Secondary ion mass spectrometry

CHAPTER 4.7

Secondary ion mass spectrometry Kaija Schaepea, Harald Jungnickelb, Thomas Heinricha, Jutta Tentschertb, Andreas Luchb, Wolfgang E.S. Ungerc a Bundesanstalt f€ ur Materialforschung und -pr€ ufung (BAM), Berlin, Germany German Federal Institute for Risk Assessment, Berlin, Germany c Bundesanstalt f u €r Materialforschung und -pr€ ufung (BAM), Berlin, Germany b

Abbreviations bPEI CS CID CRM DC DESI DE ESA FTICR FTMS FWHM GCIB MAF MALDI MSI NCM NIST NP PCA PEC PEI ROI SAMs SIMS ToF-SIMS TRIFT

branched polyethylenimine cellulose sulphate collision-induced dissociation certified reference material direct current desorption electrospray ionization delayed extraction electrostatic analyzers Fourier transform ion cyclotron resonance Fourier transform mass spectrometry full width at half maximum gas cluster ion beam maximum autocorrelation factors matrix-assisted laser desorption/ionization mass spectrometry imaging lithium–nickel–cobalt–manganese oxide National Institute for Standards and Technology nanoparticle principal component analysis polyelectrolyte complex polyethylenimine region of interest self-assembled monolayers secondary ion mass spectrometry time-of-flight secondary ion mass spectrometry triple-focusing time of flight

Introduction In secondary ion mass spectrometry (SIMS), a focused beam of so-called primary ions bombards the surface of a sample and releases secondary ions from defined spots on the surface of the sample, which are subsequently analyzed in a mass analyzer [1]. Characterization of Nanoparticles https://doi.org/10.1016/B978-0-12-814182-3.00025-0

© 2020 Elsevier Inc. All rights reserved.

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SIMS has its origins in inorganic materials science and semiconductor analysis and was the first technique available for mass spectrometry imaging (MSI) [2]. Together with matrix-assisted laser desorption/ionization (MALDI) and desorption electrospray ionization (DESI), SIMS is one of the most frequently employed desorption/ionization MSI techniques. It emerged in the late 1960s and was commercialized by Benninghoven and his group at M€ unster in the late 1980s, who created a basis for time-of-flight SIMS (ToF-SIMS) to become the most dominant and versatile instrumental setup until today, although magnetic sector and quadrupole instruments are still extensively used for inorganic materials, such as semiconductors, metals, ceramics, and geological materials. Technical developments in the past 20 years led to its increasing utilization in a wide range of fields such as geology, cosmochemistry, materials research, medical research, and the life sciences. The following chapter will focus on the application of SIMS to nanoparticle analysis exclusively. This following section is supposed to give an overview of the basic principles of SIMS and describe the most common instrumentation. Followingly, some typical modes of operation will be presented and selected applications will be highlighted. Disadvantages and limitations are also discussed along with current developments.

Basic principles The SIMS technique is inherently surface sensitive with the information typically coming from the first few atomic layers, which is equal to a depth information of only few nanometers, typically in the range of 2 to 5 nm [3]. The lateral resolution is routinely in the cellular range of <10 μm [4], but depending on the measurement mode that is employed, it can be reduced down to <100 nm [5]. The specialized CAMECA NanoSIMS instrument provides the best lateral resolution of all MSI methods being routinely in the range of 50 nm. The lateral resolution can be determined by the use of the BAM-L200 CRM as shown in Fig. 1 for a TOF-SIMS 5 instrument (IONTOF GmbH, M€ unster, Germany). With this characteristic, SIMS is the only MSI method able to resolve nanoscaled objects. Therefore, together with other methods such as X-ray photoelectron spectroscopy and Auger electron spectroscopy, SIMS fulfils the criteria for surface chemical analysis of nanoparticles. A scheme of the basic principle of SIMS is presented in Fig. 2. Briefly, SIMS instruments use an ion gun to produce a precisely focused energetic primary ion beam (typically between 25 and 30 keV kinetic energy) that bombards the analyte surface. Throughout the primary ion bombardment, a collision cascade is induced in the upper surface layers and as a consequence of this energy dissipation, bonds are broken and secondary particles are emitted. The majority of the emitted particles are neutrals, but a small percentage (
1%) is positively or negatively charged and, depending on the electric field applied

Secondary ion mass spectrometry

Fig. 1 Determination of lateral resolution in ToF-SIMS: Al+ secondary ion map and profile along a section of the AlGaAs/GaAs stripe pattern at the surface of the certified reference material BAML200 acquired with a TOF-SIMS 5 and Bi3++ as primary ions. It shows that an effective lateral resolution of re ¼ 27.2 nm is obtained. The image is determined by a line spread function with a FWHM of 28.2 nm characterizing the primary ion beam profile. Detailed measurement and data analysis conditions and procedures are mentioned in Ref. [6]; see also ISO/TR 19319:2013 [7] and subsequent ISO 18516:2019 [8]. (Reprinted by permission from SpringerNature: Springer Berlin Heidelberg Senoner, M., Maaßdorf, A., Rooch, H. et al. Anal Bioanal Chem (2015) 407: 3211. https://doi. org/10.1007/s00216-014-8135-7), © Springer-Verlag Berlin Heidelberg 2014.)

