa Kito; Masanori Okamoto; Shuichiro Suzuki; Kenji Sano; Hiroyuki Kato


リン酸化処理PEEKに対する骨芽細胞の細胞応答性評価
日本整形外科学会雑誌,93(8):S1945-S1945 2019(Sep.)
Author:上田 勝也; 傍島 淳; 吉田 和薫; 鎌仲 貴之; 羽二生 久夫; 沖原 巧; 森山 茂章; 西村 直之; 岡本 正則; 青木 薫; 齋藤 直人


カーボンナノホーンに対する骨関連細胞の細胞応答性評価
日本整形外科学会雑誌,93(8):S1944-S1944 2019(Sep.)
Author:上田 勝也; 傍島 淳; 吉田 和薫; 鎌仲 貴之; 佐々木 純; 羽二生 久夫; 西村 直之; 岡本 正則; 青木 薫; 齋藤 直人


癌転移骨環境における抗癌剤複合carbon fiberの評価
日本整形外科学会雑誌,93(8):S1857-S1857 2019(Sep.)
Author:鎌仲 貴之; 出田 宏和; 佐々木 純; 傍島 淳; 吉田 和薫; 滝沢 崇; 岡本 正則; 青木 薫; 羽二生 久夫; 加藤 博之; 齋藤 直人


改良型チタンファイバープレートの骨補填材としての有用性の検討
日本整形外科学会雑誌,93(8):S1631-S1631 2019(Sep.)
Author:三村 哲彦; 滝沢 崇; 中山 昇; 羽二生 久夫; 青木 薫; 岡本 正則; 鎌仲 貴之; 佐々木 純; 出田 宏和; 高橋 淳; 齋藤 直人


Combined treatment using Mohs' paste and neoadjuvant chemotherapy for giant gluteal soft tissue sarcoma with malignant fungating wound: a case report
JOURNAL OF SURGICAL CASE REPORTS,(5) 2019(May)
Author:Kazuaki Nemoto; Masanori Okamoto; Munehisa Kito; Kaoru Aoki; Shuichiro Suzuki; Akira Takazawa; Yasuo Yoshimura; Hiroyuki Kato
Abstract:A malignant fungating wound is a cutaneous infiltration of malignant tumor or metastatic lesion that develop into ulceration. Local control is often difficult to obtain, because the Quality of Life of patients can decrease considerably due to bleeding, exudation, odor and pain from the wound. There are few studies in the literature that report the use of Mohs' paste for soft tissue sarcoma with malignant fungating wound. We report a case resulting in good local control for a patient with dedifferentiated liposarcoma with gluteal ulceration by the combined use of Mohs' paste and chemotherapy as a pre-operative adjuvant therapy. Mohs' paste controlled the infection, odor and exudation in approximately 2 weeks, and good visualization of the surgical field was obtained due to tumor volume reduction. We found that Mohs' paste is effective as a neoadjuvant therapy for disintegrated soft tissue sarcoma.


前腕軟部肉腫の術後機能
The Japanese Journal of Rehabilitation Medicine,56(特別号):3-5 2019(May)
Author:青木 薫; 岡本 正則; 池上 章太; 滝沢 崇; 堀内 博志; 高沢 彰; 吉村 康夫


Using the Barthel Index to Assess Activities of Daily Living after Musculoskeletal Tumour Surgery: A Single-centre Observational Study
Prog Rehabil Med,4:20190010 2019(Mar. 26)
Author:Okamoto M, Kito M, Yoshimura Y, Aoki K, Suzuki S, Tanaka A, Takazawa A, Yoshida K, Ido Y, Ishida T, Kawasaki K, Kato H.
Abstract:Prog Rehabil Med


Organ accumulation and carcinogenicity of highly dispersed multi-walled carbon nanotubes administered intravenously in transgenic rasH2 mice
INTERNATIONAL JOURNAL OF NANOMEDICINE,14(14):6465-6480 2019
Author:Atsushi Sobajima; Hisao Haniu; Hiroki Nomura; Manabu Tanaka; Takashi Takizawa; Takayuki Kamanaka; Kaoru Aoki; Masanori Okamoto; Kazushige Yoshida; Jun Sasaki; Kumiko Ajima; Chika Kuroda; Haruka Ishida; Satomi Okano; Katsuya Ueda; Hiroyuki Kato; Naoto Saito
Abstract:Purpose: Multiwalled carbon nanotubes (MWCNTs) have been known to enter the circulatory system via the lungs from inhalation exposure; however, its carcinogenicity and subsequent accumulation in other organs have not been adequately reported in the literature. Moreover, the safety of MWCNTs as a biomaterial has remained a matter of debate, particularly when the material enters the circulatory system. To address these problems, we used carcinogenic rasH2 transgenic mice to intravenously administer highly dispersed MWCNTs and to evaluate their carcinogenicity and accumulation in the organs.Methods: Two types of MWCNTs (thin-and thick-MWCNTs) were intravenously administered at a high dose (approximately 0.7 mg per kg body weight) and low dose (approximately 0.07 mg per kg body weight).Results: MWCNTs showed pancreatic accumulation in 3.2% of mice administered with MWCNTs, but there was no accumulation in other organs. In addition, there was no significant difference in the incidence of tumor among the four MWCNTs-administered groups compared to the vehicle group without MWCNTs administration. Blood tests revealed elevated levels in mean red blood cell volume and mean red blood cell hemoglobin level for the MWCNTs-administered group, in addition to an increase in eotaxin.Conclusion: The present study demonstrated that the use of current technology to sufficiently disperse MWCNTs resulted in minimal organ accumulation with no evidence of carcinogenicity.


Clinical outcome of osteosarcoma and its correlation with programmed death-ligand 1 and T cell activation markers
ONCOTARGETS AND THERAPY,12:2513-2518 2019
Author:Kazushige Yoshida; Masanori Okamoto; Jun Sasaki; Chika Kuroda; Haruka Ishida; Katsuya Ueda; Satomi Okano; Hirokazu Ideta; Takayuki Kamanaka; Atsushi Sobajima; Takashi Takizawa; Munehisa Kito; Kaoru Aoki; Takeshi Uemura; Hisao Haniu; Hiroyuki Kato; Naoto Saito
Abstract:Purpose: Although both anti-PD-1 antibody and treatments using anti-PD-L1 antibody are currently in clinical use, their therapeutic effects vary according to cancer type. One of the factors accounting for this variability is the expression level of the immune checkpoint molecule that differs between cancer types; thus, it is important to clarify the relationship between clinical outcomes and immune checkpoint molecules for all types of human cancer. The purpose of this study is to evaluate the clinical outcome of osteosarcoma in relation to PD-L1, PRF, GZMB, and IFN gamma expression.Methods: Using 19 clinical specimens of osteosarcoma, we examined the expression of PD-L1, PRF, GZMB, and IFN. in relation to their clinical outcomes.Results: PD-L1 expression correlated with early metastatic formation in clinical specimens of osteosarcoma, and the group with highly expressed functional markers for T cells such as PRF and GZMB resulted in a long overall survival time.Conclusion: This is the first study to elucidate the clinical outcomes of osteosarcoma in relation to PD-L1, PRF, GZMB, and IFN gamma expression. This study provides valuable information regarding the clinical indication and prediction of effect for anti-PD-1 antibody in osteosarcoma.


The status quo of treatment and clinical outcomes for patients over 80 years of age with high-grade soft tissue sarcoma: report from the soft tissue tumor registry in Japan
JAPANESE JOURNAL OF CLINICAL ONCOLOGY,48(10):900-905 2018(Oct.)
Author:Masanori Okamoto; Munehisa Kito; Yasuo Yoshimura; Kaoru Aoki; Shuichiro Suzuki; Atsushi Tanaka; Akira Takazawa; Kazushige Yoshida; Hiroyuki Kato
Abstract:Objective: The purpose of this study is to clarify the status quo of management and clinical outcome of treatments for oldest-old (>= 80 years) patients with high-grade soft tissue sarcomas in Japan.Method: The present study was conducted using data from the Soft Tissue Tumor Registry in Japan. There were 956 oldest-old patients with soft tissue sarcoma who were registered from 2006 to 2012. Among them, cases with incomplete data, low-grade soft tissue sarcoma and those who underwent treatment at other institutions were excluded from analysis.Results: We examined 451 cases of high-grade soft tissue sarcoma in oldest-old patients. Three-hundred fifty-one cases (77.8%) were surgically managed, while 100 cases were conservatively managed. In patients aged 85 years and older, 73.1% underwent surgical treatment. A significantly higher proportion of patients underwent conservative therapy in oldest-old patients aged 85 years or older (P = 0.036), patients with deep-seated tumors (P = 0.027) and patients with distant metastases at the first visit (P = 0.000). The median follow-up period was 18.9 months (range, 0.2-83.1). Risk factors for overall survival were extracompartmental tumor progression (P = 0.014) and presence of distant metastases at the first visit (P = 0.000).Conclusion: We reported the status quo of treatment and clinical outcome for oldest-old patients with high-grade soft tissue sarcoma in Japan. Although surgery is the primary treatment for soft tissue sarcoma, a significantly higher proportion of patients underwent conservative therapy over surgical treatment in patients aged 85 years or older, patients with deep-seated tumors and patients with distant metastases.


癌転移骨環境における抗癌剤付加カーボンファイバーの評価
日本整形外科学会雑誌,92(8):S1809-S1809 2018(Aug.)
Author:鎌仲 貴之; 佐々木 純; 傍島 淳; 吉田 和薫; 滝沢 崇; 岡本 正則; 青木 薫; 羽二生 久夫; 齋藤 直人; 加藤 博之


Examining the Validity of Efforts of the Muscular Dystrophy Medical Network in Nagano : A Questionnaire Study
信州医学雑誌,66(3):205-212 2018(Jun. 10)
Author:Nishizawa, Hitomi; Takahashi, Hiroko; Aoki, Kaoru; Kosho, Tomoki; Inaba, Yuji; Nakamura, Akinori
Abstract:信州医学雑誌


骨肉腫に対する古典的Wntシグナル阻害因子スクレロスチンの抗腫瘍効果
日本整形外科学会雑誌,92(6):S1459-S1459 2018(Jun.)
Author:岡本 正則; 吉田 和薫; 佐々木 純; 青木 薫; 高沢 彰; 鈴木 周一郎; 吉村 康夫; 鬼頭 宗久; 羽二生 久夫; 傍島 淳; 鎌仲 貴之; 根本 和明; 齋藤 直人; 加藤 博之


Titanium Fiber Plates for Bone Tissue Repair
ADVANCED MATERIALS,30(4):- 2018(Jan.)
Author:Takashi Takizawa; Noboru Nakayama; Hisao Haniu; Kaoru Aoki; Masanori Okamoto; Hiroki Nomura; Manabu Tanaka; Atsushi Sobajima; Kazushige Yoshida; Takayuki Kamanaka; Kumiko Ajima; Ayumu Oishi; Chika Kuroda; Haruka Ishida; Satomi Okano; Shinsuke Kobayashi; Hiroyuki Kato; Naoto Saito
Abstract:Titanium plates are widely used in clinical settings because of their high bone affinity. However, owing to their high elastic modulus, these plates are not suitable for bone repair since their proximity to the bone surface for prolonged periods can cause stress shielding, leading to bone embrittlement. In contrast, titanium fiber plates prepared by molding titanium fibers into plates by simultaneously applying compression and shear stress at normal room temperature can have an elastic modulus similar to that of bone cortex, and stress shielding will not occur even when the plate lies flush against the bone's surface. Titanium fibers can form a porous structure suitable for cell adhesion and as a bone repair scaffold. A titanium fiber plate is combined with osteoblasts and shown that the titanium fiber plate is better able to facilitate bone tissue repair than the conventional titanium plate when implanted in rat bone defects. Capable of being used in close contact with bone for a long time, and even capable of promoting bone repair, titanium fiber plates have a wide range of applications, and are expected to make great contributions to clinical management of increasing bone diseases, including bone fracture repair and bone regenerative medicine.


