Advances in Surface Plasmon Resonance Sensing with Nanoparticles

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Advances in Surface Plasmon Resonance Sensing with Nanoparticles and Thin Films: Nanomaterials, Surface Chemistry, and Hybrid Plasmonic Techniques Nanomaterials developed for localized surface plasmon resonance (LSPR) are increasingly integrated to classical prism-based SPR sensors, providing enhanced sensitivity and lower detection limits. The unique properties of these novel nanomaterials in addition to novel surface chemistry to minimize nonspecific adsorption and surface plasmon-coupled techniques with other spectroscopic or mass spectrometry techniques are highlighted in this article. Olivier R. Bolduc and Jean-Francois Masson* Departement de Chimie, Universite de Montreal, C.P. 6128 Succ. Centre-Ville, Montreal, Quebec, Canada, H3C 3J7

Robert Gates

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urface plasmon resonance (SPR) based techniques exploit the optical phenomena of a fixed wavelength resonance involving the free electrons at the surface of a metal. The most striking evidence of this optical phenomenon can be observed from the coloration of metallic nanoparticles (NPs). For example, gold no longer exhibits the characteristic yellow of bulk gold when the size of gold particles is in the nanometer range (i.e., 13 nm spherical gold nanoparticles appears bright red).1 This optical phenomenon is explained by the fact that light of the appropriate wavevector can enter resonance with the free electrons of the metal, exciting a collective oscillation of the free r 2011 American Chemical Society

electron in the metal (namely, the surface plasmon) and causing the attenuation of the intensity of the light beam at a specific wavelength (Figure 1). The simplicity of the measurement explains in part the increasing popularity of localized surface plasmon resonance (LSPR). In this embodiment of SPR, sensing is typically performed using a UV
vis instrument for NPs in solution or nanostructured substrates immobilized on a transparent surface, while dark-field microscopy can also be used for NPs immobilized on a solid support.2 In addition to be dependent on the nature and shape of the metallic nanomaterials,1,3 the coloration of light absorbed is influenced by the dielectric constant or refractive index (RI) of the chemical environment in close proximity to the NP. The wavelength of the light entering resonance red shifts with increasing RI of the solution, typically referred to as the bulk sensitivity (expressed in nm/RIU). SPR is responsive within a sensing volume of a few tens to hundreds of nanometers,4 limited by the penetration depth SPR probes into the solution. The shift in wavelength observed in SPR sensing is also a function of the number or size of the molecules adsorbed on a metallic surface, this concept being the basics of SPR sensors.5 SPR materials that have a short penetration depth will generally be more sensitive to the formation of a molecular adsorbate, thus to the detection of analytes. As for most analytical techniques, high sensitivity (related to large color changes) is an active area of research in SPR sensing to further improve detection of an even lower concentration of analytes. SPR sensing offers many advantages in comparison to enzyme-linked immunosorbent assay (ELISA) or to other optical techniques such as fluorescence and radio-labeling for the realtime monitoring of molecular interactions. The sensitivity to RI of SPR sensors implies no labeling of the analyte and a quasiuniversal response to a broad range of molecules. Thus, selectivity of SPR sensors mostly relies on the performance of a molecular recognition element, often immobilized via a chemically layer at the surface of the SPR sensor (examples include DNA, antibodies, enzymes, and aptamers) to specifically capture Published: August 15, 2011 8057

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Figure 2. Various nanomaterials that were employed for both LSPR and SPR sensors: (A) nanoparticle dimer and (B) nanoparticle aggregate for enhanced sensitivity due to plasmonic coupling, (C) nanograting, (D) nanotriangle arrays, and (E) nanohole arrays.

Figure 1. Schematic representation of biosensing experiments with LSPR. (A) Biosensing scheme on a Au nanoparticle, onto which a chemical layer is deposited to selectively capture a molecule in the presence of interfering agents. (B) Excitation in extinction spectroscopy by a beam of light entering resonance at a specific wavelength with the free electron cloud. (C) The extinction spectrum red shifts with binding of molecules to the Au nanoparticle.

the analyte and the absence of nonspecific interactions of the surface chemistry to avoid false positive detection. Detection of analytes is carried in real-time by establishing the time course of the response of the SPR sensor. Calibration curves are established with a standard solution of the analyte, and the response is typically linear over a few orders of magnitude around the thermodynamical dissociation constant of the analyte/molecular receptor system.

