Abstract
Tip enhanced Raman scattering (TERS) is an emerging technique that uses a metalized scanning probe microscope tip to spatially localize electric fields that enhances Raman scattering enabling chemical imaging on nanometer dimensions. Arising from the same principles as surface enhanced Raman scattering (SERS), TERS offers unique advantages associated with controling the size, shape, and location of the enhancing nanostructure. In this article we discuss the correlations between current understanding of SERS and how this relates to TERS, as well as how TERS provides new understanding and insights. The relationship between plasmon resonances and Raman enhancements is emphasized as the key to obtaining optimal TERS results. Applications of TERS, including chemical analysis of carbon nanotubes, organic molecules, inorganic crystals, nucleic acids, proteins, cells and organisms, are used to illustrate the information that can be gained. Under ideal conditions TERS is capable of single molecule sensitivity and sub-nanometer spatial resolution. The ability to control plasmonic enhancements for chemical analysis suggests new experiments and opportunities to understand molecular composition and interactions on the nanoscale.
Reviewed Publication:
Lewis Aaron
1 Introduction
The near-field interaction between light and metallic, or metalized, scanning probe microscope tips has transformed Raman scattering into a method capable of providing chemical specificity, single molecule sensitivity, and nanometer spatial resolution. Since the initial demonstration of tip-enhanced Raman scattering (TERS) more than a decade ago [1–3], significant progress has been made in our understanding of the mechanisms that give rise to these enhancements and also the utilization of these enhancements in a variety of applications. Some of the most impressive results include single nanometer resolution and single molecule detection [4–7]. A variety of different experimental configurations have been developed to address different chemical questions. It is the intent of this review to assess current understanding of the mechanisms that give rise to TERS, to show how TERS has been applied to chemical analysis, and to address the future potential for Raman on the nanoscale.
The initial demonstrations of TERS involved bringing an etched gold wire or silver nanoparticle vapor deposited onto the apex of an atomic force microscope (AFM) tip into the focus of a Raman spectrometer and collecting the enhanced Raman scattering [1–3]. Models have shown that an etched metal tip and metal nanoparticle behave qualitatively similar, with respect to the electric field induced by a localized surface plasmon resonance [8]. In either case, the local electric field generated in TERS tip enhances the Raman scattering from molecules in close proximity, generally a few nanometers, or on the nanoscale.
The conceptual model of a TERS tip as a single, controlled, nanoparticle enables the community to utilize the existing knowledge of surface enhanced Raman scattering (SERS), which has benefitted from an additional 20+ years of research. It was recognized that enhancements in SERS are correlated to plasmon resonances [9]. The advent of controlled nanostructures, with well-defined plasmon resonances, transformed SERS into an ultrasensitive detection method [10–17], which includes TERS.
Mie theory calculations for a small spherical silver particle indicate the electromagnetic enhancement achieved when the plasmon resonance is excited is on the order of 104–105 [18]. This enhanced electric field decays quite rapidly, localizing signals to the dimensions of the particle [19]. Pointed metal probes have also been investigated for other near-field microscopies [8]. Illumination of pointed probes has been shown to concentrate the electromagnetic radiation at the apex of the tip [20]. The local field at the apex provides a near-field light source, which can induce scattering on the dimensions of the tip. Inspired by the invention of the scanning tunneling microscope (STM), Wessel postulated that the Raman scattering from an excited nanoparticle on the apex of an STM tip could be used for nanoscale Raman microscopy [21]. Kawata and Inouye further suggested the enhanced fields in apertureless near-field microscopy correlated with surface enhanced spectroscopies [22]. Ultimately it was shown that moving the nanoparticle on the end of a scanning probe microscope tip or a pointed metal probe, enables mapping of chemical composition with spatial resolution below the optical diffraction limit [23–25].
2 Plasmon enhanced Raman scattering
2.1 SERS and TERS
A thorough review of SERS is beyond the scope of this article and excellent reviews on the topic are available [11, 26, 27]; however, it is useful to discuss some key points to facilitate the discussion of TERS. Indeed several groups are using SERS and TERS comparisons to interpret signals observed [28–30].
The strongest enhancements in SERS are attributed to localized surface plasmon resonances (LSPR) [9]. The collective excitation of conduction band electrons in a nanostructure, an LSPR, results in a strong local electric field. Since Raman scattering is proportional to the electric field, molecules that experience this increased local electric field generate enhanced scattering. The scattering intensity is wavelength dependent, and the plasmon resonance frequency varies with different metals. Figure 1 shows the resulting field around a gold nanoparticle and the relationship between polarization and the enhanced electric field. The plasmon mode is excited along the incident laser polarization and directs the orientation of the electric field around the nanoparticle.
The Mie Scattering calculation of the electric field around a 40 nm gold nanoparticle excited by a 633 nm plane wave shows the enhancement along the polarization vector of the excitation field.
Empirical measurements have shown the SERS intensity decays rapidly as you move some distance (d) away from the nanoparticle with radius (r) [19]:
The distance dependence of the enhanced field provides a first order estimate for the spatial resolution in TERS imaging. The relationship between curvature and signal decay suggests that using sharp points and small particles as TERS tips will improve imaging resolution.
In addition to amplifying the excitation field, the LSPR acts as an antenna and will re-radiate the Raman scattering from molecules in the near field. The combination of these two effects is commonly referred to as the E4 approximation [31, 32], where the enhancement factor (EF) is governed by these two separate effects as shown in equation 2:
In equation 2, the change in the electric field that excites the molecules (Eexc) and the emitted Raman photon (Eemm) are normalized to the incident laser (E0). Because the wavelength difference between the excitation and emission is generally small, it is often ignored; however, enhancement bandwidth can vary if the plasmon resonance is not broad relative to the difference in these frequencies. The increases in electric fields are the calculated enhancement relative to spontaneous Raman, which arises from incident radiation (E0).
As illustrated in Figure 1, the electromagnetic enhancement attendant to a small spherical particle is small and dependent upon illumination at its plasmon resonance frequency. For an isolated particle with proper excitation, enhancement factors are a modest 105 [11]. To put this enhancement factor into context, an enhancement of 108 is needed to detect the Raman scattering from a single rhodamine 6G molecule [33]. The transformation of TERS into a single molecule method requires additional enhancement.
The largest enhancements in SERS are obtained in the junction between two nanostructures, commonly referred to as “hotspots” [13, 34–36]. The signal from hotspots is reported to dominate the observed Raman spectrum [37]. An electromagnetic field of 108 is commonly obtained in a 1 nm gap between two silver nanoparticles [34].
By analogy, the largest enhancements in TERS involve the use of “gap modes”, where the TERS tip is brought into close proximity to a metallic surface. Work by Pettinger and colleagues, has shown that as the TERS tip approaches a metallic surface, an image dipole is induced in the surface that acts in the manner of a second nanoparticle [38, 39]. The gap resonance frequency is a function of tip-substrate separation, the size of TERS tip, and metal(s) used. Figure 2 shows the parallels between the gap mode configuration and the classic nanoparticle dimer. The calculation in Figure 2 was performed for gold nanoparticles with 633 nm excitation, a common experimental condition. The scattered electric field is an order of magnitude larger in the gap junction than around an isolated nanoparticle. With 100 nm nanoparticles, the calculated scattered electric field is even larger, owing to improved overlap between the excitation laser and emitted Raman photons with the plasmon resonance. Proper configuration of the gap provides an enhancement that is sufficiently strong to detect the Raman scattering from a single molecule [5]. The use of a metal surface to enhance TERS signals has become known as gap-mode TERS and it has seen use with both STM [39–44] and AFM [45, 46] based TERS instruments. In the absence of a gap-mode, most TERS measurements require acquisitions on the order of a few seconds to generate appreciable signals from collections of molecules [47, 48].
![Figure 2 (A) The conceptual illustration of the gap mode described by Pettinger and workers is compared with (B) the Mie scattering calculation of two 40 nm gold spheres separated by 2 nm and 633 nm plane wave excitation. The calculation uses identical conditions to Figure 1 and shows the field confined within the gap increases by an order of magnitude compared with the isolated particle. Panel (A) is reproduced with permission from Ref. [38].](/document/doi/10.1515/nanoph-2013-0040/asset/graphic/nanoph-2013-0040_fig2.jpg)
(A) The conceptual illustration of the gap mode described by Pettinger and workers is compared with (B) the Mie scattering calculation of two 40 nm gold spheres separated by 2 nm and 633 nm plane wave excitation. The calculation uses identical conditions to Figure 1 and shows the field confined within the gap increases by an order of magnitude compared with the isolated particle. Panel (A) is reproduced with permission from Ref. [38].
From Eq. 2, it is clear that to obtain the maximum enhancement both the excitation and emission frequencies need to be in resonance with the plasmon mode, and thus enhanced. Computational work by Schatz and coworkers has further shown the importance of dipole re-radiation (Eemm) observed in Raman enhancement [49]. Work by LeRu and Etchegoin has shown that E4 is only true for a molecule with its transition dipole parallel to the electric field that results from a polarization parallel to the aligned NPs, thereby maximizing coupling of the electric fields [50, 51]. Conveniently, the conditions for optimum SERS are also satisfied in gap-mode TERS experiments.
The importance of overlap with the plasmon resonance has had interesting consequences for the Raman signals observed in SERS. Early SERS studies in aggregated nanoparticles showed that enhancement correlated with overlap with plasmon modes [15]. Van Duyne and colleagues further showed that maximum enhancement arose when exciting Raman with a laser frequency at higher energy than the plasmon mode, thereby increasing overlap with the emitted Raman scattering [19]. Recently, Halas and Nordlander have investigated the interference between plasmons in aggregated systems and shown dramatic changes in the observed SERS spectrum [52].
