Latest Articles Include:
- Quantifying the biodistribution of nanoparticles
- Nat Nanotechnol 6(12):755 (2011)
Article preview View full access options Nature Nanotechnology | Correspondence Quantifying the biodistribution of nanoparticles * Xiao He1 * Zhiyong Zhang1 * Jinsen Liu2 * Yuhui Ma1 * Peng Zhang1 * Yuanyuan Li1 * Zhenqiang Wu2 * Yuliang Zhao1 * Zhifang Chai1 * Affiliations * Corresponding authorsJournal name:Nature NanotechnologyVolume: 6,Page:755Year published:(2011)DOI:doi:10.1038/nnano.2011.219Published online06 December 2011 To the Editor Yamashita et al. (Nature Nanotech.6, 321–328; 2011) report that silica and titanium dioxide (TiO2) nanoparticles with diameters of 70 nm and 35 nm, respectively, can cross the placental barrier in pregnant mice. Using transmission electron microscopy (TEM), the researchers claim that nanoparticles are found in the liver and brain of the fetus1. Although TEM is useful for the qualitative examination of nanoparticles, it is not sensitive enough for studying the trans-placental transport of TiO2 nanoparticles. Subject terms: * Nanoparticles * Environmental, health and safety issues Article preview Read the full article * Instant access to this article: US$18 Buy now * Subscribe to Nature Nanotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Author information Article tools * Print * Email * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, and Key Laboratory of Nuclear Analytical Techniques, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China * Xiao He, * Zhiyong Zhang, * Yuhui Ma, * Peng Zhang, * Yuanyuan Li, * Yuliang Zhao & * Zhifang Chai * School of Biological Science and Engineering, South China University of Technology, Guangzhou 510641 China * Jinsen Liu & * Zhenqiang Wu Corresponding authors Correspondence to: * Zhiyong Zhang or * Yuliang Zhao Author Details * Xiao He Search for this author in: * NPG journals * PubMed * Google Scholar * Zhiyong Zhang Contact Zhiyong Zhang Search for this author in: * NPG journals * PubMed * Google Scholar * Jinsen Liu Search for this author in: * NPG journals * PubMed * Google Scholar * Yuhui Ma Search for this author in: * NPG journals * PubMed * Google Scholar * Peng Zhang Search for this author in: * NPG journals * PubMed * Google Scholar * Yuanyuan Li Search for this author in: * NPG journals * PubMed * Google Scholar * Zhenqiang Wu Search for this author in: * NPG journals * PubMed * Google Scholar * Yuliang Zhao Contact Yuliang Zhao Search for this author in: * NPG journals * PubMed * Google Scholar * Zhifang Chai Search for this author in: * NPG journals * PubMed * Google Scholar Additional data - Quantifying the biodistribution of nanoparticles
- Nat Nanotechnol 6(12):755 (2011)
Article preview View full access options Nature Nanotechnology | Correspondence Quantifying the biodistribution of nanoparticles * Yasuo Tsutsumi1 * Yasuo Yoshioka1 * Affiliations * Corresponding authorJournal name:Nature NanotechnologyVolume: 6,Page:755Year published:(2011)DOI:doi:10.1038/nnano.2011.220Published online06 December 2011 To the Editor In general, transmission electron microscopy (TEM) and quantitative methods such as inductively coupled plasma-mass spectrometry (ICP-MS) are used to study the biodistribution of nanomaterials. For example, ICP-MS can detect the elements of nanomaterials and evaluate their biodistribution quantitatively. However, ICP-MS cannot distinguish between elements that are inherent to the nanomaterials and those that are cleaved or released from them. But, unlike ICP-MS, TEM can detect the presence of nanomaterials and identify their location within tissues and cells. Even though the TEM images in our study1 provide only qualitative information, TEM is invaluable for identifying the biodistribution of the silica and TiO2 nanoparticles. Subject terms: * Nanoparticles * Environmental, health and safety issues Article preview Read the full article * Instant access to this article: US$18 Buy now * Subscribe to Nature Nanotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Author information Article tools * Print * Email * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * Department of Toxicology and Safety Science, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan. National Institute of Biomedical Innovation, 7-6-8, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan The Center for Advanced Medical Engineering and Informatics, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan * Yasuo Tsutsumi & * Yasuo Yoshioka Corresponding author Correspondence to: * Yasuo Tsutsumi Author Details * Yasuo Tsutsumi Contact Yasuo Tsutsumi Search for this author in: * NPG journals * PubMed * Google Scholar * Yasuo Yoshioka Search for this author in: * NPG journals * PubMed * Google Scholar Additional data - Our choice from the recent literature
- Nat Nanotechnol 6(12):756 (2011)
Article preview View full access options Nature Nanotechnology | Research Highlights Our choice from the recent literature Journal name:Nature NanotechnologyVolume: 6,Page:756Year published:(2011)DOI:doi:10.1038/nnano.2011.229Published online06 December 2011 Nature479, 208–211 (2011) © RANDY WIND/MARTIN ROELFS It is relatively easy to make a molecule rotate on a surface with the help of thermal energy. Controlling the direction of rotation is more difficult, but has been achieved with rotary motors powered by light, chemical and electrical energy. Similar challenges are encountered when trying to control the translational motion of a molecule over a surface, though previous systems have been limited to those that diffused along the surface or were dragged by the tip of a scanning tunnelling microscope (STM). Syuzanna Harutyunyan, Karl-Heinz Ernst, Ben Feringa and colleagues have now shown that a molecule containing four rotary motors can be driven over a metal surface using electrons. Subject terms: * Molecular machines and motors * Surface patterning and imaging * Photonic structures and devices * Environmental, health and safety issues * Computational nanotechnology Article preview Read the full article * Instant access to this article: US$32 Buy now * Subscribe to Nature Nanotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Author information Article tools * Print * Email * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Additional data - Nanoelectronics: A closer look at charge drag
- Nat Nanotechnol 6(12):757-758 (2011)
Article preview View full access options Nature Nanotechnology | News and Views Nanoelectronics: A closer look at charge drag * Markus Büttiker1 * Rafael Sánchez2 * Affiliations * Corresponding authorsJournal name:Nature NanotechnologyVolume: 6,Pages:757–758Year published:(2011)DOI:doi:10.1038/nnano.2011.197Published online30 October 2011 The observation that charges flowing through one quantum wire can drag charges in a second, unconnected wire either forwards or backwards requires a re-interpretation of Coulomb drag. Subject terms: * Electronic properties and devices Article preview Read the full article * Instant access to this article: US$18 Buy now * Subscribe to Nature Nanotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Author information Article tools * Print * Email * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * Markus Büttiker is in the Department of Theoretical Physics, University of Geneva, 24 Quai E. Ansermet, 1211 Geneva, Switzerland * Rafael Sánchez is in the Instituto de Ciencia de Materiales de Madrid (CSIC), Sor Juana Inés de la Cruz 3, Cantoblanco, 28049 Madrid, Spain Corresponding authors Correspondence to: * Markus Büttiker or * Rafael Sánchez Author Details * Markus Büttiker Contact Markus Büttiker Search for this author in: * NPG journals * PubMed * Google Scholar * Rafael Sánchez Contact Rafael Sánchez Search for this author in: * NPG journals * PubMed * Google Scholar Additional data - Nanoparticles: Barrier thickness matters
- Nat Nanotechnol 6(12):758-759 (2011)
Article preview View full access options Nature Nanotechnology | News and Views Nanoparticles: Barrier thickness matters * Berthold Huppertz1Journal name:Nature NanotechnologyVolume: 6,Pages:758–759Year published:(2011)DOI:doi:10.1038/nnano.2011.206Published online06 November 2011 Signals that damage cells grown underneath a cellular barrier are transmitted only when the barrier is more than one layer thick. Subject terms: * Nanomedicine * Environmental, health and safety issues Article preview Read the full article * Instant access to this article: US$18 Buy now * Subscribe to Nature Nanotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Author information Article tools * Print * Email * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * Berthold Huppertz is in the Institute of Cell Biology, Histology and Embryology of the Medical University of Graz, Graz 8010, Austria Corresponding author Correspondence to: * Berthold Huppertz Author Details * Berthold Huppertz Contact Berthold Huppertz Search for this author in: * NPG journals * PubMed * Google Scholar Additional data - Nanopores: Water flow at the flip of a switch
- Nat Nanotechnol 6(12):759-760 (2011)
Article preview View full access options Nature Nanotechnology | News and Views Nanopores: Water flow at the flip of a switch * Ulrich Rant1Journal name:Nature NanotechnologyVolume: 6,Pages:759–760Year published:(2011)DOI:doi:10.1038/nnano.2011.215Published online06 December 2011 Artificial nanopores with hydrophobic surface patches can be reversibly filled with water by applying electric fields. Subject terms: * Nanofluidics * Structural properties Article preview Read the full article * Instant access to this article: US$18 Buy now * Subscribe to Nature Nanotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Author information Article tools * Print * Email * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * Ulrich Rant is at the Walter Schottky Institut and the Institute for Advanced Study, Technische Universität München, 85748 Garching, Germany Corresponding author Correspondence to: * Ulrich Rant Author Details * Ulrich Rant Contact Ulrich Rant Search for this author in: * NPG journals * PubMed * Google Scholar Additional data - Lipid structures: A brief history of multisomes
- Nat Nanotechnol 6(12):761-762 (2011)
Article preview View full access options Nature Nanotechnology | News and Views Lipid structures: A brief history of multisomes * David Needham1Journal name:Nature NanotechnologyVolume: 6,Pages:761–762Year published:(2011)DOI:doi:10.1038/nnano.2011.218Published online06 December 2011 Lipid monolayers and bilayers can stabilize networks of water droplets inside larger drops of oil to create structures that could have a range of applications. Subject terms: * Nanobiotechnology * Nanosensors and other devices Article preview Read the full article * Instant access to this article: US$18 Buy now * Subscribe to Nature Nanotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Author information Article tools * Print * Email * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * David Needham is in the Department of Mechanical Engineering and Material Science, Duke University, Durham North Carolina 27708, USA Competing financial interests D. Needham is co-inventor of droplet interface bilayers, owned by Oxford University. Corresponding author Correspondence to: * David Needham Author Details * David Needham Contact David Needham Search for this author in: * NPG journals * PubMed * Google Scholar Additional data - Challenges and opportunities for structural DNA nanotechnology
- Nat Nanotechnol 6(12):763-772 (2011)