between the extractor and the sample, is accessible for analysis by a mass spectrometer. Because of the comparably high energy of the primary ion transferred to the surface species, this process leads to extensive fragmentation and rearrangement of atoms. The extent of fragmentation depends on the energy per atom of the primary ion projectile. Due to the limited mass range of ejected secondary ions, usually below m/z 1000, ToF-SIMS is primarily used for the analysis of inorganics; elemental ions; and small analytes such as drugs, small peptides, and certain lipids. Due to the even higher fragmentation and limited mass resolving power of the analyzer, as will be explained in the section ‘Sector field SIMS’, CAMECA’s NanoSIMS sector field instrument is exclusively employed for the analysis of elemental ions. Imaging in terms of ion intensity maps is obtained by scanning the focused primary ion beam over a certain region of interest (ROI) on the sample by the use of deflection

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Fig. 2 SIMS principle: The primary ion gun produces a highly focused energetic primary ion beam that induces a collision cascade in the surface near layer. Secondary ions are emitted and local mass spectra detected. By scanning the primary ion beam over the sample, imaging of a certain raster is provided by means of surface analysis, here SIMS. Exemplarily, a cell containing TiO2 NPs is imaged. Additionally, a sputter gun can be employed to sputter a whole surface layer away and perform consecutive analysis by means of the primary ion gun. Like that, depth information is provided, and depth profiles can be obtained. An example is shown at the bottom of the right box where the sharp features (green in the electronic version) relate to the titania NPs and the broad features before and after (red in the electronic version) to the organic material.

plates (cf. Fig. 3). The SIMS technique is inherently destructive as only sputtered material can be analyzed. Therefore, the term static SIMS refers to an experiment, where the primary ion dose is so low that random primary ion bombardment will only impact undamaged surface, that is, every surface spot is only struck once. Primary ions can be monatomic ions (e.g. Au+ and Bi+) or cluster ions (e.g. Au+n , Bi+n , C+60, and Ar+n>100). For the analysis of organic and biological surfaces, a clear trend towards the development and application of cluster ion sources with large n is observed. These cluster ions distribute their energy equally over all n atoms forming the cluster when they break apart upon their impact with the surface. Like that, cluster ions distribute the energy closer to the surface than monatomic ions resulting in a larger yield of sputtered material. This in turn provides a much softer ionization with reduced fragmentation and generates increased intensities in the higher mass range. However, these cluster beams

Secondary ion mass spectrometry

ESA 1

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Fig. 3 Scheme of typical ToF-SIMS instrument setups. The secondary ion generation process is the same in both instruments. (Left) A pulsed primary ion gun is focused on and scanned over the sample surface, where it induces a collision cascade that leads to the emission of secondary ions. The extractor is provided with a specific extraction voltage to extract either positively or negatively charged secondary ions. According to their mass-to-charge ratio, the ions are separated by their time of flight through the flight tube and finally registered and counted on the multichannel plate within the detector. The image was kindly provided by IONTOF GmbH, M€ unster, Germany. (Right) Secondary ions are extracted into the parallel imaging MS/MS spectrometer. This spectrometer combines the three electrostatic analyzers (ESAs) of the TRIFT (MS1) with a linear TOF (MS2) employed for MS/MS product ion analyses of selected precursor ions, which have been subject to collision-induced dissociation (CID). The image was kindly provided by Physical Electronics, INC. (PHI), CHANHASSEN, United States.

often provide reduced lateral resolution when n is in the range of >1000 compared with monatomic ion beams, because focusing them to small spot sizes is more challenging due to space charge problems [9].

3D analysis: Depth profiling SIMS offers the unique possibility to perform direct depth profiling. In biological SIMS, a C+60 or argon cluster beam is usually applied for this purpose, while in inorganic SIMS cesium or oxygen primary ions are typically employed as sputter species. With the sputter ion species, a surface layer can be etched, and the freshly exposed layer can consecutively be analyzed with either the sputtering source or another ‘analytical’ primary ion beam.

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Sputter process and basic SIMS equation The basic SIMS equation that describes the so-called sputtering process, which stands for the ionization and secondary ion emission process, is given in the following: Isq ¼ Ip Y αθs T

(1)

Iqs ¼ secondary ion intensity of an atomic or molecular fragment s with charge state q Ip ¼primary ion current Y ¼ sputter yield of respective material α ¼ionization probability of the positive/negative ion (different for each ion and material combination) θs ¼ fractional volume of s within the surface layer T ¼ transmission efficiency of the analyzing system at the specific m/z, energy, and angular distribution of the secondary ion (how efficient the secondary ions are transported through various lenses, apertures, the mass analyzer, and up to the detector) It is important to notice that the ionization probability is a fragment-specific parameter. It changes with concentration and also strongly depends on the surrounding matrix. This phenomenon is called matrix effect and arises from the electronic processes that lead to secondary ion formation and desorption. This accounts for SIMS being nonquantitative except in special circumstances. Usually, only semiquantitative analysis is available, while quantitative measurements require calibration samples. For semiconductor materials, dopants implanted using high-energy ions are often used where the implanted dose can be accurately determined from current measurements. These materials provide excellent quantification. A limited number of those calibration materials are certified reference materials available from institutions such as the National Institute for Standards and Technology (NIST). Using them, a traceable determination of relative sensitivity factors for specific fragments and matrices is possible [10].