The importance of the overlap between the electric fields and the Plasmon resonance has also impacted TERS results. A striking recent result, overlap of the gap-resonance with the Raman emission was shown to be critical in obtaining sub-nanometer TERS spatial resolution [7]. The resolution demonstrated is better than would be predicted by Eq. 1, indicating that other effects are important in determining TERS spatial resolution. A quick inspection of the electric field intensity calculated in Figure 2B suggests the highest enhancement is confined to a few nanometers. Other work has shown that dramatic signal increases can be obtained in TERS from increased overlap with plasmon resonances. It was shown that varying the thickness of a metal film beneath a sharp metal TERS tip tuned the resonance associated with the gap and impacted the TERS response [53]. The red-shifted plasmon resonance from the interaction of a nanoparticle TERS tip and an isolated nanoparticle results in increased TERS emission when excited with a red laser [54]. The interactions with the resulting plasmon resonances from interacting nanostructures appears to be an important factor for high sensitivity and high resolution TERS.
2.2 Unique aspects of TERS
Whereas the understanding of SERS effects benefitted from reproducible nanostructures, TERS offers the additional advantage of controlled manipulation of the nanostructures. TERS imaging of chemical properties at the nanoscale derives from the ability to precisely position the metal nanostructure. This ability to control the position of the nanoparticle opens additional avenues of research unique to TERS.
The controlled interaction between two nanoparticles is one example. SERS experiments rely on searching to find nanoparticle aggregates that can be modeled to explain observed Raman enhancements and plasmonic effects. TERS experiments have shown the same effects in a reproducible manner. Olk and coworkers demonstrated increased Raman enhancements observed in dimer particles by moving a nanoparticle on the apex of an AFM tip over a nanoparticle on a substrate [55]. They were able to match the observed Raman enhancements to the expected fields calculated in finite element models. The plasmon resonance that acts to enhance Raman scattering has been calculated to depend on the size, shape, and position of nanoparticles in simple dimer assemblies [56] as well as complex aggregates [52, 57].
Different size and shape nanostructures can also be used for TERS tips. The two most commonly recognized TERS tips are etched metal wires and silver island films deposited on pyramidal AFM tips [58, 59]. However, a single nanoparticle on the end of AFM cantilevers is also seeing increased use in TERS experiments [60, 61]. Given what is known about plasmon resonances in nanoparticles and the impact on Raman enhancements, tip construction clearly plays a role in TERS signals. A numerical simulation comparing pointed probes, spherical nanoparticles, and triangular nanoparticles as TERS tips showed differences in the enhanced bandwidth associated with different tips [62]. An experimental comparison of the plasmon resonances, Raman enhancements and image resolution with different types of TERS tips has not been reported; nonetheless, the ability to control the nanostructure shape is a unique aspect of TERS.
The ability to use an STM tip for TERS has enabled other interesting experiments associated with tunneling currents through gap junctions. Zhang and coworkers noted a change in TERS signal intensity associated with the tunneling current in their experiments [7]. It was reported that tunneling occurs in nanometer gaps associated with significant changes to plasmon resonances observed [63]. In this tunneling experiment, two Au nanoparticles on conductive AFM tips were manipulated with respect to each other while monitoring the plasmon resonances and tunneling current. In addition to plasmonic changes, applying a bias across a gap with simultaneous conductance monitoring shows changes in the TERS signal attributed to molecules in on and off states [64].
Given the connections between Raman enhancements and plasmon modes, the ability to control nanostructures enables TERS to provide unique insights into fundamentals associated with plasmon-enhanced spectroscopies.
3 Experimental TERS configurations
To take advantage of enhanced Raman signal from TERS, a number of different instrument configurations have been developed to address different experiments. Perhaps the most fundamental difference is the use of a scanning tunneling microscope (STM) or atomic force microscopy (AFM) to control the position of the tip. The difference in feedback mechanism provides utility in different experiments. The tunneling current can regulate the height of an STM tip over the surface, which can be beneficial for tuning gap resonances. However, STM requires a conductive substrate, while AFM does not. This leads to the ability to image far more substrates with AFM but with reduced z-axis resolution compared to STM. Each approach has its advantages and both approaches have yielded impressive results.
A second consideration is how the excitation laser couples with the metallic tip to promote enhancement of the sample. Figure 3 shows various configurations that are used to direct the laser to the apex of the AFM or STM tip. The polarization of light, as shown above, orients the electric fields around the TERS tip. In general a polarization normal to the surface is required for optimal results [65]. While focusing linear polarized light will enhance scattering from samples in close proximity to the tip [66], it has been shown that a radial polarized laser beam will generate a longitudinal mode at the focus of the laser beam increasing the interaction [20, 67, 68].
Experimental TERS configurations are shown: (A) bottom illumination, (B) side illumination, (C) top illumination with a parabolic mirror, (D) top illumination.
The first configuration (Figure 3A), and perhaps conceptually most straightforward, is to bring the tip into the focus of an inverted microscope [1, 69]. In this configuration the tip comes from the top and the light is excited and collected from a high numerical aperture objective beneath the sample [1]. Focusing radial polarization through a high numerical aperture results in regions of the focus that are polarized in and out of the sample plane, which promotes interactions between the tip and sample [66, 70]. High sensitivity TERS measurements have been performed using thin, optically transparent, metal plates [45, 46]. In these experiments, silver and gold plates provide a gap-mode enhancement but also allow the Raman scattering to be collected from below. Kawata and colleagues, to generate high-resolution TERS images, demonstrated an interesting time-gated approach. With the AFM used for TERS operating in tapping mode and locked in on the oscillation frequency, they were able to image carbon nanotubes with nanometer spatial resolution [6]. This was possible due to the electric field being confined to a region within 3 nm of the tip.
The inverted microscope approach works well for transparent samples; however opaque and thick samples present challenges to this configuration.
Side illumination (Figure 3B) of the TERS tip provides a solution for non-transparent samples as well as the use of linear polarization. Illuminating the surface from an oblique angle using a laser polarized along the tip-sample axis, provides efficient enhancement beneath the tip. Using this strategy, TERS enhancements with metal-coated silicon cantilevers as high as 350% have been obtained relative to the far-field signal [71]. While side illumination has shown substantial enhancements, the method has been reported to be difficult to align and prone to complications from the shadow of the tip [71]. Interestingly, side illumination of an STM tip was used to image single molecules [7]. As noted in the earlier discussion of plasmon effects, this result required a gap plasmon ideally tuned to observe the TERS signal.
Figure 3C shows an elegant approach reported by Pettinger and coworkers, which made use of a custom parabolic mirror with an STM tip passing through the mirror to the focal point [72]. A modification of bottom-illumination, a radial polarized laser passes around the sample and is then focused by a parabolic mirror onto the apex of the SPM tip. This configuration was used to achieve single molecule detection and imaging with 15 nm spatial resolution [5].
Another straightforward approach to TERS is to use tips that are optically accessible from above in a back-scattering configuration (Figure 3D). This approach was first demonstrated by Sun and Shen using an AFM within an upright microscope [73, 74]. The use of radial polarization at intermediate numerical aperture (NA=0.45–0.7) was shown to increase TERS signals over linear polarized light [48, 65]. The enhancements observed with radial polarization in a back-scattering TERS configuration are comparable to that reported from physically manipulating a Au nanoparticle into close proximity of a carbon nanotube [75]. The key advantage of radial polarization is to orient the plasmon oscillation beneath the tip increasing the field that interacts with the sample. Figure 4 shows a line scan across bundles of carbon nanotubes dispersed on a substrate. Using radial polarization enabled chemical mapping with improved spatial resolution and registry with the AFM measured topography of the sample in a top-illumination configuration [48].
![Figure 4 (A) The AFM topography of carbon nanotube bundles on a surface is shown. (B) The TERS scan along the diagonal shows changes in the radial breathing modes associated with different nanotube diameters. (C) The TERS intensity profiles are shown for different radial breathing modes observed. Figure adapted with permission from Ref. [48].](/document/doi/10.1515/nanoph-2013-0040/asset/graphic/nanoph-2013-0040_fig4.jpg)
(A) The AFM topography of carbon nanotube bundles on a surface is shown. (B) The TERS scan along the diagonal shows changes in the radial breathing modes associated with different nanotube diameters. (C) The TERS intensity profiles are shown for different radial breathing modes observed. Figure adapted with permission from Ref. [48].
An alternative approach that also incorporates an AFM into an upright microscope has been proposed by Kazarian and coworkers [76]. By offsetting the excitation beam with respect to the center of the back-aperture of the microscope objective, the laser illuminates the tip from only one side, providing a similar coupling between the laser polarization and metal tip as the side-illumination geometry (above) but with the convenience of a commercial microscope for sample positioning.
4 Applications of TERS
The ability to control plasmon enhancements enables chemical investigations with nanometer spatial resolution that have been used in a variety of fields from material science and catalysis to biology and medicine. In the next sections we look at how TERS has been used to investigate different systems and what information has been gained.
4.1 Carbon nanotubes and other carbon allotropes
Their small size and large Raman cross-section have made carbon nanotubes and related materials natural samples to study with TERS. The G and G’ modes of carbon nanotubes provide excellent contrast in TERS experiments [77]. Information regarding the size and chirality of individual carbon nanotubes can be derived from the frequency of the radial breathing modes [78, 79]. The different modes in carbon nanotubes were shown to have different polarization dependencies associated with the symmetry of the nanotubes [80]. TERS investigations of nanotubes prepared by different methods has also shown changes in the resulting nanotube properties [78]. Changes induced in carbon nanotubes by applying a local force with an AFM tip have also been detected by TERS [81].
