Music of Molecules

As we have seen, detecting the presence of a given substance at the molecular level, down to a single molecule, remains a considerable challenge for many nanosensor applications that range from nanobiotechnology research to environmental monitoring and antiterrorist or military applications.
Currently, chemical functionalization techniques are used to specify what a nanoscale detector will sense. For biological molecules, this might mean developing an antibody–antigen (i.e. lock and key) pair, or an alternative synthetically generated ligand. For gases, it is much more challenging to develop the right ‘glue’ that sticks a given gas—and only that gas—to a substrate. Thus, for many gas-sensing applications, appropriate functionalization may not even be possible.
The advantage of spectroscopic techniques—measuring and interpreting electromagnetic spectra arising from either emission or absorption of radiant energy by various substances—such as Raman, infrared, and NMR spectroscopy is that they are label-free, i.e. they require no preconditioning in order to identify a given analyte. They are also highly selective, capable of distinguishing species that are chemically or functionally very similar. On the downside, spectroscopic methods face enormous challenges in measuring dilute concentrations of an analyte and generally involve the use of large, expensive equipment.
‘‘We have been working on ways to overcome the functionalization bottleneck in sensing and, instead of trying to see a molecule by using photons or electrons—as in optical spectroscopy or electron microscopy—we have been using vibrational energy exchange to in effect ‘listen’ to the vibrations of the molecule,’’ says Jeffrey Grossman. ‘‘The concept is much like bringing a set of
nano tuning forks up to a molecule and seeing which ones become excited.Those would form a chord of ‘notes’ that are unique to that particular molecule.Thus, the molecule can be identified.’’
In his work, Grossman, who leads the Computational Nanoscience Group at the University of California, Berkeley and is Executive Director of Berkeley’s Center of Integrated Nanomechanical Systems, has been taking advantage of the unique manner in which vibrational energy transfers between nanoscale objects, with applications spanning chemical, biological, radiation, and even acoustic sensing.
‘‘The scientific core of our work is aimed at utilizing the unique way in whichmechanical energy—in other words, heat—is exchanged at the nanoscale’’ Grossman explains. ‘‘Specifically, we have shown that if one nanoscale object vibrates at the same frequency as another, ‘in resonance’, then it is possible for these two objects to exchange heat extremely efficiently. Conversely, if they are not vibrating at the same frequency then the flow of heat is blocked and little ono energy is exchanged.’’
In essence, what Grossman and his group have done is to demonstrate that one can take advantage of this nanomechanical exchange of energy for detection or characterization of an unknown molecule type. They have termed their novel chemical detection technique nanomechanical resonance spectroscopy (NRS). NRS basically employs an array of nanomechanical resonators that are used to directly interrogate a heated (‘thermally excited’) analyte’s vibrational frequencies.
They laid some of the groundwork for the theory behind nanomechanical energy exchange, which allowed them to demonstrate this effect. The proposed NRS sensor could ‘listen to the music’ a molecule makes without needing to adhere the molecule to a surface, thereby allowing for continuous measurements with little or no cleaning, resetting, or degradation of the sensor. The result would be a nanodetection system that could detect many different species
without functionalization chemistry steps. The NRS has become possible with the ability to synthesize nanoscale objects that resonate at the same frequencies as the natural vibrations of molecules. Figure 1.3

The work in Grossman’s group is part of an emerging field of study of frequency-dependent thermal phenomena in nanoscale systems, i.e. recognizing and exploiting the wave nature of heat. In these small systems the macroscopic concept of temperature (the time-averaged thermal energy) is insufficient to describe how a system will behave.
Grossman points out that one must also take into account how the thermal energy is distributed in frequency; this distribution can influence the way in which heat is transported, or blocked, as well as how heat effects other important properties such as electron transport.
‘‘There are other researchers who are studying the importance of the frequency dependence of heat in nanostructures, for example in thermoelectric materials, or in thermally rectifying materials,’’ he says. ‘‘However, our work is unique in proposing an application that depends solely on frequency-dependent phenomena and also by utilizing these phenomena for label-free detection.’’
‘‘One could envision several NRS device set-ups’’ says Grossman. ‘‘For example, a series of CNTs of differing length (or radius) suspended over a trench, similar to the strings in a harp. Alternatively one could pass analytes through holes in graphene membranes or over substrates coated in fullerenes of different radius. The design of a practical NRS is more limited by capabilities for detecting the excitation of a vibrational mode than the ability to fabricate nanoscale devices.’’
The number of applications for a sensitive, label-free detection system is quite extensive. It could be extremely useful in areas such as medicine, homeland security, environmental monitoring, and clean energy and water.
Research in this area of thermal phenomena and heat flow at the nanoscale is just beginning. ‘‘With the development of theory for describing heat transport in nanoscale systems and advances in nanoscale fabrication and characterization techniques, we are now well equipped to study these phenomena,’’ says Figure 1.3 Left:Illustration of nanotube or nanowire when its fundamental mode of oscillation is unexcited(bottom)or excited(top).Right: analogy with a piano—the frequency of oscillation of the nanotube or nanowire can be thought of as a note on a piano.
Grossman. ‘‘As a result we should look forward to the development of more
applications that exploit the wave nature of heat.’’
Featured scientist: Jeffrey Grossman
Organization: Center of Integrated Nanomechanical Systems (COINS),
University of California, Berkeley, CA, USA
Relevant publication: P. Alex Greaney, Jeffrey C. Grossman:
Nanomechanical resonance spectroscopy: a novel route to
ultrasensitive label-free detection. Nano Lett., 8, 2648–2652.
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Nano-Society
www.rsc.org/nanoscience

