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Full size image. Table 1 Toxicity of GFNs in organs. Full size table. Toxicity in internal organs
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Fig. 1
Graphene materials and their biological interactions. ( A ) A parameter space for the most widely used graphene materials can be described by the dimensions and surface functionalization of the material, the latter defined as the percentage of the carbon atoms in sp3 hybridization. Green squares represent epitaxially grown graphene; yellow, mechanically exfoliated graphene; red, chemically exfoliated graphene; blue, graphene oxide. Note that a number of other graphene-related materials (such as graphene quantum dots and graphene nanoribbons) are also being used in experiments. ( B ) Possible interactions between graphene-related materials with cells (the graphene flakes are not to scale). (a) Adhesion onto the outer surface of the cell membrane. (b) Incorporation in between the monolayers of the plasma membrane lipid bilayer. (c) Translocation of membrane. (d) Cytoplasmic internalization. (e) Clathrin-mediated endocytosis. (f) Endosomal or phagosomal internalization. (g) Lysosomal or other perinuclear compartment localization. (h) Exosomal localization. The biological outcomes from such interactions can be considered to be either adverse or beneficial, depending on the context of the particular biomedical application. Different graphene-related materials will have different preferential mechanisms of interaction with cells and tissues that largely await discovery. [90] Copyright (2014), with permission from American Association for Advancement of Science
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Toxicity of GFNs in organs
The toxicity and biocompatibility of GFNs has been observed and assessed through theoretical and animal model studies. At present, there are a mass of data demonstrating the toxicity of GFNs in different organs or systems in animals, so that it is hard to list all the data in this review. Thus we summarized a certain number literature and chose some in vivo toxicological studies of GFNs listed in Table 1.
Table 1 Toxicity of GFNs in organs
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Toxicity in internal organs
GO can result in acute inflammation response and chronic injury by interfering with the normal physiological functions of important organs [32, 81]. Oral gavage experiments did not show detectable absorption of GO through the gastrointestinal tract [95]. Interesting, a low dose of GO caused serious damage to the gastrointestinal tract after maternal mice drank a GO suspension rather than a high-dose of GO because a low dose of GO without agglomeration can easily attach to the gastrointestinal surface and cause destruction through its abundant sharp edges [53]. GFNs caused inflammation and remained in the lung on day 90 after a single intratracheal instillation, and even translocated to lung lymph nodes by a nose-only inhalation [96, 97]. A high dose of GO that forms aggregations can block pulmonary blood vessels and result in dyspnea [50, 98], and platelet thrombi were observed at high concentrations of 1 and 2 mg/kg body weight via intravenous injection [89]. GO reportedly disrupted the alveolar-capillary barrier, allowing inflammatory cells to infiltrate into the lungs and stimulate the release of pro-inflammatory cytokines [99]. Fibrosis and inflammation could be verified by the increased levels of the protein markers collagen1, Gr1, CD68 and CD11b in the lungs. The use of Tween 80 to disperse FLG or a pluronic surfactant to disperse graphene was suggested to reduce the likelihood of lung fibrosis formation in cells or mice, whereas lung fibrosis was observed when graphene was suspended with bovine serum albumin (BSA) [100]. In addition, radioactive isotopes can be delivered into the lungs, accompanied by a depth distribution of 125I-NGO in the lungs, and the isotopes might deposit there and result in mutations and cancers [30]. However, recent publications claimed no obvious pathological changes in mice exposed to low dosages of GO and functionalized graphene by intravenous injection, including aminated GO (GO-NH2), poly(acrylamide)-functionalized GO (GO-PAM), poly(acrylic acid)-functionalized GO (GO-PAA) and GO-PEG; only GO-PEG and GO-PAA induced less toxicity than pristine GO in vivo [31, 79, 89]. So the functional groups of GFNs and the working concentration or aggregate state largely influence the toxicity of GFNs. Recently, the ways to modify the functional group of GFNs, decrease the working concentration or change the aggregate condition are usually used to decrease the toxicity of GFNs.
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