Nature Nanotechnology | Review Challenges and opportunities for structural DNA nanotechnology * Andre V. Pinheiro1 * Dongran Han1, 2 * William M. Shih3, 4, 5 * Hao Yan1, 2 * Affiliations * Corresponding authorsJournal name:Nature NanotechnologyVolume: 6,Pages:763–772Year published:(2011)DOI:doi:10.1038/nnano.2011.187Published online06 November 2011 Abstract * Abstract * Author information Article tools * Full text * Print * Email * pdf options * download pdf * view interactive pdfpowered by ReadCube * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg DNA molecules have been used to build a variety of nanoscale structures and devices over the past 30 years, and potential applications have begun to emerge. But the development of more advanced structures and applications will require a number of issues to be addressed, the most significant of which are the high cost of DNA and the high error rate of self-assembly. Here we examine the technical challenges in the field of structural DNA nanotechnology and outline some of the promising applications that could be developed if these hurdles can be overcome. In particular, we highlight the potential use of DNA nanostructures in molecular and cellular biophysics, as biomimetic systems, in energy transfer and photonics, and in diagnostics and therapeutics for human health. View full text Subject terms: * Molecular self-assembly * Nanobiotechnology Figures at a glance * Figure 1: Examples of structural DNA nanotechnology. , Seeman's original proposal consisted of using immobile DNA junctions (left) to build 3D scaffolds that could be used to organize proteins (right)1. , Important milestones in structural DNA nanotechnology: the first wireframe 3D cube10 (left), DNA origami (centre) and a 3D periodic structure composed of tensegrity triangles (right). , DNA periodic arrays composed of double-crossover tiles (left), 4 × 4 tiles (centre left), three-point star tiles (centre right) and double-crossover-tile-based algorithmic assembly of Sierpinski triangles (right). , Three-dimensional DNA origami: a hollow box (left pair of images), a multi-layer square nut (centre left pair), a square-toothed gear (centre right pair) and a nanoflask (right pair). , DNA nanostructure-directed patterning of heteroelements: double-crossover tiles for the organization of gold nanoparticle arrays (left), DNA origami for the assembly of carbon nanotubes (centre left), biotin–streptavidin protein patterning of 4 �! � 4 tiles (centre), aptamer-directed assembly of thrombin arrays on triple crossover tiles (centre right), and Snap-tag and His-tag mediated orthogonal decoration of DNA origami (right). Figures reproduced with permission from: , Nadrian C. Seeman (left), ref. 42, © 2006 NPG (centre), ref. 38, © 2009 NPG (right); , ref. 19, © 1998 NPG (left), ref. 22, © 2003 AAAS (centre left), ref. 24, © 2005 ACS (centre right), ref. 30, courtesy of P. Rothemund (right); , ref. 43, © 2009 NPG (left), ref. 47, © 2009 NPG (centre left), ref. 49, © 2009 AAAS (centre right), ref. 50, © 2011 AAAS (right); , ref. 62, © 2004 ACS (left), ref. 75, © 2010 NPG (centre left), ref. 22, © 2003 NPG (centre), ref. 53, © 2005 Wiley (centre right), ref. 57, © 2010 Wiley (right). * Figure 2: Challenges for DNA nanostructures. , Expanding size and complexity. Two main approaches are being explored to overcome the current dependence of the structural DNA nanotechnology community on the viral M13 genome: the use of longer DNA scaffold strands (top left) to fold larger structures (top right), or the assembly of pre-formed structures for the constructions of supramolecular assemblies (bottom). , New functional nanostructures. The functionalization of specific protein surface residues (dark blue circles on the light blue proteins) with oligonucleotides, and subsequent purification, would allow for an extra dimension of positioning control of the protein into a DNA template. , New generation of DNA walkers (green spheres with purple legs) with programmable routines and/or sensitive to state changes, such as light, for the selection of routes in multi-path systems. , In vivo selection and amplification of DNA nanostructures. Creating procedures for the selection and evolution of biocompatible/bioactive s! hapes through environmental conditioning, or using cellular replication machinery for the high-throughput production of DNA structures, should lead to new applications of DNA nanotechnology. * Figure 3: DNA nanotechnology for biophysical studies. , DNA origami can act as fully addressable molecular pegboards that can be used as molecular rulers for the organization of heteroelements (blue and red spheres). The purple and green blocks can be any DNA structure that directs the sphere position along a platform. A particularly interesting application is the spatial arrangement of enzyme components of cascade reactions. The relative positions of components can be designed with nanometre accuracy, possibly allowing biochemists to suppress diffusion-dependent effects in cascade reactions. This would open classic biochemical systems to new functional properties, and potential improved performances, distinct from bulk reaction measurements. Moreover, such assemblies could be used as models of intracellular compartmentalization or in vivo clustering. , When current real-time measurement tools are employed, many in vivo interactions elude detection. Fluorescence, and in particular Förster resonance energy transfer, or single-d! ye fluorescent markers, yield narrow snapshots of in vivo reality. DNA scissors, tweezers or tensegrity structures (shown as cross-like structures within translucent pink oval, which represents a cell) may be used for real-time and dynamic measurement of target protein activity, or the specific detection and size estimation of protein complexes required for cellular functions. The DNA nanostructure switches conformation to accompany changes in the shape and size of target structures in their native medium: this allows them to serve as relays between the length scales associated with interactions between protein constructs such as DNA-promoter complexes (~10s of nanometres) and those associated with fluorescence reporting (a few nanometres or less). Two such structures are shown here. * Figure 4: DNA nanostructures as biomimetic and in vivo active systems. Aldaye and co-workers recently reported the assembly of two enzymes of a hydrogen-production cascade reaction using RNA arrays, which led to improved yields122. In vivo replication of complex DNA structures allows intracellular components (blue, pink and yellow objects) to be organized with tighter and more complex spatial control for the study of cellular properties or new capabilities due to the cytosol clustering effect. Conversely, DNA structures can be designed and 'expressed' that fold into biomimetic structures, such as DNA-based nanopores, channels or pumps, introducing artificial layers of cell communication and interaction with its external medium. Also, DNA nanostructures can induce immune responses and actively modulate cell–cell communication on clustering and spatial organization of membrane protein markers, or, in a more abstract concept, acting as specific cell–cell glue (here shown as light blue and red rods connecting the dark blue and pink cells). * Figure 5: DNA nanotechnology for energy transfer and photonics. DNA nanostructures provide a useful tool for the organization of photonic components in a linear fashion or in branched networks. The modularity of assembly, along with the plethora of DNA functionalization of photonic components, allows for the construction of photonic molecular circuits. Light-harvesting complexes can be spatially clustered and aligned, where sequential energy or charge-transfer processes lead to optimized channelling efficiency, to create a new generation of photonic wires, plasmonic or conducting devices (blue, green and red spheres and orange rods represent photonic components that can serve as light-harvesting and energy-transfer materials). Enzymes or membrane complexes (uneven green spheres) can be used as final energy or electron acceptors, acting as molecular transducer units, where light is transformed into chemical potential (represented by the transformation of substrate (triangles) into a higher-energy product (stars)). Physical separation of p! hotonic components creates a new layer of spectral separation, allowing the construction of larger and more complex photonic circuitry. * Figure 6: Structural DNA nanotheranostics. DNA structures can be used to build disease-targeting units for diagnostics and therapeutics (or 'theranostics'). Hollow structures are designed in a modular fashion, where multiple pharmacologically active species can be caged into different compartments. Advances in DNA computing may allow the detection of several disease markers (such as interaction between aptamers and membrane receptors, or hormone-activated switches) that are input into a programmed response. The use of multiple input stimuli for the controlled release of drugs may increase drug delivery specificity. This way, the presence of pathogens or multiple cancer markers, for example, can be simultaneously analysed, triggering suitable therapeutics. The magnitude and duration of the response can also be programmed, from continuous cargo release to threshold-controlled dumping. Such a system might be regarded as a platform model of an artificial immune system. Author information * Abstract * Author information Affiliations * Center for Single Molecule Biophysics, The Biodesign Institute, Arizona State University, Tempe, Arizona 85287, USA * Andre V. Pinheiro, * Dongran Han & * Hao Yan * Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287, USA * Dongran Han & * Hao Yan * Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA * William M. Shih * Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA * William M. Shih * Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02138, USA * William M. Shih Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Hao Yan or * William M. Shih Author Details * Andre V. Pinheiro Search for this author in: * NPG journals * PubMed * Google Scholar * Dongran Han Search for this author in: * NPG journals * PubMed * Google Scholar * William M. Shih Contact William M. Shih Search for this author in: * NPG journals * PubMed * Google Scholar * Hao Yan Contact Hao Yan Search for this author in: * NPG journals * PubMed * Google Scholar Additional data - Electrical contacts to one- and two-dimensional nanomaterials
- Nat Nanotechnol 6(12):773-783 (2011)
Nature Nanotechnology | Review Electrical contacts to one- and two-dimensional nanomaterials * François Léonard1 * A. Alec Talin2 * Affiliations * Corresponding authorsJournal name:Nature NanotechnologyVolume: 6,Pages:773–783Year published:(2011)DOI:doi:10.1038/nnano.2011.196Published online27 November 2011Corrected online28 November 2011 Abstract * Abstract * Change history * Author information Article tools * Full text * Print * Email * pdf options * download pdf * view interactive pdfpowered by ReadCube * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Existing models of electrical contacts are often inapplicable at the nanoscale because there are significant differences between nanostructures and bulk materials arising from unique geometries and electrostatics. In this Review, we discuss the physics and materials science of electrical contacts to carbon nanotubes, semiconductor nanowires and graphene, and outline the main research and development challenges in the field. We also include a case study of gold contacts to germanium nanowires to illustrate these concepts. View full text Subject terms: * Carbon nanotubes and fullerenes * Electronic properties and devices * Synthesis and processing Figures at a glance * Figure 1: Examples of nanomaterial-based devices. , A photovoltaic device that uses an array of semiconducting nanowires (red) contacted by a transparent conductive top electrode. , A carbon nanotube field-effect transistor. Current flow between source and drain electrodes (top and bottom, respectively) is controlled by a gate electrode (not shown). , A chem-bio sensor using a nanowire functionalized with antibodies that bind to specific proteins, affecting the conductivity between two metallic electrodes. A third, gate electrode is also sometimes used in these devices. , A three-dimensional Li-ion battery showing an array of anode nanowires (brown) coated with a thin solid electrolyte (gold) surrounded by a cathode matrix (pink). , Thermoelectric power generation occurs when charge flows owing to a heat gradient, in this case along a nanowire array. The device can also be used for cooling, by forcing charge to flow in the other direction. , A graphene nanoscale electromechanical system. A graphene membrane vibrates due to ! an oscillating gate voltage; the motion is detected by measuring the current flowing through the graphene. , Light emission from a carbon nanotube device occurs when electrodes and holes injected from opposite electrodes meet and recombine. A gate electrode is used to tune the emission intensity. , Graphene-based spintronics. One ferromagnetic metal contact injects spin-polarized charges into graphene, and a second ferromagnetic contact extracts the charge in a spin-dependent fashion. All of the devices shown rely on charge injection through a contact between a metal and a nanostructure. Panels reproduced with permission from: , ref. 1, © 2009 AIP; , ref. 2, © 2009 ACS; , ref. 3, © 2008 ECS; , ref. 4, © 2009 NPG; , © IBM; , Roland Kawakami, Univ. California, Riverside. * Figure 2: Contact geometries. , Two examples of end-bonded contacts to nanostructures. The top row shows a transmission electron micrograph image of a carbon nanotube end-bonded to Ti contacts (), with a schematic atomic representation (). The bottom row shows a scanning electron micrograph (SEM) image of a Si nanowire end-bonded to Ni2Si () and a schematic (). , An example of a side contact to a nanostructure. A SEM mage shows a single carbon nanotube encapsulated by several electrodes (), and an illustration shows the contact geometry (). The