Different aggregation and shape characteristics of carbon materials affect biological responses in RAW264 cells
INTERNATIONAL JOURNAL OF NANOMEDICINE,13:6079-6088 2018
Author:Chika Kuroda; Katsuya Ueda; Hisao Haniu; Haruka Ishida; Satomi Okano; Takashi Takizawa; Atsushi Sobajima; Takayuki Kamanaka; Kazushige Yoshida; Masanori Okamoto; Tamotsu Tsukahara; Yoshikazu Matsuda; Kaoru Aoki; Hiroyuki Kato; Naoto Saito
Abstract:Introduction: Carbon nanotubes (CNTs) have various shapes, including needle-like shapes and curled shapes, and the cytotoxicity and carcinogenicity of CNTs differ depending on their shapes and surface modifications. However, the biological responses induced by CNTs and related mechanisms according to the dispersion state of CNTs have not been extensively studied.Materials and methods: We prepared multi walled CNTs (MWCNTs) showing different dispersions and evaluated these MWCNTs in RAW264 cells to determine cytotoxicity, cellular uptake, and immune responses. Furthermore, RAW264 cells were also used to compare the cellular uptake and cytotoxicity of fibrous MWCNTs and spherical carbon nanohoms (CNHs) exhibiting the same degree of dispersion.Results: Our analysis showed that the cellular uptake, localization, and inflammatory responses of MWCNTs differed depending on the dispersion state. Moreover, there were differences in uptake between MWCNTs and CNHs, even showing the same degree of dispersion. These findings suggested that receptors related to cytotoxicity and immune responses di tiered depending on the aggregated state of MWCNTs and surface modification with a dispersant. Furthermore, our results suggested that the receptors recognized by the cells differed depending on the particle shape.Conclusion: Therefore, to apply MWCNTs as a biomaterial, it is important to determine the carcinogenicity and toxicity of the CNTs and to examine different biological responses induced by varying shapes, dispersion states, and surface modifications of particles.


Massive trapezial metastasis from gastric adenocarcinoma resected and reconstructed with a vascularized scapular bone graft A case report
MEDICINE,96(50):- 2017(Dec.)
Author:Masanori Okamoto; Hiroshi Yamazaki; Yasuo Yoshimura; Kaoru Aoki; Atsushi Tanaka; Hiroyuki Kato
Abstract:Rationale: Isolated metastasis to the hand bones is very rare. Only seven cases of metastasis to the trapezium have been reported. To the best of our knowledge, this is the first report of a single metastasis to the trapezium from a gastric adenocarcinoma.Patient concerns: A 62-year-old man presented with pain and massive swelling in the right carpometacarpal joint of the thumb.Diagnoses: The patient was diagnosed with trapezial metastasis of advanced gastric adenocarcinoma.Interventions: The patient underwent systemic chemotherapy with cisplatin and S-1, radiotherapy to the metastatic bone, and treatment with denosumab. One year later, the huge metastatic tumor was resected, and the hand was reconstructed using vascularized scapular bone.Outcomes: Eighteen months postoperatively, the patient was satisfied with the appearance of the reconstructed hand and was able to use his right thumb in activities of daily living.Lessons: Although rare, metastasis to the trapezium should be considered in patients with persistent and progressive thumb CMC joint pain.


Initial clinical presentation of single soft tissue metastasis of medullary thyroid carcinoma without primary tumor in the thyroid gland
WORLD JOURNAL OF SURGICAL ONCOLOGY,15:- 2017(Dec.)
Author:Masanori Okamoto; Akira Takazawa; Kaoru Aoki; Yasuo Yoshimura; Hiroyuki Kato; Toshiaki Otsuki; Kazuma Maeno; Tomonobu Koizumi
Abstract:Background: Single soft tissue metastasis of medullary thyroid carcinoma is extremely rare. In addition, several occult medullary thyroid carcinomas with distant metastasis were reported, but undetectable primary lesion at diagnosis was also extremely rare.Case presentation: A 74-year-old man was admitted to our hospital because of a painful nodule in his left buttock for over 1 year. Needle biopsy was performed, and the histological findings revealed adenocarcinoma positive for thyroid transcription factor-1. No evidence of a primary tumor, including the lung and thyroid gland, could be found elsewhere despite detailed examinations, including thyroid echography, chest computed tomography, and fluorodeoxyglucose-positron emission tomography. The soft tissue tumor was resected with a wide margin. Immunohistochemical analysis showed the tumor cells to be positive for cytokeratin-AE1/3, cytokeratin 7, synaptophysin, chromogranin A, calcitonin, and carcinoembryonic antigen, but negative for cytokeratin 20, Napsin A, Pax8, and p40, resulting in a diagnosis of metastasis of medullary thyroid carcinoma.Conclusion: Initial presentation with a single metastasis to soft tissue and undetectable primary tumor in the thyroid gland is an extremely rare clinical manifestation in patients with medullary thyroid carcinoma.


Clinical outcomes of patients 80 years of age and older with soft tissue sarcoma
JOURNAL OF ORTHOPAEDIC SCIENCE,22(5):951-957 2017(Sep.)
Author:Masanori Okamoto; Yasuo Yoshimura; Kaoru Aoki; Munehisa Kito; Atsushi Tanaka; Shuichiro Suzuki; Akira Takazawa; Ken'ichi Isobe; Hiroyuki Kato
Abstract:Objectives: Although soft tissue sarcoma (STS) is rare, its incidence is increasing among older patients. Few studies have compared the outcomes between conservative and surgical treatments for STS patients aged >= 80 years. We assessed the outcomes of both treatments in this population and the association between older age and surgical outcome.Methods: We recruited consecutive patients with STS aged >= 80 years treated at our institution between January 2006 and May 2014. We recommended surgical resection for all patients without multiple distant metastases. Overall survival and sarcoma-specific survival were assessed using the Kaplan-Meier method.Results: Of the 39 patients with STS who presented at our institution, 37 were included in this analysis (19 men and 18 women with a median age of 85 [range 80-94] years). Tumors were classified as Stage IB (n = 3), IIA (n = 6), IIB (n = 3) or III (n = 24). Four patients underwent conservative therapy and 33 underwent surgical resection. The most common tumor site was the lower extremity, and the majority of tumors were classified as undifferentiated pleomorphic sarcoma. The follow-up rate was 100%. One-year sarcoma-specific survival rates were 25.0% in the conservative therapy group and 90.9% in the surgical resection group. No associations were found between age >= 85 years and perioperative complications or clinical outcome.Conclusions: Surgical resection had relatively few complications, given the age group, and improved the prognosis of older patients with STS. Surgical resection of STS with curative intent should be considered in older patients. (C) 2017 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.


骨組織修復のためのチタンファイバープレート
信州医学雑誌,65(4):234-235 2017(Aug.)
Author:滝沢 崇; 青木 薫; 岡本 正則; 田中 学; 傍島 淳; 吉田 和薫; 鎌仲 貴之; 加藤 博之; 羽二生 久夫; 安嶋 久美子; 大石 歩; 黒田 千佳; 石田 悠; 齋藤 直人; 中山 昇


骨肉腫に対する抗PD-1抗体の有用性の検討
日本整形外科学会雑誌,91(8):S1820-S1820 2017(Aug.)
Author:吉田 和薫; 岡本 正則; 青木 薫; 鎌仲 貴之; 傍島 淳; 滝沢 崇; 田中 学; 羽二生 久夫; 薄井 雄企; 高沢 彰; 吉村 康夫; 齋藤 直人; 加藤 博之


多層カーボンナノチューブ複合ポリエチレンから作製した擬似摩耗粉の細胞毒性
日本整形外科学会雑誌,91(8):S1663-S1663 2017(Aug.)
Author:傍島 淳; 羽二生 久夫; 綱嶋 義貴; 沖原 巧; 青木 薫; 岡本 正則; 安嶋 久美子; 田中 学; 滝沢 崇; 吉田 和薫; 鎌仲 貴之; 加藤 博之; 齋藤 直人


β-TCP製スキャフォルドの連通多孔構造の違いによる骨再生能評価
日本整形外科学会雑誌,91(8):S1659-S1659 2017(Aug.)
Author:鎌仲 貴之; 齋藤 直人; 羽二生 久夫; 岡本 正則; 青木 薫; 田中 学; 滝沢 崇; 傍島 淳; 吉田 和薫; 加藤 博之


カーボンナノチューブ複合超高分子量ポリエチレンの骨組織親和性
日本整形外科学会雑誌,91(8):S1541-S1541 2017(Aug.)
Author:青木 薫; 岡本 正則; 滝沢 崇; 傍島 淳; 吉田 和薫; 鎌仲 貴之; 加藤 博之; 薄井 雄企; 田中 学; 西村 直之; 綱嶋 義貴; 羽二生 久夫; 齋藤 直人


骨組織修復のためのチタンファイバープレート
日本整形外科学会雑誌,91(8):S1539-S1539 2017(Aug.)
Author:滝沢 崇; 中山 昇; 羽二生 久夫; 青木 薫; 岡本 正則; 田中 学; 傍島 淳; 吉田 和薫; 鎌仲 貴之; 安嶋 久美子; 加藤 博之; 齋藤 直人


三次元配向連通孔ハイドロキシアパタイト製骨再生用スキャフォルドの物理化学・生体外・生体内的評価
日本整形外科学会雑誌,91(8):S1537-S1537 2017(Aug.)
Author:田中 学; 鎌仲 貴之; 傍島 淳; 吉田 和薫; 青木 薫; 岡本 正則; 佐々木 純; 岩浅 智哉; 三村 哲彦; 羽二生 久夫; 齋藤 直人; 加藤 博之


Development of a System for Evaluating Drugs Using Isolated Lymphatic Vessels
JOURNAL OF PHARMACOLOGICAL SCIENCES,133(3):S264-S264 2017(Mar.)
Author:Kuroda, Chika; Ajima, Kumiko; Haniu, Hisao; Tsukahara, Tamotsu; Matsuda, Yoshikazu; Aoki, Kaoru; Kato, Hiroyuki; Saito, Naoto
Abstract:JOURNAL OF PHARMACOLOGICAL SCIENCES


