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NANOBIOTECHNOLOGY A new look for nanopore sensing Coating solid-state nanopores with fluid lipid bilayers can reduce the translocation speeds of molecules and prevent the nanopores from clogging. Tim Albrecht

iological and solid-state nanopores ++ have been explored for applications in Proteins Bsingle-molecule biosensing, protein detection and ultrafast, label-free DNA Lipid 1–3 sequencing . Nanopore-based sequencing, bilayer in particular, is expected to be an easy-to- use and portable technology that will be Si N useful in point-of-care diagnostics. However, 3 4 Si3N4 the lack of spatial resolution and molecular Nanopore specificity associated with nanopores has Specific hindered their use as tools for routine Translocation fast receptors Slower translocation sensing and sequencing applications, as ––and unspecific with specific recognition has the difficulty of controlling the speed at which molecules translocate through Figure 1 | Comparison of a conventional nanopore sensor and the fluid-coated nanopore sensor. nanopores. Furthermore, there are problems Left: Schematic showing the conventional nanopore sensor. Translocation of proteins is fast and with mechanical instability and clogging that non-specific, and the overcrowding of biomolecules inside the nanopore often leads to clogging. have been only partly overcome so far4–6. Right: Nanopore sensors coated with a fluid lipid bilayer contain receptors that allow specific binding Writing in Nature Nanotechnology, of proteins. Translocation is slower and individual translocation events can more easily be resolved. The Michael Mayer of the University of Michigan fluidity of the pore walls also prevents clogging. and colleagues7 at the University of Arkansas and the University of California, San Diego, report that they have addressed some of these Similar but much more efficient nanopore mobility of the lipid bilayer on the solid problems by coating solid-state nanopores sensors have been found in the olfactory support allows ions and proteins in solution, with a fluid lipid bilayer, which allows the systems of insects. Rather than attempting and notably surface-bound proteins, surface chemistry to be tailored and pore to detect extremely low concentrations of to be dragged through the nanopore diameters to be tuned (Fig. 1). By embedding pheromones directly, the external skeleton to give a characteristic change in its specific molecular receptors into the lipid of an insect contains nanopores that are conductance. Although proteins in solutions bilayer, proteins could be preconcentrated on coated with a mobile fluid lipid bilayer. The generally translocate very quickly (on the the lipid and selectively translocated through bilayer, which contains specific receptors, microsecond timescale) and are extremely the nanopore. The fluidity of the pore walls allows odorant molecules to bind and be difficult to detect, proteins that are bound allowed for fine-tuning of the translocation preconcentrated before being transported to receptors in fluid walls are more easily speed, simply by choosing a lipid bilayer to the olfactory neurons in the antennae of detected. Because the translocation speed with the right viscosity, and prevented the the insects. of receptor-bound proteins depends on the nanopores from clogging. Inspired by this, Mayer and co-workers viscosity of the lipids, choosing the right The total speed of a nanopore sensor made a nanopore that was 20–30 nm wide, lipid with the most suitable viscosity offers is determined by the translocation speed and also 20–30 nm deep, in a silicon nitride fine control over the translocation process. of an individual biomolecule through the membrane, and then coated it with a fluid Lipids that are more viscous and have nanopore and the time required to collect lipid bilayer by exposing the membrane longer hydrophobic chains could slow down a statistically significant amount of data. to a suspension of unilamellar liposomes. translocation speeds by up to two orders Translocation frequency, which is the Similar to the receptors on the nanopores of magnitude. number of translocation events per unit in insects, the bilayer contains biotin groups Another advantage of using the fluid time, depends on the concentration of the that act as specific molecular receptors for lipids is that a potentially large range of biomolecule and this typically cannot be streptavidin, anti-biotin antibody fragments receptor molecules can be integrated varied at will. Concentrations that are too and other biotin-binding proteins. Although into the bilayer and, depending on the low result in a low translocation frequency the solution concentration of the analytes target molecule in solution, a new level of and potentially very long measurement of interest in this case is so small that they molecular specificity can be introduced to times, whereas concentrations that are too probably remain undetected, their high nanopore-based sensing. Differentiating high may lead to overcrowding inside the affinity to biotin leads to a significant between protein species in classical pore, and possibly even clogging, owing preconcentration on the lipid-bilayer surface. nanopore sensors is a huge challenge to the simultaneous translocation of On application of an electric field across because proteins with similar size and several biomolecules. the nanopore membrane, the inherent charge result in similar translocation