four-probe geometry shown in () uses two electrodes to apply a voltage, and two electrodes to measure current, reducing the effect of contact resistance on the measurement. Panels reproduced with permission from: , ref. 6, © 1999 AAAS; , ref. 7, © 2003 APS; , ref. 8, © 2008 AIP; , ref. 9, © 2004 EDP. * Figure 3: Band alignment at metal/nanostructure interfaces. , Band diagram for a Schottky contact, showing the top of the valence band (Ev), the bottom of the conduction band (Ec), the Fermi level (EF), the Schottky barrier (ϕb) and the depletion width W. , Band alignment for an n-type ohmic contact. , For a contact between a metal and a metallic nanostructure, the presence of a tunnel barrier (with a profile that is determined by the workfunctions of the two metals Φ1 and Φ2) can govern the contact properties. , In the simplest case, ϕb is determined by the difference between the metal workfunction Φ and the semiconductor electron affinity χ. However, in the near-interface region of a metal–semiconductor junction, interaction with the metal causes electronic states to appear in the bandgap of the semiconductor; associated with these states is a charge neutrality level denoted by the green line. In general, the metal Fermi level will not be at the charge neutrality level, and a local band bending can occur in the semiconducto! r to pin the Fermi level there. * Figure 4: Charge injection at metal–nanostructure contacts. , Thermionic emission over a Schottky barrier. , Tunnelling through a Schottky barrier. , Electron–hole recombination in the depletion region (electrons and holes are represented by filled and open circles, respectively). , The contact transfer length, LT, is the length over which injection occurs from a metal that is side contacted to another material. , Charge injection from metal electrodes into an organic thin film can be improved by attaching nanotube arrays to the electrodes, as shown in the left panel. The middle panel shows a transmission electron micrograph image of the attached tubes, and the right panel shows that the resulting source–drain current is higher than that measured when using bare Ti or bare Au electrodes. Panel reproduced with permission from ref. 31, © 2009 ACS. * Figure 5: Formation of the different phases of nickel silicide. , Ni-silicides typically observed for a thin Ni film deposited on a (100) oriented Si wafer. As the annealing temperature is increased for a thin film on (100) Si, δ-Ni2Si forms first owing to its large interdiffusion coefficient; NiSi forms at a higher temperature when all of the δ-Ni2Si is consumed, and remains stable up to ~700 °C when the final phase, NiSi2 begins to nucleate. , The nickel silicides formed at contacts between Ni electrodes and Si nanowires depend on the crystallographic orientation of the nanowire. The presence of oxide on the nanowire surface and the starting amount of Ni can also affect the resulting silicide phase. For θ-Ni2Si/(112)Si nanowires, outgrowing whiskers form above 700 °C owing to the high compressive stress39. * Figure 6: Au–nanoparticle–Ge-nanowire contacts. , Scanning electron microscopy image of a Ge nanowire (green) with a Au nanoparticle (brown) at its summit, contacted by a conducting probe (grey), and the resulting current–voltage curve. , Measured current–voltage characteristics for nanowires of different diameters. , Low bias conductance and ideality factor n (shown in the inset) as a function of diameter. The solid and dashed lines are calculated using a diameter-dependent and diameter-independent recombination time, respectively. , Sketch of the system used for numerical simulations, showing electric field lines. , Calculated band bending along the length of the nanowire for three nanowire diameters. The conduction band has positive energy, and the valence band negative energy. , A large Schottky barrier prevents electron injection into the nanowire conduction band (left). Instead, charge injection is dominated by electron–hole recombination in the depletion region. Panels – reproduced with permission from ref.! 16, © 2009 APS. * Figure 7: Opportunities and challenges for research and development. , Atomistic modelling of nanocontacts is needed to understand electronic and structural properties. The structure of an Al contact to a Si nanowire is illustrated. , Experimental techniques to characterize the structural and electronic properties of buried interfaces can aid in understanding the behaviour of metal contacts to nanostructures. Electron tomography images show that a thin coating of Ti wets the carbon nanotube uniformly along its length (left panel) and in cross-section (right panel), preserving the shape of the nanotube. , Experiments and theory are needed to understand dopant distribution in nanostructures. The panel shows a cross-sectional image of P dopants (grey dots) in a Ge (blue dots) nanowire obtained using atom probe tomography. The image and the measured dopant concentration shown in the main panel indicate that dopant distribution is nonuniform in the radial direction. Triangular points have a higher ratio of Ge:P precursors than the square points. ,! New approaches are needed to make contacts to arrays of nanostructures. A carbon nanotube array is end-bonded at each end to metallic contacts. Alternatives include side contacts to the top layer of nanotubes or metal infiltration. , New approaches for the fabrication of contacts include ultrasonic welding, which binds carbon nanotubes to electrodes, reducing the contact resistance. , Transparent contacts to nanostructures are needed to enable photovoltaic devices, and can be made using transparent conducting oxides (TCO) such as indium tin oxide, as well as graphene or carbon nanotubes. A solar cell consisting of an ordered array of GaAs nanopillars with p-doped cores and n-doped shells, surrounded by a resin (benzocyclobutene, BCB) and contacted with a TCO is shown. Panels reproduced with permission from: , ref. 66, © 2000 APS; , ref. 60, © 2007 ACS; , ref. 61, © 2009 NPG; , ref. 62, © 2006 IOP; , ref. 65, © 2011 ACS. Change history * Abstract * Change history * Author informationCorrected online 28 November 2011In the version of this Review originally published online, equation (2) appeared incorrectly. This has now been corrected in all versions of the Review Author information * Abstract * Change history * Author information Affiliations * Sandia National Laboratories, Livermore, California, 94551, USA * François Léonard * Center for Nanoscale Science and Technology, National Institute of Standards and Technology, Gaithersburg, Maryland, 20899, USA * A. Alec Talin Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * François Léonard or * A. Alec Talin Author Details * François Léonard Contact François Léonard Search for this author in: * NPG journals * PubMed * Google Scholar * A. Alec Talin Contact A. Alec Talin Search for this author in: * NPG journals * PubMed * Google Scholar Additional data - A decision-directed approach for prioritizing research into the impact of nanomaterials on the environment and human health
- Nat Nanotechnol 6(12):784-787 (2011)
Nature Nanotechnology | Letter A decision-directed approach for prioritizing research into the impact of nanomaterials on the environment and human health * Igor Linkov1 * Matthew E. Bates1 * Laure J. Canis1 * Thomas P. Seager2 * Jeffrey M. Keisler3 * Affiliations * Contributions * Corresponding authorJournal name:Nature NanotechnologyVolume: 6,Pages:784–787Year published:(2011)DOI:doi:10.1038/nnano.2011.163Received03 May 2011Accepted31 July 2011Published online02 October 2011 Abstract * Abstract * Author information * Supplementary information Article tools * Full text * Print * Email * pdf options * download pdf * view interactive pdfpowered by ReadCube * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg The emergence of nanotechnology has coincided with an increased recognition of the need for new approaches to understand and manage the impact of emerging technologies on the environment and human health. Important elements in these new approaches include life-cycle thinking, public participation and adaptive management of the risks associated with emerging technologies and new materials1. However, there is a clear need to develop a framework for linking research on the risks associated with nanotechnology to the decision-making needs of manufacturers, regulators, consumers and other stakeholder groups2, 3. Given the very high uncertainties associated with nanomaterials and their impact on the environment and human health, research resources should be directed towards creating the knowledge that is most meaningful to these groups. Here, we present a model (based on multi-criteria decision analysis and a value of information approach) for prioritizing research strategies in a! way that is responsive to the recommendations of recent reports on the management of the risk4, 5 and impact of nanomaterials on the environment and human health6. View full text Subject terms: * Environmental, health and safety issues Figures at a glance * Figure 1: MCDA/VoI framework for prioritizing research into the impact of nanomaterials on the environment and human health. The decision-making process involves different stakeholders who place different weights on different decision criteria. We can view the process as starting at manufacturing companies, where designers and developers need to select a particular technology for a particular task (such as the synthesis of single-walled carbon nanotubes). Experts assess each proposed technology relative to the decision criteria through probability distributions based on experimental science or experience. The MCDA model integrates all of this information by comparing the technologies to determine which performs best on each criterion, and computes an overall preference score across criteria for each technology for each stakeholder group. The VoI investigation explores the uncertainty in the MCDA results to determine how new information gained through research might impact the selection decision. If the overall score for a particular stakeholder group can be significantly improved by establishing t! echnological details with certainty, then a research programme that is capable of providing this information may be highly valuable to those stakeholders. * Figure 2: Model results showing decision recommendations in the base case and the relative importance of different types of research. , MCDA results for the single-walled carbon nanotube case study show the likelihood that a particular synthesis technology (arc, CVD, HiPCO or laser) will be most preferred by each stakeholder group (manufacturers, consumers, regulators and environmental groups) given current knowledge and uncertainties. A balanced case that gives equal weight to the five decision criteria (see main text) is shown on the right. Most stakeholders are likely to prefer HiPCO, but further research may help some stakeholders differentiate between the arc, HiPCO and laser approaches. , VoI analysis reveals the potential for different types of research to change the expected confidence that each stakeholder group will have in its choice of technology. The blue portion of each bar represents the average decision confidence (net flow) in the preferred technology for each stakeholder group in the base case, and also for the balanced weighting scenario. The red portion indicates the improvement in aver! age decision confidence that occurs when new information on manufacturing becomes available through research. The green portion indicates the improvement that occurs when new information on health becomes available. The purple portion indicates the additional synergistic improvement that occurs when new information on both manufacturing and health becomes available simultaneously. Author information * Abstract * Author information * Supplementary information Affiliations * US Army Engineer Research and Development Center, US Army Corps of Engineers, 696 Virginia Road, Concord, Massachusetts 01742-2718, USA * Igor Linkov, * Matthew E. Bates & * Laure J. Canis * Global Institute of Sustainability and the School of Sustainable Engineering and the Build Environment, Arizona State University, PO Box 875306, Tempe, Arizona 85287-5306, USA * Thomas P. Seager * Department of Management Science and Information Systems, College of Management, University of Massachusetts Boston, M-5-249, 100 Morrissey Boulevard, Boston, Massachusetts 02125-3393, USA * Jeffrey M. Keisler Contributions I.L. developed the overall approach and application framework and guided the preparation of the manuscript. L.J.C. performed background research and developed an initial model. T.P.S. provided contributions on life cycle assessment and decision analysis. J.M.K. guided the VoI analysis. M.E.B. completed the model and performed all calculations. All authors discussed the results and co-wrote the paper. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Igor Linkov Author Details * Igor Linkov Contact Igor Linkov Search for this author in: * NPG journals * PubMed * Google Scholar * Matthew E. Bates Search for this author in: * NPG journals * PubMed * Google Scholar * Laure J. Canis Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas P. Seager Search for this author in: * NPG journals * PubMed * Google Scholar * Jeffrey M. Keisler Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary information (849 KB) Supplementary information Additional data - Skin-like pressure and strain sensors based on transparent elastic films of carbon nanotubes