Graphene has also been investigated by TERS with mixed results. The planar symmetry of graphene has been reported to suppress certain modes in TERS analysis [82]. As discussed above, TERS has a strong polarization normal to sample surface. These effects have also been reported to affect signal intensities commonly used to determine the number of graphene sheets [83]. Similar to carbon nanotubes, defects and pressure induced frequency shifts have been observed [84, 85].
Amorphous carbon has also been detected by TERS. In many ways, this is the bane of TERS experiments. The high fields associated with Raman enhancement can destroy molecules leaving carbon residues [86, 87]. Similarly, the high sensitivity of TERS can detect dirt in the air and artifacts arising from contamination can be problematic [88].
4.2 Silicon, semiconductors, and other crystalline materials
Similar to carbon nanotubes, silicon has a large Raman cross-section and has been explored with TERS [89]. Some of the earliest demonstrations of TERS probed the silicon phonon mode at 520 cm-1 [90]. Shifts in the Si-Si phonon at 520 cm-1 are associated with strain, and TERS mapping of the Si phonon provides images of this strain in different materials [91, 92]. The crystalline properties of Si materials have shown polarization dependent effects in TERS measurements [71, 93].
Germanium has also been investigated, often in conjunction with Si [93–95]. An interesting result showed asymmetric broadening of bands was observed that corresponded to decreases in the nanowire diameter [96]. The authors attributed the effect to changes in phonon confinement.
Other semiconductors, such as CdS, GaN, and GaAs, also show strong TERS signals [97, 98]. Blinking observed in CdS and Si films was determined not to originate from charge transfer, by obtaining TERS spectra with a conducting and dielectric coated tip [99]. Changes in crystalline properties in GaN films [100], as well as wires [101] have been studied. Polarization effects were shown to alter the intensity of phonons observed in GaAs films [98].
TERS has also been used for nano-crystallography [102, 103]. Many crystalline materials present interesting challenges associated with the large far-field signal observed. Ferroelectric domains were identified in BaTiO3 [104]. Mode selection associated with crystalline properties was observed in LiNbO3 [105].
4.3 Organic polymers and molecules
Organic molecules have been used to demonstrate a variety of processes. From composite materials, single molecule detection, photocatalysis, and molecular imaging, these molecules have provided tremendous insight into the chemistry at the nanoscale.
Block co-polymers and polymer blends are materials that naturally lend themselves to TERS characterization. The ratio of polymer components can result in nanoscopic domains with distinct chemical signatures. Indeed several examples of polymers have been reported. Domains of polystyrene and polyisoprene were identified in a thin film using aromatic ring stretches at 1002 cm-1 and 1602 cm-1 to identify polystyrene and carbon double bond vibrations at 1664 cm-1 to denote polyisoprene. Poly-3-hexyl-thiophene (P3HT) and phenyl-C61-butyric acid methyl ester (PCBM), a commonly used blend for solar cells, showed thiophene bands at 1450 cm-1; however, the authors reported no observable signal form PCBM [106]. Temporal signal variations in the TERS signal from PEDOT/PSS films suggested thermal diffusion within the blend [99]. Phase separation in poly(methyl methacrylate) (PMMA)/poly(styrene-co-acrylonitrile) (SAN) was followed by observing TERS spectral changes in marker bands at 800 cm-1 and 1002 cm-1 for PMMA and SAN, respectively [107].
In the polymer systems, extended pi-systems show good responses. Similarly, organic molecules with analogous properties have also been studied by TERS. Brilliant cresyl blue, nile blue, rhodamine, and malachite green isothiocyanate are common dye molecules studied [1, 5, 41, 42, 65, 108–111]. The large SERS and TERS signals associated with these molecules lend themselves naturally to single molecule demonstrations [5, 108]. Similarly, dyes attached to other materials, for example TiO2, can be detected in TERS [112]. An interesting observation reported from experiments on crystal violet is only Raman bands associated with carbon double bonds are observed [113].
Self assembled monolayers of amines and thiols have also been investigated. Common probe molecules include pyridines, aromatic thiols, and benzotriazole [59, 114–119]. Patterning of different molecules and imaging by TERS has been demonstrated [120]. The plasmon driven conversion of 4-nitrobenzenethiol into dimercaptoazobenzene was monitored with TERS measurements of the 1336 cm-1 band of NO2 and 1432 cm-1 N=N stretch [121, 122].
Other organo-metallic molecules such as Cobalt tetraphenylporpherine have been investigated and TERS signals are obtained that can identify if CO or NO is ligated to the molecule [123]. Ordered layers of copper phthalocyanine were observed on Ag(111) surfaces [124]. Most impressively, meso-tetrakis(3,5- di-tertiarybutylphenyl)-porphyrin molecule on a Ag(111) surface was imaged with sub-nanometer resolution, identifying parts of the molecule based on vibrational contrast [7].
4.4 Biomolecules and cells
The identification of molecules in biological systems with nanometer spatial resolution has transformative potential for elucidating chemical interactions in nature. Unlike many of the organic molecules noted earlier, the Raman cross-sections of biomolecules can vary substantially and has met a bit more controversy in interpreting results.
Some of the first biomolecules to be studied by TERS were nucleic acids. One of the original reports was the TERS spectra of the pyrimidine bases (thymine and cytosine), which suggested TERS signals could be used for DNA sequencing [125]. All four DNA bases were detected in picomole quantities using gap-mode TERS [40]. A single strand of RNA homopolymer [4] and small DNA fragments [126] were imaged further showing the utility of TERS for sequencing. The hydrogen bonding between adenine and thymine bases was detected by spectral changes [127]. Changes in modes observed in nucleic acids have also been attributed to the orientation of the molecules on the surface [128].
Amino acids, the building blocks of proteins, have yielded interesting results as well. The oxidized glutathione peptide in gap-mode TERS showed bands from the carboxyl terminus at 1408 cm-1, cysteine carbon sulfur stretches at 750 cm-1, and bands attributed to the amide I and amide III modes [46]. Histidine was reported to adsorb to silver plates in two different orientations and show bands associated with the imidazole ring and carboxyl moiety [45]. Studies of cysteine on gold nanoplates showed bands attributable to the C-S bond and the carboxylic acid group [129]. Studies of aromatic amino acids phenylalanine, tryptophan, and tyrosine on gold nanoplates showed marker bands that could be used for identification and evidence of a flat orientation on the Au substrate surface [129].
TERS has been demonstrated to be sensitive to the sub-regions of the proteins. Strong aromatic heme bands were detected at times and amino acid signals from the protein in other spectra in studies of cytochrome c [130]. Nano-oxidation sites were detected in hemoglobin crystals identifying the oxidation state of the iron in the heme-moiety [131].
Biotin functionalized nanoparticles bound to streptavidin were shown to produce spectra consisting predominantly of the aromatic amino acids that form the biotin binding site in the protein when detected with a TERS tip [54]. In a follow-up study, it was shown that distinctive peaks are observed when the protein is located in the gap between the nanoparticle and TERS tip and when the protein binds outside the gap junction [28]. Figure 5 shows the spectra that are obtained from TERS and SERS experiments using biotin functionalized nanoparticles to enhance the streptavidin’s Raman scattering. The data agree with SERS studies that the parts of the protein closest to the nanoparticle are preferentially enhanced [132]. Thus, differences in the spectra obtained in different configurations supports the detection of proteins on the glass substrate and not in gap junctions. Recent SERS studies show that significant, single molecule detection level, enhancements are observed in aggregated nanoparticles at locations outside the gap junctions [133]. The ability to use bound nanoparticles to enhance protein TERS signals suggests an alternative to metal substrates to produce gap-mode like enhancements for studying proteins.
![Figure 5 The SERS spectrum from streptavidin is obtained from biotinylated (1) and bare gold (2) nanoparticles are shown to agree well with the TERS spectrum obtained from streptavidin bound to a bare (4) and a biotinylated (5) nanoparticle detected with a nanoparticle TERS tip. The SERS spectrum of the biotinylated nanoparticles is shown (3). The yellow highlights indicate Raman bands that are observed when the streptavidin is in a gap junction. The absence of these bands in (5) supports the detection of streptavidin outside the gap junction. Adapted from Ref. [28] with permission from The Royal Society of Chemistry.](/document/doi/10.1515/nanoph-2013-0040/asset/graphic/nanoph-2013-0040_fig5.jpg)
The SERS spectrum from streptavidin is obtained from biotinylated (1) and bare gold (2) nanoparticles are shown to agree well with the TERS spectrum obtained from streptavidin bound to a bare (4) and a biotinylated (5) nanoparticle detected with a nanoparticle TERS tip. The SERS spectrum of the biotinylated nanoparticles is shown (3). The yellow highlights indicate Raman bands that are observed when the streptavidin is in a gap junction. The absence of these bands in (5) supports the detection of streptavidin outside the gap junction. Adapted from Ref. [28] with permission from The Royal Society of Chemistry.
Recently some controversy has stirred over reports of signals associated with the amide I mode in proteins (~1650–1680 cm-1). A few groups have reported structural changes in proteins by mapping the amide I frequency in proteins [89, 134–137]. Other groups do not report observing the amide I mode [28, 54], and others claim the mode is not detectable in TERS raising questions about signals observed elsewhere [29, 138, 139]. Suppression of the amide I signal by large amino acid side groups (e.g., – aromatic amino acids) has been put forward as one explanation [30]. The differences in observed signals are reminiscent of the well-known challenges in SERS, where different SERS substrates give different signals. In one report, the observance of amide I modes in SERS was noted to vary between SERS substrates [139]. SERS has been shown to be exquisitely sensitive to the plasmonic environment [57], suggesting differences in the way these TERS measurements are made (e.g., – tip design) may have similar effects.