’ ADVANCES IN LSPR SENSING The development of novel plasmonic materials of greater sensitivity to bulk RI leads to larger changes in the SPR response and lower detection limits. In the past decade, colloidal chemistry has been greatly refined to yield metallic NPs of various shapes and materials, including spheres, rods, cubes, rice, and pyramidshaped NPs.3 The excitation wavelength and sensitivity strongly depend on the geometrical aspects of the NPs. Although extensive research has been devoted to optimizing the analytical properties of metallic NPs, there is still no concensus on the optimal shape and size of the NP. Nanospheres are the simplest to manufacture but suffer from low sensitivity at around 76 nm/ RIU.6 Au nanorods exhibit greater sensitivity than nanospheres (366 nm/RIU)6 and are excited in the near-infrared, a spectral window relatively exempt of interferences, but long-term stability of Au nanorods should be improved for sensing applications. Other structures such as cubes, pyramids, and hollow spheres are excellent substrates for surface enhanced Raman scattering, but they have not been extensively employed in SPR sensing. The recent advances in generating controlled size NPs and nanostructured materials enabled the development of new analytical methods exploiting LSPR sensing. Several of these analytical strategies exploit a phenomenon referred to as plasmonic coupling.7 Metallic NP located in close proximity (within a few nanometers) to a Au film or another metallic NP leads to large changes in coloration,8 which may provide sufficient sensitivity for single molecule detection.9 With the design of a colorimetric sensor based on the aggregation of Au NP, proteins, enzymes, and DNA interactions can be efficiently monitored.6 Aggregation can be induced by analytes with multiple binding

sites or by the interaction of binding partners located on different nanoparticles (Figure 2A,B). The colorimetric sensors can also be integrated to an immunochromatographic test-strip10 or a paper-based detection scheme,11 which is envisioned to produce low cost biosensors. Different applications other than sensing are envisioned. Au NPs are being investigated for photothermal therapy, exploiting the dissipation of heat around Au NP when excited by a laser beam to kill cancer cells.12 With the appropriate surface chemistry to recognize tumors, this approach may lead to tumor staining and minimally invasive treatment. A limitation of this cancer therapy treatment is due to the shallow penetration distance of light rays in tissues due to absorption and scattering. The manufacturing of nanostructured surfaces has also produced a plethora of different plasmonic materials immobilized to a substrate. Thereby, SPR sensing chips can be manufactured, facilitating multiplexing of nanoparticle-based SPR sensors.13 For example, focus ion beam milling, e-beam or photolithography, and colloidal lithography techniques13,14 were employed to manufacture nanostructured plasmonic sensors, such as nanotriangle arrays, films over nanospheres, nanocrescents, nanohole arrays, and a variety of other exotic structures. Chip-based LSPR sensors are being developed in a test-strip with an optical reader device or in a multiplexed array of sensors.15 These advances in nanomaterials have significantly impacted sensors based on LSPR, by providing reproducible methods for synthesizing or manufacturing nanostructures on an easy to handle substrate, improving sensitivity and with the development of colorimetric assays for biomolecules. SPR Sensing Using Instruments Based on the Kretschmann Configuration. Most commercial instruments exploit a different configuration of SPR sensors based on a thin metallic film.16 With this SPR material, direct excitation by light of the surface plasmon does not occur. With the use of the Kretschmann geometry, consisting of a thin metallic film supported on a dielectric medium (typically glass prism), the photon is converted to a surface plasmon polariton propagating along the metal surface. The intensity of light decreases, through loss to the metal films, for specific angle-wavelength couples in the visiblenear infrared (Vis-NIR) region. The SPR response is measured by a minimum in the angle, common to commercial instruments, or a wavelength reflectance spectrum. Again, this minimum shifts in angle or wavelength with increasing RI. SPR sensing experiments are performed on several different types of instruments, which can be categorized as angle scanning, wavelength scanning, and imaging SPR.16,17 Angle scanning instruments are the most common of commercial instruments, which are typically achieved by optical (beam focused on the glass|metal interface) or mechanical (stepwise scanning the angle of the light beam with opto-mechanical parts) methods. These instruments provide the capacity to analyze samples on a few channels (usually on the order of 4
8 channels) with excellent sensitivity. Imaging 8058

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Figure 3. Schematic representation of a (A) direct immunoassay, (B) competitive inhibition assay, (C) sandwich assay, (D) sandwich assay amplified with Au nanoparticle (Au NP), (E) sandwich assay using surface enhanced Raman scttering (SERS), and (F) sandwich assay using surface plasmon coupled fluorescence spectroscopy (SPFS).

