Long-term biopersistence of tangled oxidized carbon nanotubes inside and outside macrophages in rat subcutaneous tissue

Because of their mechanical strength, chemical stability, and low molecular weight, carbon nanotubes (CNTs) are attractive biological implant materials. Biomaterials are typically implanted into subcutaneous tissue or bone; however, the long-term biopersistence of CNTs in these tissues is unknown. Here, tangled oxidized multi-walled CNTs (t-ox-MWCNTs) were implanted into rat subcutaneous tissues and structural changes in the t-ox-MWCNTs located inside and outside of macrophages were studied for 2 years post-implantation. The majority of the large agglomerates were present in the intercellular space, maintained a layered structure, and did not undergo degradation. By contrast, small agglomerates were found inside macrophages, where they were gradually degraded in lysosomes. None of the rats displayed symptoms of cancer or severe inflammatory reactions such as necrosis. These results indicate that t-ox-MWCNTs have high biopersistence and do not evoke adverse events in rat subcutaneous tissue in vivo, demonstrating their potential utility as implantable biomaterials.

[1]  T. Ichihashi,et al.  Single-shell carbon nanotubes of 1-nm diameter , 1993, Nature.

[2]  S. C. O'brien,et al.  C60: Buckminsterfullerene , 1985, Nature.

[3]  R. Hurt,et al.  Nanotoxicology: the asbestos analogy revisited. , 2008, Nature nanotechnology.

[4]  David A. Leigh,et al.  Cover Picture: Light‐Driven Transport of a Molecular Walker in Either Direction along a Molecular Track (Angew. Chem. Int. Ed. 1/2011) , 2011 .

[5]  Kunihiro Tsuchida,et al.  Fabrication of ZnPc/protein nanohorns for double photodynamic and hyperthermic cancer phototherapy , 2008, Proceedings of the National Academy of Sciences.

[6]  Maurizio Prato,et al.  Making carbon nanotubes biocompatible and biodegradable. , 2011, Chemical communications.

[7]  Maurizio Prato,et al.  Functionalized carbon nanotubes for probing and modulating molecular functions. , 2010, Chemistry & biology.

[8]  P. Tran,et al.  Carbon nanofibers and carbon nanotubes in regenerative medicine. , 2009, Advanced drug delivery reviews.

[9]  M. Hashida,et al.  Photothermic regulation of gene expression triggered by laser-induced carbon nanohorns , 2012, Proceedings of the National Academy of Sciences.

[10]  Larry L. Hench,et al.  Biomaterials, artificial organs and tissue engineering , 2005 .

[11]  Paola Nicolussi,et al.  Functionalized multiwalled carbon nanotubes as ultrasound contrast agents , 2012, Proceedings of the National Academy of Sciences.

[12]  M. Dresselhaus,et al.  Structure and intercalation of thin benzene derived carbon fibers , 1989 .

[13]  Y. Kim,et al.  Carbon nanotubes with high bone-tissue compatibility and bone-formation acceleration effects. , 2008, Small.

[14]  Hui Hu,et al.  Bone cell proliferation on carbon nanotubes. , 2006, Nano letters.

[15]  J. Nagy,et al.  Structural defects play a major role in the acute lung toxicity of multiwall carbon nanotubes: physicochemical aspects. , 2008, Chemical research in toxicology.

[16]  M. Yudasaka,et al.  A photo-thermal-electrical converter based on carbon nanotubes for bioelectronic applications. , 2011, Angewandte Chemie.

[17]  K Kostarelos,et al.  Promises, facts and challenges for carbon nanotubes in imaging and therapeutics. , 2009, Nature nanotechnology.

[18]  B. Harrison,et al.  Surface Studies on Graphite: Acidic Surface Oxides, , 1972 .

[19]  A. Bianco,et al.  Oxidative biodegradation of single- and multi-walled carbon nanotubes. , 2011, Nanoscale.

[20]  Zhuang Liu,et al.  Selective probing and imaging of cells with single walled carbon nanotubes as near-infrared fluorescent molecules. , 2008, Nano letters.

[21]  Maurizio Prato,et al.  Asbestos-like pathogenicity of long carbon nanotubes alleviated by chemical functionalization. , 2013, Angewandte Chemie.

[22]  S. Toyokuni,et al.  Diameter and rigidity of multiwalled carbon nanotubes are critical factors in mesothelial injury and carcinogenesis , 2011, Proceedings of the National Academy of Sciences.

[23]  K. Machida,et al.  Carcinogenicity evaluation for the application of carbon nanotubes as biomaterials in rasH2 mice , 2012, Scientific Reports.

[24]  Y. Liu,et al.  Understanding the toxicity of carbon nanotubes. , 2013, Accounts of chemical research.

[25]  W. G. LIGHT,et al.  Surface charge and asbestos toxicity , 1977, Nature.

[26]  S. Iijima Helical microtubules of graphitic carbon , 1991, Nature.

[27]  Judith Klein-Seetharaman,et al.  Carbon nanotubes degraded by neutrophil myeloperoxidase induce less pulmonary inflammation. , 2010, Nature nanotechnology.

[28]  W. Krätschmer,et al.  Solid C60: a new form of carbon , 1990, Nature.

[29]  F. Toma,et al.  Potentiometric titration as a straightforward method to assess the number of functional groups on shortened carbon nanotubes , 2010 .