Novel Spectroscopic Technique could Revolutionize Chemical Analysis

Laser-based analytical techniques such as Raman spectroscopy, fluorescence spectroscopy or the state-of-the-art laser-induced breakdown spectroscopy (LIBS) are highly sophisticated techniques for analyzing minute amounts of matter with regard to its structure, elemental composition, and other chemical properties.LIBS has been shown to be capable of analyzing extremely small samples with high sensitivity—nanolitre volumes with levels of detection in water of one part per million. LIBS works by focusing short laser pulses on to the surface of a
sample to create a hot plasma with temperatures of 10 000–20 000 1C. The plasma emits radiation that allows the observation of the characteristic atomic emission lines of the elements. The downside is that LIBS is complicated by the need for multiple laser pulses to generate asufficiently hot plasma and the need for focusing and switching a powerful laser, requiring relatively large and expensive instruments.
Research coming out of Drexel University has shown that light emitted from a new form of cold plasma in liquid—field emission generated, highly nonequilibrium, and high energy density—permits optical emission spectroscopy (OES) analysis of the elemental composition of solutions within nanoseconds from femtolitre (10–15 L) volumes.
‘‘We were able to generate, for the first time, a nonthermal corona discharge in liquid around electrodes with ultrasharp tips and around nanowires,’’ says Yury Gogotsi. ‘‘We have demonstrated that plasmas created with 50 nm probe tips or carbon nanotubes (CNTs)—what we have termed nanoscale corona discharge probes (NCDPs)—dispersed in solution allow simultaneous chemical analysis of multiple dissolved elements within nanoseconds. Time-resolved OES of NCDPs demonstrates narrow spectral lines that prove very useful for simple yet sensitive multi-elemental analysis, thus opening new possibilities in chemical detection, environmental monitoring, medicine, and many other applications.’’
Gogotsi, a professor in the Department of Materials Science and Engineering, heads the A.J. Drexel Nanotechnology Institute at Drexel University, and has worked with colleagues Gary Friedman from Drexel’s Department of Electrical and Computer Engineering; Alexander Gutsol (currently with Chevron); and Alexander Fridman (director of the A.J. Drexel Plasma Institute).
Gogotsi says that the OES method proposed by the Drexel scientists can be applied for ultra-fast, time-resolved, multi-elemental analysis of liquid in microfluidic reactors, living biological systems, or environmental sensors andfor diagnostics of femtolitre volumes with 1 mm or better spatial resolution. ‘‘Using this method, we have detected one part-per-million concentrations of sodium, calcium, and other elements in aqueous solutions.’
In comparison to LIBS, the researchers found that the observed spectra are of better quality, have significantly smaller analytical volumes, and are accomplished using drastically simpler, smaller, and less expensive equipment and materials. Furthermore, OES can be performed remotely, using nanorods and nanotubes dispersed in fluid.
The team describes how in a typical experiment, a tungsten wire with a tip sharpened to less than 50nm radius was used to generate the corona discharge. Negative corona discharges at the tips have been demonstrated in all cases. The pulsed voltage source provides 2–30 kV pulses 10–500 ns in duration at approximately 30 Hz repetition rate, achieving negative corona for a 50 nm radius tip with as little as 3 kV.
‘‘Considering existing theories of discharge initiation in liquids and our current experiments, there are several factors that contribute to the reasons why the NCDP is different from the streamer coronas previously observed in liquid and specifically why the two initial stages of the negative corona are observed,’’Gogotsi explains. ‘‘Our study is the first that simultaneously combines short rise-time voltages, nanosecond-duration pulses, high temporal resolution emission spectra, and most importantly, nanoscale tips.’’
The Drexel team is hopeful that the OES nanoscale probes may open a new era in micro/nanoscale chemical, environmental, and biological sensing and detection techniques.
‘‘Just as the discovery of AFM changed the world of microscopy, the OES nanoscale probes may change the world of chemical analysis, replacing the large and expensive instruments that are used for elemental analysis or measurements of cation concentration in thousands of labs worldwide by simple,portable, and very inexpensive tools that also add analytical capabilities not
available today, e.g. fast simultaneous quantitative analysis of multiple cations in solution,’’ says Gogotsi.
With regard to the nonthermal plasma in liquid, nanoscale corona discharge OES is presented as only the first of many potential applications for this newly discovered tool; applications in nanopatterning and surface functionalization as well as tools for cellular surgery are readily conceivable. Gogotsi and his colleagues expect this research to affect a broad spectrum of fields ranging from pharmaceuticals and biomedicine to nanotechnology and fundamental plasma chemistry.
Featured scientist: Yury Gogotsi
Organization: A.J. Drexel Nanotechnology Institute, Philadelphia, PA
(USA)
Relevant publication: David Staack, Alexander Fridman, Alexander
Gutsol, Yury Gogotsi, Gary Friedman: Nanoscale corona discharge
in liquids, enabling nanosecond optical emission spectroscopy.
Angew. Chem., Int. Ed., 47, 8020–8024.
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Nano-Society
www.rsc.org/nanoscience