Examples of cells and organisms studied by TERS include: Staphylococcus epidermidis [140, 141], HaCaT cells [142], tobacco mosaic virus [143], pox and adeno viruses [144], colon cancer cells [145, 146], rod photoreceptor cells [48], erythrocytes [47], and Halobacterium salinarum [147]. Because TERS images are typically collected using raster scanning that requires each nanometer pixel to be acquired in series, the acquisition time for each image is long. The 105–108 cm2/s diffusion constants associated with the motion of membrane biomolecules means that molecules can easily be oversampled or missed entirely during the course of a scan, complicating analysis in live cells [140]. In fixed cellular systems [47, 48, 142, 146], this can be tolerated; however, individual cells are commonly 10’s of micrometers in size, making the experiment time prohibitive to image regions larger than a single micrometer with nanometer resolution.
One approach that offers potential for the investigation of intact membranes is the use of functionalized nanoparticles that bind to membrane receptors. In situ work with streptavidin discussed above suggests that the TERS signals, which originate from the interaction of a TERS tip with a nanoparticle bound to a protein, provide information about the bound protein. Work in cells has shown that nanoparticles can be bound to membranes of intact cells and detected by TERS [145], providing additional enhancement for detection. Figure 6 illustrates this “targeted-TERS” approach to resolve some of the challenges associated with single cell studies. The dark-field image identifies the region of the membrane to image and coupling between the TERS tip and bound nanoparticle increases signal intensity locally. Initial experiments using antibodies to target the nanoparticles showed TERS signals primarily consisting of the antibodies; however, in areas where the nanoparticle probes aggregated, bands attributable to other molecules are observed.
![Figure 6 (A) The dark-field image of a cancer cell labelled with antibody-functionalized nanoparticles is shown. (B) The TERS image of the area of the cell in the red box is mapped at 1575 cm-1. (C) The TERS spectra obtained from the pixels in the white box marked in the inset of (B) are shown. The Raman bands at 1350 and 1485 cm-1 are attributable to the antibody on the nanoparticles, while the other bands arise from the cellular microenvironment. Reproduced with permission from Ref. [145].](/document/doi/10.1515/nanoph-2013-0040/asset/graphic/nanoph-2013-0040_fig6.jpg)
(A) The dark-field image of a cancer cell labelled with antibody-functionalized nanoparticles is shown. (B) The TERS image of the area of the cell in the red box is mapped at 1575 cm-1. (C) The TERS spectra obtained from the pixels in the white box marked in the inset of (B) are shown. The Raman bands at 1350 and 1485 cm-1 are attributable to the antibody on the nanoparticles, while the other bands arise from the cellular microenvironment. Reproduced with permission from Ref. [145].
The challenges associated with live cells also apply to cell membrane studies, including model membranes. The short-range enhancement from the tip means almost all cell studies are actually probing the membrane, investigations into possible domain formation have been tantalizing yet difficult to perform. Only a small number of reports have been made thus far. Phase separated domains of deuterated saturated lipids and protonated unsaturated lipids were imaged [148]. A streptavidin containing phospholipid film showed spectral differences attributed to putative domains [149]. A fundamental challenge to studying membranes is TERS in solution has been difficult [115]. Advances in technology may help resolve this problem soon.
5 Challenges and opportunities going forward
TERS has tremendous potential to elucidate chemical properties from complex samples on molecular dimensions. The recent demonstration of single molecule imaging captures much of the promise of the technique [7]. In this experiment, they were able to resolve parts of the molecule and explain the observed signals from the quantum calculations of the molecule probed. This rational signal and agreement with quantum mechanical calculations is impressive and represents future opportunities. This experiment, while impressive, was performed in ultra high vacuum at four Kelvin with a strong Raman scattering molecule on a metallic substrate; essentially ideal conditions. The challenge for the future is to use TERS to analyze complex systems under in situ and ultimately in vitro and in vivo conditions. To address these challenges, advances in instrumentation, methodology and understanding of the Raman enhancements will be important. The approach using functionalized nanoparticles targeted to specific proteins on intact cell membranes [145], albeit still in its infancy, is one approach that shows promise. Other advances in methodology will most definitely prove useful.
Controversy over signals and the perception of irreproducible signals has hampered the use of SERS and somewhat sullied its reputation. As TERS has become more widely used and more systems have been investigated, discrepancies in the signals observed between research groups are beginning to arise in the TERS community as well. A recent article by the Zenobi group attempted to clarify signals observed in TERS and SERS experiments [29]. A common misconception in SERS is “new” bands appear, where in reality carefully characterized systems can explain the origin and temporal changes of bands observed either from metal coordination, molecular orientation, or contamination. One drawback to doing ultrasensitive analysis is the possibility of detecting a contaminant, even transiently. Approaches have been suggested to avoid carbonaceous signals and other interferences [115, 150].
In addition to the controversy over signals observed in protein analysis, discrepancies have been reported in TERS experiments involving nucleic acids. Gap mode detection of nucleic acids with an STM TERS-tip showed spectra that resembled SERS results of the same nucleotides [40]. This is in contrast to the TERS spectra reported using silver island coated AFM tips, where the observed spectra more closely resembled the conventional Raman spectrum of the nucleotide [125]. It will be important to reconcile such controversies and identify the origins of signal differences to maintain confidence in reported results. Given the identified role of plasmonics in SERS, and the increased ability to control plasmon resonances in TERS, it should be possible to explain experimental differences.
Effects other than plasmonic enhancement can give rise to artifactual signals in TERS experiments [151]. It was shown that scattering artifacts can yield increased Raman intensities [152]. Effective practices have been reported to insure that TERS spectra and images provide accurate representations of the samples [150]. Imaging experiments that show the near-field resolution of the signal can assist in verifying the origin of the enhanced Raman scattering.
Understanding the fundamentals of plasmonics as they apply to enhanced spectroscopies will be key to future progress in TERS. Since everything scatters light, the universality of TERS to investigate materials makes it a highly promising technique. New experiments that account for the multitude of effects occurring on the molecular scale will enable TERS to further unveil processes on the nanoscale.
References
[1] Stöckle RM, Suh YD, Deckert V, Zenobi R. Nanoscale chemical analysis by tip-enhanced Raman spectroscopy. Chem Phys Lett 2000;318:131–6.10.1016/S0009-2614(99)01451-7Search in Google Scholar
[2] Hayazawa N, Inouye Y, Sekkat Z, Kawata S. Metallized tip amplification of near-field Raman scattering. Opt Commun 2000;183:333–6.10.1016/S0030-4018(00)00894-4Search in Google Scholar
[3] Anderson MS. Locally enhanced Raman spectroscopy with an atomic force microscope. Appl Phys Lett 2000;76:3130–2.10.1063/1.126546Search in Google Scholar
[4] Bailo E, Deckert V. Tip-enhanced Raman spectroscopy of single RNA strands: towards a novel direct-sequencing method. Angew Chem, Int Ed 2008;47:1658–61.10.1002/anie.200704054Search in Google Scholar PubMed
