Embedded Plasmonic Nanomenhirs as Location-Specific Biosensors

Letter pubs.acs.org/NanoLett

Embedded Plasmonic Nanomenhirs as Location-Specific Biosensors Karthik Kumar,*,† Andreas B. Dahlin,‡ Takumi Sannomiya,§ Stefan Kaufmann,† Lucio Isa,† and Erik Reimhult*,∥ †

Department of Materials, Laboratory for Surface Science and Technology, Swiss Federal Institute of Technology (ETH Zürich), CH-8093 Zürich, Switzerland ‡ Department of Electrical Engineering, Institute for Biomedical Engineering, Laboratory of Biosensors and Bioelectronics, Swiss Federal Institute of Technology (ETH Zürich), CH-8092 Zürich, Switzerland § Department of Metallurgy and Ceramics Science, Tokyo Institute of Technology, S8-6, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8552, Japan ∥ Department of Nanobiotechnology, Institute for Biologically Inspired Materials, University of Natural Resources and Life Sciences Vienna, A-1190 Vienna, Austria S Supporting Information *

ABSTRACT: We introduce a novel optical biosensing platform that exploits the asymmetry of nanostructures embedded in nanocavities, termed nanomenhirs. Upon oblique illumination using plane polarized white light, two plasmonic resonances attributable to the bases and the axes of the nanomenhirs emerge; these are used for location-specific sensing of membrane-binding events. Numerical simulations of the near field distributions confirmed the experimental results. As a proof-of-concept, we present a model biosensing experiment that exploits the dual-sensing capability, the size selectivity offered by the sensor geometry, and the possibility to separately biochemically modify the nanomenhirs and the nanocavities for the specific binding of lipid membrane structures to the nanomenhirs. KEYWORDS: Biosensing, nanoplasmonics, asymmetric nanostructures, location specificity, nanopatterning, liposome, supported lipid bilayers, evanescent

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themselves over nanometer distances; as we demonstrate in this work, nanoplasmonics can provide such high locationspecific sensitivity. Most of the biosensing with nanoplasmonic structures has been performed on symmetric structures, such as nanospheres or on structures where the plasmons have been excited orthogonal to an axis of symmetry as for nanoholes and nanorings.7,8 Such structures exhibit a single resonance with a quasi-uniform field distribution around the structure that can be used for sensing. Introducing at least one axis of asymmetry in the nanoplasmonic structure or its environment gives rise to multiple resonances, each of which could potentially simultaneously be used for a different sensing purpose, for example, site or size specific sensing. While many structures with reduced symmetry have been investigated and the existence of multiple hot spots with different resonance wavelengths is wellestablished, the integration of such sensor elements into biosensor platforms where multiple resonances can be

ne of the major promises of nanoplasmonics for biosensing has been the miniaturization of the sensing elements made of metal nanostructures to allow for the sensing and detection of a single or very few objects with nanoscale dimensions. Evanescent fields are induced by the resonant collective charge oscillations of the subwavelength metal nanostructures, known as plasmons, when irradiated with light. The far-field optical response is sensitive to the local refractive index of the environment surrounding individual nanostructures; this creates the potential to use such nanostructures as refractometric sensors.1 Single-molecule nanoplasmonic sensor arrays can easily be produced on a large scale with the variety of available surface-based nanofabrication techniques and have the added advantage of needing only very inexpensive light sources and detection modules.2−4 Admittedly, surface-based nanoplasmonics has yet to make a real impact as a general biosensing method, mainly due to its (incorrectly) perceived lack of sensitivity5,6 and lack of precise quantification of response compared to its better-established macroscopic sister technique, surface plasmon resonance (SPR) sensing. An area where nanoplasmonics has the potential to vastly outperform conventional SPR is in sensing local and sitespecific binding events controlled by the nanostructures © 2013 American Chemical Society

Received: September 15, 2013 Revised: October 28, 2013 Published: November 4, 2013 6122