Direct Imaging Technology

Magnetic resonance imaging (MRI) is a powerful imaging technology that serves as a noninvasive method to render images of the inside of an object. During an MRI scan, the nuclei of an object’s hydrogen atoms align with the scanner’s powerful, uniform magnetic field. Pulses of radio waves are then sent into the scanner that knock these hydrogen nuclei out of their normal position.After the radio wave pulsing stops, the nuclei realign back into their proper position. During this realignment process, the nuclei send out signals. These signals are captured by the computer system that analyzes and translates them into an image of the object being scanned.
MRI is primarily used in medical imaging to demonstrate pathological or physiological alterations of living tissues. It also has uses outside the medical field, for instance as a nondestructive testing method to characterize the quality of products such as produce and timber. ConventionalMRI usually operates at the scale of millimetres to micrometres—3 mm at best—which is good enough
for the mostly medical diagnostic purposes it is used for. Researchers have now shown that the imaging of nuclear spins using magnetic resonance, the basis for MRI, can be pushed to sub-100 nm resolution, into the nanoscale realm. Theydemonstrated that, using an emerging technique based on force detection, they can image nuclear spins with a sensitivity that is 60 000 times better than MRI.The resolution is about 30 times better than the most advanced conventional
MRI imaging. By improving this technique, researchers will be able to push deeper into the nanorange and approach the capability needed for direct 3-D imaging of individual macromolecules.
As MRI increasingly finds applications in material and biological sciences,scientists are trying to find ways to overcome its sensitivity limitations and push its resolution into the nanorange and, ultimately, the atomic scale. Magnetic resonance force microscopy (MRFM) seems to be the solution.
‘‘Our MRFM method measures a very tiny magnetic force between the nuclei in the sample and a nearby nanomagnet,’’ explains John Mamin. ‘‘Many common types of atoms, including hydrogen, fluorine, phosphorus, copper,and aluminium, have nuclei that are very weakly magnetic. Sometimes this basic magnetic property is referred to as the nuclear ‘spin’. MRI typically uses the magnetism of hydrogen nuclei contained in water. In our work, we use the
How Can You ‘See’, ‘Feel’ or ‘Hear’ Something so Incredibly Tiny?magnetism of fluorine nuclei contained in a small sample of calcium fluoride, though we can also use hydrogen.’’ Mamin is a member of an IBM team at the company’s Almaden Research center in California that succeeded, for the first time, in pushing NMR imaging below the 100nm threshold.
MRFM uses a magnetic tip and an ultrasensitive cantilever to sense the magnetic force generated between the tip and spins in a sample. Unlike the permanent magnet tips previously used for MRFM detection of electron spin resonance, the tips used by the IBM researchers are based on a thin film of magnetic material that has a high magnetic moment, but is magnetically soft.‘‘The tips we developed are compatible with sample-on-cantilever experiments,’’says Mamin. ‘‘In such an experiment, the sample is placed on the distal end of an ultra-sensitive cantilever situated above the magnetic tip. By choosing the sample-on-cantilever configuration, rather than tip-on-cantilever, we eliminated the magnetic damping that occurs when a soft magnetic tip vibrates in the presence of an external magnetic field.’’
The ability to image a single molecule with atomic resolution would have a huge impact in structural biology, in particular the area of protein structure determination—an important and famously difficult problem—and would aid the development of new drugs. It also could revolutionize the study of materials, ranging from pharmaceuticals to integrated circuits,for which a detailed understanding of the atomic structure is essential. Knowing the exact location of specific atoms within nanoelectronic structures,for example, would enhance designers’ insight into manufacture and performance.
The IBM team is motivated by the prospect of developing such a tool—the ‘holy grail’ of molecular imaging—an instrument that is able to perform direct,3-D imaging of complex structures such as molecules with atomic resolution.‘‘Our detection limit of about 1000 nuclear spins is a significant step toward the goal of detecting a single nuclear spin,’’ says Mamin. ‘‘The best conventional MRI today requires at least 100 million nuclear spins to obtain a detectable
signal. If we can achieve single spin detection in the future, this would open up the possibility of taking 3-D MRI images of the atoms in a molecule.Obviously, there is still considerable progress needed to extend our capability to the single spin level.’’
‘‘The main issues are related to the very tiny magnetic forces that must be detected. Better nanomagnetic tips are needed to generate stronger force signals, and noise reduction will also be key. There is still a lot of room for innovation in these areas.’’
Featured scientist: John Mamin
Organization: IBM Almaden Research Center, San Jose, CA, USA
Relevant publication: H. J. Mamin, M. Poggio, C. L. Degen, D. Rugar:
Nuclear magnetic resonance imaging with 90-nm resolution. Nat.
Nanotechnol., 2, 301–306.
Source
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www.rsc.org/nanoscience

