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WIREs Nanomed Nanobiotechnol
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Cytotoxicity of graphene: recent advances and future perspective

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Abstract Graphene, a unique two‐dimensional single‐atom‐thin nanomaterial with exceptional structural, mechanical, and electronic properties, has spurred an enormous interest in many fields, including biomedical applications, which at the same time ignites a growing concern on its biosafety and potential cytotoxicity to human and animal cells. In this review, we present a summary of some very recent studies on this important subject with both experimental and theoretical approaches. The molecular interactions of graphene with proteins, DNAs, and cell membranes (both bacteria and mammalian cells) are discussed in detail. Severe distortions in structures and functions of these biomacromolecules by graphene are identified and characterized. For example, the graphene is shown to disrupt bacteria cell membranes by insertion/cutting as well as destructive extraction of lipid molecules directly. More interestingly, this cytotoxicity has been shown to have implications in de novo design of nanomedicine, such as graphene‐based band‐aid, a potential ‘green’ antibiotics due to its strong physical‐based (instead of chemical‐based) antibacterial capability. These studies have provided a better understanding of graphene nanotoxicity at both cellular and molecular levels, and also suggested therapeutic potential by using graphene's cytotoxicity against bacteria cells. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials
All‐atom molecular dynamics simulations of corner piercing of a monolayer graphene across a lipid bilayer. (a) Simulations directly showing that the corner piercing proceeds spontaneously. (b) Graphene‐bilayer interaction energy as a function of the penetration distance, showing the existence of an energy barrier of about 5 kBT associated with corner piercing. The mean value of interaction energy is obtained from 11 independent simulation runs and the error bars show standard deviation. The relatively large fluctuations of interaction energy at large penetration distance are mainly due to random translational and rotational movements of graphene relative to the bilayer membrane and random configurational changes of individual lipids adjacent to the graphene. (c) Analytical model of corner piercing. (Reprinted with permission from Ref . Copyright 2013 PNAS)
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Coarse‐grained molecular dynamics simulations of interactions between a lipid bilayer and (a–d) a small graphene flake, or (e–h) a large 5‐layer graphene sheet with staggered stacking and roughened edge topography; (i) the normalized free energy of the system as a function of the graphene orientation when one of the sharpest corners is fixed at a distance of 0.5 nm above the bilayer. Note that (a–d) and (f–h) are time sequences; (e) is an experimental graphene edge structure. (Reprinted with permission from Ref . Copyright 2013 PNAS)
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Graphene microsheets cutting into three types of cells (Scale bars, 2 µm). (a) Corner penetration observed for a graphene sheet of micron‐scale lateral dimension on the surface of a human lung epithelial cell at low and high magnification. (b) Edge penetration of multiple microsheets (G) into a macrophage (M), (c) Edge penetration for a 5 µm graphene sheet interacting with primary human keratinocytes, in which the edge entry appears to have been nucleated at an asperity or protrusion (thick yellow arrow). (d) Corner penetration mode at the surface of a primary human keratinocyte. The graphene microsheets have layer numbers that range from 4 to 25. (Reprinted with permission from Ref . Copyright 2013 PNAS).
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Cellular uptake and internalization of few‐layer graphene microsheets. (a) and (b) Confocal images of human lung epithelial cells (a and b) and mouse macrophages (c) exposed to graphene microsheets (0.5–25 µm lateral dimension) after 24 and 5 h, respectively. The nuclei in (a) and (b), are visualized (blue fluorescence) with 4′,6‐diamidino‐2‐phenylindole (DAPI). The microtubules of the lung epithelial cells (a and b) are visualized using antitubulin β antibodies conjugated with FITC (green fluorescence), whereas the actin cytoskeleton of macrophages shown in (c) is visualized using rhodamine‐phalloidin (red fluorescence). In unexposed lung epithelial cells ( a and b‐insert), cytoplasmic microtubules (MT) form a linear network spanning across the cytoplasm. Internalized graphene flakes (yellow arrows; a and b) physically displace the linear microtubular network. In unexposed macrophages (c‐insert), filamentous actin (F) is organized into aggregates beneath the plasma membrane. Internalized graphene flakes with large lateral dimension (yellow arrow, c) induce dense aggregates of actin filaments while submicron graphene sheets (yellow arrow head, c) do not disrupt the actin cytoskeleton. Transmission electron micrographs of macrophages (d) and lung epithelial cells (e) exposed to 10 ppm FLG sheets (∼800 nm in lateral dimension) for 5 and 24 h show localization in the cytoplasm within membrane‐bound vacuoles (blue inserts). Graphene microsheets inside vacuoles appear as electron‐dense linear sections (d inset) or irregular flakes (e inset). (Reprinted with permission from Ref . Copyright 2013 PNAS)
