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Intranasal exposure to amorphous nanosilica particles could activate intrinsic coagulation cascade and platelets in mice

Tokuyuki Yoshida1, Yasuo Yoshioka1*, Saeko Tochigi1, Toshiro Hirai1, Miyuki Uji1, Ko-ichi Ichihashi1, Kazuya Nagano2, Yasuhiro Abe3, Haruhiko Kamada24, Shin-ichi Tsunoda24, Hiromi Nabeshi5, Kazuma Higashisaka1, Tomoaki Yoshikawa1 and Yasuo Tsutsumi124*

Author Affiliations

1 Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan

2 Laboratory of Biopharmaceutical Research, National Institute of Biomedical Innovation, 7-6-8 Saitoasagi, Ibaraki, Osaka 567-0085, Japan

3 Cancer Biology Research Center, Sanford Research/USD, 2301 E. 60th Street N, Sioux Falls SD 57104, USA

4 The Center for Advanced Medical Engineering and Informatics, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan

5 Division of Foods, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan

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Particle and Fibre Toxicology 2013, 10:41  doi:10.1186/1743-8977-10-41

Published: 20 August 2013



Nanomaterials with particle sizes <100 nm have been already applied in various applications such as cosmetics, medicines, and foods. Therefore, ensuring the safety of nanomaterials is becoming increasingly important. Here we examined the localization and biological responses of intranasally administered amorphous nanosilica particles in mice, focusing on the coagulation system.


We used nanosilica particles with diameters of 30, 70, or 100 nm (nSP30, nSP70, or nSP100 respectively), and conventional microscale silica particles with diameters of 300 or 1000 nm (mSP300 or mSP1000, respectively). BALB/c mice were intranasally exposed to nSP30, nSP70, nSP100, mSP300, or mSP1000 at concentrations of 500 μg/mouse for 7 days. After 24 hours of last administration, we performed the in vivo transmission electron microscopy analysis, hematological examination and coagulation tests.


In vivo transmission electron microscopy analysis showed that nanosilica particles with a diameter <100 nm were absorbed through the nasal cavity and were distributed into liver and brain. Hematological examination and coagulation tests showed that platelet counts decreased and that the activated partial thromboplastin time was prolonged in nSP30 or nSP70-treated groups of mice, indicating that nanosilica particles might have activated a coagulation cascade. In addition, in in vitro activation tests of human plasma, nanosilica particles had greater potential than did conventional microscale silica particles to activate coagulation factor XII. In nanosilica-particle-treated groups, the levels of soluble CD40 ligand, and von Willebrand factor which are involved in stimulating platelets tended to slightly increase with decreasing particle size.


These results suggest that intranasally administered nanosilica particles with diameters of 30 and 70 nm could induce abnormal activation of the coagulation system through the activation of an intrinsic coagulation cascade. This study provides information to advance the development of safe and effective nanosilica particles.

Nanomaterials; Silica; Platelet; Coagulation