Nanoparticles inside Intact Cells

Even less invasive than these optical nanoprobes is a novel ultrasonic holography technique that provides a noninvasive way of looking inside a cell.
Nanomaterial-based drug delivery and nanotoxicology are two of the areas that require sophisticated methods and techniques for characterizing, testing, and imaging nanoparticulate matter inside the body. In particular, the potential risk factors of certain nanomaterials have become a topic of heated discussion.Most, if not all, toxicological studies on nanoparticles rely on current methods,practices, and terminology as gained and applied in the analysis of micro- and ultrafine particles and mineral fibers. The development of novel imaging techniques that can visualize local populations of nanoparticles at nanometer resolution within the structures of cells—without destroying or damaging the cells—is therefore important.
Researchers in the United States have demonstrated that at ultrasonic frequencies, intracellular nanomaterial causes sufficient wave scattering that a probe outside the cell can respond to it.
‘‘The novelty of our findings lies in the fact that it provides an alternative way of studying a cell under ambient conditions, i.e. without placing it in a vacuum,coating it with a metal, bombarding it with electrons, or inserting other molecules, as is the case with other techniques such as electron microscopy or fluorescent tagging,’’ explains Ali Passian, a researcher with the Nanoscale Science and Devices Group at the Oak Ridge National Laboratory (ORNL) in Tennessee, USA.
‘‘The use of nanomaterials is becoming ubiquitous and there is therefore a pressing need to understand how engineered nanomaterials interact with biological species,’’ Passian says. ‘‘Health effects and environmental factors are currently of major importance in our group at ORNL and a lot of our research resources have been focused on tackling the associated problems.’’
He points out that with this novel imaging technique, scientists do not need to cut up the cell or inject artificial light-emitting molecules to find out whether or not a certain type of nanomaterial is present inside it. This avoids altering the intracellular configuration when attempting to pinpoint the nanoparticles.
The relatively new technique known as scanning near field ultrasound holography (SNFUH) is a revolutionary approach which provides noninvasive nanoscale imaging capabilities for deeply buried and embedded structures. It offers the ability to acquire simultaneous topography and holography information with nanoscale image resolution. SNFUH synergistically integrates three disparate approaches: a unique combination of SPM platform (which enjoys excellent lateral and vertical resolution) coupled to microscale ultrasound source and detection (which facilitates ‘looking’ deeper into structures, section by section) and a novel holography approach (to enhance phase resolution and phase coupling in imaging).
Applying these techniques to biological structures, it becomes possible to image soft samples and probe structures that are below their surfaces. For instance, if a cell is oscillated at megahertz frequencies using a piezoelectric crystal, the ultrasonic waves traveling through the oscillating cell structure may weakly drive an AFM cantilever that is in contact with the cell surface, as long
as the elastic properties of the cell can support a propagation mode in the ultrasonic spectrum.
In their work, Passian and his team explored the viability of SNFUH as a technique to probe cellular uptake of nanoparticles. Specifically, they tried to determine the cellular fate of single-walled carbon nanohorns (carbon nanotubes aggregates having conical tips are referred to as carbon nanohorns)using a mouse model to detect and visualize particles within lavage cells and blood.
‘‘We found that the nanoparticles cause sufficient phase change for it to be measured with an external probe,’’ he describes the research findings. ‘‘Bear in mind that the nanoparticles were not artificially placed within the cell but got there as a result of exposing a living mouse to carbon nanohorns and then sacrificing the mouse a few days later and preparing the sample cells.’’ ‘‘The sizes of these particles are statistically consistent with the size distribution (70–110 nm) established from analyzing several AFM images of the nanohorn solution, indicating that individual nanoparticles, rather than larger aggregates, were taken up by the macrophages,’’ explains Passian.
‘‘The contrast measures the phase of the local tip–cell surface coupling and originates from the difference in elasticity and density between the nanohorns and the cell.’’
This work clearly demonstrates that specific problems that require subsurface knowledge can be tackled using this technique. This will mostly benefit research areas such as nanotoxicological investigations, drug delivery, and pharmaceutical work where, so far, most studies can only target the surface of samples and suffer from the lack of probes that can, with nanoscale resolution, provide information on what may be within a sample.
Passian explains the team’s next challenge: ‘‘Our next step is to enable our approach to visualize the interior of a cell in its natural milieu, that is, in a fluid.’’
Featured scientist: Ali Passian
Organization: Nanoscale Science and Devices Group, Oak Ridge
National Laboratory, Oak Ridge, TN, USA
Relevant publication: Laurene Tetard, Ali Passian, Katherine T.
Venmar, Rachel M. Lynch, Brynn H. Voy, Gajendra Shekhawat,
Vinayak P. Dravid, Thomas Thundat: Imaging nanoparticles in cells
by nanomechanical holography. Nat. Nanotechnol., 3, 501–505.
Source
Nano-Society
www.rsc.org/nanoscience