In Vitro and In Vivo Evaluation of a Three-Dimensional Porous Multi-Walled Carbon Nanotube Scaffold for Bone Regeneration
NANOMATERIALS,7(2) 2017(Feb.)
Author:Manabu Tanaka; Yoshinori Sato; Mei Zhang; Hisao Haniu; Masanori Okamoto; Kaoru Aoki; Takashi Takizawa; Kazushige Yoshida; Atsushi Sobajima; Takayuki Kamanaka; Hiroyuki Kato; Naoto Saito
Abstract:Carbon nanotubes (CNTs) have attracted a great deal of attention for the biological and medical science fields because of their characteristic physical and biological properties. In this study, we investigated the capacity of the 3D porous CNT scaffold (CNT porous block; CNTp) for bone regenerative medicine. Surface observations using a scanning electron microscope (SEM), crystal depositions on the surface of CNTps immersed in simulated body fluid (SBF), and evaluations of protein adsorption and controlled releasing were conducted to assess physical properties. The cell proliferation and cell morphology were observed using SEM and fluorescent microscopy. CNTps were implanted into critical-size mouse calvarial defects and evaluated for their osteoconductive ability and in vivo controlled release of recombinant human BMP-2 (rhBMP-2). Interconnected porous HA ceramics (IP-CHAs) were used for comparison. CNTps have multiporous structures with interporous connections with networks of multiwalled CNTs. Crystals containing calcium and phosphate were deposited in CNTps and on the surface of the CNT networks by immersing CNTps in SBF. CNTps adsorbed more significantly and released protein more gradually than IP-CHAs. Preosteoblasts seeded onto CNTps filled pores with stretched actin filaments and filopodia. Compared with IP-CHAs, CNTps showed significantly higher cell proliferation, better osteoconduction, and more bone generation with rhBMP-2. In this study, CNTps demonstrated good osteoconductive ability, cell attachment and proliferation capacity, and growth factor retaining ability. CNTps have the potential not only as artificial bones for the treatment of bone defects, but also as scaffolds for regenerative medicine using tissue engineering approaches.


A three-dimensional block structure consisting exclusively of carbon nanotubes serving as bone regeneration scaffold and as bone defect filler
PLOS ONE,12(2):- 2017(Feb.)
Author:Manabu Tanaka; Yoshinori Sato; Hisao Haniu; Hiroki Nomura; Shinsuke Kobayashi; Seiji Takanashi; Masanori Okamoto; Takashi Takizawa; Kaoru Aoki; Yuki Usui; Ayumu Oishi; Hiroyuki Kato; Naoto Saito
Abstract:Many recent studies have been conducted to assess the ability of composite materials containing carbon nanotubes (CNTs) with high bone affinity to serve as scaffolds in bone regenerative medicine. These studies have demonstrated that CNTs can effectively induce bone formation. However, no studies have investigated the usefulness of scaffolds consisting exclusively of CNTs in bone regenerative medicine. We built a three-dimensional block entity with maximized mechanical strength from multi-walled CNTs (MWCNT blocks) and evaluated their efficacy as scaffold material for bone repair. When MWCNT blocks containing recombinant human bone morphogenetic protein-2 (rhBMP-2) were implanted in mouse muscle, ectopic bone was formed in direct contact with the blocks. Their bone marrow densities were comparable to those of PET-reinforced collagen sheets with rhBMP-2. On day 1 and day 3, MC3T3-E1 preosteoblasts were attached to the scaffold surface of MWCNT blocks than that of PET-reinforced collagen sheets. They also showed a maximum compression strength comparable to that of cortical bone. Our MWCNT blocks are expected to serve as bone defect filler and scaffold material for bone regeneration.


Physico-Chemical, In Vitro, and In Vivo Evaluation of a 3D Unidirectional Porous Hydroxyapatite Scaffold for Bone Regeneration
MATERIALS,10(1) 2017(Jan.)
Author:Manabu Tanaka; Hisao Haniu; Takayuki Kamanaka; Takashi Takizawa; Atsushi Sobajima; Kazushige Yoshida; Kaoru Aoki; Masanori Okamoto; Hiroyuki Kato; Naoto Saito
Abstract:The unidirectional porous hydroxyapatite HAp (UDPHAp) is a scaffold with continuous communicated pore structure in the axial direction. We evaluated and compared the ability of the UDPHAp as a three-dimensional (3D) bone tissue engineering scaffold to the interconnected calcium porous HAp ceramic (IP-CHA). To achieve this, we evaluated in vitro the compressive strength, controlled rhBMP-2 release behavior, adherent cell morphology, cell adhesion manner, and cell attachment of UDPHAp. As a further in vivo experiment, UDPHAp and IP-CHA with rhBMP-2 were transplanted into mouse calvarial defects to evaluate their bone-forming ability. The Results demonstrated that the maximum compressive strengths of the UDPHAp was 7.89 +/- 1.23 MPa and higher than that of IP-CHA (1.92 +/- 0.53 MPa) (p = 0.0039). However, the breaking energies were similar (8.99 +/- 2.72 vs. 13.95 +/- 5.69 mJ, p = 0.055). The UDPHAp released rhBMP-2 more gradually in vivo. Cells on the UDPHAp adhered tightly to the surface, which had grown deeply into the scaffolds. A significant increase in cell number on the UDPHAp was observed compared to the IP-CHA on day 8 (102,479 +/- 34,391 vs. 32,372 +/- 29,061 estimated cells per scaffold, p = 0.0495). In a mouse calvarial defect model, the percentages of new bone area (mature bone + trabecular bone) in the 2x field were 2.514% +/- 1.224% for the IP-CHA group and 7.045% +/- 2.055% for the UDPHAp group, and the percentage was significantly higher in the UDPHAp group (p = 0.0209). While maintaining the same strength as the IP-CHA, the UDPHAp with 84% porosity showed a high cell number, high cell invasiveness, and excellent bone formation. We believe the UDPHAp is an excellent material that can be applied to bone regenerative medicine.


Clinical outcome of dedifferentiated liposarcoma in the extremities: A retrospective case series of 7 patients
Journal of Orthopaedic Science,21(5):673-677 2016(Sep. 01)
Author:Munehisa Kito; Yasuo Yoshimura; Ken'ichi Isobe; Kaoru Aoki; Shuichiro Suzuki; Atsushi Tanaka; Masanori Okamoto; Kenji Sano; Hiroyuki Kato
Abstract:Background Wide resection is the generally recommended surgical treatment for dedifferentiated liposarcoma (DDLPS) in the extremities. However, it may be appropriate to distinguish the surgical margin of low-grade atypical lipomatous tumor (ALT)/well-differentiated liposarcoma (WDLPS) area from the high-grade dedifferentiated area, because the low- and high-grade areas can be clearly separated, both radiologically and histologically. This study re-evaluated the details of surgical margin of DDLPS in the extremities, and aimed to investigate the optimal surgical margin and the usefulness of adjuvant therapy for DDLPS in the extremities. Methods Seven patients diagnosed with DDLPS in the extremities and treated between 1995 and 2013 were analyzed. The use of adjuvant therapy before and after surgery was assessed, and the surgical margins for the ALT/WDLPS and dedifferentiated areas were re-evaluated by using the specimens resected at surgery. Subsequently, the recurrence rates, metastatic rates, and oncological outcomes were examined. Results Four and three patients had wide (adequate wide margin, n = 3 inadequate wide margin, n = 1) and marginal margins for the dedifferentiated area, respectively, while three and four patients had wide (adequate wide margin, n = 2 inadequate wide margin, n = 1) and marginal margins for the ALT/WDLPS area, respectively. Postoperative radiotherapy was performed in three patients with an inadequate wide margin or a marginal margin for the dedifferentiated area. No patient had local recurrence. Distant metastases occurred in two patients. These patients died of their disease. The other five patients were disease-free. Conclusion The ALT/WDLPS and dedifferentiated areas in the tumor margin may be better to be considered separately in determining the appropriate resection extent for DDLPS in the extremities. Postoperative radiotherapy may provide good local control for cases with a narrow surgical margin.


多孔質に成型した多層カーボンナノチューブブロック体の骨形成への影響
信州医学雑誌,64(4):214-214 2016(Aug.)
Author:田中 学; 滝沢 崇; 野村 博紀; 小林 伸輔; 岡本 正則; 高梨 誠司; 青木 薫; 加藤 博之; 佐藤 義倫; 薄井 雄企; 齋藤 直人; 羽二生 久夫; Zhang Mei


多層カーボンナノチューブのラット膝関節内注射による他臓器への移行の検討
日本整形外科学会雑誌,90(8):S1814-S1814 2016(Aug.)
Author:傍島 淳; 齋藤 直人; 羽二生 久夫; 青木 薫; 岡本 正則; 田中 学; 滝沢 崇; 吉田 和薫; 大石 歩; 安嶋 久美子; 黒田 千佳; 加藤 博之


チタンペーパーの骨再生における足場材としての有用性の検討(その2)
日本整形外科学会雑誌,90(8):S1812-S1812 2016(Aug.)
Author:滝沢 崇; 齋藤 直人; 中山 昇; 羽二生 久夫; 青木 薫; 岡本 正則; 田中 学; 傍島 淳; 吉田 和薫; 大石 歩; 安嶋 久美子


非古典経路のWNT5Aは骨肉腫においてLRP5/6の発現を調節する
日本整形外科学会雑誌,90(8):S1799-S1799 2016(Aug.)
Author:岡本 正則; 吉田 和薫; 青木 薫; 鬼頭 宗久; 田中 厚誌; 鈴木 周一郎; 高沢 彰; 福澤 拓馬; 薄井 雄企; 羽二生 久夫; 小林 伸輔; 田中 学; 吉村 康夫; 小林 泰浩; 加藤 博之; 齋藤 直人


配向連通多孔体ハイドロキシアパタイト担体のin vitroおよびin vivoにおける骨再生能評価
日本整形外科学会雑誌,90(8):S1721-S1721 2016(Aug.)
Author:田中 学; 齋藤 直人; 羽二生 久夫; 野村 博紀; 小林 伸輔; 岡本 正則; 青木 薫; 滝沢 崇; 傍島 淳; 吉田 和薫; 加藤 博之


Peapod様カーボンナノチューブのバイオレスポンス評価
The Journal of Toxicological Sciences,41(Suppl.):S318-S318 2016(Jun.)
Author:羽二生 久夫; 小林 伸輔; 鶴岡 秀志; 丸山 佳与; 松田 佳和; 青木 薫; 岡本 正則; 田中 学; 滝沢 崇; 傍島 淳; 吉田 和薫; 薄井 雄企; 加藤 博之; 齋藤 直人


多層カーボンナノチューブの異なる分散条件による細胞応答性
The Journal of Toxicological Sciences,41(Suppl.):S218-S218 2016(Jun.)
Author:黒田 千佳; 羽二生 久夫; 傍島 淳; 野村 博紀; 生田 太郎; 安嶋 久美子; 岡本 正則; 田中 学; 滝沢 崇; 吉田 和薫; 青木 薫; 齋藤 直人