dx.doi.org/10.1021/nl403445f | Nano Lett. 2013, 13, 6122−6129

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approximation, only a single plasmon mode is excited in the plane of the symmetric bases of the nanomenhirs. By simply rotating the substrate such that the nanomenhir sample is obliquely illuminated by plane polarized light, two plasmon modes, one along the nanomenhir axis and one across its base, can simultaneously be excited (see Figure 1). Each mode corresponds to the enhancement of the evanescent field at a different position, so-called “hot spot”, on the nanomenhir; simultaneous sensing can thus be performed with the sensitivity localized to different positions on the same particle and spatial resolution obtained. When, as in Figure 1, the nanomenhir is fabricated within a cavity of similar nanoscale dimensions, the localization and directionality of the hot spot sensing can be used to address and differentiate between different types of binding events controlled by the nanostructure; this is of particular use to address supramolecular structures of nanoscale dimensions such as supported lipid bilayers and liposomes. Liposomes and supported lipid bilayers are models of cell membranes, which can be used to investigate, for example, the nearly one-third of naturally occurring proteins residing within the cell membrane;11 these are prime drug targets12 for which good biosensing strategies that have to rely on membranes are currently lacking.13 The principles guiding the measurements using the nanomenhir sensor substrates will first be illustrated by a section on multiple multipole simulations performed to verify the robustness of the intuitive model for nanomenhir plasmonic excitation outlined above. We subsequently present proof-ofprinciple studies of this novel nanoplasmonic sensor design by the experimental detection of the localized binding of liposomes to one part of the sensor structure while detecting small protein binding to another part of the structure. Simulations were conducted on an idealized gold nanomenhir with a base diameter and height of 100 nm (corresponding to the fabricated dimensions) and with a periodic boundary condition of 250 nm. To avoid singularities the tip of the nanomenhir as well as the edge of the base were rounded to a radius of 6.42 and 8 nm, respectively, and the base of the nanomenhir was made slightly smaller than the diameter of the cavity. The goal was to understand and predict the extinction spectra and the near field of resonances of separated nanomenhirs in a periodic array when irradiated by planepolarized light. The simulations were performed using the multiple-multipole program (MMP) code of the OpenMax software package.14−16 Figure 2 shows the results obtained from the simulations of the idealized nanomenhir sensor substrates when orthogonally and obliquely (45°) illuminated by plane polarized light. It is not obvious from the extinction spectra in air (Figure 2A) that two separate plasmons can be excited, as both the orthogonally excited and obliquely excited extinction spectra have a single excitation peak, although the extinction peak at 590 nm corresponding to the oblique illumination of the nanomenhir array is broader and red-shifted compared to its orthogonally illuminated counterpart at 570 nm. However, the field strength plot in Figure 2A,i reveals that, on orthogonal illumination, a single centrosymmetric hotspot develops at the base of the nanomenhir, while upon oblique illumination three hot spots appear in the field strength plot (Figure 2A,ii). Two of the hot spots appear at the base of the nanomenhirs and one at the tip. The similar dipolar axis dimensions (∼100 nm) imply that the individual excitations corresponding to the base and tip of the

individually addressed is lacking. One difficulty to overcome is the fabrication of oriented structures that have multiple symmetry axes with corresponding distinct resonances such that suitable surface chemistries can be applied for biosensing. Another difficulty that may arise is the capability to effectively excite asymmetric structures, such that the separate modes are simultaneously excited but still separately resolved. In this study, uniaxially aligned nanomenhirs inside silicon nitride nanocavities are fabricated as sensor elements (see Figure 1 inset) and investigated for their novel sensing

Figure 1. Schematic representation of nanomenhir array sensing principle. (A) For samples which are orthogonally illuminated by plane-polarized light, only a single mode along the base of each nanomenhir is excited (see inset for geometry of a single nanomenhir within the silicon nitride matrix). (B) When the sample is tilted 45° such that the structures on the sample are obliquely illuminated, two modes, one along the base and one along the central axis, are excited in each nanomenhir.

capabilities. The idealized shape of the sensor element is a cone and nanocone arrays have previously been fabricated by, for example, Kern et al. by ion milling9 and by us and others by shadow deposition and lift-off.10 Nanocones fabricated in cavities through shadow deposition have a rugged shape, and thus a more descriptive name would be nanomenhirs. When the nanomenhir array is orthogonally illuminated, in a dipole 6123


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Figure 2. Simulation results of nanomenhir sensor arrays. The dimensions for the simulations were chosen to match the experimentally obtained values for the nanomenhirs: base diameter 100 nm, height 100 nm, and with the edges rounded to have a radius of ∼7 nm. (A) Illumination of sensor arrays in air. Both orthogonal (blue) and oblique (red) illumination of the nanomenhirs produce a single excitation peak at 570 nm and 590 nm, respectively. The electric field plot (relative field strength in logarithmic scale) for the orthogonal illumination suggests that only the plasmon at the base of the nanomenhirs is excited (i); the electric field plot for the oblique illumination suggests that plasmons along both the base axis and the central axis are excited (ii). (B) Illumination of sensor arrays in water. The orthogonal illumination of the nanomenhirs produces a single excitation peak at 580 nm (blue), similar to the illumination of the sample array in air, with a plasmon along the base of the nanomenhir (i). Upon oblique illumination of the sample array, two distinct excitation peaks are observed, at 610 and 690 nm. The corresponding field plots suggest that at 610 nm (ii), the plasmon at the base of the nanomenhir is strongly excited, while at 690 nm (iii) the plasmon along the central axis of the nanomenhirs is strongly excited.