Surface charging Often, the samples of interest within surface science are insulating materials. As an effect of the impact of the positively charged primary ion beam, not only secondary ions of both charge states but also secondary electrons are emitted from the surface. This leads to a localized positive surface charging, which changes the secondary ion energy and with that its flight time and trajectory. The usual technique to compensate these unwanted effects is by irradiation of the sample surface with low energy electrons of below 20 eV, often referred to as ‘electron flooding’. The positively charged regions attract these electrons, and the surface potential will approximately become equal to the potential on the electron emitter.

Secondary ion mass spectrometry

Sample preparation and requirements NPs and related samples are typically provided as dispersion or powder; see Chapter 4. 2. For SIMS investigation, the samples have to be high-vacuum compatible, exhibit a flat surface with minimum topography, and must not contain any ‘lose parts’ that might enter and harm the mass analyzer. Due to the high sensitivity of the technique, only highpurity solvents should be used. Furthermore, it is recommended to wear silicone-free gloves, tools, and sample containers while sample handling to avoid contamination. Silicones typically spread out across the sample and will overwhelm the SIMS spectrum of the sample to be analyzed. Engineered nanoparticles Usually, NPs have to be deposited onto a substrate (e.g. a silicon wafer) for ToF-SIMS measurements. Different deposition methods have to be employed depending on whether the particles are provided as dispersion or lose powder. In the first case, appropriate methods include drop casting or spin coating the dispersion onto the substrate or vice versa dipping the wafer substrate into the dispersion. In the second case, a nanoparticle powder can also be dispersed in an appropriate solvent and treated as already described. Alternatively, the powder is mounted on the wafer by using doublesided adhesive and conductive tape or by pressing it into a thin high-purity indium foil. A further option is to press the powder itself into a pellet or disc. The properties of the NPs such as conductivity, size, density, etc. and the intended distribution on the wafer surface as well-separated particles, densely packed multilayer, or random pile determine which deposition method is most suitable. For more details regarding the deposition methods for nanoparticle dispersions and powders, see Chapter 4.2. Nanoparticles in organic and complex matrices The rapid scientific progress in nanotechnology leads not only to sophisticated material engineering but also to modern medical nanodiagnostic systems and intelligent drug delivery systems. Those tools come along with the need for analytical quality control of the newly developed nanomaterials, wherein ToF-SIMS plays a crucial role. The analysis of nano-objects such as NPs in various matrices requires a number of techniques for sample preparation. Especially tissue and cell samples are very delicate and tend to be destroyed in the high vacuum needed for SIMS analysis. Normal freezing along with the formation of ice crystals would lead to the bursting of cells and has to be avoided. Therefore, tissues and cells generally require some fixation before analysis. This can be a chemical fixation, where typically aldehydes fix the cell membranes by linking their membrane proteins, or cryofixation. Cryofixation, typically fast freezing of cells in liquid nitrogen–cooled propane and analysis in the frozen-hydrated state, is another technique that allows nanoparticle analysis

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in complex biological matrices. Fast freezing does not lead to ice crystal formation but forms amorphous ice that keeps the membranes intact. This guarantees that cellular and tissue structures remain in their native biological state avoiding damage caused by water crystallization processes and simultaneously maintain the exact chemical distribution of all cell metabolites and cell membrane compounds [11].

Instrumentation Several options for mass analysis are available in MSI and SIMS specifically. Examples are quadrupoles, magnetic and electrostatic sectors, time-of-flight tubes, ion traps, orbital trapping mass analyzers, and Fourier transform ion cyclotron resonance (FTICR) mass analyzers. Nowadays, commercially available SIMS instruments are ToF-SIMS instruments equipped with either a single-stage reflectron or a triple-focusing time-of-flight (TRIFT) spectrometer providing time-of-flight mass analysis or, in the case of the NanoSIMS instrument, sector field designs.

Pulsed primary beam ToF-SIMS The advantages of ToF-systems are its versatility combining a high transmission efficiency with a high mass range that is technically unlimited though a natural limit is introduced by reduced secondary ion intensities with increasing m/z (cf. section ‘Basic principles’), fast repetition rates, and a high mass accuracy and mass resolving power R ¼ M/ΔM ¼ 5000 to 60,000 by FWHM definition [12,13]. On top of that, these analyzers are comparably cost-efficient and provide fast acquisition times. Schematic diagrams of recent instrument designs are shown in Fig. 3. In brief, for secondary ion detection, the secondary ions are accelerated through an extraction plate held at a fixed potential V. After passing this extraction plate, they have equal kinetic energy and enter an evacuated flight tube, which typically incorporates a reflectron (electrostatic ion mirror) that compensates for slight differences in the ions’ kinetic energies (cf. Fig. 3 left image). Eq. (2) correlates the kinetic energy of a secondary ion with its time of flight through the flight tube:  2 1 1 L Ekin ¼ q  Uacc ¼ mv2 ¼ m ¼ const: (2) 2 2 t with Uacc ¼acceleration voltage (V) L¼length of the flight tube (m) t ¼time of flight (s) The dimensionless charge number z is the quantized value of electric charge and can followingly be expressed as q¼ze with

(3)

Secondary ion mass spectrometry

z ¼dimensionless charge number q ¼electric charge (C) e ¼ elementary-charge constant (C) Following Eqs. (2) and (3), the mass-to-charge ratio m/z, which is defined as a dimensionless quantity formed by dividing the mass number [m] of an ion by its charge number [z] [14], can be obtained as a function of the time of flight t: m 2eUacc t 2 ¼ z L2