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Graphene nanosheet insertion and lipid extraction. (a) Graphene nanosheet insertion and lipid extraction in the outer membrane (Pure POPE); and (b) in the inner membrane (3:1 Mixed POPE‐POPG). Water is shown in ice‐blue, and the phospholipids in tan lines with hydrophilic charged atoms in color spheres (hydrogen in white, oxygen in red, nitrogen in blue, and phosphorus in orange). The graphene sheet is shown as a yellow‐bonded sheet with a large sphere marked at one corner as the restrained atom in simulations. Those extracted phospholipids are shown in larger spheres with hydrogen in white, oxygen in red, nitrogen in blue, carbon in cyan, and phosphorus in orange. (Reprinted with permission from Ref . Copyright 2013 Nature Nanotechnology)
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Morphology of Escherichia coli exposed to graphene oxide nanosheets. (a)–(f) Transmission electron microscopy images showing E. coli undergoing changes in morphology after incubation with 100 µg/mL graphene‐oxide nanosheets at 37°C for 2.5 h. Three stages of destruction can be seen: (a) Initial morphology of E. coli (control or Stage 1; two individual TEM images (inset and main image) are shown, the scale bar applies to both)). (b and c) Partial damage of cell membranes with some bacteria showing lower density of surface phospholipids (Stage II). Arrows indicate Type B mechanism, where graphene nanosheets extract phospholipids from the cell membrane. (d–f) Three representative images showing the complete loss of membrane integrity, with some showing ‘empty nests’ and missing cytoplasm (Stage III). (d, f) Representative images showing Type A mechanism, where graphene nanosheets cut off large areas of membrane surfaces. (Reprinted with permission from Ref . Copyright 2013 Nature Nanotechnology)
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Self‐assembly of DNA segments on graphene layers. Snapshots were taken at (a) t = 0 nanoseconds, (b) t = 8 nanoseconds, (c) t = 16 nanoseconds, (d) t = 42 nanoseconds. Both top view and side view are shown for each snapshot. Color scheme: gray (C), red (O), blue (N), yellow (P), and white (H). (Reprinted with permission from Ref . Copyright 2011 Journal of Physical Chemistry)
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Boxplot for the interaction energy between each residue of HP35 and graphene, (5, 5)‐SWCNT, and C60. For every point of the boxplot, the middle bold line in the box indicates the median of the data, the upper/lower edge of the box indicates the upper/lower quartile (the 75th/25th percentile) of the data, and the end of whiskers indicates the maximum and the minimum of the data. The color of the points indicates the probability of the residue in contact with the graphene (see text for more details): 0–20% (red), 20–40% (orange), 40–60% (green), 60–80% (cyan), and 80–100% (blue). (Reprinted with permission from Ref . Copyright 2011 Journal of Physical Chemistry)
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A representative trajectory of HP35 adsorbing onto the graphene. (a) Representative snapshots at various time points. The proteins are shown in cartoons with red helix and green loop, and the graphene is shown in wheat. The aromatic residues which form the π–π stacking interactions are shown in blue stick, while the rest shown in green. (b) The contacting surface area of HP35 with the graphene. (c) The RMSD of HP35 from its native structure and the number of residues in the α‐helix structure. (d) The distance between the graphene and the aromatic residues, including F35, W23, F10, F17, and F06. In order to make the adsorbing process clearer, the x‐axis had been truncated and rescaled. The figures were plotted by program R. (Reprinted with permission from Ref . Copyright 2011 Journal of Physical Chemistry)
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Antibacterial activity of Cotton‐graphene‐oxide (GO) and inactivation efficiency for GO modified cotton fabrics. About 100 μL elute was vaccinated in agar plate and then incubated overnight (a). Inactivation efficiency for GO modified cotton fabrics tested by Escherichia coli (b) and Bacillus subtilis (c). (Reprinted with permission from Ref . Copyright 2013 Advanced Healthcare Material)
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Preparation of graphene‐oxide (GO) modified cotton fabrics by means of adsorption (Cotton‐GO), radiation‐induced crosslinking (Cotton‐rx‐GO), and chemical crosslinking (Cotton‐cx‐GO). (Reprinted with permission from Ref . Copyright 2013 Advanced Healthcare Material)
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Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease
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