from 570 nm to 610 nm. Further, when the nanomenhir array in water is obliquely illuminated (Figure 2B, red plot), two separate excitation peaks are observed at 610 nm and 690 nm, respectively. Observations of the field strength plot at 610 nm (Figure 2B,ii) under oblique illumination suggest that the base of the nanomenhir is more strongly excited than the tip of the nanomenhir, which agrees with the observation at this wavelength at orthogonal illumination. At 690 nm (Figure 2B,iii) the hotspot at the tip of the nanomenhir is much more strongly excited (∼100 times higher intensity) than the base of the nanomenhir. Clearly, the different sensitivities to the

nanomenhirs could be too close together to be individually resolved in the extinction spectra. Upon immersion in water, one expects a separation of overlapping extinction peaks if the refractive index sensitivity (the near field) of one mode is less focused to the surrounding walls and more toward the ambient medium. A dramatic change in the simulated extinction spectra is indeed observed when the medium surrounding the nanomenhirs is changed from air to water (Figure 2B); the wavelength of the excitation peak in the blue plot corresponding to the orthogonal illumination of the nanomenhir array is shifted toward red 6124


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water mixtures were used (0−35 wt % glycerol, RI 1.333− 1.377) (Figure 4B and C).20,21 The samples were orthogonally and obliquely illuminated with p-polarized light. For the orthogonally illuminated sample only one extinction peak was present (Figure 4B), similar to that observed in Figure 2Bi, whose peak wavelength position red-shifted with increasing bulk RI. For the obliquely illuminated sample two separated peaks were observed (Figure 4C) similar to those of Figure 2B,ii and B,iii, which red-shifted as the bulk RI was increased. The wavelength shifts, and the peak width changes were, however, different for the two peaks. The respective peak wavelength shifts were approximately linear with refractive index change, making it possible to define the following sensitivities in the probed range: 53.4 nm/RIU for the orthogonally illuminated peak; 67.6 nm/RIU for the shorter wavelength peak at oblique illumination; and 241.2 nm/RIU for the long wavelength peak at oblique illumination. Variations in the peak position were observed which corresponded to slight variations in the tilt angles. Although there appears to be a large difference in the sensitivities of the individual peaks based only on the peak shift, it is relevant to note that the peak magnitude should also be considered when determining the absolute sensitivity of a specific plasmonic mode; this will be discussed later. Material-specific surface functionalization and nanoscale patterning of liposomes were conducted to demonstrate the unique abilities of the nanomenhir array sensor to perform biosensor measurements with spatial sensitivity as shown in Figure 5. A relevant test of this sensor principle is the detection of liposome binding exclusively to the tip of the nanomenhir. The silicon nitride nanocavity substrate was rendered inert through the use of PLL-g-PEG, as liposomes can also bind to oxidized silicon nitride surfaces and form supported lipid bilayers which spread along the cavity walls.17 Therefore, the assembly of a lipid repelling coating specifically on the silicon nitride is required to exclusively sense liposome assembly at the tip apex. The PLL-g-PEG was displaced by streptavidin on the gold nanomenhirs, as streptavidin has a higher affinity to gold than the PLL-g-PEG.22 The nanomenhir sensor substrate was subsequently exposed to biotinylated vesicles with a mean diameter of 70 nm (determined by DLS). The resulting surface functionalization is displayed in Figure 5 and consists of a PEGbrush on the oxidized silicon nitride walls of the cavities and streptavidin coated Au nanomenhirs to which biotin functionalized molecules can bind specifically. Note that while both extinction peaks behave in a qualitatively similar fashion during incubation with PLL-g-PEG and streptavidin, biotinylated vesicles only attach to the tips of the nanomenhirs (Figure 5A); this is evidenced by a redshift at the wavelengths corresponding to the plasmon mode of the tip of the nanomenhirs. The mode corresponding to the base is almost insensitive to the adsorption (Figure 5B). It is likely that the residual faint red shift recorded for the base resonance is due to the slight overlap by the two plasmon resonance peaks since the peak shifts are monitored by centroid tracking without peak deconvolution.21 As demonstrated by the results in Figure 5, the selective molecular assembly patterning results in the capture of liposomes within the apex hot spot. The liposomes do not penetrate into the nanocavity and are sensed by the resonance at this tip. The resonance at the base is unaffected by the events at the top of the nanocavity due to the strong localization of the hot spot; it therefore monitors the bulk solution phase