The dispersion state of tangled multi-walled carbon nanotubes affects their cytotoxicity.
Nanomaterials,6 2016
Author:Kuroda C; Haniu H; Ajima K; Tanaka M; Sobajima A; Ishida H; Tsukahara T; Matsuda Y; Aoki K; Kato H; Saito N


A recurrent solitary fibrous tumor of the thigh with malignant transformation: A case report
INTERNATIONAL JOURNAL OF SURGERY CASE REPORTS,21:111-114 2016
Author:Yasuo Yoshimura; Kenji Sano; Ken-ichi Isobe; Kaoru Aoki; Munehisa Kito; Hiroyuki Kato
Abstract:INTRODUCTION: We describe an unusual case of a uniformly high-grade malignant solitary fibrous tumor (SFT) of the thigh with recurrence after wide resection in a 31-year-old man.PRESENTATION OF CASE: Our current case showed a long-term benign course before the operation, although the subcutaneous tumor was larger than 10 cm at presentation. The SFT was diagnosed by needle biopsy, and wide resection was performed. Histological findings showed proliferation of capillaries surrounded by masses of spindle-shaped cells without any cytologic atypia, and the percentage of MIB-1-positive nuclei was 2.1%. However, a rapidly enlarging recurrent tumor was observed 11 months after the operation. A second wide resection for the recurrent tumor was performed. Histologically, the tumor cells uniformly displayed significant cytologic atypia and pleomorphism, and had 40-50 mitoses per 10 high-power fields. The proportion of MIB-1-positive nuclei was 48%. Consequently, the tumor was diagnosed as a SFT with malignant transformation.DISCUSSION: The malignant transformation described in past studies showed high-grade areas within benign, low-grade, or intermediate-grade SFTs. Therefore, in contrast to our case, uniformly high-grade malignant histological findings at recurrence were not described.CONCLUSION: Even if a tumor is non-malignant during the clinical course, as confirmed by tissue biopsy, the possibility of tumor progression to high-grade sarcoma at recurrence should be considered, and the treatment strategy should be determined carefully. (C) 2016 The Authors. Published by Elsevier Ltd. on behalf of IJS Publishing Group Ltd.


Specific biological responses of the synovial membrane to carbon nanotubes
SCIENTIFIC REPORTS,5:- 2015(Sep.)
Author:Hiroki Nomura; Seiji Takanashi; Manabu Tanaka; Hisao Haniu; Kaoru Aoki; Masanori Okamoto; Shinsuke Kobayashi; Takashi Takizawa; Yuki Usui; Ayumu Oishi; Hiroyuki Kato; Naoto Saito
Abstract:Biological evaluation of carbon nanotubes (CNTs) is typically performed in the lung or abdominal cavity; however, biological reactions to CNTs are predicted to be markedly different in other tissues. In applications of CNTs as reinforcement for artificial joints and drug delivery systems, including their use in bone regeneration, the intra-articular synovial membrane makes contact with the CNTs. Herein, we analyzed the reaction of the synovial membrane with multiwalled CNTs (MWCNTs). Injection of MWCNTs into rat knee joints revealed their dose-dependent incorporation into deep synovial membranes and the formation of granulation tissue, without long-term inflammation. MWCNTs were incorporated into human fibroblast-like synoviocytes (HFLSs), with less cytotoxicity than that observed in macrophages (RAW264 cells). Moreover, MWCNTs inhibited the release of cytokines and chemokines from HFLSs. The reaction of the synovial membrane with MWCNTs differed from that observed in other tissues; thus, detailed biological evaluation at each target site is necessary for clinical applications.


骨肉腫モデルマウスに対するカーボンナノチューブの効果
日本整形外科学会雑誌,89(8):S1799-S1799 2015(Sep.)
Author:青木 薫; 高梨 誠司; 岡本 正則; 小林 伸輔; 野村 博紀; 田中 学; 滝沢 崇; 大石 歩; 加藤 博之; 薄井 雄企; 羽二生 久夫; 齋藤 直人


Porous multi-walled carbon nanotube block(p-MWCNT block)の骨形成への影響
日本整形外科学会雑誌,89(8):S1585-S1585 2015(Sep.)
Author:田中 学; 齋藤 直人; Zhang Mei; 佐藤 義倫; 滝沢 崇; 野村 博紀; 小林 伸輔; 岡本 正則; 青木 薫; 薄井 雄企; 羽二生 久夫; 加藤 博之


チタンペーパーの骨再生における足場材としての有用性の検討
日本整形外科学会雑誌,89(8):S1581-S1581 2015(Sep.)
Author:滝沢 崇; 田中 学; 齋藤 直人; 羽二生 久夫; 中山 昇; 青木 薫; 岡本 正則; 高梨 誠司; 小林 伸輔; 野村 博紀; 加藤 博之


Mini Open Foraminotomy for Cervical Radiculopathy: A Comparison of Large Tubular and TrimLine Retractors
ASIAN SPINE JOURNAL,9(4):548-552 2015(Aug.)
Author:Masashi Uehara; Jun Takahashi; Shugo Kuraishi; Masayuki Shimizu; Shota Ikegami; Toshimasa Futatsugi; Kaoru Aoki; Keijiro Mukaiyama; Nobuhide Ogihara; Hiroyuki Hashidate; Hiroki Hirabayashi; Hiroyuki Kato
Abstract:Study Design: Retrospective chart review.Purpose: A comparison of mini open foraminotomy (MOF) for cervical radiculopathy using either large tubular (LT) or TrimLine (TL) retractors.Overview of Literature: Posterior foraminotomy relieves compression of the cervical nerve root in radiculopathy patients. However, invasion of the paravertebral muscle may cause major problems in these patients. To address these problems, we performed MOF.Methods: Twenty cervical radiculopathy patients (16 male and 4 female) who underwent MOF between May 2004 and August 2011 were assigned to LT and TL groups. Each group contained 10 subjects. Surgical and clinical outcomes were compared.Results: The average operating time in the TL group was significantly shorter than that in the LT group. The final follow-up mean neck disability indices significantly improved compared to the preoperative values (LT group, 12.0 +/- 7.8 vs. 28.0 +/- 9.4; TL group, 6.0 +/- 5.9 vs. 21.9 +/- 10). The final follow-up neck pain visual analog scale (VAS) scores also decreased significantly from the preoperative of 8.0 +/- 1.5 and 2.5 +/- 2.5 to the final follow-up values of 2.2 +/- 2.2 and 1.0 +/- 2.5 in the LT and TL groups, respectively. The recovery rate for the neck pain VAS score was 70.0 +/- 31.9 in the LT group and 87.0 +/- 32.0 in the TL group, thus suggesting no significant difference between the two groups.Conclusions: MOF with the TL retractor is an easy and safe procedure. Furthermore, the use of the TL retractor allows for a minimally invasive and effective surgical treatment of cervical radiculopathy patients.


重金属粒子を内包したカーボンナノチューブによるMRIを使用した体内動態評価法
信州医学雑誌,63(4):261-262 2015(Aug.)
Author:小林 伸輔; 青木 薫; 高梨 誠司; 岡本 正則; 野村 博紀; 田中 学; 滝沢 崇; 加藤 博之; 鶴岡 秀志; 羽二生 久夫; 齋藤 直人; 薄井 雄企


An advanced in situ imaging method using heavy metal-doped hollow tubes to evaluate the biokinetics of carbon nanotubes in vivo
NPG ASIA MATERIALS,7:- 2015(Jul.)
Author:Shinsuke Kobayashi; Shuji Tsuruoka; Yuki Usui; Hisao Haniu; Kaoru Aoki; Seiji Takanashi; Masanori Okamoto; Hiroki Nomura; Manabu Tanaka; Shigetoshi Aiso; Misae Saito; Hiroyuki Kato; Naoto Saito
Abstract:The biosafety of carbon nanotubes (CNTs) is a concern, and CNT biokinetics is a key biosafety issue. CNTs labeled with carbon isotopes, functionalized with moieties, or coated with colloidal metal particles have been used to monitor CNT biokinetics, though major technical issues (such as isotope preparation and handling or change in CNT surface properties) remain. The present report aims at establishing an advanced and simple in situ imaging method of CNTs monitoring in vivo involving the use of CNTs filled with heavy metal particles (peapods). Gadolinium (Gd)-peapods containing GdCl3 were synthesized using double-walled CNTs. The limits of Gd-peapods detection on magnetic resonance imaging (MRI) in solutions and agarose gel cubes were 1.3 mu g ml(-1) and 4 mu g ml(-1), respectively. The peapods in rats was easily visualized by MRI and the change in signal intensity was dose dependent. This newly developed method can be used to monitor CNT biokinetics in vivo without tedious tissue preparation.


in vitroでのPeapod-CNTの生体応答
The Journal of Toxicological Sciences,40(Suppl.):S247-S247 2015(Jun.)
Author:丸山 佳与; 羽二生 久夫; 小林 伸輔; 鶴岡 秀志; 松田 佳和; 青木 薫; 岡本 正則; 高梨 誠司; 野村 博紀; 田中 学; 滝沢 崇; 大石 歩; 薄井 雄企; 齋藤 直人


脳関連細胞種での多層カーボンナノチューブによる生物学的応答
The Journal of Toxicological Sciences,40(Suppl.):S245-S245 2015(Jun.)
Author:羽二生 久夫; 齋藤 直人; 丸山 佳与; 松田 佳和; 青木 薫; 高梨 誠司; 岡本 正則; 小林 伸輔; 野村 博紀; 田中 学; 滝沢 崇; 大石 歩; 薄井 雄企; 加藤 博之


Endocytosis of Multiwalled Carbon Nanotubes in Bronchial Epithelial and Mesothelial Cells
BIOMED RESEARCH INTERNATIONAL,2015:- 2015
Author:Kayo Maruyama; Hisao Haniu; Naoto Saito; Yoshikazu Matsuda; Tamotsu Tsukahara; Shinsuke Kobayashi; Manabu Tanaka; Kaoru Aoki; Seiji Takanashi; Masanori Okamoto; Hiroyuki Kato
Abstract:Bronchial epithelial cells and mesothelial cells are crucial targets for the safety assessment of inhalation of carbon nanotubes (CNTs), which resemble asbestos particles in shape. Intrinsic properties of multiwalled CNTs (MWCNTs) are known to cause potentially hazardous effects on intracellular and extracellular pathways. These interactions alter cellular signaling and affect major cell functions, resulting in cell death, lysosome injury, reactive oxygen species production, apoptosis, and cytokine release. Furthermore, CNTs are emerging as a novel class of autophagy inducers. Thus, in this study, we focused on the mechanisms of MWCNT uptake into the human bronchial epithelial cells (HBECs) and human mesothelial cells (HMCs). We verified that MWCNTs are actively internalized into HBECs and HMCs and were accumulated in the lysosomes of the cells after 24-hour treatment. Next, we determined which endocytosis pathways (clathrin-mediated, caveolae-mediated, and macropinocytosis) were associated with MWCNT internalization by using corresponding endocytosis inhibitors, in two nonphagocytic cell lines derived from bronchial epithelial cells and mesothelioma cells. Clathrin-mediated endocytosis inhibitors significantly suppressed MWCNT uptake, whereas caveolae-mediated endocytosis and macropinocytosis were also found to be involved in MWCNT uptake. Thus, MWCNTs were positively taken up by nonphagocytic cells, and their cytotoxicity was closely related to these three endocytosis pathways.