- Nat Nanotechnol 6(12):788-792 (2011)
Nature Nanotechnology | Letter Skin-like pressure and strain sensors based on transparent elastic films of carbon nanotubes * Darren J. Lipomi1, 4 * Michael Vosgueritchian1, 4 * Benjamin C-K. Tee2, 4 * Sondra L. Hellstrom3 * Jennifer A. Lee1 * Courtney H. Fox1 * Zhenan Bao1 * Affiliations * Contributions * Corresponding authorJournal name:Nature NanotechnologyVolume: 6,Pages:788–792Year published:(2011)DOI:doi:10.1038/nnano.2011.184Received07 September 2011Accepted27 September 2011Published online23 October 2011Corrected online28 October 2011 Abstract * Abstract * Change history * Author information * Supplementary information Article tools * Full text * Print * Email * pdf options * download pdf * view interactive pdfpowered by ReadCube * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Transparent, elastic conductors are essential components of electronic and optoelectronic devices that facilitate human interaction and biofeedback, such as interactive electronics1, implantable medical devices2 and robotic systems with human-like sensing capabilities3. The availability of conducting thin films with these properties could lead to the development of skin-like sensors4 that stretch reversibly, sense pressure (not just touch), bend into hairpin turns, integrate with collapsible, stretchable and mechanically robust displays5 and solar cells6, and also wrap around non-planar and biological7, 8, 9 surfaces such as skin10 and organs11, without wrinkling. We report transparent, conducting spray-deposited films of single-walled carbon nanotubes that can be rendered stretchable by applying strain along each axis, and then releasing this strain. This process produces spring-like structures in the nanotubes that accommodate strains of up to 150% and demonstrate conducti! vities as high as 2,200 S cm−1 in the stretched state. We also use the nanotube films as electrodes in arrays of transparent, stretchable capacitors, which behave as pressure and strain sensors. View full text Subject terms: * Carbon nanotubes and fullerenes * Nanomaterials * Structural properties Figures at a glance * Figure 1: Effects of applied strain on films of spray-coated carbon nanotubes on PDMS substrates. , Change in resistance ΔR/R0 versus strain ε for a nanotube film on a PDMS substrate. When the film is strained (arrow, bottom left), ΔR/R0 increases, and remains constant as the strain is released. When the strain is increased again, ΔR/R0 remains constant, and then increases when ε exceeds the value at which the strain was released before. This sequence is repeated up to ΔR/R0 ≈ 5 and ε ≈ 150%. , ΔR/R0 versus time in response to four cycles of stretching from 0 to 50%. , Resistance versus number of stretches (on a log scale) over 12,500 cycles of stretching to 25%. * Figure 2: Evolution of morphology of films of carbon nanotubes with stretching. Schematics (left) and corresponding AFM phase images (right) of nanotube films as deposited (), under strain (), stretched and released along one axis (), and stretched and released along two axes (). The bundles are considerably longer than the individual nanotubes within them. Dashed and solid white boxes highlight the bundles of nanotubes buckled along the horizontal and vertical axes, respectively. Scale bars, 600 nm. * Figure 3: Use of stretchable nanotube films in compressible capacitors that can sense pressure and strain. , Schematic showing a stretchable capacitor with transparent electrode (top), and the same capacitor after being placed under pressure (left) and being stretched (right). ,, Change in capacitance ΔC/C0 versus pressure P () and strain ε (). ,, ΔC/C0 versus time t over four cycles of applied pressure () and stretching (). * Figure 4: Summary of processes used to fabricate arrays of transparent, compressible, capacitive sensors. Spray-coating through a stencil mask produces lines of randomly oriented nanotubes (step 1). A one-time application of strain and release produces waves in the direction of strain (step 2). A second patterned substrate is positioned (face to face) over the first (step 3). The two substrates are bonded together using Ecoflex silicone elastomer, which, when cured, serves as a compressible dielectric layer (step 4). Drops of a liquid metal, EGaIn, make conformal contact with the termini of the nanotube electrodes and are embedded within the device. Copper nanowires connect the device to an LCR meter in the laboratory. * Figure 5: Images showing the characteristics of a 64-pixel array of compressible pressure sensors. , Photograph of the device, with enhanced contrast to show the lines of nanotubes (scale bar, 1 cm). , Photograph of the same device reversibly adhered to a backlit liquid-crystal display. , Map of the estimated pressure profile over a two-dimensional area based on the change in capacitance registered by a central pixel and its four nearest neighbours when a pressure of 1 MPa is applied to the central pixel (scale bar, 2 mm). , Image of the device being deformed by hand. Change history * Abstract * Change history * Author information * Supplementary informationCorrected online 28 October 2011In the version of this Letter originally published online, the colour scale in Fig. 5c should have read 'x10−2'. This has been corrected in all versions of the Letter. Author information * Abstract * Change history * Author information * Supplementary information Primary authors * These authors contributed equally to this work * Darren J. Lipomi, * Michael Vosgueritchian & * Benjamin C-K. Tee Affiliations * Department of Chemical Engineering, Stanford University, Stanford, California 94305, USA * Darren J. Lipomi, * Michael Vosgueritchian, * Jennifer A. Lee, * Courtney H. Fox & * Zhenan Bao * Department of Electrical Engineering, Stanford University, Stanford, California 94305, USA * Benjamin C-K. Tee * Department of Applied Physics, Stanford University, Stanford, California 94305, USA * Sondra L. Hellstrom Contributions D.J.L. and Z.B. conceived the project. D.J.L., M.V. and B.C-K.T. performed and designed the experiments. S.L.H. prepared the materials and developed the conditions used to dope the nanotube films. J.A.L. deposited additional nanotube films. J.A.L. and C.H.F. performed experiments on resistance versus strain. D.J.L., B.C-K.T., M.V., S.L.H. and Z.B. analysed the data. D.J.L. wrote the paper. All authors discussed the results and commented on the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Zhenan Bao Author Details * Darren J. Lipomi Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Vosgueritchian Search for this author in: * NPG journals * PubMed * Google Scholar * Benjamin C-K. Tee Search for this author in: * NPG journals * PubMed * Google Scholar * Sondra L. Hellstrom Search for this author in: * NPG journals * PubMed * Google Scholar * Jennifer A. Lee Search for this author in: * NPG journals * PubMed * Google Scholar * Courtney H. Fox Search for this author in: * NPG journals * PubMed * Google Scholar * Zhenan Bao Contact Zhenan Bao Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Change history * Author information * Supplementary information PDF files * Supplementary information (1,331 KB) Supplementary information Additional data - Positive and negative Coulomb drag in vertically integrated one-dimensional quantum wires
- Nat Nanotechnol 6(12):793-797 (2011)
Nature Nanotechnology | Letter Positive and negative Coulomb drag in vertically integrated one-dimensional quantum wires * D. Laroche1, 2 * G. Gervais1 * M. P. Lilly2 * J. L. Reno2 * Affiliations * Contributions * Corresponding authorJournal name:Nature NanotechnologyVolume: 6,Pages:793–797Year published:(2011)DOI:doi:10.1038/nnano.2011.182Received03 August 2011Accepted23 September 2011Published online30 October 2011 Abstract * Abstract * Author information Article tools * Full text * Print * Email * pdf options * download pdf * view interactive pdfpowered by ReadCube * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Electron interactions in and between wires become increasingly complex and important as circuits are scaled to nanometre sizes, or use reduced-dimensional conductors1 such as carbon nanotubes2, 3, 4, 5, 6, nanowires7, 8, 9, 10 and gated high-mobility two-dimensional electron systems11, 12, 13. This is because the screening of the long-range Coulomb potential of individual carriers is weakened in these systems, which can lead to phenomena such as Coulomb drag, where a current in one wire induces a voltage in a second wire through Coulomb interactions alone. Previous experiments have demonstrated Coulomb electron drag in wires separated by a soft electrostatic barrier of width ≳80 nm (ref. 12), which was interpreted as resulting entirely from momentum transfer. Here, we measure both positive and negative drag between adjacent vertical quantum wires that are separated by ~15 nm and have independent contacts, which allows their electron densities to be tuned independently. We ! map out the drag signal versus the number of electron sub-bands occupied in each wire, and interpret the results both in terms of momentum-transfer and charge-fluctuation induced transport models. For wires of significantly different sub-band occupancies, the positive drag effect can be as large as 25%. View full text Subject terms: * Electronic properties and devices Figures at a glance * Figure 1: Schematics of the fabrication process of the vertically coupled quantum circuits. , Diagram of the double quantum wires device subsequent to mesa etching, Ge–Au–Ni–Au ohmic contacts deposition and annealing. For visibility purposes, the scale bar in the x–y direction (50 µm) is dramatically larger than the one in the z-direction (1.5 µm). , Diagram showing the deposited upper pinch-off and plunger Ti–Au gates. The off-mesa section of the gates is patterned using photolithography, and electron-beam lithography is used to define the on-mesa gates. , Diagram after the epoxy-bond-and-stop-etch (EBASE) procedure. Note that due to a flipping process following the new substrate bonding, the upper 2DEG is now at the bottom. Similarly, the upper gates are now buried between the mesa and the epoxied GaAs. The original substrate has been lapped and etched down to ~300 nm. , Diagram showing the final layout of the double quantum wires device after an Al2O3 insulating layer is deposited, vias are etched through the device to connect the upper gates and the! ohmic contacts to the surface, and another set of Ti–Au split gates is deposited. See Methods for more details. * Figure 2: Split gates design generating the double quantum wire structure. , Schematic of the active part of the double quantum wires device. The EBASE process causes the lower gates and lower 2DEG to be above the upper gates and 2DEG. , Schematic of the active part of the device when a suitable bias is applied on all four split gates, effectively coupling both circuits solely through 1D regions. The T-shaped pinch-off gates are simultaneously adjusted to deplete their respective 2DEG, effectively preventing any current flow in the section of the layer underneath (above) the lower wire (upper wire) and creating two independently contacted 2DEGs. Using the plunger gates, two quantum wires are then formed. , Scanning electron microscope images of the device. The LPL and pinch-off gates are visible on the surface of the device. , Zoom-in on the interacting region of the device. See Methods for more details. * Figure 3: Characterization of the non-ballistic quantum wires. ,, Conductance (grey) and corrected conductance (black) in the lower wire (left axis) and in the upper wire (blue and dark blue curves respectively, right axis) as a function of LPL voltage for fixed UPL = −0.23 V and similar sub-band occupancies in both wires () and fixed UPL = −0.34 V and significantly different sub-band occupancies in both wires (). For the corrected conductance, 1.25 kΩ (5.00 kΩ) series resistance was subtracted from the lower (upper) wire conductance. , Derivative of the lower wire conductance as a function of LPL voltage. Conductance plateau-like features appear as black and blue stripes