refractive index of the surroundings for the two resonances make them well-separated in water. The implication here is that in water a single measurement of the change in local refractive index at the various hotspots on the simulated nanomenhir structure can resolve the local environment and thereby independently detect binding events at two locations separated by only 100 nm along the nanomenhenhir surface. Arrays of nanomenhirs were fabricated as described in the Supporting Information and detailed in a previous work.10,17−19 Figure 3 shows the results of various characterization methods

Figure 3. Results of fabrication of the nanomenhirs. The base diameter as well as height of the nanomenhirs was determined to be approximately 100 nm. The tip radius was estimated to be ∼10 nm. (A) SEM micrograph of array of embedded nanomenhirs in the silicon nitride matrix. (B) SEM micrograph of a single nanomenhir sectioned using a focused ion beam. (C) AFM image of surface, confirming that the tips of the nanomenhirs are below the silicon nitride surface.

that were employed to investigate the nanomenhir substrates. From the SEM micrograph in Figure 3A, we can observe that all nanocavities have a nanomenhir within them. The triangular cross-section of each single nanomenhir was revealed when sectioned using a focused ion beam and concurrently imaged as shown in Figure 3B. Atomic force microscopy was employed to probe the surface of the nanomenhir array sensor and to study the protrusion of the nanomenhir tip and shape (Figure 3C). It was observed that the tips of the nanomenhirs did not extend beyond the top surface of the sensor ensuring similar dimensions to the simulated structure. While the tip curvature could not be exactly determined, it was concluded that it was lower than that of the imaging AFM tip (∼5−10 nm). Extinction spectra of the nanomenhir substrates were collected in air (Figure 4A) and correlate well with the spectra obtained in the MMP simulations presented in Figure 2A. To characterize and calibrate the sensitivity of the nanomenhir samples to bulk refractive index (RI) changes, eight glycerol− 6125


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Figure 4. Experimental extinction spectra from nanomenhir substrates. (A) Extinction spectra in air. The solid plot indicates the extinction spectrum of the nanomenhir sensor orthogonally in air, while the dotted plot indicates the extinction spectrum obliquely in air. The dotted plot shows a clear broadening with respect to the solid plot. (B,i) Extinction spectra of orthogonally illuminated nanomenhir substrate in water/glycerol mixtures. The solid plot represents the extinction spectrum in the presence of water, while the dotted lines represent the spectra obtained for successively higher concentrations in 5 wt % steps of glycerol in water. Note that only a single peak is observed, similar to Figure 2A. (B,ii) The differential extinction spectra of individual glycerol/water mixtures as compared to the water mixtures showed a steady evolution of a single peak. (C,i) Extinction spectra of obliquely illuminated nanomenhir substrates in water/glycerol mixtures. The solid plot represents the extinction spectrum in the presence of water, while the dotted lines represent the spectra obtained for successively higher concentrations of glycerol in water. Note that two peaks are observed, similar to Figure 2B. (C,ii) The differential extinction spectra of individual glycerol/water mixtures as compared to the water mixtures showed a steady evolution of two equivalent peaks.

of the hot spots and the distance separating the hot spots. Figure SI-2 shows the simulated decay of the field enhancement at the hot spots at their respective maximum excitation wavelength at oblique incidence. The enhancement decays rapidly for each hot spot, confining the major part of the sensitivity of both hot spots to ∼10 nm. Thus, according to the simulations the current nanomenhir structure is not limited to discriminating between 70 nm vesicles and 4 nm proteins, but most likely nondeformable objects down to ∼25 nm in diameter can be registered predominantly by the apex mode, while objects smaller than 10 nm are strongly detected by the base mode. While the bulk refractive index sensitivity is shown in Figure 4 and discussed below, we can also conclude from the real-time data for the protein adsorption in Figure 5 that the background noise level of each resonance is below 0.05% of the response measured for a monolayer of proteins (streptavidin) adsorbed on the surface. Very small analytes (a fraction of a protein)