Nanoprobes and Biosensors

During the past two decades, biosensors have been developed for environmental,industrial, and biomedical diagnostics. The application of nanotechnology to biosensor design and fabrication promises to revolutionize diagnostics and therapy at the molecular and cellular levels. The convergence of nanotechnology, biology, and photonics opens the possibility of detecting and
manipulating atoms and molecules using a new class of fiberoptic biosensing and imaging nanodevices. These nanoprobes and nanosensors have the potential for a wide variety of medical uses at the cellular level.
The potential for monitoring in vivo biological processes within single living cells, e.g. the capacity to sense individual chemical species in specific locations within a cell, will greatly improve our understanding of cellular function,thereby revolutionizing cell biology. Over the past few years, nanoprobes have already demonstrated the capability to perform biologically relevant measurements inside single living cells.
A fiberoptic nanosensor is a nanoscale probe that basically consists of a biologically or chemically sensitive layer that is covalently attached to an optical transducer. Biological sensing elements can be either a biological molecular species (e.g. an antibody, an enzyme, a protein, or a nucleic acid) or a living biological system (e.g. cells, tissue, or whole organisms) that uses a biochemical mechanism for recognition. In the case of a receptor-based nanosensor, an interaction between the immobilized receptor and its substrate—the molecule it binds to—produces a perturbation that the optical transducer converts to an electrical signal via laser-induced fluorescence.
Tuan Vo-Dinh, professor of biomedical engineering and chemistry and director of the Fitzpatrick Institute for Photonics at Duke University’s Pratt School of Engineering, in the USA, has devoted extensive research and development to the development of a variety of fiberoptic chemical nanosensors and nanobiosensors.
Vo-Dinh explains that preparing fiberoptic nanosensors is fairly straightforward if one has the right tools and good practice. ‘‘Using the so-called ‘heat and pull’ method, a micron-scale diameter silica optical fiber is placed in a commercially available puller that heats the fiber using a carbon dioxide laser and then pulls the fiber to the desired thickness, usually between 20 and 100nm in diameter. The pulled fiber is then cut in half, yielding two nanoscale fiber tips. Subsequently, vapor deposition is used to deposit a thin layer of silver, aluminium, or gold on the side walls of the tip, followed by a two-step chemical treatment of the tip that provides covalent attachment points for the biosensor molecules.’’
The need for fast and specific assays has induced researchers to explore alternative optical detection technologies for diagnostic applications. In addition to the nanobisensor technology, Vo-Dinh and co-workers have developeda new type of nanoprobe using Raman and surface enhanced Raman spectroscopy (SERS) detection.
‘‘Because of the inherently small Raman cross-section, Raman spectroscopy has not been widely used in the past for trace analysis,’’ says Vo-Dinh.‘Nevertheless, there has been a renewed interest in Raman techniques as a result of the discovery of the SERS effect.’’ In SERS, the Raman effect is found to be greatly enhanced when it is close to a rough metal surface consisting of gold or silver nanoparticles, as a result of surface plasmon resonance. In recent years it has been demonstrated that detection of single molecules with SERS is possible.
Vo-Dinh points out that a significant advantage of nanobiosensors for cell monitoring is the minimal invasiveness of the technique. This makes optical nanobiosensors promising tools for dynamic analyses of proteins in biochemical pathways within single living cells.
‘‘These optical nanoprobes provide a new method in cell-based assays offering highly miniaturized nanoscale devices that make cell-based analysis accessible at the single-cell level,’’ says Vo-Dinh. ‘‘Future applications of optical nanoprobes could include multianalyte detection and analysis of protein-protein interactions and similar analyses of other proteins involved in cellular biochemical pathways
Featured scientist: Tuan Vo-Dinh
Organization: Fitzpatrick Institute for Photonics, Duke University’s
Pratt School of Engineering, Durham, NC, USA
Relevant publication: Tuan Vo-Dinh, Paul Kasili, Musundi Wabuyele:
Nanoprobes and nanobiosensors for monitoring and imaging
individual living cells. Nanomed. Nanotechnol. Biol. Med. 2, 22–30.