[5] Steidtner J, Pettinger B. Tip-enhanced Raman spectroscopy and microscopy on single dye molecules with 15 nm resolution. Phys Rev Lett 2008;100:236101/1–236101/4.10.1103/PhysRevLett.100.236101Search in Google Scholar PubMed
[6] Ichimura T, Fujii S, Verma P, Yano T, Inouye Y, Kawata S. Subnanometric near-field Raman investigation in the vicinity of a metallic nanostructure. Phys Rev Lett 2009;102:186101–4.10.1103/PhysRevLett.102.186101Search in Google Scholar PubMed
[7] Zhang R, Zhang Y, Dong ZC, Jiang S, Zhang C, Chen LG, Zhang L, Liao Y, Aizpurua J, Luo Y, Yang JL, Hou JG. Chemical mapping of a single molecule by plasmon- enhanced Raman scattering. Nature 2013;498: 82–6.10.1038/nature12151Search in Google Scholar PubMed
[8] Novotny L, Stranick SJ. Near-field optical microscopy and spectroscopy with pointed probes. Annu Rev Phys Chem 2006;57:303–31.10.1146/annurev.physchem.56.092503.141236Search in Google Scholar PubMed
[9] Moskovits M. Surface-enhanced spectroscopy. Rev Mod Phys 1985;57:783–826.10.1103/RevModPhys.57.783Search in Google Scholar
[10] Graham D, Stevenson R, Thompson DG, Barrett L, Dalton C, Faulds K. Combining functionalised nanoparticles and SERS for the detection of DNA relating to disease. Faraday Discuss 2011;149:291–9.10.1039/C005397JSearch in Google Scholar PubMed
[11] Stiles PL, Dieringer JA, Shah NC, Van Duyne RP. Surface-enhanced Raman spectroscopy. Annu Rev Anal Chem 2008;1:601–26.10.1146/annurev.anchem.1.031207.112814Search in Google Scholar
[12] Qian X-M, Nie SM. Single-molecule and single-nanoparticle SERS: from fundamental mechanisms to biomedical applications. Chem Soc Rev 2008;37:912–20.10.1039/b708839fSearch in Google Scholar
[13] Camden JP, Dieringer JA, Zhao J, Van Duyne RP. Controlled plasmonic nanostructures for surface-enhanced spectroscopy and sensing. Accounts Chem Res 2008;41:1653–61.10.1021/ar800041sSearch in Google Scholar
[14] Banholzer MJ, Millstone JE, Qina L, Mirkin CA. Rationally designed nanostructures for surface-enhanced Raman spectroscopy. Chem Soc Rev 2008;37:885–97.10.1039/b710915fSearch in Google Scholar
[15] Michaels AM, Jiang J, Brus L. Ag nanocrystal junctions as the site for surface-enhanced Raman scattering of single Rhodamine 6G molecules. J Phys Chem B 2000;104:11965–71.10.1021/jp0025476Search in Google Scholar
[16] Kneipp K, Wang Y, Kneipp H, Perelman LT, Itzkan I, Dasari RR, Feld MS. Single molecule detection using surface-enhanced Raman scattering (SERS). Phys Rev Lett 1997;78:1667–70.10.1103/PhysRevLett.78.1667Search in Google Scholar
[17] Nie SM, Emery SR. Probing single molecules and single nanoparticles by surface-enhanced Raman scattering. Science 1997;275:1102–6.10.1126/science.275.5303.1102Search in Google Scholar
[18] Kerker M. Electromagnetic model for surface-enhanced Raman-scattering (Sers) on metal colloids. Acc Chem Res 1984;17:271–7.10.1021/ar00104a002Search in Google Scholar
[19] McFarland AD, Young MA, Dieringer JA, Van Duyne RP. Wavelength-scanned surface-enhanced Raman excitation spectroscopy. J Phys Chem B 2005;109;11279–85.10.1021/jp050508uSearch in Google Scholar
[20] Novotny L, Sanchez EJ, Xie XS. Near-field optical imaging using metal tips illuminated by higher-order Hermite-Gaussian beams. Ultramicroscopy 1998;71:21–9.10.1016/S0304-3991(97)00077-6Search in Google Scholar
[21] Wessel J. Surface-enhanced optical microscopy. J Opt Soc Am B: Opt Phys 1985;2:1538–41.10.1364/JOSAB.2.001538Search in Google Scholar
[22] Inouye Y, Kawata S. Near-field scanning optical microscope with a metallic probe tip. Opt Lett 1994;19:159–61.10.1364/OL.19.000159Search in Google Scholar PubMed
[23] Deckert-Gaudig T, Deckert V. Tip-enhanced Raman scattering (TERS) and high-resolution bio nano-analysis—a comparison. Phys Chem Chem Phys 2010;12:12040–9.10.1039/c003316bSearch in Google Scholar PubMed
[24] Yeo B-S, Stadler J, Schmid T, Zenobi R, Zhang W. Tip-enhanced Raman spectroscopy – Its status, challenges and future directions. Chem Phys Lett 2009;472:1–13.10.1016/j.cplett.2009.02.023Search in Google Scholar
[25] Pettinger B. Tip-enhanced Raman spectroscopy (TERS). In: Kneipp K, Moskovits M, Kneipp H, editors. Surface-enhanced Raman scattering: physics and applications. Berlin: Springer, 2006:217–40.Search in Google Scholar
[26] Kneipp J, Kneipp H, Kneipp K. SERS-a single-molecule and nanoscale tool for bioanalytics. Chem Soc Rev 2008;37: 1052–60.10.1039/b708459pSearch in Google Scholar PubMed
[27] McNay G, Eustace D, Smith WE, Faulds K, Graham D. Surface-enhanced Raman scattering (SERS) and surface-enhanced resonance Raman scattering (SERRS): a review of applications. Appl Spectrosc 2011;65:825–37.10.1366/11-06365Search in Google Scholar PubMed
[28] Wang H, Schultz ZD. The chemical origin of enhanced signals from tip-enhanced Raman detection of functionalized nanoparticles. Analyst 2013;138:3150–7.10.1039/c3an36898jSearch in Google Scholar PubMed PubMed Central
[29] Blum C, Schmid T, Opilik L, Weidmann S, Fagerer SR, Zenobi R. Understanding tip-enhanced Raman spectra of biological molecules: a combined Raman, SERS and TERS study. J Raman Spectrosc 2012;43:1895–904.10.1002/jrs.4099Search in Google Scholar
[30] Kurouski D, Postiglione T, Deckert-Gaudig T, Deckert V, Lednev IK. Amide I vibrational mode suppression in surface (SERS) and tip (TERS) enhanced Raman spectra of protein specimens. Analyst 2013;138:1665–73.10.1039/c2an36478fSearch in Google Scholar PubMed PubMed Central
[31] Wang DS, Kerker M. Enhanced Raman-scattering by molecules adsorbed at the surface of colloidal spheroids. Physical Review B 1981;24:1777–90.10.1103/PhysRevB.24.1777Search in Google Scholar
[32] Kerker M, Wang DS, Chew H. Surface enhanced Raman-scattering (Sers) by molecules adsorbed at spherical-particles. Appl Optics 1980;19:4159–74.10.1364/AO.19.004159Search in Google Scholar PubMed
[33] Etchegoin PG, Le Ru EC. A perspective on single molecule SERS: current status and future challenges. Phys Chem Chem Phys 2008;10;6079–89.10.1039/b809196jSearch in Google Scholar PubMed
[34] Wustholz KL, Henry AI, McMahon JM, Freeman RG, Valley N, Piotti ME, Natan MJ, Schatz GC, Van Duyne RP. Structure-activity relationships in gold nanoparticle dimers and trimers for surface-enhanced Raman spectroscopy. J Am Chem Soc 2010;132:10903–10.10.1021/ja104174mSearch in Google Scholar PubMed
[35] Alexander KD, Skinner K, Zhang S, Wei H, Lopez R. Tunable SERS in gold nanorod dimers through strain control on an elastomeric substrate. Nano Lett 2010;10:4488–93.10.1021/nl1023172Search in Google Scholar PubMed
[36] Dadosh T, Sperling J, Bryant GW, Breslow R, Shegai T, Dyshel M, Haran G, Bar-Joseph I. Plasmonic control of the shape of the Raman spectrum of a single molecule in a silver nanoparticle dimer. Acs Nano 2009;3:1988–94.10.1021/nn900422wSearch in Google Scholar PubMed
[37] Fang Y, Seong N-H, Dlott DD. Measurement of the distribution of site enhancements in surface-enhanced Raman scattering. Science 2008;321:388–92.10.1126/science.1159499Search in Google Scholar PubMed
[38] Pettinger B, Domke KF, Zhang D, Picardi G, Schuster R. Tip-enhanced Raman scattering: influence of the tip-surface geometry on optical resonance and enhancement. Surface Science 2009;603:1335–41.10.1016/j.susc.2008.08.033Search in Google Scholar
[39] Pettinger B, Domke KF, Zhang D, Schuster R, Ertl G. Direct monitoring of plasmon resonances in a tip-surface gap of varying width. Phys Rev B 2007;76:113409.10.1103/PhysRevB.76.113409Search in Google Scholar
[40] Domke KF, Zhang D, Pettinger B. Tip-enhanced Raman spectra of picomole quantities of DNA nucleobases at Au(111). J Am Chem Soc 2007;129:6708–9.10.1021/ja071107qSearch in Google Scholar PubMed
[41] Domke KF, Zhang D, Pettinger B. Toward Raman fingerprints of single dye molecules at atomically smooth Au(111). J Am Chem Soc 2006;128:14721–7.10.1021/ja065820bSearch in Google Scholar PubMed
[42] Pettinger B, Ren B, Picardi G, Schuster R, Ertl G. Nanoscale probing of adsorbed species by tip-enhanced Raman spectroscopy. Phys Rev Let 2004;92:096101/1–096101/4.10.1103/PhysRevLett.92.096101Search in Google Scholar
[43] Pettinger B, Picardi G, Schuster R, Ertl G. Surface-enhanced and STM tip-enhanced Raman spectroscopy of CN− ions at gold surfaces. J Electroanal Chem 2003;554–555:293–9.10.1016/S0022-0728(03)00242-0Search in Google Scholar