SPR sensors consists of an intensity measurement of a reflected beam incident at a single angle and wavelength couple.18 Shifting of the SPR response creates a change of intensity captured by an imaging camera. Regions specific to different analytes are defined on the SPR sensor (approximately 102
103 regions). Imaging SPR sensors are advantageous due to the multiplexing capacity for the analysis of several analytes.19 SPR sensing based on the Kretschmann configuration has become a mature technique for label-free biomolecular interaction analysis (BIA). This niche of SPR sensing has been especially exploited in biological sciences for the determination of binding constants and the identification of binding partners. The antibody/antigen couple has a dissociation constant in the nanomolar range, leading to detection limits within the low nanomolar or high picomolar range with SPR sensing for the label-free and direct detection of biomolecules. Medical field, bacteriology, virology, cell biology, proteomics, and molecular engineering exploited the potential of SPR to detect, quantify, or to elucidate the mechanism of molecular interactions for binding partners involved in diseases.20 In particular, SPR sensors are suited to quantify diagnostic molecules (biomarkers) with delays as short as 5 min for diseases such as insulinoma (LOD = 1 ppb via indirect inhibition assay) or in the case of serious conditions such as myocardial infarctions through the monitoring of myoglobin level (LOD = 2.5 ppb).21 In addition, hormones (LOD varies from picograms/milliliter to nanograms/milliliter) were also detected with SPR sensors.22 Many applications involving SPR sensing of molecules at the nanomolar range were developed for the pharmaceutical industry including real-time monitoring of available drug in biofluids, screening for drug candidates,23 and membrane receptor screening.24 In cases of weak SPR response, such as for small molecules or analytes found at low concentration, sensitivity is improved by increasing the RI change generated by the adsorption of the analyte. For example, competitive assays with a tagged analyte,21 amplification with a secondary antibody tagged with a Au nanoparticle,25 aggregation of a network of Au NP,26 enzyme amplification27 or polymer growth28 (Figure 3), and development of plasmonic materials of greater sensitivity to RI, all demonstrated improved detection limits (Figure 2C
E). Competitive assays consist of a molecule tagged with entity bearing a large RI change, which enters competition with the analyte for the molecular receptor. Noteworthily, tagging the analyte must not alter its binding capacity toward the molecular receptor immobilized on the SPR sensor; a limitation of the approach. For