Source
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www.rsc.org/nanoscience

Through Nanopores

There is a significant and growing need across the research and medical communities forlow-cost, high-throughput DNA separation and quantification techniques. The isolation of DNA is a prerequisite for many molecular biology techniques and experiments. Although single-molecule techniques such as Elemans’ STM technique afford extremely high sensitivity, so far such experiments have remained within the confines of academic and research laboratories. The primary reasons for this relate to throughput speed, detection efficiencies, and analysis times. For example, in a conventional solution-based single-molecule detection experiment, one can only detect approximately 10 000 molecules per minute, or one molecule every 6 ms. Although this may sound a lot, consider that a small drop of water (B5 ml) contains B1.67 1023 molecules.
At this speed you would need over 100 trillion years to detect all the water molecules in that single drop. Using a novel nanopore array developed by researchers in the UK, expect to be able to detect up to 1 million molecules simultaneously in the same 6 ms time window (and bringing the timeframe for analyzing the molecules in a single water drop down to some 60 billion years—
about five times the estimated age of the universe).
The above example exaggerates a bit, of course. Compared to a water molecule, which is very small (it consists of only three atoms with an overall diameter of less than 0.3 nm), a DNA molecule is very large. In the real world you would never analyze a drop of DNA but much, much smaller quantities; even then, existing methods are considered to be unacceptably slow. Although it is now several years since the completion of the rough draft of the human genome was announced in 2003, much effort is still focused on identifying genes responsible for specific biological functions or diseases, and determining the DNA sequence bearing this information.
‘‘In recent years, the creation of nanochannels or nanopores in thin membranes has attracted much interest because of the potential to isolate and sense single DNA molecules while they translocate through the highly confined channels,’’ Joshua Edel, a lecturer in micro- and nanotechnology at Imperial College London, explains. ‘‘Nanopores for such applications have already been fabricated, but in all studies to date the detection of translocation events is
performed electrically by measuring the ionic current.
Edel’s group, together with collaborators from Drexel University, presented proof-of-concept studies that describe a novel approach for optically detecting DNA translocation events through an array of solid-state nanopores which allows for ultra-high-throughput parallel detection at the single-molecule level.
‘‘The single-molecule studies performed by Guillaume Chansin, a PhD student within my research group, are very exciting and novel from a technological perspective,’’ says Edel. ‘‘Firstly, this work is the first demonstration of using fluorescence detection to monitor translocation events within a nanopore array.Secondly, this is the first true demonstration of an approach leading towards high through put single-molecule detection confined within nanofluidic structures.’’
This technique functions by electrokinetically driving DNA strands through submicron-sized holes (in this case 300 nm) on an aluminium/silicon nitride membrane. During the translocation process, the molecules are confined to the walls of the nanofluidic channels, allowing 100% detection efficiency.Importantly, the opaque aluminium layer acts as an optical barrier between the illuminated region and the analyte reservoir. In these conditions, high-contrast
imaging of single-molecule events can be performed.
Edel notes that the majority of work to date using nanopores utilizes ionic blockage currents to monitor translocation events. ‘‘Unfortunately, simply measuring blockage currents can only be performed in a single pore,’’ he says.‘‘One of our motivations for using optical detection was to ensure we can probe multiple holes simultaneously, allowing for true high-throughput detection.
Our results indicate that it is possible to obtain high spatial resolution DNA analysis while independently controlling the applied voltage that drives the molecules into the nanopore. A critical feature of the generic approach is the possibility of parallelizing molecular analysis by probing an entire array of nanopores under uniform illumination.’’
According to Edel, there are plenty of potential applications including DNA sequencing, fragment sizing, sieving, separations, and rare event diagnostics. ‘‘For example, using analytical technologies that exist today it is essentially impossible to detect a single DNA strand within a standard blood sample (of a few millilitres) within a reasonable time frame. The technology we describe can potentially allow for such detection to be performed both rapidly and efficiently.’’
It seems that nanopore research is an exciting and growing field. Expect optical detection to play a dominant role in the future of this technology.
Featured scientist: Joshua Edel
Organization: Imperial College London, UK
Relevant publication: Guillaume A. T. Chansin, Rafael Mulero, Jongin
Hong, Min Jun Kim, Andrew J. deMello, Joshua B. Edel: Singlemolecule
spectroscopy using nanoporous membranes. Nano Lett., 7,
2901–2906.