多層カーボンナノチューブの関節内への単回投与と分割投与による滑膜反応の比較
日本整形外科学会雑誌,88(8):S1703-S1703 2014(Aug.)
Author:野村 博紀; 羽二生 久夫; 小林 伸輔; 岡本 正則; 高梨 誠司; 青木 薫; 薄井 雄企; 加藤 博之; 齋藤 直人


カーボンナノチューブ複合PEEKの骨組織親和性
日本整形外科学会雑誌,88(8):S1703-S1703 2014(Aug.)
Author:青木 薫; 清水 政幸; 高梨 誠司; 岡本 正則; 小林 伸輔; 野村 博紀; 田中 学; 加藤 博之; 薄井 雄企; 西村 直之; 湯谷 知世; 羽二生 久夫; 齋藤 直人


多層カーボンナノチューブのマクロファージに対する影響と骨溶解に関連したケモカイン分泌量の変化の検討
日本整形外科学会雑誌,88(8):S1627-S1627 2014(Aug.)
Author:野村 博紀; 羽二生 久夫; 田中 学; 小林 伸輔; 岡本 正則; 高梨 誠司; 青木 薫; 薄井 雄企; 加藤 博之; 齋藤 直人


Multi-walled carbon nanotube(MWCNT)blockの骨形成への影響
日本整形外科学会雑誌,88(8):S1488-S1488 2014(Aug.)
Author:田中 学; 野村 博紀; 小林 伸輔; 岡本 正則; 高梨 誠司; 青木 薫; 薄井 雄企; 羽二生 久夫; 齋藤 直人; 佐藤 義倫


Wnt5aはSp7を介してLRP5/6の発現を上昇させ、骨芽細胞分化を促進する
日本整形外科学会雑誌,88(8):S1413-S1413 2014(Aug.)
Author:岡本 正則; 上原 俊介; 前田 和洋; 山下 照仁; 薄井 雄企; 羽二生 久夫; 青木 薫; 高梨 誠司; 小林 伸輔; 野村 博紀; 田中 学; 加藤 博之; 齋藤 直人; 高橋 直之; 小林 泰浩


Wnt5aはLRP5/6の発現と古典経路を調節し、骨芽細胞分化を促進する
信州医学雑誌,62(4):259-259 2014(Aug.)
Author:岡本 正則; 羽二生 久夫; 青木 薫; 高梨 誠司; 小林 伸輔; 野村 博紀; 田中 学; 加藤 博之; 宇田川 信之; 上原 俊介; 山下 照仁; 高橋 直之; 小林 泰浩; 前田 和洋; 薄井 雄企; 齋藤 直人


BEAS-2B細胞の多層カーボンナノチューブの取り込み
The Journal of Toxicological Sciences,39(Suppl.):S341-S341 2014(Jul.)
Author:丸山 佳与; 羽二生 久夫; 薄井 雄企; 青木 薫; 高梨 誠司; 岡本 正則; 小林 伸輔; 野村 博紀; 田中 学; 松田 佳和; 加藤 博之; 齋藤 直人


Safe Clinical Use of Carbon Nanotubes as Innovative Biomaterials
CHEMICAL REVIEWS,114(11):6040-6079 2014(Jun.)
Author:Naoto Saito; Hisao Haniu; Yuki Usui; Kaoru Aoki; Kazuo Hara; Seiji Takanashi; Masayuki Shimizu; Nobuyo Narita; Masanori Okamoto; Shinsuke Kobayashi; Hiroki Nomura; Hiroyuki Kato; Naoyuki Nishimura; Seiichi Taruta; Morinobu Endo


Influence of CNF content on microstructure and fracture toughness of CNF/alumina composites
JOURNAL OF THE CERAMIC SOCIETY OF JAPAN,122(1424):292-299 2014(Apr.)
Author:Naoki Ueda; Tomohiko Yamakami; Tomohiro Yamaguchi; Yuki Usui; Kaoru Aoki; Morinobu Endo; Naoto Saito; Seiichi Taruta
Abstract:Dense 0.4-5.0 wt% carbon nanofiber (CNF)/alumina composites were fabricated by plasma activated sintering. The microstructure-particularly the CNFs distribution-of composites containing different amounts of CNFs was observed in detail, and the influence of the additive amounts of CNF on the microstructure and the fracture toughness of the composites were investigated. The ratio of CNFs distributed individually in the composites decreased with an increase in the addition of CNFs, and the other CNFs formed bundles; notably three-quarters of the CNFs formed bundles in the 5.0 wt% CNF/alumina composite. The alumina grain size distribution of the composites became narrower to smaller grain size side and the average alumina grain size of the composites decreased with an increase in the addition of CNFs from 0.4 to 1.6 wt%. However, the average alumina grain size of the composites did not vary greatly with an increase in the addition of CNFs from 1.6 to 5.0 wt%, because the CNF bundles formed in the 2.5 and 5.0 wt% CNF/alumina composites lowered the grain growth retardation effect of the CNFs. The 1.6 wt% CNF/alumina composite exhibited the highest fracture toughness, because three-fifths of the CNFs distributed individually and uniformly in alumina grain boundaries. (C) 2014 The Ceramic Society of Japan. All rights reserved.


Biological responses according to the shape and size of carbon nanotubes in BEAS-2B and MESO-1 cells
INTERNATIONAL JOURNAL OF NANOMEDICINE,9:1979-1990 2014
Author:Hisao Haniu; Naoto Saito; Yoshikazu Matsuda; Tamotsu Tsukahara; Yuki Usui; Kayo Maruyama; Seiji Takanashi; Kaoru Aoki; Shinsuke Kobayashi; Hiroki Nomura; Manabu Tanaka; Masanori Okamoto; Hiroyuki Kato
Abstract:This study aimed to investigate the influence of the shape and size of multi-walled carbon nanotubes (MWCNTs) and cup-stacked carbon nanotubes (CSCNTs) on biological responses in vitro. Three types of MWCNTs - VGCF (R)-X, VGCF (R)-S, and VGCF (R) (vapor grown carbon fibers; with diameters of 15, 80, and 150 nm, respectively) - and three CSCNTs of different lengths (CS-L, 20-80 mu m; CS-S, 0.5-20 mu m; and CS-M, of intermediate length) were tested. Human bronchial epithelial (BEAS-2B) and malignant pleural mesothelioma cells were exposed to the CNTs (1-50 mu g/mL), and cell viability, permeability, uptake, total reactive oxygen species/superoxide production, and intracellular acidity were measured. CSCNTs were less toxic than MWCNTs in both cell types over a 24-hour exposure period. The cytotoxicity of endocytosed MWCNTs varied according to cell type/size, while that of CSCNTs depended on tube length irrespective of cell type. CNT diameter and length influenced cell aggregation and injury extent. Intracellular acidity increased independently of lysosomal activity along with the number of vacuoles in BEAS-2B cells exposed for 24 hours to either CNT (concentration, 10 mu g/mL). However, total reactive oxygen species/superoxide generation did not contribute to cytotoxicity. The results demonstrate that CSCNTs could be suitable for biological applications and that CNT shape and size can have differential effects depending on cell type, which can be exploited in the development of highly specialized, biocompatible CNTs.


Culture medium type affects endocytosis of multi-walled carbon nanotubes in BEAS-2B cells and subsequent biological response
Toxicology in Vitro,27(6):1679-1685 2013(Sep.)
Author:Hisao Haniu; Naoto Saito; Yoshikazu Matsuda; Tamotsu Tsukahara; Kayo Maruyama; Yuki Usui; Kaoru Aoki; Seiji Takanashi; Shinsuke Kobayashi; Hiroki Nomura; Masanori Okamoto; Masayuki Shimizu; Hiroyuki Kato
Abstract:We examined the cytotoxicity of multi-walled carbon nanotubes (MWCNTs) and the resulting cytokine secretion in BEAS-2B cells or normal human bronchial epithelial cells (HBEpCs) in two types of culture media (Ham's F12 containing 10% FBS [Ham's F12] and serum-free growth medium [SFGM]). Cellular uptake of MWCNT was observed by fluorescent microscopy and analyzed using flow cytometry. Moreover, we evaluated whether MWCNT uptake was suppressed by 2 types of endocytosis inhibitors. We found that BEAS-2B cells cultured in Ham's F12 and HBEpCs cultured in SFGM showed similar biological responses, but BEAS-2B cells cultured in SFGM did not internalize MWCNTs, and the 50% inhibitory concentration value, i.e., the cytotoxicity, was increased by more than 10-fold. MWCNT uptake was suppressed by a clathrin-mediated endocytosis inhibitor and a caveolae-mediated endocytosis inhibitor in BEAS-2B cells cultured in Ham's F12 and HBEpCs cultured in SFGM. In conclusion, we suggest that BEAS-2B cells cultured in a medium containing serum should be used for the safety evaluation of nanomaterials as a model of normal human bronchial epithelial cells. However, the culture medium composition may affect the proteins that are expressed on the cytoplasmic membrane, which may influence the biological response to MWCNTs. © 2013 The Authors.


Preoperative radiographic and histopathologic evaluation of central chondrosarcoma
ARCHIVES OF ORTHOPAEDIC AND TRAUMA SURGERY,133(9):1225-1231 2013(Sep.)
Author:Yasuo Yoshimura; Ken-ichi Isobe; Hideki Arai; Kaoru Aoki; Munehisa Kito; Hiroyuki Kato
Abstract:Distinguishing grade 1 chondrosarcoma from grade 2 chondrosarcoma is critical both for planning the surgical procedure and for predicting the outcome. We aimed to review the preoperative radiographic and histologic findings, and to evaluate the reliability of preoperative grading.We retrospectively reviewed the medical records of 17 patients diagnosed with central chondrosarcoma at our institution between 1996 and 2011. In these cases, we compared the preoperative and postoperative histologic grades, and evaluated the reliability of the preoperative histologic grading. We also assessed the preoperative radiographic findings obtained using plain radiography, computed tomography (CT), and magnetic resonance imaging (MRI).Preoperative histologic grade was 1 in 12 patients, 2 in 4 patients, and 3 in 1 patient. However, 6 of the 12 cases classified as grade 1 before surgery were re-classified as grade 2 postoperatively. In the radiographic evaluation, grade 1 was suspected by the presence of a ring-and-arc pattern of calcification on plain radiography and CT and entrapped fat and ring-and-arc enhancement on MRI. Grades 2 and 3 were suspected by the absence of calcification and the presence of cortical penetration and endosteal scalloping on plain radiography and CT, as well as soft-tissue mass formation on MRI.Although the combination of radiographic interpretation and histologic findings may improve the accuracy of preoperative grading in chondrosarcoma, the establishment of a standard evaluation system with the histologic and radiographic findings and/or the development of new biologic markers are necessary for preoperative discrimination of low-grade chondrosarcoma from high-grade chondrosarcoma.