[44] Pettinger B, Picardi G, Schuster R, Ertl G Surface-enhanced and STM-tip-enhanced Raman spectroscopy at metal surfaces. Single Molecules 2002;3:285–94.10.1002/1438-5171(200211)3:5/6<285::AID-SIMO285>3.0.CO;2-XSearch in Google Scholar
[45] Deckert-Gaudig T, Deckert V. Tip-enhanced Raman scattering studies of histidine on novel silver substrates. J Raman Spectrosc 2009;40:1446–51.10.1002/jrs.2359Search in Google Scholar
[46] Deckert-Gaudig T, Bailo E, Deckert V. Tip-enhanced Raman scattering (TERS) of oxidised glutathione on an ultraflat gold nanoplate. Phys Chem Chem Phys 2009;11:7360–2.10.1039/b904735bSearch in Google Scholar
[47] Wood BR, Bailo E, Khiavi MA, Tilley L, Deed S, Deckert-Gaudig T, McNaughton D, Deckert V. Tip-Enhanced Raman Scattering (TERS) from Hemozoin Crystals within a Sectioned Erythrocyte. Nano Lett 2011;11:1868–73.10.1021/nl103004nSearch in Google Scholar
[48] Schultz ZD, Stranick SJ, Levin IW. Advantages and artifacts of higher order modes in nanoparticle-enhanced backscattering Raman imaging. Anal Chem 2009;81: 9657–63.10.1021/ac901789wSearch in Google Scholar
[49] Ausman LK, Schatz GC. On the importance of incorporating dipole reradiation in the modeling of surface enhanced Raman scattering from spheres. J Chem Phys 2009; 131:10.Search in Google Scholar
[50] Le Ru EC, Etchegoin PG. Rigorous justification of the [E](4) enhancement factor in surface enhanced Raman spectroscopy. Chem Phys Lett 2006;423:63–6.10.1016/j.cplett.2006.03.042Search in Google Scholar
[51] Le Ru EC, Grand J, Felidj N, Aubard J, Levi G, Hohenau A, Krenn JR, Blackie E, Etchegoin PG. Experimental verification of the SERS electromagnetic model beyond the vertical bar E vertical bar(4) approximation: polarization effects. J Phys Chem C 2008;112:8117–21.10.1021/jp802219cSearch in Google Scholar
[52] Ye J, Wen F, Sobhani H, Lassiter JB, Van Dorpe P, Nordlander P, Halas NJ. Plasmonic nanoclusters: near field properties of the fano resonance interrogated with SERS. Nano Lett 2012;12:1660–7.10.1021/nl3000453Search in Google Scholar
[53] Uetsuki K, Verma P, Nordlander P, Kawata S. Tunable plasmon resonances in a metallic nanotip-film system. Nanoscale 2012;4:5931–5.10.1039/c2nr31542dSearch in Google Scholar PubMed
[54] Carrier SL, Kownacki CM, Schultz ZD. Protein-ligand binding investigated by a single nanoparticle TERS approach. Chem Commun 2011;47:2065–7.10.1039/c0cc05059hSearch in Google Scholar PubMed PubMed Central
[55] Olk P, Renger J, Härtling T, Wenzel MT, Eng LM. Two particle enhanced nano Raman microscopy and spectroscopy. Nano Lett 2007;7:1736–40.10.1021/nl070727mSearch in Google Scholar PubMed
[56] Shao L, Fang C, Chen H, Man YC, Wang J, Lin HQ. Distinct plasmonic manifestation on gold nanorods induced by the spatial perturbation of small gold nanospheres. Nano Lett 2012;12:1424–30.10.1021/nl2041063Search in Google Scholar PubMed
[57] Halas NJ, Lal S, Chang WS, Link S, Nordlander P. Plasmons in strongly coupled metallic nanostructures. Chem Rev 2011;111:3913–61.10.1021/cr200061kSearch in Google Scholar PubMed
[58] Deckert-Gaudig T, Bailo E, Deckert V. Perspectives for spatially resolved molecular spectroscopy – Raman on the nanometer scale. J Biophotonics 2008;1:377–89.10.1002/jbio.200810019Search in Google Scholar PubMed
[59] Wang X, Liu Z, Zhuang M-D, Zhang H-M, Wang X, Xie Z-X, Wu D-Y, Ren B, Zhong-Qun T. Tip-enhanced Raman spectroscopy for investigating adsorbed species on a single-crystal surface using electrochemically prepared Au tips. Appl Phys Lett 2007;91:101105/1–101105/3.10.1063/1.2776860Search in Google Scholar
[60] Barsegova I, Lewis A, Khatchatouriants A, Manevitch A, Ignatov A, Axelrod N, Sukenik C. Controlled fabrication of silver or gold nanoparticle near-field optical atomic force probes: enhancement of second-harmonic generation. Appl Phys Lett 2002;81:3461–3.10.1063/1.1507618Search in Google Scholar
[61] Bharadwaj P, Beams R, Novotny L. Nanoscale spectroscopy with optical antennas. Chem Sci 2011;2:136–40.10.1039/C0SC00440ESearch in Google Scholar
[62] Mishra N, Kumar GVP. Near-field optical analysis of plasmonic nano-probes for top-illumination tip-enhanced Raman scattering. Plasmonics 2012;7:359–67.10.1007/s11468-011-9316-2Search in Google Scholar
[63] SavageKJ, Hawkeye MM, Esteban R, Borisov AG, Aizpurua J, Baumberg JJ. Revealing the quantum regime in tunnelling plasmonics. Nature 2012;491:574–7.10.1038/nature11653Search in Google Scholar PubMed
[64] Liu Z, Ding SY, Chen ZB, Wang X, Tian JH, Anema JR, Zhou XS, Wu DY, Mao BW, Xu X, Ren B, Tian ZQ. Revealing the molecular structure of single-molecule junctions in different conductance states by fishing-mode tip-enhanced Raman spectroscopy. Nat Commun 2011;2:1310/1–1310/6.10.1038/ncomms1310Search in Google Scholar PubMed PubMed Central
[65] Schultz ZD, Stranick SJ, Levin IW. Tip-enhanced Raman spectroscopy and imaging: an apical illumination geometry. Appl Spectrosc 2008;62:1173–9.10.1366/000370208786401635Search in Google Scholar PubMed PubMed Central
[66] Bouhelier A, Beversluis MR, Novotny L. Near-field scattering of longitudinal fields. Appl Phys Lett 2003;82:4596–8.10.1063/1.1586482Search in Google Scholar
[67] Youngworth KS, Brown TG. Focusing of high numerical aperture cylindrical-vector beams. Opt Express 2000;7:77–87.10.1364/OE.7.000077Search in Google Scholar PubMed
[68] Chen W, Zhan Q. Numerical study of an apertureless near field scanning optical microscope probe under radial polarization illumination. Opt Express 2007;15:4106–11.10.1364/OE.15.004106Search in Google Scholar PubMed
[69] Vannier C, Yeo B-S, Melanson J, Zenobi R. Multifunctional microscope for far-field and tip-enhanced Raman spectroscopy. Rev Sci Instrum 2006;77:023104/1–023104/5.10.1063/1.2162449Search in Google Scholar
[70] Hayazawa N, Saito Y, Kawata S. Detection and characterization of longitudinal field for tip-enhanced Raman spectroscopy. Appl Phys Lett 2004;85:6239–41.10.1063/1.1839646Search in Google Scholar
[71] Lee N, Hartschuh RD, Mehtani D, Kisliuk A, Maguire JF, Green M, Foster MD, Sokolov AP. High contrast scanning nano-Raman spectroscopy of silicon. J Raman Spectrosc 2007;38:789–96.10.1002/jrs.1698Search in Google Scholar
[72] Steidtner J, Pettinger B. High-resolution microscope for tip-enhanced optical processes in ultrahigh vacuum. Review of Scientific Instruments 2007;78:103104.10.1063/1.2794227Search in Google Scholar PubMed
[73] Sun WX,Shen ZX. Apertureless near-field scanning Raman microscopy using reflection scattering geometry. Ultramicroscopy 2003;94:237–44.10.1016/S0304-3991(02)00334-0Search in Google Scholar
[74] Sun WX, Shen ZX. Near-field scanning Raman microscopy using apertureless probes. J Raman Spectrosc 2003;34:668–76.10.1002/jrs.1063Search in Google Scholar
[75] Tong LM, Li Z, Zhu T, Xu H, Liu Z. Single gold-nanoparticle-enhanced Raman scattering of individual single-walled carbon nanotubes via atomic force microscope manipulation. Journal of Physical Chemistry C 2008;112:7119–23.10.1021/jp7102484Search in Google Scholar
[76] Chan KLA, Kazarian SG. Tip-enhanced Raman mapping with top-illumination AFM. Nanotechnology 2011;22:175701.10.1088/0957-4484/22/17/175701Search in Google Scholar PubMed
[77] Hartschuh A, Sánchez EJ, Xie XS, Novotny L. High-resolution near-field Raman microscopy of single-walled carbon nanotubes. Phys Rev Lett 2003;90:095503.10.1103/PhysRevLett.90.095503Search in Google Scholar PubMed
[78] Anderson N, Hartschuh A, Cronin S, Novotny L. Nanoscale vibrational analysis of single-walled carbon nanotubes. J Am Chem Soc 2005;127:2533–7.10.1021/ja045190iSearch in Google Scholar PubMed
[79] Anderson N,Hartschuh A, Novotny L. Chirality changes in carbon nanotubes studied with near-field Raman spectroscopy. Nano Lett 2007;7:577–82.10.1021/nl0622496Search in Google Scholar PubMed
[80] Saito Y, Hayazawa N, Kataura H, Murakami T, Tsukagoshi K, Inouye Y, Kawata S. Polarization measurements in tip-enhanced Raman spectroscopy applied to single-walled carbon nanotubes. Chem Phys Lett 2005;410:136–41.10.1016/j.cplett.2005.05.003Search in Google Scholar
[81] Yano T-a, Verma P, Saito Y, Ichimura T, Kawata S. Pressure-assisted tip-enhanced Raman imaging at a resolution of a few nanometers. Nat Photonics 2009;3:473–7.10.1038/nphoton.2009.74Search in Google Scholar