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Touchy-Feely

Our sense of touch connects us to the world around us and it is an integral part of how we experience things, both physically and emotionally. In the virtual world of remote-control robots, scientific models, or computer games, users generally lack tactile, or haptic,2 feedback, which either makes delicate manipulative tasks difficult or keeps the subject purely visual and often inscrutable (such as an electron microscope image of a nanoscale object). The desire for natural and intuitive human machine interaction has led to the inclusion of haptics in human–machine interfaces. The user is able to control inputs to the system through hand movements and in turn receives feedback through tactile stimulation in the hands. Sophisticated, state-of-the-art haptic user-interface software is capable of adding interactive, realistic virtual touch
capabilities to human–computer interactions. Among the uses are medical applications, remote vehicle or robotic control, military applications, and video games. Users are said to feel realistic weight, shape, texture, dimension, dynamics, and force effects. Applying the use of real-time virtual reality and multisensory user interface to nanoscience, scientists in France have begun to
open up the otherwise only scientifically described reality of the nanoworld to a nonscientific public.
‘‘A central challenge is how we can put our hands on scientifically explored parts of reality that cannot be reached by our senses and whose rules are completely foreign to our representation of reality,’’ Joe¨ l Chevrier tells us. ‘‘Since science is full of abstract descriptions, it is hard to represent it in an easy way. But thanks to computer sciences and robotics we now have the necessary tools to use human senses to explore, in real time, model worlds as they are described by science, or even true reality when coupling these multisensory interfaces to real nanosensors and nanoactuators.’’
Chevrier, a professor at the Universite´ Joseph Fourier in Grenoble, France,together with his collaborators hopes to open up a completely new field for our perception. This new ‘playground’—using haptic, vision, and sound interfaces—is the world we live in; but explored at scales entirely foreign to everything we experience around us.
‘‘In the nanoworld simulacrum that we have begun to build, object identification will be based on the intrinsic physical and chemical properties of the probed entities, on their interactions with sensors, and on the final choices made in building a multisensory interface so that these objects become coherent elements of the human sphere of action and perception,’’ says Chevrier
In other words, we might be able to touch, feel, and interact with the nanoworld which otherwise is not open to our direct experience. Chevrier hopes that this will be a major step in helping nonscientists understand nanosciences and nanotechnologies. The scientifically described part of our reality—much of what mathematics, physics, or chemistry is about—is usually inaccessible to
people not trained in these subjects, i.e. to most of us. Opening up this part of reality to everybody could go a long way in creating interest in science education and science careers, and help a better-informed public to lead a more objective discussion on the pros and cons of nanotechnologies.
Rather than using the abstract descriptions and experiments of a classical science education, the French team has begun to use real-time virtual reality combined with a multisensory human–machine interface to allow the direct perception of and interaction with the nanoworld.‘‘One way to develop this extension of the sphere where our senses are efficient can be based on nanosensors and nanoactuators,’’ explains Chevrier.‘‘Another approach is to use virtual environments which can bring the nanoworld to us through real-time multisensory interfaces. This can dramatically enhance the possibilities for easy exploration of remote realities foreign to our senses and can trigger spontaneous motivation in users, similar to what we observe in video game players.
Chevrier and his team have built a virtual AFM and coupled it to an advanced haptic interface as well as a sonification and visualization system. The resulting instrument allows its user to experience contact of a surface at the nanoscale. About 10 000 people used this demonstrator during three exhibitions in Grenoble, Paris, and Geneva.
A central part of this concept is not a new idea. It actually goes back to the earliest days of experimental science: Galileo’s use of a telescope to observe the Moon and coming to the immediate conclusion that theMoon is Earth-like. As Galileo immediately emphasized, this dramatic change in the human representation of the universe is caused by direct use of senses technically extended by an instrument, and not by a posteriori rational demonstration.
‘‘Our proposal can be seen as a revival of this famous tale,’’ says Chevrier.‘‘There is a major difference, however. Two points can illustrate the need for new approaches in implementing the nanoscale in virtual environments
(1) As we gradually approach the nanoscale, continuous description no longer stands and the molecular, discontinuous structure of matter is revealed. Atomic scale is a radical rupture with our common experience that is based on the objective existence of isolated continuous objects.
(2) Can we manage to ‘see’ and ‘touch’ an electron, a particle that has a mass and an electric charge but has no classical spatial extension in the sense of a material sphere, although it is at the root of the stability of matter? In fact, seeing or touching an electron has no intrinsic meaning. Electronbased objects can, however, be created and our interaction with these unusual objects defined.’’
Almost all scientific data today is represented visually. That’s why we have all these amazing electron microscope images and artists’ impressions of nanoscale objects. That’s also why most people can’t really get a grip (literally) on scientific discoveries unless they result in a better TV set or more stain-resistant shirts. Enriching the visual component with interactive tactile and sound aspects, and wrapping the whole thing into a virtual reality environment, will give us a much richer and more real experience of these objects.
At the Center for Cognitive Ubiquitous Computing (CUbiC) at Arizona State University in the USA they have developed some interesting haptic visualization schemes. Many object features are easy to invoke in human memory and are presented through tactile cueing. There are, however, some features that are not primary haptic features but may contribute to further
knowledge of the object. One example is the weight of the object. At CUbiC they have developed a haptic visualization scheme for the presentation of weight. In this scheme, a user is able to bounce the virtual object off an imaginary surface. When the object hits back, it generates a vibrotactile stimulation analogous to its weight.
Even if technology will one day offer us sophisticated tools to explore the nanoworld with our senses, the question is whether we will be able to really grasp it. Imagine an atom. Chances are you are seeing a Nagaoka .