カーボンナノチューブ(CNT)に対する細胞反応の定量的評価法の開発 ONE TO ONE法
信州医学雑誌,61(4):249-249 2013(Aug.)
Author:高梨 誠司; 羽二生 久夫; 石垣 範雄; 青木 薫; 清水 政幸; 岡本 正則; 小林 伸輔; 野村 博紀; 加藤 博之; 薄井 雄企; 齋藤 直人


Peapod-CNTによるカーボンナノチューブの体内動態評価方法の開発(第2報)
日本整形外科学会雑誌,87(8):S1481-S1481 2013(Aug.)
Author:小林 伸輔; 羽二生 久夫; 薄井 雄企; 青木 薫; 石垣 範雄; 清水 政幸; 高梨 誠司; 岡本 正則; 野村 博紀; 加藤 博之; 齋藤 直人


多層カーボンナノチューブ(multi wall carbon nanotubes, MWCNT)の関節内での反応とサイトカイン、ケモカイン分泌量
日本整形外科学会雑誌,87(8):S1475-S1475 2013(Aug.)
Author:野村 博紀; 羽二生 久夫; 小林 伸輔; 高梨 誠司; 岡本 正則; 青木 薫; 清水 政幸; 薄井 雄企; 齋藤 直人


遺伝子導入発癌性マウス(rasH2マウス)を用いたCNT発癌性評価
日本整形外科学会雑誌,87(8):S1474-S1474 2013(Aug.)
Author:高梨 誠司; 羽二生 久夫; 薄井 雄企; 青木 薫; 石垣 範雄; 清水 政幸; 岡本 正則; 小林 伸輔; 野村 博紀; 加藤 博之; 齋藤 直人


カーボンナノチューブの肉腫細胞に対するdrug delivery systemとしての可能性
日本整形外科学会雑誌,87(8):S1462-S1462 2013(Aug.)
Author:青木 薫; 羽二生 久夫; 清水 政幸; 岡本 正則; 高梨 誠司; 小林 伸輔; 野村 博紀; 加藤 博之; 薄井 雄企; 齋藤 直人


培養液による多層カーボンナノチューブのBEAS-2B細胞におけるバイオレスポンスへの影響
The Journal of Toxicological Sciences,38(Suppl.):S345-S345 2013(Jun.)
Author:羽二生 久夫; 齋藤 直人; 松田 佳和; 丸山 佳与; 薄井 雄企; 青木 薫; 高梨 誠司; 小林 伸輔; 野村 博紀; 岡本 正則; 清水 政幸; 加藤 博之


Carcinogenicity evaluation for the application of carbon nanotubes as biomaterials in rasH2 mice (vol 2, pg 498, 2012)
SCIENTIFIC REPORTS,3 2013(Apr.)
Author:Seiji Takanashi; Kazuo Hara; Kaoru Aoki; Yuki Usui; Masayuki Shimizu; Hisao Haniu; Nobuhide Ogihara; Norio Ishigaki; Koichi Nakamura; Masanori Okamoto; Shinsuke Kobayashi; Hiroyuki Kato; Kenji Sano; Naoyuki Nishimura; Hideki Tsutsumi; Kazuhiko Machida; Naoto Saito


Microstructure development and fracture toughness of acid-treated carbon nanofibers/alumina composites
JOURNAL OF THE CERAMIC SOCIETY OF JAPAN,120(1408):560-568 2012(Dec.)
Author:Naoki Ueda; Tomohiko Yamakami; Tomohiro Yamaguchi; Kunio Kitajima; Yuki Usui; Kaoru Aoki; Morinobu Endo; Naoto Saito; Seiichi Taruta
Abstract:In this study, carbon nanofibers (CNFs) having different amounts of defect were prepared by acid-treating for 0.5, 1 and 5 h and were combined with alumina. Then, the influence of the amount of defect on the CNFs on microstructure development of the CNFs/alumina composites and relationship between the fracture toughness and the average alumina grain size was investigated. The intensity ratio of D-band to G-band (D/G) in Raman spectra of the CNFs increased from 0.34 for pristine CNFs to 0.95 for the CNFs acid-treated for 5 h with the acid-treatment time, which indicates that the amount of defect on the CNFs increased with the acid-treatment time. The alumina grain growth in the dense composites sintered at 1200-1300 degrees C was not influenced by the amount of defect on the CNFs, however, the composite containing CNFs having the moderate amount of defect (D/G = 0.56) showed the slowest alumina grain growth rate at 1350-1450 degrees C. The fracture toughness of the composites containing the CNFs acid-treated for 0.5 h increased with a decrease in average alumina grain size and reached 5.6 MPa.m(0.5) at the average alumina grain size of 0.84 mu m, which was 60% higher value compared to monolithic alumina (3.5 MPa.m(0.5)). However, fracture toughness of the composites containing CNFs acid-treated for 1 and 5 h increased with a decrease in average alumina grain size, showed the maximum values of 5.0 and 4.5 MPa.m(0.5) at average alumina grain sizes of 1.3 and 1.6 mu m, respectively, and decreased as the average alumina grain size decreased further. The maximum fracture toughness of the composite containing the CNFs acid-treated for 5 h was lower than that of the composite containing the CNFs acid-treated for 1 h. (C)2012 The Ceramic Society of Japan All rights reserved.


強化材としてカーボンナノチューブを複合したアルミナセラミックスの生体親和性および骨親和性
日本整形外科学会雑誌,86(8):S1052-S1052 2012(Aug.)
Author:荻原 伸英; 青木 薫; 清水 政幸; 羽二生 久夫; 高梨 誠司; 岡本 正則; 加藤 博之; 薄井 雄企; 樽田 誠一; 中山 昇; 齋藤 直人


多層カーボンナノチューブのバイオマテリアルとしての安全性
信州医学雑誌,60(4):217-217 2012(Aug.)
Author:原 一生; 青木 薫; 薄井 雄企; 清水 政幸; 石垣 範雄; 荻原 伸英; 中村 恒一; 高梨 誠司; 岡本 正則; 小林 伸輔; 羽二生 久夫; 加藤 博之; 齋藤 直人


Biocompatibility and bone tissue compatibility of alumina ceramics reinforced with carbon nanotubes
NANOMEDICINE,7(7):981-993 2012(Jul.)
Author:Nobuhide Ogihara; Yuki Usui; Kaoru Aoki; Masayuki Shimizu; Nobuyo Narita; Kazuo Hara; Koichi Nakamura; Norio Ishigaki; Seiji Takanashi; Masanori Okamoto; Hiroyuki Kato; Hisao Haniu; Naoko Ogiwara; Noboru Nakayama; Seiichi Taruta; Naoto Saito
Abstract:The addition of carbon nanotubes (CNTs) remarkably improves the mechanical characteristics of base materials. CNT/alumina ceramic composites are expected to be highly functional biomaterials useful in a variety of medical fields. Biocompatibility and bone tissue compatibility were studied for the application of CNT/alumina composites as biomaterials. Methods & results: Inflammation reactions in response to the composite were as mild as those of alumina ceramic alone in a subcutaneous implantation study. In bone implantation testing, the composite showed good bone tissue compatibility and connected directly to new bone. An in vitro cell attachment test was performed for osteoblasts, chondrocytes, fibroblasts and smooth muscle cells, and CNT/alumina composite showed cell attachment similar to that of alumina ceramic. Discussion & conclusion: Owing to proven good biocompatibility and bone tissue compatibility, the application of CNT/alumina composites as biomaterials that contact bone, such as prostheses in arthroplasty and devices for bone repair, are expected.


Carcinogenicity evaluation for the application of carbon nanotubes as biomaterials in rasH2 mice
SCIENTIFIC REPORTS,2:498 2012(Jul.)
Author:Seiji Takanashi; Kazuo Hara; Kaoru Aoki; Yuki Usui; Masayuki Shimizu; Hisao Haniu; Nobuhide Ogihara; Norio Ishigaki; Koichi Nakamura; Masanori Okamoto; Shinsuke Kobayashi; Hiroyuki Kato; Kenji Sano; Naoyuki Nishimura; Hideki Tsutsumi; Kazuhiko Machida; Naoto Saito
Abstract:The application of carbon nanotubes (CNTs) as biomaterials is of wide interest, and studies examining their application in medicine have had considerable significance. Biological safety is the most important factor when considering the clinical application of CNTs as biomaterials, and various toxicity evaluations are required. Among these evaluations, carcinogenicity should be examined with the highest priority; however, no report using transgenic mice to evaluate the carcinogenicity of CNTs has been published to date. Here, we performed a carcinogenicity test by implanting multi-walled CNTs (MWCNTs) into the subcutaneous tissue of rasH2 mice, using the carbon black present in black tattoo ink as a reference material for safety. The rasH2 mice did not develop neoplasms after being injected with MWCNTs; instead, MWCNTs showed lower carcinogenicity than carbon black. Such evaluations should facilitate the clinical application and development of CNTs for use in important medical fields.


Carbon Nanotubes Induce Bone Calcification by Bidirectional Interaction with Osteoblasts
ADVANCED MATERIALS,24(16):2176-2185 2012(Apr.)
Author:Masayuki Shimizu; Yasuhiro Kobayashi; Toshihide Mizoguchi; Hiroaki Nakamura; Ichiro Kawahara; Nobuyo Narita; Yuki Usui; Kaoru Aoki; Kazuo Hara; Hisao Haniu; Nobuhide Ogihara; Norio Ishigaki; Koichi Nakamura; Hiroyuki Kato; Masatomo Kawakubo; Yoshiko Dohi; Seiichi Taruta; Yoong Ahm Kim; Morinobu Endo; Hidehiro Ozawa; Nobuyuki Udagawa; Naoyuki Takahashi; Naoto Saito


Manufacturing Strategy for Multiwalled Carbon Nanotubes as a Biocompatible and Innovative Material
Journal of Nanotechnology,2012:937819-937819 2012
Author:Haniu, Hisao; Saito, Naoto; Matsuda, Yoshikazu; Usui, Yuki; Aoki, Kaoru; Shimizu, Masayuki; Ogihara, Nobuhide; Hara, Kazuo; Takanashi, Seiji; Okamoto, Masanori; Nakamura, Koichi; Ishigaki, Norio; Tsukahara, Tamotsu; Kato, Hiroyuki
Abstract:We investigated the relationship between differences in multiwalled carbon nanotubes (MWCNTs) and the biological responses they elicit in order to develop biocompatible MWCNTs. We exposed human bronchial epithelial (BEAS-2B) cells to two sizes and six grades of MWCNTs and measured the resulting cell viability, total reactive oxygen and/or nitrogen species (tROS/RNS) production, and cytokine secretion. Although differences in cellular tROS production were associated with differences in grades of MWCNTs, the graphitization temperature of MWCNTs apparently did not influence tROS production. However, cell viability was affected by MWCNT graphitization temperature and diameter. Moreover, cytokine secretion was apparently affected by treatment temperature, but not MWCNT diameter. We concluded that the highest temperature resulted in the most biocompatibility because impurities and carbon defects were removed from the MWCNTs. However, other mechanisms are possible. Therefore, it is important to optimize each type of MWCNT by monitoring biological responses that type elicits during the manufacturing stage for applications involving biology and medicine.