(4)

The ToF analyzer is typically combined with a multichannel plate for ion detection and counting. An unargued advantage of the high transmission ToF analyzer is the ability to simultaneously detect and analyze almost all secondary ions generated from a primary ion pulse. The combination of a ToF-SIMS with an ultrahigh resolving orbital trapping mass analyzer is now available, which provides a mass resolving power of up to 240,000 @ m/z 200 together with a high mass accuracy in the low ppm range [15]. Additionally, this analyzer enables MS/MS analysis. For MS/MS, so-called parent ions are fragmented in a characteristic manner using a collision gas and subsequently re-analyzed in the mass analyzer. This methodology, in combination with accurate mass information, is a key method in analytical chemistry for compound identification. Another instrument vendor supplies a ToF-SIMS with a triple ion focusing time-offlight (TRIFT) analyzer (cf. Fig. 3 right image) [16,17] that consists out of three 90 degrees sector electrostatic analyzers and the additional capability to perform tandem MS product ion analysis of targeted precursor ions simultaneously and in parallel by help of an additional (linear) TOF [18]. Among the advantages of the TRIFT analyzer design are a wide acceptance angle and large kinetic energy band-pass for the secondary ions.

Unpulsed primary beam ToF-SIMS The research group from Prof. Vickerman (Manchester University, Manchester, the United Kingdom) in collaboration with the Ionoptika Ltd. (Southampton, the United Kingdom) developed a new concept for ToF-SIMS chemical imaging overcoming limitations from conventional ToF-SIMS imaging experiments such as prolonged duty cycles, a lack in sensitivity, and lower mass resolving power [19–22]. By the introduction of an unpulsed primary beam (DC mode) combined with a linear buncher and a harmonic reflectron ToF analyzer, the instrument’s mass resolving power is nearly independent from the primary ion formation process including any pulse length, topography, and sputter events. For the first time in the SIMS community, the J105 3D Chemical Imager instrument provided an additional MS/MS capability for improved compound identification. These capabilities are prerequisites, especially for the analysis of subcellular

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distribution patterns of chemicals from biological samples like tissue and cellular systems and NPs therein.

Sector field SIMS In CAMECA’s NanoSIMS instrument, typically Cs+ or O as the most electropositive/ negative primary ion species is employed in an unpulsed manner for effective analyte ionization. For mass analysis and detection, a double-focusing device incorporating electrostatic and magnetic sectors is employed that comes with the fact that only a limited number of secondary ion species, preselected by their m/z, can be analyzed at once. Currently, this number is limited to 7 in the current NanoSIMS 50L model [23]. Therefore, untargeted analysis is hindered, but the instrument provides great facilities for isotopic and trace element analysis at excellent spatial resolution, down to 50 nm, at, however, inferior mass resolving power (R < 10,000) when compared with ToF-SIMS or Fourier transform mass spectrometry-based SIMS instruments.

Analytical modes ToF-SIMS In ToF-SIMS, the primary ion beam can be employed in different modes of operation depending on the analytical requirements in terms of lateral resolution, mass resolving power (in the SIMS community often referred to as ‘mass resolution’), ion yield/sensitivity and acquisition time, etc. As a consequence of basic physical laws, each operation mode is a compromise, and the best lateral resolution, mass resolving power, and intensity/lowest acquisition time cannot be achieved simultaneously. In brief, the primary ion beam is operated in a pulsed manner, and the pulse length defines the number of primary ions per shot. For intensity reasons, it seems practical to increase this pulse length as it will directly increase the secondary ion yield. However, a longer pulse length translates into a time uncertainty. In combination with the time-of-flight mass analyzer employed to determine the mass-to-charge ratio (m/z), this uncertainty directly translates into a m/z uncertainty that reduces the mass resolving power. Spatial or lateral resolution is ultimately limited by the focus or, in other words, the beam diameter. A perfectly focused beam accounts, however, for a loss in intensity as a smaller surface area is irradiated by the beam. In between these constraints, several modes of operation have been established, and the most prominent beam focusing modes being the high-current/bunched (spectrometry) and burst alignment/fast imaging mode [24,25] are highlighted and explained in the following including some specific adaptations and new techniques that are specifically adapted to NP characterization.