Figure 1.1 The classic atomic model created by Hantaro Nagaoka
In 1904, a Japanese physicist named Hantaro Nagaoka created the classic atom image with planet-like electrons orbiting around a nucleus.
This is the picture that many people have in mind—cute, but wrong. Reality at the atomic scale is much, much weirder: atoms are mostly empty space and the solid world we experience around us is an illusion. Timothy Ferris has described this nicely in his book Coming of Age in the Milky Way
‘‘A bar of gold, though it looks solid, is composed almost entirely of empty space. The nucleus of each of its atoms is so small that if one atom were enlarged a million billion times, until its outer electron shell was as big as greater Los Angeles, its nucleus would still be only about the size of a compact car parked downtown. The electron shells would be zones of insubstantial lightning, each a mile or so thick, separated by many miles of space. Nor, to return to the old classical metaphor, does a cue ball strike a billiard ball. Rather, the negatively charged fields of the two balls repel each other; on the subatomic scale, the billiard balls are as spacious as galaxies, and were it not for their electrical charges they could, like galaxies, pass right through each other
unscathed.’
So, while your ‘reality’ tells you that you are sitting in your chair right now as you are reading this, reality at the subatomic level means that you are not really in contact with your chair—thanks to the repulsion of the chair’s electrons and your own, you are actually floating on it at a height of a fraction of a nanometer. The point is that, even if we might have the tools one day to trulyexperience the nanoworld, its rules are so foreign to our human experience that we might not be able to comprehend it anyway.
Of course, this first instrument built by Chevrier’s team in Grenoble is more Galileo telescope than Hubble space observatory. But it is an interesting beginning that one day might result in virtual worlds that will allow us to go all weird at the nanoscale.
Featured scientist: Joe¨ l Chevrier
Organization: Universite´ Joseph Fourier, Grenoble, France
Relevant publication: Implementation of perception and action at
nanoscale. Proceedings of ENACTIVE/07, 4th International
Conference on Enactive Interfaces, Grenoble, France, 19–22
November 2007.
Source
Nano-Society
www.rsc.org/nanoscience