[82] Domke KF, Pettinger B. Tip-enhanced Raman spectroscopy of 6H-SiC with graphene adlayers. Selective suppression of E1 modes. J Raman Spectrosc 2009;40:1427–33.10.1002/jrs.2434Search in Google Scholar
[83] Saito Y, Verma P, Masui K, Inouye Y, Kawata S. Nano-scale analysis of graphene layers by tip-enhanced near-field Raman spectroscopy. J Raman Spectrosc 2009;40:1434–40.10.1002/jrs.2366Search in Google Scholar
[84] Stadler J, Schmid T, Zenobi R. Nanoscale chemical imaging of single-layer graphene. ACS Nano 2011;5:8442–8.10.1021/nn2035523Search in Google Scholar PubMed
[85] Snitka V, Rodrigues RD, Lendraitis V. Novel gold cantilever for nano-Raman spectroscopy of graphene. Microelectron Eng 2011;88:2759–62.10.1016/j.mee.2011.02.046Search in Google Scholar
[86] Chaigneau M, Picardi G, Ossikovski R. Tip enhanced Raman spectroscopy evidence for amorphous carbon contamination on gold surfaces. Surf Sci 2010;604:701–5.10.1016/j.susc.2010.01.018Search in Google Scholar
[87] Richards D, Milner RG, Huang F, Festy F. Tip-enhanced Raman microscopy: practicalities and limitations. J Raman Spectrosc 2003;34:663–7.10.1002/jrs.1046Search in Google Scholar
[88] Domke KF, Zhang D, Pettinger B. Enhanced Raman spectroscopy: single molecules or carbon? J Phys Chem C 2007;111:8611–6.10.1021/jp071519lSearch in Google Scholar
[89] Hermann P, Fabian H, Naumann D, Hermelink A. Comparative study of far-field and near-field Raman spectra from silicon-based samples and biological nanostructures. J Phys Chem C 2011;115:24512–20.10.1021/jp206659zSearch in Google Scholar
[90] Sun W, Shen Z. A practical nanoscopic Raman imaging technique realized by near-field enhancement. Mat Phys Mech 2001;4:17–21.Search in Google Scholar
[91] Hayazawa N, Motohashi M, Saito Y, Ishitobi H, Ono A, Ichimura T, Verma P, Kawata S. Visualization of localized strain of a crystalline thin layer at the nanoscale by tip-enhanced Raman spectroscopy and microscopy. J Raman Spectrosc 2007;38:684–96.10.1002/jrs.1728Search in Google Scholar
[92] Saito Y, Motohashi M, Hayazawa N, Iyoki M, Kawata S. Nanoscale characterization of strained silicon by tip-enhanced Raman spectroscope in reflection mode. Appl Phys Lett 2006;88:143109/1–143109/3.10.1063/1.2191949Search in Google Scholar
[93] Motohashi M, Hayazawa N, Tarun A, Kawata S. Depolarization effect in reflection-mode tip-enhanced Raman scattering for Raman active crystals. J Appl Phys 2008;103:034309/ 1–034309/9.10.1063/1.2837837Search in Google Scholar
[94] Hermann P, Hecker M, Chumakov D, Weisheit M, Rinderknecht J, Shelaev A, Dorozhkin P, Eng LM. Imaging and strain analysis of nano-scale SiGe structures by tip-enhanced Raman spectroscopy. Ultramicroscopy 2011;111:1630–5.10.1016/j.ultramic.2011.08.009Search in Google Scholar PubMed
[95] Hecker M, Roelke M, Hermann P, Zschech E, Vartanian V. Strain distribution analysis in Si/SiGe line structures for CMOS technology using Raman spectroscopy. J Phys: Conf Ser 2010;209:012008.10.1088/1742-6596/209/1/012008Search in Google Scholar
[96] Ogawa Y, Yuasa Y, Minami F, Oda S. Tip-enhanced Raman mapping of a single Ge nanowire. Appl Phys Lett 2011;99:053112/1–053112/3.10.1063/1.3621856Search in Google Scholar
[97] Mehtani D, Lee N, Hartschuh RD, Kisliuk A, Foster MD, Sokolov AP. Nano-Raman spectroscopy with side-illumination optics. J Raman Spectrosc 2005;36:1068–75.10.1002/jrs.1409Search in Google Scholar
[98] Gucciardi PG, Valmalette J-C. Different longitudinal optical-transverse optical mode amplification in tip enhanced Raman spectroscopy of GaAs(001). Appl Phys Lett 2010;97:263104/ 1–263104/3.10.1063/1.3532841Search in Google Scholar
[99] Agapov RL, Malkovskiy AV, Sokolov AP, Foster MD. Prolonged Blinking with TERS Probes. J Phys Chem C 2011;115:8900–5.10.1021/jp111762uSearch in Google Scholar
[100] Matsui R, Verma P, Ichimura T, Inouye Y, Kawata S. Nanoanalysis of crystalline properties of GaN thin film using tip-enhanced Raman spectroscopy. Appl Phys Lett 2007;90:061906/1–061906/3.10.1063/1.2458343Search in Google Scholar
[101] Marquestaut N, Talaga D, Servant L, Yang P, Pauzauskie P, Lagugné-Labarthet F. Imaging of single GaN nanowires by tip-enhanced Raman spectroscopy. J Raman Spectrosc 2009;40:1441–5.10.1002/jrs.2404Search in Google Scholar
[102] Berweger S, Raschke MB. Signal limitations in tip-enhanced Raman scattering: the challenge to become a routine analytical technique. Anal Bioanal Chem 2010;396:115–23.10.1007/s00216-009-3085-1Search in Google Scholar PubMed
[103] Neacsu CC, Berweger S, Raschke MB. Tip-enhanced Raman imaging and nanospectroscopy: sensitivity, symmetry, and selection rules. NanoBiotechnology 2009;3:172–96.10.1007/s12030-008-9015-zSearch in Google Scholar
[104] Berweger S, Neacsu CC, Mao Y, Zhou H, Wong SS, Raschke MB. Optical nanocrystallography with tip-enhanced phonon Raman spectroscopy. Nat Nanotechnol 2009;4:496–9.10.1038/nnano.2009.190Search in Google Scholar PubMed
[105] Berweger S, Raschke MB. Polar phonon mode selection rules in tip-enhanced Raman scattering. J Raman Spectrosc 2009;40:1413–9.10.1002/jrs.2407Search in Google Scholar
[106] Zhang D, Wang X, Braun K, Egelhaaf H-J, Fleischer M, Hennemann L, Hintz H, Stanciu C, Brabec CJ, Kern DP, Meixner AJ. Parabolic mirror-assisted tip-enhanced spectroscopic imaging for non-transparent materials. J Raman Spectrosc 2009;40:1371–6.10.1002/jrs.2411Search in Google Scholar
[107] Xue L, Li W, Hoffmann GG, Goossens JGP, Loos J, de With G. High-resolution chemical identification of polymer blend thin films using tip-enhanced Raman mapping. Macromolecules 2011;44:2852–8.10.1021/ma101651rSearch in Google Scholar
[108] Sonntag MD, Klingsporn JM, Garibay LK, Roberts JM, Dieringer JA, Seideman T, Scheidt KA, Jensen L, Schatz GC, Van Duyne RP. Single-molecule tip-enhanced Raman spectroscopy. J Phys Chem C 2012;116:478–83.10.1021/jp209982hSearch in Google Scholar
[109] Stadler J, Schmid T, Zenobi R. Nanoscale chemical imaging using top-illumination tip-enhanced Raman spectroscopy. Nano Lett 2010;10:4514–20.10.1021/nl102423mSearch in Google Scholar PubMed
[110] Yeo B-S, Schmid T, Zhang W, Zenobi R. Towards rapid nanoscale chemical analysis using tip-enhanced Raman spectroscopy with Ag-coated dielectric tips. Anal Bioanal Chem 2007;387:2655–62.10.1007/s00216-007-1165-7Search in Google Scholar PubMed
[111] Pettinger B, Ren B, Picardi G, Schuster R, Ertl G. Tip-enhanced Raman spectroscopy (TERS) of malachite green isothiocyanate at Au(111): bleaching behavior under the influence of high electromagnetic fields. J Raman Spectrosc 2005;36:541–50.10.1002/jrs.1332Search in Google Scholar
[112] Pan D, Klymyshyn N, Hu D, Lu HP. Tip-enhanced near-field Raman spectroscopy probing single dye-sensitized TiO2 nanoparticles. Appl Phys Lett 2006;88:093121/1–093121/3.10.1063/1.2176865Search in Google Scholar
[113] Pienpinijtham P, Han XX, Suzuki T, Thammacharoen C, Ekgasit S, Ozaki Y. Micrometer-sized gold nanoplates: starch-mediated photochemical reduction synthesis and possibility of application to tip-enhanced Raman scattering (TERS). Phys Chem Chem Phys 2012;14:9636–41.10.1039/c2cp40330gSearch in Google Scholar PubMed
[114] You Y, Purnawirman NA, Hu H, Kasim J, Yang H, Du C, Yu T, Shen Z. Tip-enhanced Raman spectroscopy using single-crystalline Ag nanowire as tip. J Raman Spectrosc 2010;41:1156–62.10.1002/jrs.2559Search in Google Scholar
[115] Schmid T, Yeo B-S, Leong G, Stadler J, Zenobi R. Performing tip-enhanced Raman spectroscopy in liquids. J Raman Spectrosc 2009;40:1392–9.10.1002/jrs.2387Search in Google Scholar
[116] Picardi G, Chaigneau M, Ossikovski R, Licitra C, Delapierre G. Tip enhanced Raman spectroscopy on azobenzene thiol self-assembled monolayers on Au(111). J Raman Spectrosc 2009;40:1407–12.10.1002/jrs.2362Search in Google Scholar
[117] Liu Z, Wang X, Dai K, Jin S, Zeng Z-C, Zhuang M-D, Yang Z-L, Wu D-Y, Ren B, Tian Z-Q. Tip-enhanced Raman spectroscopy for investigating adsorbed nonresonant molecules on single-crystal surfaces: tip regeneration, probe molecule, and enhancement effect. J Raman Spectrosc 2009;40:1400–6.10.1002/jrs.2431Search in Google Scholar