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© 2011 Macmillan Publishers Limited. All rights reserved news & views characteristics and are thus not specific This new technology is not restricted research and, more generally, biological enough, especially in complex mixtures. to improving the sensing performance of nanotechnology as a whole. ❐ Finally, the fluidity of the lipid bilayer inside nanopore devices. The idea of being able the nanopore also reduces the likelihood of to deliver certain molecules, say proteins Tim Albrecht is in the Department of Chemistry, pores being clogged by protein aggregates, or enzymes, to a well-defined location Imperial College London, Exhibition Road, addressing another major issue in nanopore on the nanopore could also be applied to London SW7 2AZ, UK. sensing. Amyloid-beta proteins that are used assemble particular types of molecules, e-mail: [email protected] as a model system were shown to translocate supramolecular structures or more smoothly through the pores. complex molecular ‘machines’ at or inside References 7 8 Mayer and colleagues have essentially the nanopore . This may offer interesting 1. Dekker, C. Nature Nanotech. 2, 209–215 (2007). killed four birds with one stone with the prospects for the design of single-molecule 2. Kasianowicz, J. J., Robertson, J. W. F., Chan, E. R., Reiner, J. E. & new approach. The fluid lipids have allowed devices or biological/solid-state hybrid Stanford, V. M. Ann. Rev. Anal. Chem. 1, 737–766 (2008). specific proteins from dilute solutions to be structures potentially for many devices in 3. Branton, D. et al. Nature Biotechnol. 26, 1146–1153 (2008). concentrated and translocated at frequencies parallel, say on a wafer scale. 4. Clarke, J. et al. Nature Nanotech. 4, 265–270 (2009). 5. Kleefen, A. et al. Nano Lett. 10, 5080–5087 (2010). much higher than expected from the The introduction of the ‘fluid-wall 6. Ivanov, A. P. et al. Nano Lett. 11, 279–285 (2011). solution concentration and without clogging technology’ seems to be just the beginning 7. Yusko, E. C. et al. Nature Nanotech. 6, 253–260 (2011). the pores. of an exciting new development in nanopore 8. Hall, A. R. et al. Nature Nanotech. 5, 874–877 (2010).

NANOELECTRONICS Making light of electrons Electrons have been channelled through graphene wires using the principles of optical guiding by fibre optic cables. David Goldhaber-Gordon

cience and technology often rely on p electrons. Furthermore, the possibility of analogy to make progress. For example, n light-like guiding in graphene is somehow Sphotonic crystals are periodic materials p more obvious than it is in conventional that allow only certain wavelengths of semiconductors. This is because the light to propagate in them, in the same relationship between the energy and way that crystalline semiconductors allow wavelength of electrons in graphene is very electrons with only certain energies to move similar to the corresponding relationship through them. Electronic counterparts of in photons, because electrons in graphene p–n junction familiar optical components such as pinhole WILLIAMS J. R. behave as if they were massless, in close sources1, interferometers2, beam splitters analogy to massless photons. In retrospect, it and electron beam lenses3,4 have also been Figure 1 | Electrons from a point source (yellow is clear that light-like electron guiding could built. These advances exploit the shared circle) travel down a graphene p–n waveguide, be done in conventional semiconductors wave nature of electrons and photons, and consisting of two hole-rich areas (p) and a central, as well, and perhaps that will be fruitfully have been made possible by developments electron-rich area (n). Electrons incident on the explored in the coming years. in semiconductor materials growth and p–n junction at glancing angles are reflected back There are two possible approaches to nanofabrication that allow the patterning of into the n-type core, whereas those incident at achieve light-like guiding of electrons in the potential energy landscape experienced larger angles escape into the p-type cladding. graphene. First, in direct analogy to a fibre by an electron on submicrometre scales The unusual bend in the escaping trajectories is optic cable, one can construct an electronic and with extremely low disorder. Now, the characteristic of a change in the sign of the index ‘cladding’ with a lower density of carriers electron has been made to mimic the photon of refraction. than in a corresponding ‘core’ to achieve so- in a new way, courtesy of graphene. Writing called optical guiding. Or, more exotically, in Nature Nanotechnology, Charles Marcus the cladding and core charge densities and co-workers at Harvard and Purdue that is surrounded by cladding (with a can be made opposite to one another, by University report that they have guided lower refractive index). Light hitting the arranging for one to carry holes and the electrons through narrow graphene channels core–cladding interface bends and, for a other electrons, resulting in p–n guiding by exploiting the same principles by which shallow enough incident angle, is trapped (Fig. 1). This gives the cladding an effectively light is guided through a fibre optic cable5. in the core. This phenomenon, known as negative index of refraction, a concept also Electronic waveguides (such as total internal reflection, allows the guiding borrowed from optics6,7. nanowires) typically work by creating a of light over tens of kilometres without the Marcus and collaborators simulate, then potential energy step that prevents mobile need for signal regeneration. build, both types of guiding configuration electrons from leaving the waveguide. Now enter graphene. In this material, in graphene wires. They focus on calculating However, an electronic analogue of the it is impossible to exclude electrons from and measuring the guiding efficiency, which optical fibre has not been demonstrated. some regions of space using simple potential is the portion of electrons injected at one Optical fibres guide light through a core energy steps, so there is a motivation end of the wire that successfully transit to region (with a high refractive index) for examining other ways of guiding the other end. A simulation of an idealized,

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