Secondary ion mass spectrometry

High mass resolving power for surface spectrometry: High-current/bunched mode (spectrometry mode) For the acquisition of spectra or imaging of features in the micrometer range or over large areas, ultimate lateral resolution is often not required, but a focus is set on mass resolving power and acquisition time. For that, a high-current bunched primary ion beam with rather short pulses in the 20 ns range is used. This raw pulse is ‘bunched’ so that the final pulse duration is around or below 1 ns, which allows for the highest achievable mass resolving power above R ¼ 104 (FWHM) @ m/z 500 but at the expense of spatial resolution, which will not be better than typically 2–5 μm [24]. It equally provides the highest target currents minimizing the acquisition time by maximizing the secondary ion yield. For NP analysis, this mode of operation is of special interest for the systematic spectral analysis (surface spectrometry) of NP ensembles and the outermost NP surface as it provides the best spectral resolution. High spatial resolution: Fast (burst alignment) and ultimate (extreme crossover) imaging Submicron lateral resolution with ToF-SIMS, the ultimate prerequisite for nanomaterial imaging, is performed with a nonbunched primary ion beam that can be further narrowed by the help of apertures [24]. In the so-called ‘fast imaging’ mode, the primary ion beam is operated in such a nonbunched way with large pulses, typically in the 100 ns region. The lateral resolution of this mode is, depending on the primary ion species chosen, between
50 and 300 nm, cf. also Fig. 1 [25,26]. As already described in the section ‘ToF-SIMS’, the pulse length leads only to nominal mass resolving power (R > 200) in this beam operation mode. Two out of three ion optical lenses are energized in this mode. Specialized imaging modes with further beam collimation and specific applications are also available [26]. These imaging modes of operation have to be employed when the ultimate goal is to visualize and image single NPs. To improve the mass resolving power in the fast imaging mode, bursting or delayed extraction can be employed. As the latter is of specific interest for the analysis of NPs, it will be highlighted in the following section. The burst mode can be derived out of the fast imaging mode. This mode, equally to the following delayed extraction mode, is not generally available on all instruments, and the interested reader is referred to Refs. [24,26,27] for more detailed information. Delayed extraction (DE) can be employed to overcome the gap between nanometer lateral resolution and poor mass resolving power that comes with the often-used operation modes in ToF-SIMS (cf. section ‘ToF-SIMS’). Additionally, it may be beneficial for (conductive) topographic samples [28]. It was first systematically described for ToF-SIMS by Vanbellingen et al. [29], even though the technique itself has already been known since the mid-20th century [30] and successfully been adapted to, for example, the MALDI-TOF community. Principally, the operation of a pulsed primary ion beam

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optimized for submicrometer lateral resolution, so with very long primary ion pulses, directly translates into different departure times of the secondary ions. In combination with a ToF mass analyzer, this time spread is retrieved in a reduced mass resolving power resulting in peaks with a width (FWHM) of
100 ns prohibiting adequate peak identification and assignment. When delayed extraction is employed, the primary ion pulse width is not anymore decisive for the mass resolving power. Properly set, the extraction delay corresponds exactly to the duration of the ion production [29] and groups the extracted secondary ions into high resolution peaks. A loss in overall total ion counts is, however, observed, which can be a consequence of different effects. First, DE induces a kinetic energy deficit that is m/z-dependent and causes especially the loss of light ions from the extraction plume before detection [29,31]. Second, the use of DE in combination with insulating and topographic samples may lead to the loss of secondary ions. This does especially apply for negative ions and has the following reason. Within the otherwise ‘field-free’ delay time, insulating samples can introduce an unspecified electric field, which causes many ions to get lost before the extraction process is actually taking place [32]. Delayed extraction is extremely important to image individual NPs that produce complex spectra due to their composition or the composition of their surrounding and/or matrix and where, consequently, high mass resolving power is crucial to differentiate between NP mass signals and other signals. Furthermore, it is advantageous in terms of the intrinsic topography that NPs come along with.

Sector field SIMS With the need for exact localization and quantification of minute impurities in geological and biological samples, in conjunction with the exact quantification of isotope abundances and ratios, came the development of sector field SIMS instruments. They are especially interesting for geochemical analysis as they combine high mass resolution and the possibility for element quantification with the limitation that only a set number of predefined ions can be analyzed simultaneously (up to seven ions). The development started with the commercialization of a double-focusing ion probe spectrometer, including a magnet and an electrostatic sector in combination with a duoplasmatron primary ion source, the IMS 101 manufactured by the American company GCA (the Geophysics Corp. of America in Bedford, Boston, the United States) [33]. Finally, the need to analyze samples with high spatial resolution resulted in the development of the NanoSIMS 50 instruments by CAMECA in 1993 [34]. This instrument uses a coaxial principle, where the same electrostatic objective lens is employed for both, the primary and the secondary ions. Therefore, the spherical aberration of the lens, that is, the large spot size, was significantly reduced down to a 50-nm primary ion beam spot size.

Secondary ion mass spectrometry

For the first time, this allowed the analysis of nanoscaled inclusions in extraterrestrial samples with exceptional high spatial resolution imaging [35].