refractive index within the pore during the adsorption of the liposomes. This result should be contrasted to the initial functionalization of the sensor substrate, using the selective adsorption of PLL-g-PEG and streptavidin, for which both resonance peaks demonstrated large shifts. The small molecules can diffuse into and assemble onto the nanomenhir and nanocavity wall structures. It is worth noting that the adsorption of these molecules within the pores displays slower kinetics than at the tip facing the bulk, as suggested by the curves in Figure 5. This is likely due to diffusion controlled binding which leads to an enhanced incident flux at protruding features, while movement of molecules into the confined geometry becomes less probable due to depletion when the top of the nanomenhir is available for binding.23,24 The principle for size-discriminated specific adsorption demonstrated here is fully scalable by changing the geometry and dimensions of the sensor element. The discrimination is limited by the size of the diffusion channel, the sensing volume 6126


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at the tip of the nanomenhir would be strengthened due to the high field enhancement at sharp corners.25 The RI sensitivity of the nanomenhir sensor was calibrated using water−glycerol mixtures,21 and it was found to be in the range that has been reported previously for similarly sized Au nanodisks and Au nanorods.26−28 Although it is conventional within the nanoplasmonics research field to express the bulk RI sensitivity of a plasmonic nanostructure in terms of resonance peak shift per RI unit (RIU), it has recently been suggested that this value does not represent actual sensor performance;20,29−34 this is because a spectrometer will record changes in relative intensity (e.g., percent, transmittance or extinction) when the actual biosensor is used. Each experiment will generate a series of extinction spectra that consist only of changes in relative intensity at different wavelengths.21 Therefore, whatever parameter (e.g., the center of mass of the resonance peak21) is used to express the sensor response, it will be based on changes in relative intensity. Thus, it is the relative intensity changes induced by changes in RI (which are rarely reported) that truly represent the sensing performance of the nanostructure. Various attempts have been made to introduce a so-called figure of merit (FOM), taking into account the peak width35,36 and even the peak magnitude.27,37 These parameters are significant improvements compared to only considering peak shift, the reason being that resonance peaks that are narrower and/or higher in magnitude give rise to greater changes in relative intensity when they shift. However, it is fully possible to achieve high-performance sensing even when the conventional FOM is practically zero.30 Sönnichsen et al. have recently proposed a different method for the determination of sensitivity for nanoplasmonic sensors based on differences in the intensity spectrum.34 They suggest using a different FOM based on the ratio of intensities to take the effects of peak height and width into account. The extinction spectra are calculated from the intensity spectrum using eq 1, adapted from the equation provided in Dahlin et al.:21

Figure 5. Schematic of sensor surface functionalization and representative measurements of sensor responses at the base and tip of the nanomenhirs for monitoring the molecular assembly. After establishing a baseline signal, the nanomenhir sensor is incubated with PLL-g-PEG for 30 min before the excess PLL-g-PEG is flushed away using HEPES buffer. Incubation of the nanomenhir sensor with streptavidin for 30 min causes a blueshift of the excitation peak from displacing the PLL-g-PEG on the nanomenhir surface, before the sensor is flushed with HEPES buffer to remove the excess streptavidin. Upon addition of Ø 70 nm biotinylated vesicles, an immediate, strong redshift in signal is observed for the plasmon excitation corresponding to the apex of the nanomenhirs (A), while only a weak redshift for the plasmon excitation corresponding to the base of the nanomenhirs is observed (B).

⎛ ⎞ Ireference(λ) ⎟⎟ E(λ , t ) = log10⎜⎜ ⎝ Icounts(λ , t ) − Idark,spectrum ⎠

(1)

where E(λ,t) is the extinction in absorbance units for each wavelength at time t, Ireference(λ) is the raw intensity data without a sample, Icounts(λ,t) is the raw intensity data spectrum acquired from the spectrometer at time t, and Idark,spectrum are the false background intensity counts. To obtain a FOM in terms of relative intensity changes, the reference extinction spectrum (in this case, ultrapure water on the nanomenhirs) simply has to be subtracted from the extinction spectra obtained upon changing the bulk RI according to the relation ΔExtinction = E2(λ,t) − E1(λ,t). The result can then be expressed in terms of extinction change per RI increase.20,30 Changes to the extinction spectra have been plotted according to this FOM against the wavelength in Figure 4B,ii and C,ii. Figure 4B,ii shows a single peak whose magnitude increases linearly when changing the bulk RI. This peak magnitude evolves at a rate of 0.472 extinction units/RIU. In Figure 4C,ii, there are two peaks whose magnitudes increase linearly when the bulk RI is changed. The rates of evolution are 0.893 and 0.922 extinction units/RIU, suggesting that the resonances here have essentially identical performance for