Basic Potential of Carbon Nanotubes in Tissue Engineering Applications
Journal of Nanomaterials,2012(2012):343747 2012
Author:Haniu, Hisao; Saito, Naoto; Matsuda, Yoshikazu; Tsukahara, Tamotsu; Usui, Yuki; Narita, Nobuyo; Hara, Kazuo; Aoki, Kaoru; Shimizu, Masayuki; Ogihara, Nobuhide; Takanashi, Seiji; Okamoto, Masanori; Kobayashi, Shinsuke; Ishigaki, Norio; Nakamura, Koichi; Kato, Hiroyuki
Abstract:Carbon nanotubes (CNTs) are attracting interest in various fields of science because they possess a high surface area-to-volume ratio and excellent electronic, mechanical, and thermal properties. Various medical applications of CNTs are expected, and the properties of CNTs have been greatly improved for use in biomaterials. However, the safety of CNTs remains unclear, which impedes their medical application. Our group is evaluating the biological responses of multiwall CNTs (MWCNTs) in vivo and in vitro for the promotion of tissue regeneration as safe scaffold materials. We recently showed that intracellular accumulation is important for the cytotoxicity of CNTs, and we reported the active physiological functions CNTs in cells. In this review, we describe the effects of CNTs in vivo and in vitro observed by our group from the standpoint of tissue engineering, and we introduce the findings of other research groups.


Effect of dispersants of multi-walled carbon nanotubes on cellular uptake and biological responses
International Journal of Nanomedicine,6(1):3295-3307-3307 2011(Dec.)
Author:Haniu, Hisao; Saito, Naoto; Matsuda, Yoshikazu; Kim, Yoong-Ahm; Park, Chul Ki; Tsukahara, Tamotsu; Usui, Yuki; Aoki, Kaoru; Shimizu, Masayuki; Ogihara, Nobuhide; Hara, Kazuo; Takanashi, Seiji; Okamoto, Masanori; Ishigaki, Norio; Nakamura, Koichi; Kato, Hiroyuki
Abstract:Although there have been many reports about the cytotoxicity of multi-walled carbon nanotubes (MWCNTs), the results are still controversial. To investigate one possible reason, the authors investigated the influence of MWCNT dispersants on cellular uptake and cytotoxicity. Cytotoxicity was examined (measured by alamarBlue® assay), as well as intracellular MWCNT concentration and cytokine secretion (measured by flow cytometry) in human bronchial epithelial cells (BEAS-2B) exposed to a type of highly purified MWCNT vapor grown carbon fiber (VGCF®, Showa Denko Kabushiki-gaisha, Tokyo, Japan) in three different dispersants (gelatin, carboxylmethyl cellulose, and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine). The authors also researched the relationship between the intracellular concentration of MWCNTs and cytotoxicity by using two cell lines, BEAS-2B and MESO-1 human malignant pleural mesothelioma cells. The intracellular concentration of VGCF was different for each of the three dispersants, and the levels of cytotoxicity and inflammatory response were correlated with the intracellular concentration of VGCF. A relationship between the intracellular concentration of VGCF and cytotoxic effects was observed in both cell lines. The results indicate that dispersants affect VGCF uptake into cells and that cytotoxicity depends on the intracellular concentration of VGCF, not on the exposed dosage. Thus, toxicity appears to depend on exposure time, even at low VGCF concentrations, because VGCF is biopersistent.


Elucidation mechanism of different biological responses to multi-walled carbon nanotubes using four cell lines
International Journal of Nanomedicine,6(1):3487-3497-3497 2011(Dec.)
Author:Haniu, Hisao; Saito, Naoto; Matsuda, Yoshikazu; Kim, Yoong-Ahm; Park, Chul Ki; Tsukahara, Tamotsu; Usui, Yuki; Aoki, Kaoru; Shimizu, Masayuki; Ogihara, Nobuhide; Hara, Kazuo; Takanashi, Seiji; Okamoto, Masanori; Ishigaki, Norio; Nakamura, Koichi; Kato, Hiroyuki
Abstract:We examined differences in cellular responses to multi-walled carbon nanotubes (MWCNTs) using malignant pleural mesothelioma cells (MESO-1), bronchial epithelial cells (BEAS-2B), neuroblastoma cells (IMR-32), and monoblastic cells (THP-1), before and after differentiation. MESO-1, BEAS-2B and differentiated THP-1 cells actively endocytosed MWCNTs, resulting in cytotoxicity with lysosomal injury. However, cytotoxicity did not occur in IMR-32 or undifferentiated THP-1 cells. Both differentiated and undifferentiated THP-1 cells exhibited an inflammatory response. Carbon blacks were endocytosed by the same cell types without lysosomal damage and caused cytokine secretion, but they did not cause cytotoxicity. These results indicate that the cytotoxicity of MWCNTs requires not only cellular uptake but also lysosomal injury. Furthermore, it seems that membrane permeability or cytokine secretion without cytotoxicity results from several active mechanisms. Clarification of the cellular recognition mechanism for MWCNTs is important for developing safer MWCNTs.


Toxicoproteomic evaluation of carbon nanomaterials in vitro
Journal of Proteomics,74(12):2703-2712-2712 2011(Nov.)
Author:Haniu, Hisao; Matsuda, Yoshikazu; Usui, Yuki; Aoki, Kaoru; Shimizu, Masayuki; Ogihara, Nobuhide; Hara, Kazuo; Okamoto, Masanori; Takanashi, Seiji; Ishigaki, Norio; Nakamura, Koichi; Kato, Hiroyuki; Saito, Naoto


DJ-1 as a potential biomarker for the development of biocompatible multiwalled carbon nanotubes
International Journal of Nanomedicine,6(1):2689-2695-2689 2011(Nov.)
Author:Haniu, Hisao; Tsukahara, Tamotsu; Matsuda, Yoshikazu; Usui, Yuki; Aoki, Kaoru; Shimizu, Masayuki; Ogihara, Nobuhide; Hara, Kazuo; Takanashi, Seiji; Okamoto, Masanori; Ishigaki, Norio; Nakamura, Koichi; Kato, Hiroyuki; Saito, Naoto


Evaluation of CNT toxicity by comparison to tattoo ink
MATERIALS TODAY,14(9):434-440 2011(Sep.)
Author:Kazuo Hara; Kaoru Aoki; Yuki Usui; Masayuki Shimizu; Nobuyo Narita; Nobuhide Ogihara; Koichi Nakamura; Norio Ishigaki; Kenji Sano; Hisao Haniu; Hiroyuki Kato; Naoyuki Nishimura; Yoong Ahm Kim; Seiichi Taruta; Naoto Saito
Abstract:The absence of an optimal nano-sized reference material has been the biggest obstacle in evaluating the safety of carbon nanotubes as biomaterials. In this study, black tattoo inks, which have a long history of use by humans, are shown to be suitable reference materials composed of nano-sized carbon black particles. We have also demonstrated that multi-walled carbon nanotubes have comparable basic safety properties to those of tattoo inks when used as biomaterials.


高齢者における歩行速度と骨盤運動の関係
日本整形外科学会雑誌,85(8):S1324-S1324 2011(Aug.)
Author:石垣 範雄; 木村 貞治; 薄井 雄企; 青木 薫; 荻原 伸英; 中村 恒一; 清水 政幸; 岡本 正則; 高梨 誠司; 原 一生; 羽二生 久夫; 加藤 博之; 齋藤 直人


多層カーボンナノチューブによる石灰化促進にはALPが重要である
日本整形外科学会雑誌,85(8):S1315-S1315 2011(Aug.)
Author:清水 政幸; 青木 薫; 成田 伸代; 原 一生; 岡本 正則; 高梨 誠司; 荻原 伸英; 石垣 範雄; 中村 恒一; 加藤 博之; 薄井 雄企; 羽二生 久夫; 齋藤 直人; 小林 泰浩; 宇田川 信之; 高橋 直之


多層カーボンナノチューブのバイオマテリアルとしての発癌性評価
日本整形外科学会雑誌,85(8):S1305-S1305 2011(Aug.)
Author:原 一生; 青木 薫; 薄井 雄企; 清水 政幸; 石垣 範雄; 荻原 伸英; 中村 恒一; 高梨 誠司; 岡本 正則; 羽二生 久夫; 加藤 博之; 齋藤 直人


多層カーボンナノチューブのバイオマテリアルとしての安全性
日本整形外科学会雑誌,85(8):S1304-S1304 2011(Aug.)
Author:原 一生; 青木 薫; 薄井 雄企; 清水 政幸; 石垣 範雄; 荻原 伸英; 中村 恒一; 高梨 誠司; 岡本 正則; 羽二生 久夫; 加藤 博之; 齋藤 直人


カーボンファイバーの骨組織再生のscaffoldとしての評価
日本整形外科学会雑誌,85(8):S1256-S1256 2011(Aug.)
Author:青木 薫; 清水 政幸; 中村 恒一; 石垣 範雄; 荻原 伸英; 原 一生; 岡本 正則; 高梨 誠司; 加藤 博之; 薄井 雄企; 金 隆岩; 齋藤 直人


多層カーボンナノチューブの細胞毒性 分散剤と細胞種の影響
The Journal of Toxicological Sciences,36(Suppl.):S107-S107 2011(Jun.)
Author:羽二生 久夫; 斎藤 直人; 松田 佳和; 塚原 完; 薄井 雄企; 青木 薫; 清水 政幸; 荻原 伸英; 原 一生; 岡本 正則; 高梨 誠司; 石垣 範雄; 中村 恒一; 加藤 博之


Metastatic Carcinoma to Subcutaneous Tissue and Skeletal Muscle: Clinicopathological Features in 11 Cases
JAPANESE JOURNAL OF CLINICAL ONCOLOGY,41(3):358-364 2011(Mar.)
Author:Yasuo Yoshimura; Ken-ichi Isobe; Tsuyoshi Koike; Hideki Arai; Kaoru Aoki; Hiroyuki Kato
Abstract:Objective: Metastatic carcinoma to subcutaneous tissue or skeletal muscle is relatively rare. The present study aimed to clarify the clinicopathological features for confirming the diagnosis as soft tissue metastasis and determining the primary site.Methods: We reviewed records of 11 patients with soft tissue metastasis who were in our institution from 1996 to 2009.Results: In 9 of 10 patients who underwent magnetic resonance imaging, findings consisted of poorly circumscribed high-intensity lesions around the tumor on T2-weighted images, irregular peritumoral enhancement and poorly enhanced lesions at the center of the tumor on T1-weighted images. Systematic immunohistochemical examination was more valuable for diagnosing as soft tissue metastasis and confirming the primary site. The expression patterns of cytokeratins 7 and 20 and tissue-specific antibodies such as thyroid transcription factor-1, MUC5AC and CDX2 were useful diagnostic markers. The primary site could be determined in five patients with cytokeratin 7/20 immunophenotype and positivity for tissue-specific antibodies. In four cases, determination of the primary site finally became possible by comparison with the histological findings of operative specimens in past carcinoma and/or in consideration of radiological findings and the results of cytokeratin 7/20 phenotyping.Conclusions: Systematic immunohistochemical examination is helpful for confirmation of the primary origin in soft tissue metastasis of carcinoma in addition to clinical information such as the history and condition of past carcinoma, radiological findings and comparison between the histology of biopsy specimens and past carcinoma.