Primary ion beam species used in SIMS In ToF-SIMS imaging, monoatomic liquid metal ion beams such as Cs+, Ga+, In+, Au+, and Bi+ [36–40] were initially used. Besides, gas ion beams like Ar+, O+2 , or Xe+ [41–43] were employed for surface spectroscopy. Monoatomic liquid metal ion beams are ideal for a high spatially resolved analysis of surfaces. Due to their small analysis spot size, their variable current control in combination with their wide energy range, they enable a high degree of experimental optimization, which is ideal for a broad variety of inorganic materials with different characteristic surface matrices [1]. The downside of monoatomic ion beams is the fact that specifically organic systems suffer from low ion yields in combination with a beam-induced damage effect (fragmentation), which spreads to lower depth layers. To record spectra that are characteristic of the nondamaged surface, the so-called ‘static SIMS’ analysis conditions need to be applied [44]. The static SIMS analysis condition is defined as the critical primary ion dose below it is statistically guaranteed that the secondary ions were generated from virgin sites of the bombarded surface. This dose is at or below 1  1013 ions/cm2 and depends on both, sample matrix and the primary ion beam, used for the specific analysis [1]. This limitation, in combination with the fact that a higher mass of the primary ion increases the secondary ion yield, caused directly the development of cluster ion beams as primary ion beams. At the turn of the 21st century, the development of cluster ion beams, especially the development of Au+n and Bi+n resulted in higher secondary ion yields for ToF-SIMS imaging experiments in combination with a high focusing capability and much faster data acquisition rates [25,45]. This resulted directly in the development of ToF-SIMS analysis for biological samples, allowing for the first time the analysis of higher mass biomolecules such as phospholipids, peptides, and other cell membrane associated biomolecules and antibiotics like gramicidin [46,47]. Besides bismuth cluster ion beams, also polyatomic primary ion beams using Buckminster fullerenes (C60) were introduced. This primary ion beam showed substantial increase in the yield of secondary ions, especially in the high mass range [48–51]. During impact, the C+60 ion breaks apart into individual atoms sharing its original kinetic energy. For example, for a 20 keV primary beam, the energy is dissipated across an area of about ˚ and the depth range that the impact cascade reaches is rather limited. Therefore, 30 A higher secondary ion yields at less fragmentation and a substantially reduced in-depth damage are obtained. C60 cluster ions were successfully used for a three-dimensional analysis of single cells using a DC continuous analysis mode as described in [52]. C60 cluster ions were also used together with a newly developed event-by-event bombardment/detection mode. Using this method, information about the chemical bonding

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of the antibody-gold NP with the immune cell membrane could be elucidated together with the capability to count antibody NPs, which are present in a defined given area of
10 nm2 on the surface of a single cell [53]. The methodology is capable to even outperform TEM analysis, the current gold standard for NP detection. Later on, the cluster ion gun development focused on argon gas cluster ion beam (GCIB) gun for sputtering and/or analysis. Initially, argon cluster GCIB were developed for the purpose of sample cleaning and polishing by Matsuo and coworkers [54]. Then, they prove especially helpful in samples, where C60 bombardment had difficulties such as organic semiconductor materials [55] and polymer depth profiling [56]. Additionally, a certain ‘cleaning up’ of spectra was observed as a result of reduced fragmentation in comparison with C+60 usage [57,58]. In summary, this short survey shows the necessity to evaluate and optimize different primary cluster ion beams for different samples (e.g. organic and inorganic nanomaterials) and to the field of view, which shall be analyzed or imaged.

Application to nanoparticles In the literature, the SIMS technique has already been applied repeatedly to the analysis of NPs, and there are some early reviews on the activities in this field [59,60]. Most of the studies focus on the surface analysis of NP ensembles alone or in complex matrices such as tissue and cells by means of spectral analysis or imaging. In the supreme discipline of single-NP analysis and especially imaging, the output obtained by SIMS is still limited. The following part shall highlight the different modes of operation of SIMS for nanomaterial analysis and underpin them with some examples.

Surface chemistry of nanoparticle ensembles The analysis of NPs’ surface chemistry is essential to identify the chemical constituents at the sample’s surface, which is often different from that of the bulk. Their identification is crucial to understand the nature and history of the sample, to determine impurities and examine special surface treatments of engineered NPs; for example, conjugations, ligands, capping, and coatings. Specifically, these slight differences in chemical composition on the very outer surface are able to determine the interaction behaviour of nanomaterials with their surroundings and influence their functionality. This can have effects not only in special applications such as sun blockers but also with respect to potential hazardous effects or desired drug response in the human body. Besides the determination of size and shape, the detailed surface chemical composition is thus needed to fully judge the NPs’ characteristics such as stability, hazard potential, and functionality. A key factor to determine these characteristics of NPs with a core–shell structure by ToF-SIMS is its superior surface sensitivity. For NPs, it is feasible to measure an ensemble, which is prepared as described in Chapter 4.2. This enables to measure their surface

CF3+

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Fig. 4 (A) Comparison between SIMS+ spectra of the naked PTFE core and the PTFE@PS core–shell particles. (B) The scores biplot for PC 1 and 2 of the NPs; (C) PC 1 loading plot; (D) PC 2 loading plot. PC 1 reveals that for a decreasing shell thickness, the SIMS spectra of the core–shell particles become more and more similar to that of the naked PTFE particles. PC 2 displays the contribution of polystyrene fragment ions to the spectra of the PTFE@PS core–shell particles and is, in that way, also sensitive to the shell thickness.

chemistry just at the outmost atom layers. The PTFE-PS core–shell NPs mentioned in the annex of Chapter 4.2 will serve as example at this point. Here, a specified polystyrene shell thickness of 48 nm should prevent the ion beam from reaching the particle’s PTFE core with a diameter of 48 nm, and therefore, fragments characteristic to PTFE should not appear in the spectra of the core–shell particles. Even for smaller shell thicknesses, this ought to apply. Nevertheless, certain fragments originating from PTFE can be identified in the spectra of the core–shell particle ensemble in Fig. 4A. Consequently, ToF-SIMS confirms that the shell is not uniform [61], or that (partially) uncoated PTFE cores are present in the sample. The pinhole structure observed in electron microscopy (see Fig. 12 in Chapter 4.2) suggests that the core material is exposed to the ion beam here. Electron microscopy, furthermore, revealed that the pinhole is larger for particles with smaller shell thicknesses, 34 and 24 nm. Therefore, significant differences in the ToFSIMS data are expected between the particles with different shell thicknesses. A multivariate data analysis method called principal component analysis (PCA) was used to further identify systematic changes in the particle structure (cf. section ‘Multivariate data analysis’). PCA is a statistical procedure that uses an orthogonal transformation to convert a set of possibly correlated variables into a set of values of linearly uncorrelated