in the figure. * Figure 4: Drag resistance of the coupled quantum circuits. , Drag resistance (red curve, left axis) is shown as a function of LPL voltage together with the conductance in the drive wire (grey curve, right axis) and in the drag wire (blue curve, right axis) for fixed UPL = −0.23 V. The presence of peaks in the drag resistance concomitant with the opening of 1D channels in either wire is highlighted by dotted lines. , Temperature dependence of the Coulomb drag signal at the peak of the positive drag regime (black curve) for UPL = −0.25 V and LPL = −1.53 V, and in the high-density negative drag regime (blue curve) for UPL = −0.15 V and LPL = −2.96 V. , Drag voltage as a function of drive current for the low-density negative drag regime, the positive drag regime and the high-density re-entrant negative drag regime. In all three regimes, the drag voltage is linear with drive current for eVdrive/Kb ≲ 3 K. The current used for the drag measurement (4.5 nA) was always within the linear drag regime. , Drag voltage as a function o! f LPL for both positive (black curve) and negative (red curve) drive currents showing that the signal is independent of the drive current direction. Author information * Abstract * Author information Affiliations * Department of Physics, McGill University, Montreal H3A 2T8, Canada * D. Laroche & * G. Gervais * Center for Integrated Nanotechnologies, Sandia National Laboratories, Albuquerque, New Mexico 87185, USA * D. Laroche, * M. P. Lilly & * J. L. Reno Contributions M.P.L. designed and conceived the experiment. J.L.R. performed the growth of the double quantum well heterostructures. D.L. fabricated and characterized the samples, and performed the Coulomb drag measurements. G.G., M.P.L. and D.L. co-wrote the Letter and all authors discussed the results and commented on the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * M. P. Lilly Author Details * D. Laroche Search for this author in: * NPG journals * PubMed * Google Scholar * G. Gervais Search for this author in: * NPG journals * PubMed * Google Scholar * M. P. Lilly Contact M. P. Lilly Search for this author in: * NPG journals * PubMed * Google Scholar * J. L. Reno Search for this author in: * NPG journals * PubMed * Google Scholar Additional data - Electric-field-induced wetting and dewetting in single hydrophobic nanopores
- Nat Nanotechnol 6(12):798-802 (2011)
Nature Nanotechnology | Letter Electric-field-induced wetting and dewetting in single hydrophobic nanopores * Matthew R. Powell1 * Leah Cleary2 * Matthew Davenport1 * Kenneth J. Shea2 * Zuzanna S. Siwy1 * Affiliations * Contributions * Corresponding authorJournal name:Nature NanotechnologyVolume: 6,Pages:798–802Year published:(2011)DOI:doi:10.1038/nnano.2011.189Received02 August 2011Accepted28 September 2011Published online30 October 2011 Abstract * Abstract * Author information * Supplementary information Article tools * Full text * Print * Email * pdf options * download pdf * view interactive pdfpowered by ReadCube * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg The behaviour of water in nanopores is very different from that of bulk water1, 2. Close to hydrophobic surfaces, the water density has been found to be lower than in the bulk3, and if confined in a sufficiently narrow hydrophobic nanopore, water can spontaneously evaporate1, 4. Molecular dynamics simulations have suggested that a nanopore can be switched between dry and wet states by applying an electric potential across the nanopore membrane5, 6, 7, 8. Nanopores with hydrophobic walls could therefore create a gate system for water, and also for ionic and neutral species. Here, we show that single hydrophobic nanopores can undergo reversible wetting and dewetting due to condensation and evaporation of water inside the pores. The reversible process is observed as fluctuations between conducting and non-conducting ionic states and can be regulated by a transmembrane electric potential. View full text Subject terms: * Nanofluidics * Structural properties Figures at a glance * Figure 1: Hydrophobic gating in a 16-nm-diameter conically shaped nanopore modified in 12 mM (trimethylsilyl)diazomethane for 15 min. ,, Current–voltage characteristic () obtained by averaging 2-min ion-current time series, with the voltage () changed in steps of 0.5 V from 0 V to +5 V, followed by a sweep from +4.5 V to −5 V and from −4.5 V to 0 V. , Example recordings for positive voltages. , Example ion current series for negative voltages. Quick opening and closing kinetics were observed for positive voltages between 2 V and 4.0 V (time series for 2 V and 3.5 V are shown). For negative voltages the pore stayed in the conducting and non-conducting states for much longer periods, on the order of tens of seconds (recordings at −1 V, −1.5 V, −2 V). All recordings were performed in an as-prepared, non-degassed solution of 1 M KCl, pH 8 (Tris buffer). Letters with asterisks in indicate time series for which averages are marked on the graph with a star. The hysteresis seen for positive voltages was not present in all voltage scans performed for this pore (Fig. 2). In other pores the hysteresis occ! urred for either of the two voltage polarities (data in Supplementary Information). The pore switching can have two-state or multiple-state character (Supplementary Figs S2–S13). * Figure 2: Reversibility of the opening and closing of a hydrophobic nanopore with voltage. Data were recorded for the same nanopore as in Fig. 1. The pore opening diameter was 16 nm, and the pore was subjected to 15 min modification in 12 mM (trimethylsilyl)diazomethane. , The voltage was manually switched between +1 V and +5 V, leading to reversible switching of the pore between non-conducting and conducting states. , Current–voltage curves obtained by averaging 2-min ion-current series recorded when the voltage was changed in steps of 0.5 V from 0 V to +5 V, followed by a sweep from +4.5 V to −5 V and from −4.5 V to 0 V. Two such voltage scans were performed (Scan 2 and Scan 3) after the data in Fig. 1 had been measured. The scans are presented in separate graphs to facilitate comparison of the hysteresis effect. The voltages scans are superimposed as one graph in Supplementary Fig. S1. All recordings were performed in an as-prepared, non-degassed solution of 1 M KCl, pH 8 (Tris buffer). * Figure 3: Hydrophobic gating studied in a degassed solution of 1 M KCl. –, The potential influence of dissolved gases on the ability of a pore to switch between conducting and non-conducting states was studied in a 16-nm-diameter pore modified in 5 mM (trimethylsilyl)diazomethane for 15 min. Ion current recordings were performed in a 1 M KCl solution that was degassed in a vacuum chamber. The voltage sweeps in (Scan 1) and (Scan 3) were repeated twice with voltage steps of 0.5 V, from 0 V to −5 V, from −4.5 V to +5 V and from +4.5 V to 0 V. Scan 2 () was performed in the voltage range −2 V to +2 V, in steps of 0.2 V. At each voltage step, the ion-current time series was recorded for 2 min. The presented current–voltage curves were obtained by averaging the ion-current time series. Details of the ion current switching in time are shown in the Supplementary Information. * Figure 4: Scheme of hydrophobic gating with an electric field. , An unmodified PET pore is hydrophilic, as indicated by a contact angle of ~60° (image in left panel) measured on a planar surface. Overnight modification of the pores in a concentrated solution of (trimethylsilyl)diazomethane led to homogeneously hydrophobic surfaces with a contact angle of ~102° (image in middle panel). , Shorter modifications performed in diluted solutions of (trimethylsilyl)diazomethane led to the formation of less hydrophobic surfaces characterized by contact angles less than 90° (Supplementary Table S2). We propose that local hydrophobic clusters are created, which induce the formation of local vapour pockets. Applying an electric field across the membrane favours filling the pore with water and therefore ionic transport. A small fragment of a polymer nanopore is presented and its shape is approximated by a cylinder. Author information * Abstract * Author information * Supplementary information Affiliations * Department of Physics and Astronomy, University of California, Irvine, California 92697, USA * Matthew R. Powell, * Matthew Davenport & * Zuzanna S. Siwy * Department of Chemistry, University of California, Irvine, California 92697, USA * Leah Cleary & * Kenneth J. Shea Contributions Z.S.S., M.D. and K.J.S. conceived the experiments. M.R.P., L.C. and M.D. performed the experiments. All authors contributed to writing the manuscript. M.R.P., L.C., M.D., K.J.S. and Z.S.S. discussed the results and explained the transient behaviour of ion current in hydrophobic pores. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Zuzanna S. Siwy Author Details * Matthew R. Powell Search for this author in: * NPG journals * PubMed * Google Scholar * Leah Cleary Search for this author in: * NPG journals * PubMed * Google Scholar * Matthew Davenport Search for this author in: * NPG journals * PubMed * Google Scholar * Kenneth J. Shea Search for this author in: * NPG journals * PubMed * Google Scholar * Zuzanna S. Siwy Contact Zuzanna S. Siwy Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary information (1,324 KB) Supplementary information Additional data - Formation of droplet networks that function in aqueous environments
- Nat Nanotechnol 6(12):803-808 (2011)
Nature Nanotechnology | Letter Formation of droplet networks that function in aqueous environments * Gabriel Villar1 * Andrew J. Heron2 * Hagan Bayley1 * Affiliations * Contributions * Corresponding authorJournal name:Nature NanotechnologyVolume: 6,Pages:803–808Year published:(2011)DOI:doi:10.1038/nnano.2011.183Received12 May 2011Accepted27 September 2011Published online06 November 2011 Abstract * Abstract * Author information * Supplementary information Article tools * Full text * Print * Email * pdf options * download pdf * view interactive pdfpowered by ReadCube * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Aqueous droplets in oil that are coated with lipid monolayers and joined through interface bilayers1, 2 are useful for biophysical measurements on membrane proteins2, 3, 4, 5. Functional networks of droplets that can act as light sensors, batteries and electrical components can also be made by incorporating pumps, channels and pores into the bilayers2, 6. These networks of droplets mimic simple tissues7, but so far have not been used in physiological environments because they have been constrained to a bulk oil phase. Here, we form structures called multisomes in which networks of aqueous droplets with defined compositions are encapsulated within small drops of oil in water. The encapsulated droplets adhere to one another and to the surface of the oil drop to form interface bilayers that allow them to communicate with each other and with the surrounding aqueous environment through membrane pores. The contents in the droplets can be released by changing the pH or temperature ! of the surrounding solution. The multicompartment framework of multisomes mimics a tissue7, 8, 9 and has potential applications in synthetic biology and medicine. View full text Subject terms: * Nanobiotechnology * Nanosensors and other devices Figures at a glance * Figure 1: Schematics and photographs of multisomes. , Illustration of a multisome. Aqueous droplets encapsulated in an oil drop are connected by lipid bilayers, which allow the droplets in the network to communicate through protein pores. Pores in bilayers at the surfaces of the aqueous droplets that protrude from the oil drop enable the network to communicate with the bulk solution. Multisomes can release the contents of encapsulated droplets by pH- or temperature-induced rupture of bilayers. , Schematic of an encapsulated two-droplet network, illustrating the lipid monolayers and bilayers. –, Photographs of multisomes containing one (), two () and three () inner droplets. Oil drops were suspended on wire loops to allow extended study. Aqueous droplets were dyed with 25 µM sulphorhodamine 101 (red) or fluorescein (green). Scale bars, 400 µm. * Figure 2: Free energy landscape. , Schematic of a multisome with a single inner aqueous droplet, showing the definition of the contact angles θi relative to the horizontal. The arrows labelled γm and γb represent the monolayer and bilayer surface tensions, respectively. , Free energy of bilayer formation for an encapsulated droplet, as a function of the contact angles θ2 and θ3. The landscape was computed assuming an oil drop radius of R1 = 400 µm, an aqueous droplet radius of R2 = 200 µm, a monolayer surface tension of γm = 5 mN m−1, and a ratio of bilayer to monolayer surface tensions of γb/γm = 0.68. Arrows indicate the direction of steepest descent. The geometry of