Application of carbon fibers to biomaterials: A new era of nano-level control of carbon fibers after 30-years of development
CHEMICAL SOCIETY REVIEWS,40(7):3824-3834 2011
Author:Naoto Saito; Kaoru Aoki; Yuki Usui; Masayuki Shimizu; Kazuo Hara; Nobuyo Narita; Nobuhide Ogihara; Koichi Nakamura; Norio Ishigaki; Hiroyuki Kato; Hisao Haniu; Seiichi Taruta; Yoong Ahm Kim; Morinobu Endo
Abstract:Carbon fibers are state-of-the-art materials with properties that include being light weight, high strength, and chemically stable, and are applied in various fields including aeronautical science and space science. Investigation of applications of carbon fibers to biomaterials was started 30 or more years ago, and various products have been developed. Because the latest technological progress has realized nano-level control of carbon fibers, applications to biomaterials have also progressed to the age of nano-size. Carbon fibers with diameters in the nano-scale (carbon nanofibers) dramatically improve the functions of conventional biomaterials and make the development of new composite materials possible. Carbon nanofibers also open possibilities for new applications in regenerative medicine and cancer treatment. The first three-dimensional constructions with carbon nanofibers have been realized, and it has been found that the materials could be used as excellent scaffolding for bone tissue regeneration. In this critical review, we summarize the history of carbon fiber application to the biomaterials and describe future perspectives in the new age of nano-level control of carbon fibers (122 references).


Fabrication and mechanical properties of high-dispersion-treated carbon nanofiber/alumina composites
JOURNAL OF THE CERAMIC SOCIETY OF JAPAN,118(1381):847-854 2010(Sep.)
Author:Naoki Ueda; Tomohiko Yamakami; Tomohiro Yamaguchi; Kunio Kitajima; Yuki Usui; Kaoru Aoki; Takefumi Nakanishi; Fumiaki Miyaji; Morinobu Endo; Naoto Saito; Seiichi Taruta
Abstract:High-dispersion-treated carbon nanofibers (CNFs) were used to fabricate uniformly-dispersed CNFs-alumina composites with enhanced mechanical properties. The treatment was effective in obtaining dense and uniform composites. The composites containing 0.4-0.8 wt CNFs were densified to a relative density of more than 99% by vacuum sintering and subsequent hot isostatic pressing, and those containing 1.6-2.5 wt % CNFs were densified to full density by plasma activated sintering. The maximum bending strength of the composites (1050 MPa) was approximately the same as the bending strength of monolithic alumina (1079 MPa). The maximum fracture toughness of the composites was 5.9 MPa.m(0.5), which was a 69% increase compared with the fracture toughness of monolithic alumina (3.5 MPa.m(0.5)). Fracture toughness (Kid increased rapidly with a decrease in alumina grain size (G), and we found that the relationship could be expressed by the following equation: K-IC = (k(1)/G(2)) k(2) (where k(1), and k(2) are constants). (C) 2010 The Ceramic Society of Japan. All rights reserved.


Multiwalled Carbon Nanotubes Specifically Inhibit Osteoclast Differentiation and Function
NANO LETTERS,9(4):1406-1413 2009(Apr.)
Author:Nobuyo Narita; Yasuhiro Kobayashi; Hiroaki Nakamura; Kazuhiro Maeda; Akiihiro Ishihara; Toshihide Mizoguchi; Yuki Usui; Kaoru Aoki; Masayuki Simizu; Hiroyuki Kato; Hidehiro Ozawa; Nobuyuki Udagawa; Morinobu Endo; Naoyuki Takahashi; Naoto Saito
Abstract:Since attention has been paid to the use of multiwalled carbon nanotubes (MWCNTs) as biornaterials in contact with bone, it is critical to understand the reaction of bone cells to MWCNTs. We show that MWCNTs inhibit osteoclastic bone resorption in vivo and that MWCNTs inhibit osteociastic differentiation and suppressed a transcription factor essential for osteoclastogenesis in vitro. These results suggest that MWCNTs have beneficial effects on bones when they are used as biornaterials.


A Thin Carbon Fiber Web as a Scaffold for Bone Tissue Regeneration
SMALL,5(13):1540-1546 2009
Author:Aoki, K; Usui, Y; Narita, N; Ogiwara, N; Ishigaki, N; Nakamura, K; Kato, H; Sano, K; Ogiwara, N; Kametani, K; Kim, C; Taruta, S; Kim, YA; Endo, M; Saito, N


Carbon nanotubes: biomaterial applications
CHEMICAL SOCIETY REVIEWS,38(7):1897-1903 2009
Author:Naoto Saito; Yuki Usui; Kaoru Aoki; Nobuyo Narita; Masayuki Shimizu; Kazuo Hara; Nobuhide Ogiwara; Koichi Nakamura; Norio Ishigaki; Hiroyuki Kato; Seiichi Taruta; Morinobu Endo
Abstract:There is increasing interest in the unique biological and medical properties of carbon nanotubes (CNTs), and it is expected that biomaterials incorporating CNTs will be developed for clinical use. There has been a great deal of progress in improving the various properties of CNTs for use in biomaterials and for promotion of tissue regeneration as scaffold materials. The effects of CNTs on cells and tissues are extremely important for their use in biomaterials. This tutorial review clarifies the current state of knowledge in the interdisciplinary field of CNT-based nanobiotechnology to determine whether CNTs may be useful in biomaterials. Future perspectives in this rapidly developing field will also be discussed.


Carbon nanotubes with high bone-tissue compatibility and bone-formation acceleration effects
SMALL,4(2):240-246 2008(Feb.)
Author:Yuki Usui; Kaoru Aoki; Nobuyo Narita; Narumichi Murakami; Isao Nakamura; Koichi Nakamura; Norio Ishigaki; Hiroshi Yamazaki; Hiroshi Horiuchi; Hiroyuki Kato; Seiichi Taruta; Yoong Ahm Kim; Morinobu Endo; Naoto Saito
Abstract:Carbon nanotubes (CNTs) have been used in various fields as composites with other substances or alone to develop highly functional materials. CNTs hold great interest with respect to biomaterials, particularly those to be positioned in contact with bone such as prostheses for arthroplasty, plates or screws for fracture fixation, drug delivery systems, and scaffolding for bone regeneration. Accordingly, bone-tissue compatibility of CNTs and CNT influence on bone formation are important issues, but the effects of CNTs on bone have not been delineated. Here, it is found that multi-walled CNTs adjoining bone induce little local inflammatory reaction, show high bone-tissue compatibility, permit bone repair, become integrated into new bone, and accelerate bone formation stimulated by recombinant human bone morphogenetic protein-2 (rhBMP-2). This study provides an initial investigational basis for CNTs in biomaterials that are used adjacent to bone, including uses to promote bone regeneration. These findings should encourage development of clinical treatment modalities involving CNTs.


Carbon nanotubes for biomaterials in contact with bone
CURRENT MEDICINAL CHEMISTRY,15(5):523-527 2008(Feb.)
Author:Naoto Saito; Yuki Usui; Kaoru Aoki; Nobuyo Narita; Masayuki Shimizu; Nobuhide Ogiwara; Koichi Nakamura; Norio Ishigaki; Hiroyuki Kato; Seiichi Taruta; Morinobu Endo
Abstract:Carbon nanotubes (CNTs) possess exceptional mechanical, thermal, and electrical properties, facilitating their use as reinforcements or additives in various materials to improve the properties of the materials. Furthermore, chemically modified CNTs can introduce novel functionalities. In the medical field, biomaterials are expected to be developed using CNTs for clinical use. Biomaterials often are placed adjacent to bone. The use of CNTs is anticipated in these biomaterials applied to bone mainly to improve their overall mechanical properties, for applications such as high-strength arthroplasty prostheses or fixation plates and screws that will not fail. In addition, CNTs are expected to be used as local drug delivery systems (DDS) and/or scaffolds to promote and guide bone tissue regeneration. However, studies examining the use of CNTs as biomaterials still are in the preliminary stages. In particular, the influence of CNTs on osteoblastic cells or bone tissue is extremely important for the use of CNTs in biomaterials placed in contact with bone, and some studies have explored this. This review paper clarifies the current state of knowledge in the context of the relationship between CNTs and bone to determine whether CNTs might perform in biomaterials in contact with bone, or as a DDS and/or scaffolding for bone regeneration.


Brothers with genu recurvatum
KNEE,14(6):500-501 2007(Dec.)
Author:Naoto Saito; Keiji Tensyo; Hiroshi Horiuchi; Kaoru Aoki; Seneki Kobayashi; Hiroyuki Kato; Tornoki Kosho
Abstract:Genu recurvatum deformity is rare, usually resulting from injury to the anterior part of the proximal tibial growth plate. However, a small group of cases have no known cause. We describe brothers with the same type of this deformity on the same side. The degree of deformity differed between them, but deformities began at the same age in both (17 years) and progressed over a short period. There was no history of trauma, or other orthopaedic or genetic disorders. These features strongly suggested involvement of heritable risk factors. (c) 2007 Elsevier B.V. All rights reserved.

研究費
科学研究費補助金(研究代表者)
2020 - 2022 , 化学療法剤複合カーボンナノチューブによる肉腫の治療 , 基盤研究(C)
2014 - 2015 , 肉腫に対する抗がん剤複合多層カーボンナノチューブの効果 , 若手研究(B)

科学研究費補助金(研究分担者)
2022 - 2026 , カーボンナノ粒子が示す特異な生体反応の解明による革新的生体材料の開発と安全性評価 , 基盤研究(A)
2015 - 2017 , 小骨固定・骨移植・骨再生・エンテーシス再建のためのチタンペーパーの開発 , 挑戦的萌芽研究
2014 - 2015 , 多層カーボンナノチューブブロックを用いたin vitroでの骨形成再現実験 , 挑戦的萌芽研究
2012 - 2016 , CNTを応用した高機能生体材料創製のためのCNT・生体界面技術の構築と安全性評価 , 基盤研究(A)
2006 - 2009 , 人工関節のための新規生体材料であるカーボンナノチューブ・セラミックス複合体の開発 , 基盤研究(A)

教育活動実績

授業等
2020 , 前期 , 義肢学
2020 , 前期 , 整形外科学
2020 , 後期 , リハビリテーション概論
2020 , 後期 , 装具学
2019 , 前期 , 義肢学
2019 , 前期 , 整形外科学
2019 , 後期 , リハビリテーション概論
2019 , 後期 , 装具学
2018 , 前期 , 整形外科学
2018 , 前期 , 義肢学
2018 , 後期 , 装具学
2018 , 後期 , リハビリテーション概論
2016 , 前期 , 体と心のリハビリテーションを考えるゼミ