[30]  Y. Nodasaka,et al.  High-resolution electron microscopy of multi-wall carbon nanotubes in the subcutaneous tissue of rats. , 2008, Journal of electron microscopy.

[31]  A. Yokoyama,et al.  In vivo rat subcutaneous tissue response of binder-free multi-walled carbon nanotube blocks cross-linked by de-fluorination , 2008 .

[32]  R. Dutton,et al.  Heparin Bonding on Colloidal Graphite Surfaces , 1963, Science.

[33]  E. Abe,et al.  An ultrastructural study on the multinucleation process of mouse alveolar macrophages induced by 1α,25‐dihydroxyvitamin D3 , 1987 .

[34]  Ross W. Ormsby,et al.  Fatigue and biocompatibility properties of a poly(methyl methacrylate) bone cement with multi-walled carbon nanotubes. , 2012, Acta biomaterialia.

[35]  A. Oberlin,et al.  Filamentous growth of carbon through benzene decomposition , 1976 .

[36]  M. S. de Vries,et al.  Cobalt-catalysed growth of carbon nanotubes with single-atomic-layer walls , 1993, Nature.

[37]  M. Prato,et al.  Carbon nanotube substrates boost neuronal electrical signaling. , 2005, Nano letters.

[38]  Yuki Usui,et al.  Biocompatibility and bone tissue compatibility of alumina ceramics reinforced with carbon nanotubes. , 2012, Nanomedicine.

[39]  P. Walker,et al.  Thermal desorption analysis of oxygen surface complexes on carbon , 1978 .

[40]  L. Goodglick,et al.  Role of reactive oxygen metabolites in crocidolite asbestos toxicity to mouse macrophages. , 1986, Cancer research.

[41]  Roberto Madeddu,et al.  Ex vivo impact of functionalized carbon nanotubes on human immune cells. , 2012, Nanomedicine.

[42]  J. Bohr,et al.  C60 a new form of carbon , 1992 .

[43]  M. Prato,et al.  Targeting carbon nanotubes against cancer. , 2012, Chemical communications.

[44]  Wei Wang,et al.  Preparation and characteristics of a binderless carbon nanotube monolith and its biocompatibility , 2008 .

[45]  J. Bokros,et al.  Carbon biomedical devices , 1977 .

[46]  B. Basu,et al.  Microstructure, mechanical properties, and in vitro biocompatibility of spark plasma sintered hydroxyapatite-aluminum oxide-carbon nanotube composite , 2010 .

[47]  Bengt Fadeel,et al.  Impaired Clearance and Enhanced Pulmonary Inflammatory/Fibrotic Response to Carbon Nanotubes in Myeloperoxidase-Deficient Mice , 2012, PloS one.

[48]  M. Yudasaka,et al.  Nano-aggregates of single-walled graphitic carbon nano-horns , 1999 .

[49]  Judith Klein-Seetharaman,et al.  Mechanistic investigations of horseradish peroxidase-catalyzed degradation of single-walled carbon nanotubes. , 2009, Journal of the American Chemical Society.

[50]  Craig A. Poland,et al.  Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study. , 2008, Nature nanotechnology.

[51]  S. Bachilo,et al.  Near-infrared fluorescence microscopy of single-walled carbon nanotubes in phagocytic cells. , 2004, Journal of the American Chemical Society.

[52]  Xinyuan Liu,et al.  Biodurability of Single-Walled Carbon Nanotubes Depends on Surface Functionalization. , 2010, Carbon.

[53]  Rodney Andrews,et al.  Protein immobilization on carbon nanotubes through a molecular adapter. , 2004, Journal of nanoscience and nanotechnology.

[54]  Y. Nodasaka,et al.  Influence of length on cytotoxicity of multi-walled carbon nanotubes against human acute monocytic leukemia cell line THP-1 in vitro and subcutaneous tissue of rats in vivo. , 2005, Molecular bioSystems.

[55]  A. Boccaccini,et al.  Carbon Nanotube Coatings on Bioglass‐Based Tissue Engineering Scaffolds , 2007 .

[56]  Y. Nodasaka,et al.  Cell Culture on a Carbon Nanotube Scaffold , 2005 .

[57]  M. Prato,et al.  In vivo degradation of functionalized carbon nanotubes after stereotactic administration in the brain cortex. , 2012, Nanomedicine.

[58]  H. Kroto,et al.  Pyrolytic carbon nanotubes from vapor-grown carbon fibers , 1995 .

[59]  A. Yokoyama,et al.  Biocompatibility and osteogenesis of refractory metal implants, titanium, hafnium, niobium, tantalum and rhenium. , 2001, Biomaterials.

[60]  N. Hackerman,et al.  Surface of a carbon with sorbed oxygen on pyrolysis , 1968 .

[61]  D. C. Koningsberger,et al.  Surface oxidation of carbon nanofibres. , 2002, Chemistry.

[62]  Yong Zhao,et al.  Enzymatic degradation of multiwalled carbon nanotubes. , 2011, The journal of physical chemistry. A.

[63]  Ivana Fenoglio,et al.  Reactivity of carbon nanotubes: free radical generation or scavenging activity? , 2006, Free radical biology & medicine.

[64]  F. Toma,et al.  Degree of chemical functionalization of carbon nanotubes determines tissue distribution and excretion profile. , 2012, Angewandte Chemie.