the multisome is depicted at various points in the landscape, including the state of minimum free energy at (θ1, θ2, θ3) = (33°, 173°, 77°). * Figure 3: Measurement of ionic currents through αHL pores. , Schematic of the measurement of ionic current flowing between an encapsulated droplet and the bulk aqueous solution, through an αHL pore inserted in the bilayer. , Stepwise increase in current indicating consecutive insertions of αHL pores into the external bilayer, at +50 mV in 500 mM KCl at pH 8.0. The peaks in the current histogram were separated by 18.6 ± 0.8 pA (mean ± s.d., n = 16), as expected for insertions of individual wild-type αHL pores. , Current blockades of a single wild-type αHL pore in the configuration shown in after adding ~10 µM γ-cyclodextrin to the bulk solution, at −50 mV in 1 M KCl at pH 8.0. The current levels of the unoccupied pore and the pore with γ-cyclodextrin bound are indicated. The γ-cyclodextrin current blockades have an amplitude of 63.7 ± 2.0% (mean ± s.d., n = 673), and the dissociation rate of γ-cyclodextrin was 4.0 ± 0.6 s−1 (mean ± s.d.). * Figure 4: Communication by diffusion through αHL pores. Fluorescence photographs and measurements of multisomes. Oil and inner droplets are outlined in the photographs where they are not visible. Inner droplets containing dextran-conjugated fluo-4 or Ca2+ are respectively labelled 'Dye' or 'Ca2+'. , Two multisomes with a single inner droplet each, in the same bulk solution; both multisomes contained the dye, and one also contained αHL. The photographs are of the droplet containing αHL, and the graph includes measurements from both droplets. Following the addition of Ca2+ to the external solution, the droplet containing αHL increased in fluorescence over ~1.5 h, whereas the droplet without protein did not. Scale bar, 300 µm. , A multisome containing a two-droplet network, in which one droplet contained Ca2+ and the other contained the dye and αHL. The dye-containing droplet increased in fluorescence, whereas the Ca2+-containing droplet did not. Scale bar, 300 µm. * Figure 5: pH- and temperature-dependent release of encapsulated contents into the aqueous environment. , pH-dependent release. A multisome is made with a mixture of DOPE and oleic acid, with one inner droplet containing Ca2+ and another dextran-conjugated fluo-4. With a decrease in pH, the multisome co-releases its contents into the bulk aqueous solution, where the two solutions mix to produce a signal that is monitored with a fluorescence microscope. , Fluorescence photographs and measurements from the experiment in . On lowering the pH of the external aqueous buffer from 8.0 to ~5.5, the inner droplets burst simultaneously, producing a transient fluorescent cloud. Scale bar, 500 µm. , Bursting temperatures of multisomes made with a mixture of DPPC and DSPC with a single inner droplet, subjected to a temperature ramp from room temperature at a rate of ~1 °C min−1 (top). Histogram of bursting temperatures (bottom). The bursting temperature was 43.6 ± 3.5 °C (mean ± s.d., n = 93), excluding the three multisomes that burst below 35 °C. Author information * Abstract * Author information * Supplementary information Affiliations * Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK * Gabriel Villar & * Hagan Bayley * Present address: Oxford Nanopore Technologies Ltd, Oxford Science Park, Oxford OX4 4GA, UK * Andrew J. Heron Contributions G.V., A.J.H. and H.B. planned the research. G.V. performed the experiments, data analysis and modelling. G.V. and H.B. wrote the paper. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Hagan Bayley Author Details * Gabriel Villar Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew J. Heron Search for this author in: * NPG journals * PubMed * Google Scholar * Hagan Bayley Contact Hagan Bayley Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary information (2,356 KB) Supplementary information Additional data - Mapping nanomechanical properties of live cells using multi-harmonic atomic force microscopy
- Nat Nanotechnol 6(12):809-814 (2011)
Nature Nanotechnology | Letter Mapping nanomechanical properties of live cells using multi-harmonic atomic force microscopy * A. Raman1, 3, 5 * S. Trigueros2, 5 * A. Cartagena1, 3 * A. P. Z. Stevenson2 * M. Susilo1 * E. Nauman1, 4 * S. Antoranz Contera2 * Affiliations * Contributions * Corresponding authorJournal name:Nature NanotechnologyVolume: 6,Pages:809–814Year published:(2011)DOI:doi:10.1038/nnano.2011.186Received01 August 2011Accepted28 September 2011Published online13 November 2011 Abstract * Abstract * Author information * Supplementary information Article tools * Full text * Print * Email * pdf options * download pdf * view interactive pdfpowered by ReadCube * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg The nanomechanical properties of living cells, such as their surface elastic response and adhesion, have important roles in cellular processes such as morphogenesis1, mechano-transduction2, focal adhesion3, motility4, 5, metastasis6 and drug delivery7, 8, 9, 10. Techniques based on quasi-static atomic force microscopy techniques11, 12, 13, 14, 15, 16, 17 can map these properties, but they lack the spatial and temporal resolution that is needed to observe many of the relevant details. Here, we present a dynamic atomic force microscopy18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 method to map quantitatively the nanomechanical properties of live cells with a throughput (measured in pixels/minute) that is ~10–1,000 times higher than that achieved with quasi-static atomic force microscopy techniques. The local properties of a cell are derived from the 0th, 1st and 2nd harmonic components of the Fourier spectrum of the AFM cantilevers interacting with the cell surface. Local stiff! ness, stiffness gradient and the viscoelastic dissipation of live Escherichia coli bacteria, rat fibroblasts and human red blood cells were all mapped in buffer solutions. Our method is compatible with commercial atomic force microscopes and could be used to analyse mechanical changes in tumours, cells and biofilm formation with sub-10 nm detail. View full text Subject terms: * Nanobiotechnology * Nanometrology and instrumentation Figures at a glance * Figure 1: Harmonic content of the AFM microcantilever as it interacts with soft living cells. , Schematic of an oscillating AFM cantilever interacting with a live cell in liquid, showing that tip–sample force nonlinearity leads to anharmonics at nωn of the drive frequency (n = 0, 2, 3, …). , Plots of cantilever harmonic amplitudes (A0, A1, A2) acquired using an acoustically excited Olympus TR800 cantilever on a live E. coli cell. The zeroth harmonic is dominant and the second harmonic amplitude is much smaller, first increasing, then decreasing on approaching the sample. , Plots of cantilever harmonic amplitudes (A0, A1) acquired using a Lorentz force excited Olympus TR400 cantilever on a live rat tail fibroblast. Here, the zeroth harmonic is dominant, and the second harmonic amplitude could not be detected at these drive amplitudes. The zeroth harmonic indicates a steady cantilever deflection component induced by the interaction forces. Insets: topography images of the cells from which the curves were acquired, using imaging parameters described in the Methods. * Figure 2: Multi-harmonic images of E. coli bacteria. , Topography image of a live E. coli cell scanned using a Lorentz force excited Olympus TR800 cantilever (see Methods). ,,,, Maps of the multi-harmonic data (A0, φ1, A2,φ2) acquired simultaneously with the topography, showing heterogeneities in local mechanical properties. –, Maps of the mean indentation (nm), local dynamic stiffness (N m−1) and damping (N s m−1) can be extracted from the measured zeroth and first harmonic data using the theory described in the text. , Map of the local second-order force gradient (N m−2), which measures the extent of nonlinearity in the local tip–sample forces. This map is extracted using the second harmonic data in conjunction with the zeroth and first harmonic data. Scale bar, 500 nm; 256 × 256 pixel image. The extracted property maps are only valid on the cell where the tip oscillation is small compared to the average indentation and not on the substrate where the tip intermittently taps on the sample. * Figure 3: Multi-harmonic images of rat fibroblasts. , Topography image of a live rat tail fibroblast cell scanned in buffer solution using a Lorentz force excited Olympus TR400 cantilever (see Methods). ,, Maps of (A0, φ1) acquired simultaneously with the topography showing high-resolution contrasts in local mechanical properties over the cell. –, Maps of the mean indentation, local storage elastic modulus and local loss modulus can be extracted from the multi-harmonic variables using the theory described in the text. Scale bar, 10 μm; 256 × 256 pixel image. The extracted property maps are only valid on the cell where the tip oscillation is small compared to the average indentation and not on the substrate where the tip intermittently taps on the sample. * Figure 4: Multi-harmonic images of a human red blood cell. , Topography image of a live human red blood cell scanned in buffer solution using a Lorentz force excited Olympus TR400 cantilever (see Methods). The absence of the characteristic biconcave topography is closely correlated to the pH and concentration of the buffer used in the experiment (Supplementary Section G). ,, Maps of (A0, φ1), showing strong contrasts in local properties between the core and the periphery of the cell. –, Maps of mean indentation, local dynamic spring constant and damping can be extracted from the multi-harmonic variables using the theory described in the text. Scale bar, 10 μm; 256 × 256 pixel image. The extracted property maps are only valid on the cell where the tip oscillation is small compared to the average indentation and not on the substrate where the tip intermittently taps on the sample. * Figure 5: Tracking time-varying changes in the mechanical properties of rat fibroblasts. A sequence of topography and (A0, φ1) images scanned in buffer solution using a Lorentz force excited Olympus TR400 cantilever (see Methods) reveals the spatiotemporal details of the changes in cytoskeleton structure of two live rat fibroblast cells at high resolution (256 × 256 pixels; image size 60 × 60 μm). Corresponding material property maps are also shown. The images clearly show the progression of local mechanical property maps of two rat fibroblast cells over a period of ~1 h with 1× PBS buffer. The extracted property maps are only valid on the cell where the tip oscillation is small compared to the average indentation and not on the substrate where the tip intermittently taps on the sample. Author information * Abstract * Author information * Supplementary information Primary authors * These authors contributed equally to this work * A. Raman & * S. Trigueros Affiliations * School of Mechanical Engineering, Purdue University, West Lafayette, Indiana, USA * A. Raman, * A. Cartagena, * M. Susilo & * E. Nauman * Department of Physics and Institute of Nanoscience for Medicine, Oxford Martin School, University of Oxford, Oxfordshire, UK * S. Trigueros, * A. P. Z. Stevenson & * S. Antoranz Contera * Birck Nanotechnology Center, Purdue University, West Lafayette, Indiana, USA * A. Raman & * A. Cartagena * Weldon School of Biomedical Engineering, West Lafayette, Indiana, USA * E. Nauman Contributions A.R. and S.T. are lead authors and contributed equally to this work. A.R. discovered the important experimental channels for material contrast. S.T., A.C., A.S, A.R., E.N. and M.S. developed experimental protocols for sample preparation. A.R., S.T. and S.C. conceived and designed the experiments. A.R. developed the theory and A.C. performed the numerical simulations and developed the code to implement the theory on the acquired AFM images. A.R., A.C., A.S. and S.T. performed the experiments. A.R. and S.T. co-wrote the paper. All authors discussed the results and commented on the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * A. Raman Author Details * A. Raman Contact A. Raman Search for this author in: * NPG journals * PubMed * Google Scholar * S. Trigueros Search for this author in: * NPG journals * PubMed * Google Scholar * A. Cartagena Search for this author in: * NPG journals * PubMed * Google Scholar * A. P. Z. Stevenson Search for this author in: * NPG journals * PubMed * Google Scholar * M. Susilo Search for this author in: * NPG journals * PubMed * Google Scholar * E. Nauman Search for this author in: * NPG journals * PubMed * Google Scholar * S. Antoranz Contera Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary information (2,152 KB) Supplementary information Additional data - Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size
- Nat Nanotechnol 6(12):815-823 (2011)