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example, environmental monitoring for toxins and pathogens greatly benefits from a simple instrument capable of rapidly detecting these analytes on-site. With the employment of competition and inhibition assays, strategies were developed to analyze the part per billion level of small molecules.21 Detection of toxins in food and water normally relies on ELISA providing robust results in a few hours but requires access to a laboratory equipped with an ELISA. The advent of a small, portable SPR instruments, their sensitivity, rapidity, and label-free detection lead to the development of handheld devices to monitor the presence of a wide variety of toxins and pollutants such as ricin (LOD = 200 ng/mL on hand-held device), enterotoxin B (LOD = 1 nM on 24-channels device), 2,4-dicychlorophenoxyacetic acid (LOD = 0.1 ppb on miniature chip), atrazine (LOD = 20 ng/L), and other biological agents.29 Molecularly imprinted polymers with Au NP imbedded in the structure of the polymer were electrodeposited on the Au surface of a SPR sensor. Capture of the analyte causes aggregation of the polymer/Au NP structure closer to the SPR sensor, amplifying the SPR response. An excellent detection limit was demonstrated for TNT (LOD = 10 fM).26 Analytes with more than one binding site for different epitopes of antibodies are suited for sandwich immunoassays. A primary antibody immobilized on the SPR surface captures the analyte, which is then reacted with a secondary antibody to amplify the response. Antibodies are large biomolecules for which SPR sensing is very sensitive, leading to lower detection limits for the analyte. If further amplification is required, the antibody may be anchored to a secondary amplification scheme, such as a metallic nanoparticle causing a large change in RI.25 In addition, protein detection can be significantly improved by enzyme amplification. In this strategy, the protein binds to an aptamer immobilized on the SPR sensor. A secondary antibody
HRP conjugate is then reacted with the immobilized proteins. The response is developed by reacting HRP with 3,30 ,5,50 -tetramethylbenzidine (TMB), which precipitates on the SPR sensor, generating a large change in RI and amplification of the SPR response.27 Another approach has exploited a secondary antibody
biotin conjugate, then reacted with streptavidin and a biotin
initiator conjugate for atom transfer radical polymerization (ATRP). The polymerization of hydroxyl-ethyl methacrylate at the SPR sensor’s surface leads to a large RI change and improved sensitivity, as demonstrated for cholera toxin.28 These examples of sandwich assays are excellent to achieve low detection limits as low as the femtomolar range. Secondary antibodies must be available for the target, and the amplification requires at least one additional step. While this may not be critical for most analysis, it may be a limitation for applications requiring a rapid response. Despite significant advances in nanomaterials in the past decade, most commercial instruments still exploit the classical 50 nm-thick Au film for high sensitivity. Improved sensitivity is achieved with excitation further in the NIR, as demonstrated by integrating a SPR sensor to a Fourier transform-infrared (FT-IR) instrument.30 Diffraction grating,31 long-range surface plasmons (LRSP),32 and micropatterned Au films33,34 have been proposed to improve on the classical thin Au film. LRSP is observed on a thin metal film suspended between two dielectrics when the surface plasma waves from the opposite sides of the thin film are coupled. Thereby, the sensitivity was reported to increase by up to 7 times32 using wavelength interrogation but can be poorer in angular interrogation.35 Patterned surfaces can also increase sensitivity of SPR sensing. A sinusoidal diffraction grating was designed to create a surface plasmon bandgap to improve by a factor of 6 the sensitivity to bulk sample.36 Enhanced sensitivity 8059

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Table 1. Studies Comparing LSPR and SPR Sensors mode of operation

ld (nm)

detection (nm)

Concanavallin A

(1) angle-scanning SPRa

102 °/RIU

200

(19 μM)

(2) LSPR on Ag nanotriangle

191

5
6

6.7

streptavidin

(1) wavelength interrogation SPR

3300

246

0.55

(10 μg/mL)43

(2) LSPR on Au nanodisks

178

30

0.57
0.63

42

a

sensitivity (nm/RIU)

0.26°

The sensitivity and penetration depth are reported as an order of magnitude for comparison purposes.16

of SPR sensing has been reported by using a diffraction grating made of Au stripes, observing large changes in diffraction efficiency at the SPR wavelength. Thereby, the authors have demonstrated the detection of femtomolar levels of DNA in a sandwich assay with Au nanoparticles.34 In addition, the use of microhole arrays excited in the Kretschmann configuration results in enhanced sensitivity to bulk RI and to the detection of proteins.33 These examples illustrate the gain in sensitivity and lower detection limits achieved by modifying the classical Au film. It is anticipated that further development of manufacturing, validation, or the reproducibility and lower detection limits with several biological systems for these nanomaterials for SPR sensing should lead to integration to commercial systems. SPR sensors can be vulnerable to a false positive response generated by the adsorption of molecules other than the targeted analyte. Thus, it is essential to develop surface chemistry that resists the adsorption of unwanted materials. Traditionally, SPR sensors are coated with a carboxymethylated-dextran (CMDextran) coating.37 This polysaccharide matrix provides ample binding sites to generate a strong response from biomolecules. However, CM-Dextran does not sufficiently resist nonspecific adsorption of other proteins contained in crude biofluids, resulting in a strong contribution of nonspecific adsorption in the measured signal. This phenomenon has greatly limited the use of commercial biosensors in crude biofluids. Therefore, most applications of SPR have been reported in buffered solutions. A common method to minimize nonspecific adsorption involves the use of blocking agents, bovine serum albumin (BSA) being the most widely used. However, BSA blocking does not sufficiently protect the surface, as albumin adsorption is only the first step of the protein adhesion cascade.38 Surface chemistry capable of reducing nonspecific adsorption and promoting immobilization of active biomolecules has been developed. Initially, polyethyleneglycol (PEG) polymer brushes have been demonstrated to significantly reduce nonspecific adsorption.39 While PEG coating provides a much better level of protection against nonspecific adsorption than CM-Dextran, some level of nonspecific adsorption remains and PEG does not possess functional groups for the attachment of molecular receptors. The latter is alleviated with PEG bearing a COOH or an acetal group in the terminal position. Recently, two different approaches based on polycarboxybetaine40 and on peptide monolayers41 were reported to lower nonspecific adsorption at levels suitable for the detection of biomolecules in undiluted blood plasma and crude serum. These reports demonstrated that biofouling on the order of a few nanograms/centimeter2 is achieved, sufficiently low for detection of proteins found at nanomolar levels in biofluids. While the published results agree that hydrophilic surface chemistry performs better than hydrophobic ones, there is no consensus on the other properties required for low nonspecific adsorption. For example, PEG is a neutral and polar molecule, polycarboxybetaine is polar and zwitterionic, and peptides monolayer can be zwitterionic, charged, or polar. Understanding the

