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Atsushi Sobajima,1 Hisao Haniu,1,2 Hiroki Nomura,1 Manabu Tanaka,1 Takashi Takizawa,1 Takayuki Kamanaka,1 Kaoru Aoki,1,3 Masanori Okamoto,1 Kazushige Yoshida,1 Jun Sasaki,1 Kumiko Ajima,2 Chika Kuroda,1,2 Haruka Ishida,2 Satomi Okano,2 Katsuya Ueda,2 Hiroyuki Kato,1 Naoto Saito1,21Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Nagano, Japan; 2Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University School of Medicine, Matsumoto, Nagano, Japan; 3Department of Applied Physical Therapy, Shinshu University School of Health Sciences, Matsumoto, Nagano, JapanPurpose: 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 tha

Chika Kuroda,1,2,* Katsuya Ueda,1,3,* Hisao Haniu,1,3–5 Haruka Ishida,1,4 Satomi Okano,1,4 Takashi Takizawa,5 Atsushi Sobajima,5 Takayuki Kamanaka,5 Kazushige Yoshida,5 Masanori Okamoto,5 Tamotsu Tsukahara,6 Yoshikazu Matsuda,7 Kaoru Aoki,8 Hiroyuki Kato,5 Naoto Saito1,3–5 1Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Asahi, Matsumoto, Nagano, Japan; 2Department of Orthopaedic Surgery, Graduate School of Medicine, Shinshu University, Asahi, Matsumoto, Nagano, Japan; 3Department of Biomedical Engineering, Graduate School of Science and Technology, Shinshu University, Asahi, Matsumoto, Nagano, Japan; 4Department of Biomedical Engineering, Graduate School of Medicine, Science and Technology, Shinshu University, Asahi, Matsumoto, Nagano, Japan; 5Department of Orthopaedic Surgery, Shinshu University School of Medicine, Asahi, Matsumoto, Nagano, Japan; 6Department of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, Bunkyo-machi, Nagasaki, Japan; 7Clinical Pharmacology Educational Center, Nihon Pharmaceutical University, Komuro, Ina-machi, Saitama, Japan; 8Physical Therapy Division, School of Health Sciences, Shinshu University, Asahi, Matsumoto, Nagano, Japan *These authors contributed equally to this work 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 multiwalled 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 cyto