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variables called principal components (PCs). These are linear combinations of so-called loadings that—in ToF-SIMS data—represent the mass-to-charge ratios in the spectra. By means of such PCs, a systematic classification of the NPs is possible. In Fig. 4B, a scores plot of PC 2 versus PC 1 is shown. One major observation can immediately be made. Although the core–shell particles are very similar, their SIMS data are well separated by its PCs. As expected, it can be observed that the thinner the shell gets, the smaller the differences become between PTFE-PS core–shell particle spectra and PTFE core spectra. It is thus feasible to systematically categorize NPs by PCA-assisted ToF-SIMS surface analysis, even though they have a very similar chemical composition. The evaluation of SIMS data using multivariate techniques enables grouping of NPs, and machine learning becomes possible.

Individual nanoparticle and agglomerate imaging by SIMS Imaging of NPs is highly desired, especially when the imaging derives further chemical information. This spatial information is needed to fully understand the interactions at the surface and the functionality of the NPs. Considering the size of NPs with below 100 nm in one dimension, CAMECA’s NanoSIMS instrument should be most suitable for single-NP imaging. Indeed, in a limited number of articles, it has been employed to the analysis of NPs [62–65], mostly in cellular environment. For instance, the interaction of engineered silver NPs differing in size and composition with the alga Raphidocelis subcapitata has been successfully studied by use of a NanoSIMS 50 ion microprobe [65]. A combination of methods, that is, darkfield light microscopy, SEM, and NanoSIMS, revealed that the majority of the Ag NPs or their dissolution products should be localized on top of the algal cell walls. Interestingly, images obtained by NanoSIMS suggest that specifically algal cells exposed to 10 nm branched polyethylenimine (bPEI) coated Ag NPs present localized NP hot spots as can be derived from Fig. 5. Tannic acid–coated Ag NPs of sizes 10 and 60 nm and also Ag@bPEI NP of size 60 nm (Fig. 5A, B, and D) show NP agglomerations and fringes at/ around the cells; Ag@bPEI NPs of size 10 nm give NP signals specifically from inside the cells highlighted as cells 10 and 11 in Fig. 5C. The detection of organic NPs in organic matrices is especially challenging due to the similarity of the components’ spectra as a result of analyte fragmentation. However, valuable results can be achieved. Exemplarily, a chemical fixation with 4% paraformaldehyde of human mesenchymal stromal cells was employed to investigate the localization of purely organic NPs within those cells. The NPs were polyelectrolyte complex (PEC) NPs made of polyethylenimine (PEI) and cellulose sulphate (CS) that were developed as potential drug carriers and coating for implant materials. The NPs were clearly localized not only within the cells as visible from ToF-SIMS images acquired from semithin sections (cf. Fig. 6) but also in-depth profiles of whole cells [66].

Secondary ion mass spectrometry

Fig. 5 Mass spectrometric images obtained with a NanoSIMS 50 instrument. Two different sorts of silver NPs were imaged in alga R. subcapitata. The secondary fragment ion 12C14N gives a cell signal shown in red (dark grey in print version), and Ag secondary ion signal is shown in green (light grey in print version). (A and B) Tannic acid (TA) coated Ag NPs and (C and D) polyethylenimine (bPEI) coated Ag NPs of different sizes. Especially, TA-coated NPs show bright agglomerations and fringes at the cell surface, while the 10 nm sized bPEI Ag NPs reveal some Ag signal from inside the cell. Individual NPs and agglomerates can equally be observed. Scale bar is 5 μm each. (Reproduced from R. Sekine, K.L. Moore, M. Matzke, P. Vallotton, H. Jiang, G.M. Hughes, J.K. Kirby, E. Donner, C.R.M. Grovenor, C. Svendsen, E. Lombi, Complementary imaging of silver nanoparticle interactions with green algae: dark-field microscopy, electron microscopy, and nanoscale secondary ion mass spectrometry, ACS Nano 11 (2017) 10894–10902. https://doi.org/10.1021/acsnano.7b04556, originally published in ACSnano under Creative Commons Attribution.)

This method was equally used to generate 3D distribution patterns of aluminium and aluminium oxide NP agglomerates within Caco-2 intestine cells [67]. Fast freezing of cells was used for the successful 3D analysis of silver NP agglomerates within THP-1 lung macrophages cell cultures [68] and Madin–Darby canine kidney II cells [69]. Nanoparticle agglomerates of ZrO2, CeO2, SiO2, and Fe2O3-SiO2 core–shell particles were also successfully visualized using ToF-SIMS within rat lung tissue sections [70–73]. For sample preparation, animals were sacrificed after exposure to the NPs by