bound to the region of interest should thus be possible to detect if we consider the small sensing volume of each hot spot. The results obtained suggest that the correlation between simulation of the array of nanomenhirs and the experiments conducted are qualitatively very similar. This similarity will allow for the fine-tuning of the shape of the nanomenhir sensing element to improve its performance. One of the observations from Figures 2A and 4A is that the two plasmon modes that were excited upon oblique illumination of the sensors in air are fairly close to each other and hence cannot be tracked individually. In water, the two modes are sufficiently far apart from each other to be sensed individually. By changing the aspect ratio of the nanomenhirs from 1:1 (height−base diameter) to 2:1 or beyond, it would be possible to separate the peak excitation of these modes further. The hotspot generated 6127


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detecting changes in bulk RI. Bulk RI sensitivity determination as per the FOM from Sönnichsen et al. seems at first glance to be incompatible with the determination purely according to peak shifts in the resonant spectrum. Specifically, when the samples are obliquely illuminated the discrepancy between the resonance peak shift sensitivities of the two extinction peaks is very large (67.6 and 241.2 nm/RIU), but the values are essentially similar in terms of extinction changes. This mismatch can be explained in terms of peak parameters. The similar performance is a result of the higher peak shift for the longitudinal mode being compensated by the fact that this peak is much lower in magnitude (not width). The Sö nnichsen method to define sensitivities is an interesting method by which it is possible to compare sensitivities across platforms for which the geometries vary, possibly providing more relevant information about the processes occurring at the nanostructure interface. We therefore conclude that the sensitivity of the two nanomenhir modes under investigation is essentially similar for biosensing, and that this method should be preferred for future comparisons with similar platforms. The similar sensitivities to bulk refractive index changes combined with the suggested localization of one of the sensor modes at the bottom and close to the wall of the nanocavity and the other sensor mode at the top and center of the nanocavity gives us the possibility to perform measurements of size exclusion and transport of biomolecular material into the nanocavity coupled to detection of events at the top of the nanocavity. The site-specific sensitivity demonstrated by our liposome binding experiments on selectively functionalized nanocavities/nanomenhirs opens the way to new potential applications. For instance, an additional interesting potential use of our platform could be the calibrated measurement of membrane processes at the membrane of immobilized liposomes, for example, transport through the membrane by aquaporins.38 The rapid decay of the evanescent field at the apex resonance makes it sensitive to changes in the refractive index over the nanometer length scale volume dominated by the lumen of the liposome; the sensor resonance at the bottom of the cavity could simultaneously be used as control for bulk changes since small analytes in the solution, in contrast to the large liposomes, can diffuse into the nanocavity. We emphasize the local calibration of the bulk refractive index change during the liquid exchange as the control sensor element is only 100 nm apart from the event to be detected. In summary, we have shown that it is possible to create dualmode plasmonic sensing arrays by embedding asymmetric nanomenhirs within a silicon nitride matrix. Due to the unique material and physical properties of this sensing array, we were able to successfully perform nanoplasmonic sensing experiments in which the spectral response provided information about where on the nanostructures molecules were bound. Additionally, a localized internal calibration for such plasmonic measurements was provided. This sensor was used to investigate size-resolved adsorption events on the nanoscale and to simultaneously probe correlated molecular events only 100 nm apart. With further refinements it could be used to measure transport across cell membranes on nanometer length scales.

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ASSOCIATED CONTENT

S Supporting Information *

Methods section describing the simulation conditions, the fabrication of the nanomenhir sensors, and the biosensing experiment. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Present Addresses

K.K.: Biomedical Research Council, Agency for Science, Technology and Research (A*STAR), Singapore 138668. A.B.D.: Department of Applied Physics, Chalmers University of Technology, 41296 Göteborg, Sweden. L.I.: Department of Materials, Laboratory for Interfaces, Soft Matter and Assembly, Swiss Federal Institute of Technology (ETH Zürich), CH-8093 Zürich, Switzerland. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank Prof. Janos Vörös, Laboratory of Biosensors and Bioelectronics, ETH Zürich for the use of equipment. The authors also thank Prof. Marcus Textor for discussions and support. This research was funded by the EU 7th framework program through the FP7-NMP-ASMENA. K.K. acknowledges financial support from the Agency for Science, Technology and Research, Singapore (A*STAR). L.I. acknowledges financial support from MC-IEF-2009-252926 for this work.

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REFERENCES

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Nano Letters

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