[118] Zhang W, Cui X, Yeo BS, Schmid T, Hafner C, Zenobi R. Nanoscale roughness on metal surfaces can increase tip-enhanced Raman scattering by an order of magnitude. Nano Lett 2007;7:1401–5.10.1021/nl070616nSearch in Google Scholar PubMed
[119] Ren B, Picardi G, Pettinger B, Schuster R, Ertl G. Tip-enhanced raman spectroscopy of benzenethiol adsorbed on Au and Pt single-crystal surfaces. Angew Chem, Int Ed 2005;44:139–42.10.1002/anie.200460656Search in Google Scholar PubMed
[120] Stadler J, Schmid T, Opilik L, Kuhn P, Dittrich PS, Zenobi R. Tip-enhanced Raman spectroscopic imaging of patterned thiol monolayers. Beilstein J Nanotechnol 2011;2:509–15.10.3762/bjnano.2.55Search in Google Scholar PubMed PubMed Central
[121] van SLEM, Deckert-Gaudig T, Mank AJ, Deckert V, Weckhuysen BM. Catalytic processes monitored at the nanoscale with tip-enhanced Raman spectroscopy. Nat Nanotechnol 2012;7:583–6.10.1038/nnano.2012.131Search in Google Scholar PubMed
[122] Sun M, Zhang Z, Xu H. In-situ plasmon-driven chemical reactions revealed by high vacuum tip-enhanced Raman spectroscopy. Sci Rep 2012;2:647/1–647/4.10.1038/srep00647Search in Google Scholar PubMed PubMed Central
[123] Domke KF, Pettinger B. In Situ discrimination between axially complexed and ligand-free Co porphyrin on Au(111) with tip-enhanced Raman spectroscopy. ChemPhysChem 2009;10:1794–8.10.1002/cphc.200900182Search in Google Scholar PubMed
[124] Jiang N, Foley ET, Klingsporn JM, Sonntag MD, Valley NA, Dieringer JA, Seideman T, Schatz GC, Hersam MC, Van Duyne RP. Observation of multiple vibrational modes in ultrahigh vacuum tip-enhanced Raman spectroscopy combined with molecular-resolution scanning tunneling microscopy. Nano Lett 2012;12:5061–7.10.1021/nl2039925Search in Google Scholar PubMed
[125] Rasmussen A, Deckert V. Surface- and tip-enhanced Raman scattering of DNA components. J Raman Spectrosc 2006;37:311–7.10.1002/jrs.1480Search in Google Scholar
[126] Hennemann LE, Meixner AJ, Zhang D. Surface- and tip-enhanced Raman spectroscopy of DNA. Spectroscopy 2010;24:119–24.10.1155/2010/428026Search in Google Scholar
[127] Zhang D, Domke KF, Pettinger B. Tip-enhanced Raman spectroscopic studies of the hydrogen bonding between adenine and thymine adsorbed on Au(111). ChemPhysChem 2010;11:1662–5.10.1002/cphc.200900883Search in Google Scholar PubMed
[128] Treffer R, Lin X, Bailo E, Deckert-Gaudig T, Deckert V. Distinction of nucleobases - a tip-enhanced Raman approach. Beilstein J Nanotechnol 2011;2:628–37.10.3762/bjnano.2.66Search in Google Scholar PubMed PubMed Central
[129] Deckert-Gaudig T, Rauls E, Deckert V. Aromatic amino acid monolayers sandwiched between gold and silver: a combined tip-enhanced Raman and theoretical approach. J Phys Chem C 2010;114:7412–20.10.1021/jp9098045Search in Google Scholar
[130] Yeo B-S, Mädler S, Schmid T, Zhang W, Zenobi R. Tip-enhanced Raman spectroscopy can see more: the case of cytochrome c. J Phys Chem C 2008;112:4867–73.10.1021/jp709799mSearch in Google Scholar
[131] Wood BR, Asghari-Khiavi M, Bailo E, McNaughton D, Deckert V. Detection of Nano-oxidation sites on the surface of hemoglobin crystals using tip-enhanced Raman scattering. Nano Lett 2012;12:1555–60.10.1021/nl2044106Search in Google Scholar PubMed
[132] Pavel I, McCarney E, Elkhaled A, Morrill A, Plaxco K, Moskovits M. Label-free SERS detection of small proteins modified to act as bifunctional linkers. J Phys Chem C 2008;112:4880–3.10.1021/jp710261ySearch in Google Scholar PubMed PubMed Central
[133] Willets KA, Stranahan SM, Weber ML. Shedding light on surface-enhanced Raman scattering hot spots through single-molecule super-resolution imaging. J Phys Chem Lett 2012;3:1286–94.10.1021/jz300110xSearch in Google Scholar PubMed
[134] Moretti M, Zaccaria RP, Descrovi E, Das G, Leoncini M, Liberale C, De Angelis F, Di Fabrizio E. Reflection-mode TERS on insulin amyloid fibrils with top-visual AFM probes. Plasmonics 2013;8:25–33.10.1007/s11468-012-9385-xSearch in Google Scholar PubMed PubMed Central
[135] Kurouski D, Deckert-Gaudig T, Deckert V, Lednev IK. Structure and composition of insulin fibril surfaces probed by TERS. J Am Chem Soc 2012;134:13323–9.10.1021/ja303263ySearch in Google Scholar PubMed PubMed Central
[136] Deckert-Gaudig T, Kaemmer E, Deckert V. Tracking of nanoscale structural variations on a single amyloid fibril with tip-enhanced Raman scattering. J Biophotonics 2012;5:215–9.10.1002/jbio.201100142Search in Google Scholar PubMed
[137] Gullekson C, Lucas L, Hewitt K, Kreplak L. Surface-sensitive Raman spectroscopy of collagen I fibrils. Biophys J 2011;100:1837–45.10.1016/j.bpj.2011.02.026Search in Google Scholar PubMed PubMed Central
[138] Paulite M, Blum C, Schmid T, Opilik L, Eyer K, Walker GC, Zenobi R. Full Spectroscopic tip-enhanced Raman imaging of single nanotapes formed from β-amyloid(1-40) peptide fragments. ACS Nano 2013;7:911–20.10.1021/nn305677kSearch in Google Scholar PubMed
[139] Blum C, Schmid T, Opilik L, Weidmann S, Fagerer SR, Zenobi R. Missing amide I mode in gap-mode tip-enhanced Raman spectra of proteins. J Phys Chem C 2012;116:23061–6.10.1021/jp306831pSearch in Google Scholar
[140] Neugebauer U, Rösch P, Schmitt M, Popp J, Julien C, Rasmussen A, Budich C, Deckert V. On the way to nanometer-sized information of the bacterial surface by tip-enhanced Raman spectroscopy. ChemPhysChem 2006;7:1428–30.10.1002/cphc.200600173Search in Google Scholar PubMed
[141] Neugebauer U, Schmid U, Baumann K, Ziebuhr W, Kozitskaya S, Deckert V, Schmitt M, Popp J. Towards a detailed understanding of bacterial metabolism: spectroscopic characterization of Staphylococcus epidermidis. ChemPhysChem 2007;8:124–37.10.1002/cphc.200600507Search in Google Scholar PubMed
[142] Böhme R, Richter M, Cialla D, Rösch P, Deckert V, Popp J. Towards a specific characterisation of components on a cell surface-combined TERS-investigations of lipids and human cells. J Raman Spectrosc 2009;40:1452–7.10.1002/jrs.2433Search in Google Scholar
[143] Cialla D, Deckert-Gaudig T, Budich C, Laue M, Möller R, Naumann D, Deckert V, Popp J. Raman to the limit: tip-enhanced Raman spectroscopic investigations of a single tobacco mosaic virus. J Raman Spectrosc 2009;40:240–3.10.1002/jrs.2123Search in Google Scholar
[144] Hermann P, Hermelink A, Lausch V, Holland G, Möller L, Bannert N, Naumann D. Evaluation of tip-enhanced Raman spectroscopy for characterizing different virus strains. Analyst 2011;136:1148–52.10.1039/c0an00531bSearch in Google Scholar PubMed
[145] Alexander KD, Schultz ZD. Tip-enhanced Raman detection of antibody conjugated nanoparticles on cellular membranes. Anal Chem 2012;84:7408–14.10.1021/ac301739kSearch in Google Scholar PubMed PubMed Central
[146] Richter M, Hedegaard M, Deckert-Gaudig T, Lampen P, Deckert V. Laterally resolved and direct spectroscopic evidence of nanometer-sized lipid and protein domains on a single cell. Small 2011;7:209–14.10.1002/smll.201001503Search in Google Scholar PubMed
[147] Deckert-Gaudig T, Böhme R, Freier E, Sebesta A, Merkendorf T, Popp J, Gerwert K, Deckert V. Nanoscale distinction of membrane patches–a TERS study of Halobacterium salinarum. J Biophotonics 2012;5:582–91.10.1002/jbio.201100131Search in Google Scholar PubMed
[148] Opilik L, Bauer T, Schmid T, Stadler J, Zenobi R. Nanoscale chemical imaging of segregated lipid domains using tip-enhanced Raman spectroscopy. Phys Chem Chem Phys 2011;13:9978–81.10.1039/c0cp02832kSearch in Google Scholar PubMed
[149] Böhme R, Cialla D, Richter M, Rösch P, Popp J, Deckert V. Biochemical imaging below the diffraction limit-probing cellular membrane related structures by tip-enhanced Raman spectroscopy (TERS). J Biophotonics 2010;3:455–61.10.1002/jbio.201000030Search in Google Scholar PubMed
[150] Stadler J, Schmid T, Zenobi R. Developments in and practical guidelines for tip-enhanced Raman spectroscopy. Nanoscale 2012;4:1856–70.10.1039/C1NR11143DSearch in Google Scholar
[151] Hecht B, Bielefeldt H, Inouye Y, Pohl DW, Novotny L. Facts and artifacts in near-field optical microscopy. J Appl Phys 1997;81:2492–8.10.1063/1.363956Search in Google Scholar
[152] Ramos R, Gordon MJ. Near-field artifacts in tip-enhanced Raman spectroscopy. Appl Phys Lett 2012;100:213111–4.10.1063/1.4722805Search in Google Scholar
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