Figure 4. Representation of dual SPR and surface enhanced Raman scattering (SERS) or surface plasmon coupled fluorescence (SPFS) instrumentation. The real-time binding response can be monitored in the Kretschmann configuration of SPR (bottom right), while the SERS (blue) and SPFS (red) responses are measured orthogonally with an instrument adapted for combined measurements (top right).

mechanism of action of nonspecific adsorption will be essential in the future development of surface chemistries toward the development of a surface inert to nonspecific adsorption.

’ COMPARATIVE STUDIES OF SPR AND LSPR Although an extensive number of articles have been published on SPR and LSPR sensing, very few studies provide a comprehensive comparison between these popular plasmonic techniques. The detection of Concanavallin A with LSPR on nanotriangle arrays was compared to angle-scanning SPR on a Biacore 1000. Both techniques demonstrated similar performances to detect this protein42 (Table 1). The association phase of Concanavallin A was similar on both substrates, but dissociation was more important on the nanotriangle arrays, explained by the symmetric function of Ag nanotriangles. Because of the influence of the excitation wavelength on the sensitivity of SPR, a comparison of Au nanodisk (λex = 700 nm) and wavelengthscanning SPR sensing was performed for streptavidin sensing.43 Although SPR sensing is 10 times more sensitive than Au nanodisks, the confinement of the SP field closer to the Au nanodisk resulted in similar results for streptavidin detection (Table 1). One minor point was noted; the surface concentration covered by molecules and the reaction kinetics (faster for Au nanodisks) differed between the two substrates. Comparative studies on a single plasmonic material exhibiting both SPR and LSPR responses would remove effects of the surface coverage and diffusion properties, which may differ for different substrates. To help answer this question, nanoporous gold surfaces were investigated with streptavidin and IgG binding and using layer-by-layer deposition.44 This study demonstrated that LSPR sensing was more sensitive to adsorption within the 8060

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’ DEVELOPMENT OF NOVEL HYPHENATED TECHNIQUES Because of the nature of the SPR principle (no molecular signature is measured), identification of molecules is not possible with SPR sensing alone. To circumvent this drawback, SPR sensing has been coupled to mass spectrometry.45 The SPR sensor provides an adequate substrate to perform BIA from the SPR sensing data and matrix-assisted laser desorption ionization (MALDI) mass spectrometry (MS). Molecular specificity of MS complements well the SPR sensing data, as demonstrated for the analysis of protein
antibody interactions.46 An integrated SPR-liquid chromatgraphy
tandem mass spectrometry (LC
MS/MS) system was also developed to follow protein interactions while being able to exploit the full potential of mass spectrometry.47 Surface plasmons generate a locally enhanced field, which can be exploited to improve the response of other spectroscopic techniques. It is acknowledged that this enhanced field is a major contributing factor to the surface enhanced Raman scattering (SERS) observed for molecular adsorbates on roughened surfaces and on nanoparticles. In addition to SERS, the surface plasmon also enhances the infrared48 and fluorescence49 response of molecules in close proximity of SPR-active materials. SPR can be performed orthogonally to these other spectroscopic techniques (Figure 4), resulting in a multifunctional sensor of improved capacity as demonstrated for Raman49 and fluorescence50 spectroscopy. Propagating SPR is performed on the glass
metal interface, while plasmon enhanced spectroscopy is measured at the metal
solution interface. Raman, IR, or fluorescently active molecules or nanoparticles can be immobilized on the Au film. Thereby, the detection may be performed directly on the analyte (if active in the complementary spectroscopic technique) or via a secondary detection scheme involving the immobilization of an antibody functionalized reporter molecule or nanoparticle. In addition, this combination of techniques can provide molecular information or amplification of the SPR response measured. To date, the techniques and instrumentation have been validated with the hybrid SPR sensors. It is anticipated that the development of actual working sensors based on these techniques will increase significantly in the next decade. ’ OUTLOOK While the various SPR techniques are definitely valuable bioanalytical tools for various applications, they are still mainly used as a research tool or in the industry for the analysis of BIA in buffered solutions. The recent development of various analytical strategies, materials, and instrumentation suggests that SPRbased techniques will move beyond buffered solutions and are thus promised to a bright future in analytical chemistry. Lower detection limits, sensors working in crude biofluids, and instrumentation providing multiple detection techniques should increase the use of SPR-based techniques in environmental, pharmaceutical, food, and medical analysis. Yet, some developments must still be performed to achieve these goals and important questions remain to be answered. In particular, what will be the importance of classical prism-based SPR versus the exponentially increasing field of LSPR? Comparative studies