Nature Nanotechnology | Article Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size * H. Cabral1 * Y. Matsumoto2 * K. Mizuno3 * Q. Chen4 * M. Murakami2 * M. Kimura2 * Y. Terada5 * M. R. Kano6 * K. Miyazono6, 7 * M. Uesaka3, 7 * N. Nishiyama2, 7 * K. Kataoka1, 2, 4, 7 * Affiliations * Contributions * Corresponding authorsJournal name:Nature NanotechnologyVolume: 6,Pages:815–823Year published:(2011)DOI:doi:10.1038/nnano.2011.166Received27 April 2011Accepted12 September 2011Published online23 October 2011 Abstract * Abstract * Author information * Supplementary information Article tools * Full text * Print * Email * pdf options * download pdf * view interactive pdfpowered by ReadCube * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg A major goal in cancer research is to develop carriers that can deliver drugs effectively and without side effects. Liposomal and particulate carriers with diameters of ~100 nm have been widely used to improve the distribution and tumour accumulation of cancer drugs, but so far they have only been effective for treating highly permeable tumours. Here, we compare the accumulation and effectiveness of different sizes of long-circulating, drug-loaded polymeric micelles (with diameters of 30, 50, 70 and 100 nm) in both highly and poorly permeable tumours. All the polymer micelles penetrated highly permeable tumours in mice, but only the 30 nm micelles could penetrate poorly permeable pancreatic tumours to achieve an antitumour effect. We also showed that the penetration and efficacy of the larger micelles could be enhanced by using a transforming growth factor-β inhibitor to increase the permeability of the tumours. View full text Subject terms: * Nanomedicine Figures at a glance * Figure 1: Construction and physicochemical properties of DACHPt-loaded micellar nanomedicines (DACHPt/m) with different diameters. , Schematic showing DACHPt/m formed through the interaction between DACHPt and the carboxylic groups of poly(glutamic acid) (green) in PEG–b-P(Glu) and P(Glu). In media containing chloride ions, DACHPt (yellow circles) is released from the micelles through ligand exchange between the carboxylic groups in P(Glu) and the chloride ions. , Changing micelle size by altering the ratio of P(Glu) from the homopolymer and the P(Glu) portion of PEG–b-P(Glu) in the mixture. Total glutamic acid residue concentration was maintained at 5 mM. , Micelles of all sizes release DACHPt at similar rates. , Micelles of all sizes incubated in cell culture media containing 10% serum at 37 °C maintained their sizes over 48 h. , Plasma clearances of micelles with different diameters follow similar trends. Data are means ± s.e.m., n = 3. * Figure 2: Anticancer activity and tumour accumulation of DACHPt/m with different diameters. –, Plots of relative tumour volumes of subcutaneous hyperpermeable murine colon adenocarcinoma (C26) () and subcutaneous hypopermeable human pancreatic adenocarcinoma BxPC3 () tumours, and accumulation of DACHPt/m in C26 () and BxPC3 () tumours. To evaluate antitumour activity, oxaliplatin was injected on days 0, 2 and 4 (dose, 8 mg kg−1) and micelles were injected on days 0, 2 and 4 (dose, 3 mg kg−1 on a platinum basis). For tumour accumulation experiments, micelles were injected at 100 μg per mouse on a platinum basis. Data are means ± s.e.m., n = 6. *P > 0.05; **P < 0.05; ***P < 0.01; ****P < 0.001. * Figure 3: Microdistribution of fluorescently labelled DACHPt/m of varying sizes in tumours. –, Histological examination of C26 tumour () and BxPC3 tumour () by H&E staining (dashed lines in show area of cancer cell nests in the BxPC3 tumour) and fluorescent microscopic images of sections of C26 () and BxPC3 () tumours 24 h after intravenous administration of fluorescent micelles with different sizes. Micelles were labelled with Alexa 594 (red). Blood vessels were marked with PECAM-1 and Alexa 488 secondary antibody (green). Scale bars, 50 µm. –, Mapping of platinum atoms from DACHPt and iron from haemoproteins in tumour sections of C26 (), BxPC3 () and a BxPC3 cancer cell nest (indicated by dashed line) () by μ-SR-XRF 24 h after administration of micelles. Scale bars, 50 µm. * Figure 4: In vivo real-time microdistribution of DACHPt/m with different diameters in tumours. ,, Microdistribution of fluorescently labelled 30 nm (green) and 70 nm (red) micelles 1 h after injection into C26 () and BxPC3 () tumours. Their colocalization is shown in yellow. Right panels in and show fluorescence intensity profile from the blood vessel (0–10 µm; grey area) to the tumour tissue (10–100 µm) in the selected region (indicated by a white rectangle) expressed as a percentage of the maximum fluorescence intensity attained in the vascular region (%Vmax). ,, Z-stack volume reconstruction of C26 () and BxPC3 () tumours 1 h after co-injection of the fluorescent micelles. , Magnification of the perivascular region (indicated by a white trapezium) of the z-stack volume image of BxPC3 tumours. ,, Distribution of 30 and 70 nm micelles 24 h after injection into C26 tumours () and BxPC3 tumours (). White arrows in indicate 70 nm micelles localizing at perivascular regions. Right panels show fluorescence intensity profile from the blood vessel (0–10 µm; grey ar! ea) to the tumour tissue (10–100 µm) in the selected region (indicated by white rectangle). * Figure 5: Effect of TGF-β inhibitor (TGF-β-I) on antitumour activity and tumour accumulation of DACHPt/m in BxPC3 tumours. , Graph showing relative tumour volume. Micelles (3 mg kg−1) were injected on days 0, 4 and 8 and TGF-β-I on days 0, 2, 4, 6 and 8. , Graph showing accumulation of 30 and 70 nm DACHPt/m in BxPC3 tumours after injection of TGF-β-I. Data are expressed as means ± s.e.m., n = 6. *P > 0.05; **P < 0.01. , Fluorescent microscopy of tumour sections 24 h after co-administration of the fluorescent micelles and TGF-β-I. Scale bars, 50 µm. , Platinum and iron mapping of tumour sections by μ-SR-XRF 24 h after administration of 30 and 70 nm micelles. Scale bars, 50 µm. ,, Intravital distribution of 30 nm (green) and 70 nm (red) micelles in BxPC3 tumours 1 h () and 24 h () after co-injection of micelles and TGF-β-I. Their colocalization is shown in yellow. Right panels show fluorescence intensity profile from the blood vessel (grey area) to the tumour tissue in the selected region (indicated by a white rectangle). Author information * Abstract * Author information * Supplementary information Affiliations * Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan * H. Cabral & * K. Kataoka * Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan * Y. Matsumoto, * M. Murakami, * M. Kimura, * N. Nishiyama & * K. Kataoka * Department of Nuclear Engineering and Management, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan * K. Mizuno & * M. Uesaka * Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan * Q. Chen & * K. Kataoka * SPring 8, JASRI, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo 679-5198, Japan * Y. Terada * Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan * M. R. Kano & * K. Miyazono * Center for NanoBio Integration (CNBI), The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan * K. Miyazono, * M. Uesaka, * N. Nishiyama & * K. Kataoka Contributions H.C. designed and performed all the experiments. Y.M. assisted with in vivo confocal microscopies. K.M. and Y.T. helped in the μ-X-ray fluorescence measurements. Q.C. performed transmission electron microscopy of the micelles. M.M and M.K. aided in the biodistribution experiments. H.C. wrote the manuscript. M.R.K., K.M. and M.U. commented on the manuscript. N.N. and K.K. edited the manuscript. K.K., with help from N.N., supervised the whole project. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * N. Nishiyama or * K. Kataoka Author Details * H. Cabral Search for this author in: * NPG journals * PubMed * Google Scholar * Y. Matsumoto Search for this author in: * NPG journals * PubMed * Google Scholar * K. Mizuno Search for this author in: * NPG journals * PubMed * Google Scholar * Q. Chen Search for this author in: * NPG journals * PubMed * Google Scholar * M. Murakami Search for this author in: * NPG journals * PubMed * Google Scholar * M. Kimura Search for this author in: * NPG journals * PubMed * Google Scholar * Y. Terada Search for this author in: * NPG journals * PubMed * Google Scholar * M. R. Kano Search for this author in: * NPG journals * PubMed * Google Scholar * K. Miyazono Search for this author in: * NPG journals * PubMed * Google Scholar * M. Uesaka Search for this author in: * NPG journals * PubMed * Google Scholar * N. Nishiyama Contact N. Nishiyama Search for this author in: * NPG journals * PubMed * Google Scholar * K. Kataoka Contact K. Kataoka Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary information (1,316 KB) Supplementary information Movies * Supplementary information (2,635 KB) Supplementary movie 1 * Supplementary information (1,507 KB) Supplementary movie 2 * Supplementary information (2,326 KB) Supplementary movie 3 * Supplementary information (2,310 KB) Supplementary movie 4 * Supplementary information (1,368 KB) Supplementary movie 5 * Supplementary information (786 KB) Supplementary movie 6 * Supplementary information (1,305 KB) Supplementary movie 7 Additional data - Signalling of DNA damage and cytokines across cell barriers exposed to nanoparticles depends on barrier thickness
- Nat Nanotechnol 6(12):824-833 (2011)
Nature Nanotechnology | Article Signalling of DNA damage and cytokines across cell barriers exposed to nanoparticles depends on barrier thickness * A. Sood1, 21 * S. Salih1, 21 * D. Roh2 * L. Lacharme-Lora1 * M. Parry1 * B. Hardiman1 * R. Keehan1 * R. Grummer3 * E. Winterhager3 * P. J. Gokhale4 * P. W. Andrews4 * C. Abbott5 * K. Forbes6 * M. Westwood6 * J. D. Aplin6 * E. Ingham7 * I. Papageorgiou7 * M. Berry8 * J. Liu8 * A. D. Dick8 * R. J. Garland9 * N. Williams9 * R. Singh10 * A. K. Simon11 * M. Lewis12 * J. Ham12 * L. Roger13 * D. M. Baird13 * L. A. Crompton14 * M. A. Caldwell14 * H. Swalwell15 * M. Birch-Machin15 * G. Lopez-Castejon16 * A. Randall17 * H. Lin18 * M-S. Suleiman18 * W. H. Evans19 * R. Newson20 * C. P. Case1 * Affiliations * Contributions * Corresponding authorJournal name:Nature NanotechnologyVolume: 6,Pages:824–833Year published:(2011)DOI:doi:10.1038/nnano.2011.188Received17 June 2011Accepted28 September 2011Published online06 November 2011 Abstract * Abstract * Author information * Supplementary information Article tools * Full text * Print * Email * pdf options * download pdf * view interactive pdfpowered by ReadCube * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg The use of nanoparticles in medicine is ever increasing, and it is important to understand their targeted and non-targeted effects. We have previously shown that nanoparticles can cause DNA damage to cells cultured below a cellular barrier without crossing this barrier. Here, we show that this indirect DNA damage depends on the thickness of the cellular barrier, and it is mediated by signalling through gap junction proteins following the generation of mitochondrial free radicals. Indirect damage was seen across both trophoblast and corneal barriers. Signalling, including cytokine release, occurred only across bilayer and multilayer barriers, but not across monolayer barriers. Indirect toxicity was also observed in mice and using ex vivo explants of the human placenta. If the importance of barrier thickness in signalling is a general feature for all types of barriers, our results may offer a principle with which to limit the adverse effects of nanoparticle exposure and offer ! new therapeutic approaches. View full text Subject terms: * Nanomedicine * Environmental, health and safety issues Figures at a glance * Figure 1: Signalling varies with thickness of BeWo barrier. –, Light micrographs of predominantly monolayered (4-day growth) (,) and bilayered (7-day growth) (,) BeWo barrier before (,) and after (,) exposure to 0.04 mg ml−1 CoCr nanoparticles (NP). ,, DNA damage in fibroblasts beneath BeWo barriers grown for different periods (days) and then exposed either to 0.04 mg ml−1 CoCr () or 0.4 mg ml−1 TiO2 () nanoparticles for 24 h. DNA damage, measured using the alkaline comet assay, is expressed as mean tail moment with 95% confidence intervals. Open bars, fibroblasts below unexposed barriers. Shaded bars, fibroblasts below nanoparticle-exposed barriers. ,, mRNA expression of pannexin 1 () and P2X7 receptor () in the barrier. (qPCR normalized to GAPDH and relative to the non-treated 4 day gene expression value.) –, Connexin immunostaining in predominantly monolayered barriers without () and with () nanoparticle exposure and in bilayered barriers without () and with () nanoparticle exposure. ***P < 0.001 (see Methods for statist! ics). * Figure 2: Oxidative stress, mitochondrial ROS or changes in oxygen level lead to DNA-damaging signalling from bilayered but not predominantly monolayered BeWo barriers. DNA damage in human fibroblasts below the BeWo barrier is presented as mean tail moment. , Effect of ATP with or without Gap 27 (GAP) or compound 17 (C17) (P2X7 antagonist) above a monolayered barrier. , Effect of antioxidant (vitamin C, VitC) or blocking mitochondrial ROS with MitoQ (MQ), or control compound TPP or catalase (Cat) on a CoCr nanoparticle-exposed (NP, 0.04 mg ml−1) bilayered barrier. ,, Induction of mitochondrial ROS by antimycin A (AMA) compared to rotanone (ROT) causes DNA damage in fibroblasts below bilayered () but not monolayered () barriers. ,, Altered oxygen (1%) from hypoxia (1%) to normoxia (21%) of bilayered () but not monolayered () barriers causes DNA damage to underlying fibroblasts, which is prevented by treatment of the barrier with MitoQ or Gap27. *P < 0.05, **P < 0.01, ***P < 0.001 (see Methods for statistics). * Figure 3: Changes in BeWo barriers after nanoparticle exposure. , mtDNA damage in barriers with (CoCr) (0.04 mg ml−1) or without (control) nanoparticle exposure including addition of Gap 27 (Gap). Error bars represent ±s.e.m. for two independent experiments, each performed twice and in triplicate. C(t) refers to the number of PCR cycles required to cross a given threshold during exponential amplification. A higher C(t) value represents an increase in mtDNA damage. , Levels of 8-oxodG in BeWo cellular DNA. Values are shown with and without nanoparticle exposure of 4- and 7-day BeWo barriers. Error bars represent s.d. of the average of three separate determinations. (The European standards committee on oxidative DNA damage (ESCODD) advocates that the background level of 8-oxodG adducts in DNA should be ~10–50 adducts per 107 deoxynucleosides, or below.) –, Western blot analyses data of the effect of CoCr nanoparticles on activation of the Akt–mTOR–HIF-1α signal transduction pathway in BeWo barriers grown for 4 days (monolayer) ! and 7 days (bilayer) with time after CoCr nanoparticle exposure: phospho- (P) and total (T) Akt (,), phospho- and total mTOR (,) and HIF-1α (,). Western blots (,) were quantified by imaging densitometry and the graphs show the mean ratios of the phosphorylated to total molecules and expressed as percent of time 0. , Mean absolute values (integrated density value) of HIF-1α expression. Grey histograms, BeWo 4-day barriers (predominantly monolayers); black histograms, BeWo 7-day barriers (bilayers). * Figure 4: DNA damage in human embryonic stem cells below nanoparticle-exposed BeWo barriers. ,, Incidence of γH2AX foci (≥4 foci/cell, ; 1–3 foci/cell, ) in undifferentiated (open histograms, Oct 4+) and differentiated (black histograms, Oct 4–) human embryonic stem cells placed below bilayered BeWo barrier exposed to 0.04 mg ml−1 CoCr nanoparticles. ***P < 0.001 (see Methods for statistics). ,, Fluorescence images showing human embryonic stem cells in which there is γH2AX staining (red foci) in Oct 4– cells (blue) compared to a lack of staining in Oct4+ cells (green) after indirect exposure to nanoparticles across bilayered BeWo cell barriers. * Figure 5: DNA damage, in vivo and ex vivo, across bilayered but not monolayered barriers. ,, Light micrographs of placentas in mice without () and with () intravascular injection of CoCr nanoparticles (0.12 mg) at 12.5 days of pregnancy. Placentas with and without exposure showed a well-developed placenta with all subpopulations of the trophoblast lineage, well-developed labyrinth (L), spongiotrophoblast (S) and glycogen cells (GC) and some giant cells (not shown in the inset). YS, yolk sac. , Levels of DNA damage (alkaline comet assay) in maternal blood, fetal/neonatal blood or liver 7 days after nanoparticle injection (0.12 mg) of pregnant mice at 9.5 or 12.5 days of pregnancy. , Levels of DNA damage in maternal blood or brain, or fetal blood, 7 days after nanoparticle injection (0.012 mg) of pregnant mice at 12.5 days of pregnancy. , Metal levels in whole fetus after nanoparticle injection (0.12 mg) of pregnant mice at 9.5 or 12.5 days of pregnancy as measured by high-resolution inductively coupled plasma mass spectrometry (Co,Cr externally accredited, Mo not ! accredited). , DNA damage (comet assay) in fibroblasts exposed to culture medium of human placental explants maintained in 21% O2, hypoxia or switched from hypoxia to 21% O2. *P < 0.05, **P < 0.01, ***P < 0.001 (see Methods for statistics). * Figure 6: Signalling occurs through a bilayered but not monolayered corneal barrier. –, Light micrographs of monolayers and bilayers before (,) and 24 h after (,) exposure to 0.04 mg ml−1 of CoCr nanoparticles. , DNA damage in underlying fibroblasts (comet assay) beneath monolayered or bilayered corneal barriers exposed to 0.04 mg ml−1 CoCr nanoparticles (above the barrier) with or without Gap 27 (GAP), MitoQ (MQ) or vitamin C (VitC) (placed above the barrier). , mRNA expression of connexin 43 (cx43) and P2Y1, P2Y2 and P2X7 receptor with β-actin (shown as control). Data shown for monolayered or bilayered corneal barrier with (NP) or without (Cont) nanoparticles exposure, with or without antioxidant MitoQ (MQ), vitamin C (Vit C) or connexin 43 blockade (Gap 27)). –, Release of EGF (), IL6 (), GMCSF (), GRO () MCP-1 () and IL8 () from nanoparticle exposed bilayered but not monolayered barriers (in the absence of underlying fibroblasts) with or without Gap 27 (GAP), MitoQ (MQ) or vitamin C (VitC) placed above the barrier. *P < 0.05, **P < 0.01, ***P < ! 0.001 (see Methods for statistics). , Telomerase activity in fibroblasts, corneal cells (CAS) and BeWo cells as normalized to no template control and expressed as log copy number determined from a standard curve (HT, heat-treated control). , Telomere lengths as estimated by STELA at the XpYp and 17p telomere. Telomere length is indicated on the left and right, and mean telomere length and s.d. are indicated below. Author information * Abstract * Author information * Supplementary information Primary authors * These authors contributed equally to the practical work * A. Sood & * S. Salih Affiliations * Bristol Musculoskeletal Research Unit, Clinical Science at North Bristol University of Bristol, Avon Orthopaedic Centre, Southmead Hospital, Bristol BS10 5NB UK * A. Sood, * S. Salih, * L. Lacharme-Lora, * M. Parry, * B. Hardiman, * R. Keehan & * C. P. Case * Department of Ophthalmology, UPMC Eye and Ear Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA * D. Roh * Institut für Molekularbiologie (Tumorforschung) Institute of Molecular Biology (Tumor Research), Universitätsklinikum Essen University Hospital Essen Hufelandstrasse, Hufelandstrasse 55 55 45122 Essen, Germany * R. Grummer & * E. Winterhager * Department of Biomedical Science, The University of Sheffield, Western Bank, Sheffield S10 2TN, UK * P. J. Gokhale & * P. W. Andrews * Department of Histopathology, Southmead Hospital, Bristol BS10 5NB, UK * C. Abbott * Maternal and Fetal Health Research Group, The University of Manchester, 5th Floor Research, St Mary's Hospital, Manchester M13 9WL, UK * K. Forbes, * M. Westwood & * J. D. Aplin * Institute of Molecular and Cellular Biology, University of Leeds, Mount Preston Street, Leeds, West Yorkshire LS2 9JT, UK * E. Ingham & * I. Papageorgiou * Ophthalmology Department, School of Clinical Sciences University of Bristol, Bristol Eye Hospital, Lower Maudlin Street, Bristol BS1 2LX, UK * M. Berry, * J. Liu & * A. D. Dick * School of Cellular and Molecular Medicine University of Bristol Office, Medical Sciences Building, University Walk, Clifton, Bristol BS8 1TD, UK * R. J. Garland & * N. Williams * Department of Cancer Studies and Molecular Medicine, University of Leicester, University Road, Leicester LE1 7RH, UK * R. Singh * The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK * A. K. Simon * Centre for Endocrine & Diabetes Sciences, Department of Medicine, Cardiff University School of Medicine, UHW Main Building, Heath Park, Cardiff CF14 4XN, UK * M. Lewis & * J. Ham * Department of Medical Genetics, Haematology & Pathology, Cardiff University School of Medicine, Henry Wellcome Building, Heath Park, Cardiff CF14 4XN, UK * L. Roger & * D. M. Baird * School of Clinical Sciences, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, UK * L. A. Crompton & * M. A. Caldwell * Dermatological Sciences, Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle NE2 4HH, UK * H. Swalwell & * M. Birch-Machin * Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, UK * G. Lopez-Castejon * School of Medical Sciences, University Walk, Bristol BS8 1TD, UK * A. Randall * Cardiac Physiology, School of Clinical Sciences University of Bristol, Level 7, Bristol Royal Infirmary, Marlborough Street, Bristol BS2 8HW, UK * H. Lin & * M-S. Suleiman * Department of Infection, Immunity & Biochemistry, Cardiff University School of Medicine, Wales Heart Research Institute, Heath Park, Cardiff CF14 4XN, UK * W. H. Evans * National Heart & Lung Institute, Imperial College, Emmanuel Kaye Building 1b, Manresa Road, London SW3 6LR, UK * R. Newson Contributions C.P.C., A.S. and S.S. conceived and designed the experiments. A.S., S.S., L.L., B.H., R.G., E.W., D.R., P.G., C.A., K.F., M.W., I.P., M.B., R.J., M.S., D.B., G.L-C., L.C., J.L., K.S., M.L., L.R., H.S., M.B.M., A.R. and H.L. performed the experiments. C.P.C., R.N., D.R., P.G., N.M., J.A., A.R., M.B.M., J.H. and K.S. analysed the data. M.S., W.H.E., I.P. and E.I. contributed materials and analysis tools. C.P.C. wrote the paper. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * C. P. Case Author Details * A. Sood Search for this author in: * NPG journals * PubMed * Google Scholar * S. Salih Search for this author in: * NPG journals * PubMed * Google Scholar * D. Roh Search for this author in: * NPG journals * PubMed * Google Scholar * L. Lacharme-Lora Search for this author in: * NPG journals * PubMed * Google Scholar * M. Parry Search for this author in: * NPG journals * PubMed * Google Scholar * B. Hardiman Search for this author in: * NPG journals * PubMed * Google Scholar * R. Keehan Search for this author in: * NPG journals * PubMed * Google Scholar * R. Grummer Search for this author in: * NPG journals * PubMed * Google Scholar * E. Winterhager Search for this author in: * NPG journals * PubMed * Google Scholar * P. J. Gokhale Search for this author in: * NPG journals * PubMed * Google Scholar * P. W. Andrews Search for this author in: * NPG journals * PubMed * Google Scholar * C. Abbott Search for this author in: * NPG journals * PubMed * Google Scholar * K. Forbes Search for this author in: * NPG journals * PubMed * Google Scholar * M. Westwood Search for this author in: * NPG journals * PubMed * Google Scholar * J. D. Aplin Search for this author in: * NPG journals * PubMed * Google Scholar * E. Ingham Search for this author in: * NPG journals * PubMed * Google Scholar * I. Papageorgiou Search for this author in: * NPG journals * PubMed * Google Scholar * M. Berry Search for this author in: * NPG journals * PubMed * Google Scholar * J. Liu Search for this author in: * NPG journals * PubMed * Google Scholar * A. D. Dick Search for this author in: * NPG journals * PubMed * Google Scholar * R. J. Garland Search for this author in: * NPG journals * PubMed * Google Scholar * N. Williams Search for this author in: * NPG journals * PubMed * Google Scholar * R. Singh Search for this author in: * NPG journals * PubMed * Google Scholar * A. K. Simon Search for this author in: * NPG journals * PubMed * Google Scholar * M. Lewis Search for this author in: * NPG journals * PubMed * Google Scholar * J. Ham Search for this author in: * NPG journals * PubMed * Google Scholar * L. Roger Search for this author in: * NPG journals * PubMed * Google Scholar * D. M. Baird Search for this author in: * NPG journals * PubMed * Google Scholar * L. A. Crompton Search for this author in: * NPG journals * PubMed * Google Scholar * M. A. Caldwell Search for this author in: * NPG journals * PubMed * Google Scholar * H. Swalwell Search for this author in: * NPG journals * PubMed * Google Scholar * M. Birch-Machin Search for this author in: * NPG journals * PubMed * Google Scholar * G. Lopez-Castejon Search for this author in: * NPG journals * PubMed * Google Scholar * A. Randall Search for this author in: * NPG journals * PubMed * Google Scholar * H. Lin Search for this author in: * NPG journals * PubMed * Google Scholar * M-S. Suleiman Search for this author in: * NPG journals * PubMed * Google Scholar * W. H. Evans Search for this author in: * NPG journals * PubMed * Google Scholar * R. Newson Search for this author in: * NPG journals * PubMed * Google Scholar * C. P. Case Contact C. P. Case Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary information (1,329 KB) Supplementary information Additional data
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