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have demonstrated similar results with both techniques for the detection of biomolecules,42,43 suggesting that the use of SPR or LSPR will be dependent on the application and instrumentation available. The scientific field of novel plasmonic structures for LSPR is expected to remain a hot topic for years to come. Moreover, will hyphenated SPR techniques become commonplace and significantly improve the sensitivity and specificity of SPR? The added specificity and sensitivity of SPR resulting from orthogonal detection of Raman, IR, or fluorescence is definitely a viable approach for improving SPR. Also, the increased response of Raman, IR, and fluorescence is also beneficial to lower detection limits. While for Raman the impact is already significant, it is likely that IR and fluorescence-based detection schemes will increasingly exploit the surface plasmon-enhanced advantages. Finally, what will be the next important challenge and major advances that will impact (bio)chemical analysis using plasmonic and SPR-based techniques?

’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Phone: +1-514-343-7342. Fax: +1-514-343-7586.

’ BIOGRAPHY Jean-Francois Masson is currently an Associate Professor of bioanalytical chemistry at the Universite de Montreal. The research interest in the Masson group focuses on the development of sensors based on surface plasmon resonance (SPR) and surface-enhanced Raman spectroscopy (SERS). The development and optimization of nanomaterials, surface chemistry stable for analysis in complex samples and small portable instrumentation are central research themes of the group. Olivier R. Bolduc is a senior Ph.D. student in the Masson group. His research interest evolves around the development of peptide surface chemistry and SPR instrumentation for medical and pharmaceutical analysis. ’ ACKNOWLEDGMENT The authors thank the National Science and Engineering Research Council (NSERC) of Canada and the Fonds Quebecois de la Recherche sur la Nature et les Technologies (FQRNT) for financial support. ’ REFERENCES (1) Eustis, S.; El-Sayed, M. A. Chem. Soc. Rev. 2006, 35, 209–217. (2) Willets, K. A.; Van Duyne, R. P. Annu. Rev. Phys. Chem. 2007, 58, 267–297. (3) Lu, X. M.; Rycenga, M.; Skrabalak, S. E.; Wiley, B.; Xia, Y. N. Annu. Rev. Phys. Chem. 2009, 60, 167–192. (4) Haynes, C. L.; Van Duyne, R. P. J. Phys. Chem. B 2001, 105, 5599–5611. (5) Malinsky, M. D.; Kelly, K. L.; Schatz, G. C.; Van Duyne, R. P. J. Am. Chem. Soc. 2001, 123, 1471–1482. (6) Sepulveda, B.; Angelome, P. C.; Lechuga, L. M.; Liz-Marzan, L. M. Nano Today 2009, 4, 244–251. (7) Jain, P. K.; Huang, X.; El-Sayed, I. H.; El-Sayad, M. A. Plasmonics 2007, 2, 107–118. (8) Jain, P. K.; Huang, W. Y.; El-Sayed, M. A. Nano Lett. 2007, 7, 2080–2088. (9) Acimovic, S. S.; Kreuzer, M. P.; Gonzalez, M. U.; Quidant, R. ACS Nano 2009, 3, 1231–1237. 8061

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