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Fig. 6 Semithin sections of human mesenchymal stromal cells cultured with PEI/CS-NP were analyzed with optical microsopy (toluidine blue stained) and with ToF-SIMS (no staining) and compared with respective controls in (D) to (F). NP-related features are visible as dark dots in the optical image (A) but a chemical information is only added by ToF-SIMS high mass resolution images (HMR) in (B) and high spatial resolution SIMS images (HSR) in (C), which confirms that the observed structures can be attributed to the NPs that can, in this case, be visualized by a characteristic secondary fragment ion at m/z ¼ 142.93 (Na2HSO4+) in green (light grey in print version), while the cell structure is shown by another specific secondary fragment ion at m/z ¼ 86.10 (C5H12N+) in red (darker grey in print version). The NP signals are not visible in respective control cells (D–F). (Reprinted by permission from SpringerNature: Springer Berlin Heidelberg, J. Kokesch-Himmelreich, B. Woltmann, et al., Anal. Bioanal. Chem. 407 (2015) 3211. https://doi.org/10.1007/s00216-015-8647-9, © Springer-Verlag Berlin Heidelberg 2014.)

instillation. For that, the lung was inflated using 5 mL of a cryomatrix, resected and snap frozen in liquid nitrogen. Transverse sections were cut from the hilar region of the left lung, air dried on ITO-coated glass slides, and kept at 20°C until ToF-SIMS analysis. Complex matrices could also be of other nature than cells and tissues. Future challenges will be hybrid materials, for example, upcoming nanocomposites.

Depth profiling of nanoparticles For NP characterization, depth profiling of single NPs would be the ultimate goal to judge the chemical distribution and its differences from the outermost surface, to shell

Secondary ion mass spectrometry

and core. Due to several reasons such as topography, energy impact, and lateral resolution, this approach is extremely challenging for SIMS. Some relevant studies show that the heating effect induced by energy impact is drastic and leads to NP melting under the sputter ion impact [74,75]. Therefore, meaningful SIMS depth profiling experiments on NPs need to develop a solution for heat dissipation and prevent NP melting. This might also explain why, up to now, there are no SIMS single-NP depth profiles. But depth profiling can also be employed to answer broader questions related to nanomaterials; for example, it can target NP ensembles, reveal intracellular structures, and decide whether NPs penetrate tissue or cells and in which organelles they are present. An example of such NP ensembles are LiNixCoyMnzO2 (with x + y + z ¼ 1, lithium–nickel–cobalt–manganese oxide (NCM)) materials, which are used as cathode materials in lithium-ion batteries. NCM is usually synthesized in such a way that secondary particle structures are formed. These consist of primary particles, whose particle size depends on the composition and the synthesis process but is typically in the range of a few nanometers to several hundred nanometers, here in the range of 100 nm. Due to the secondary particle structure, the collision momentum on the surface is distributed over several primary particles, which results in a number of secondary ions sufficient for straightforward ToF-SIMS analysis. An example of such an analysis is shown in Fig. 7. Neudeck et al. modified the surface of such NCM particles with a phosphate coating to increase battery performance and investigated the coating morphology using ToF-SIMS [76]. Fig. 7 shows 3D reconstructions of depth profiles of phosphate-typecoated NCM samples. The NCM secondary particles are shown in blue (dark grey in print version) (represented by the NiO 2 fragment), while the coating is depicted in gold–yellow (light grey in print version) (represented by the linearly combined PO 2/ PO 3 signal). It can be seen that only the surface of the secondary particles was coated, since the coating and the NCM particle signal can be clearly distinguished. In this example, the already mentioned correlation of the secondary ion intensity to the ionization probability is exploited. The coating has a relatively low concentration of 20–23 μmol/gNCM as measured by ICP-OES [76]. However, the ionization probabil ity of PO 2 and PO3 fragments is very high. Therefore, the coating can be nicely visualized by ToF-SIMS imaging and provides an instructive example for NP depth profiling. In another study, 10 keV argon cluster ions were employed to study the distribution of Ag NPs in cells [77]. This publication addressed the problems arising with differential sputter rates for the organic cell material and the metallic NPs resulting in an unintended accumulation of silver during the depth profiling, while the cell material is sputtered away (see Fig. 8). As a compromise, reduced argon cluster sizes were proposed to level the differential sputtering and reduce its effects.

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Fig. 7 3D reconstructions using depth profile data of secondary particles formed from phosphatetype-coated LiNi0.6Co0.2Mn0.2O2 (NCM622) primary NPs. The primary particle size is in the range of 100 nm. The cube size is 10  20  20 μm3. The analysis was performed in fast imaging mode with delayed extraction using an IONTOF TOF-SIMS 5 instrument. The NCM622 secondary particles are represented by the NiO 2 fragment (A), while the phosphate-type coating is  represented by the linearly combined PO 2 /PO3 signal (B). As can be seen from the combination of  the NiO fragment in blue (dark grey in print version) and PO 2 2 /PO3 signal in gold (light grey in print version) in images (D) and (E), both components can be clearly distinguished, and the coating seems to be homogeneously distributed on the secondary particle surface, indicating a successful coating process. (Reprinted with permission from S. Neudeck, et al. Molecular surface modification of NCM622 cathode material using organophosphates for improved Li-ion battery full-cells, ACS Appl. Mater. Interfaces (2018). https://doi.org/10.1021/acsami.8b04405. Copyright (2018) American Chemical Society.)

Secondary ion mass spectrometry

Fig. 8 ToF-SIMS study of cells incubated with silver NPs. (A) The ToF-SIMS image of the initial C4H8N+ secondary ion signal before sputtering is presented in green (light grey in print version) and represents the cellular material. It is overlayed with the silver secondary ion signals in red (dark grey in print version) after complete removal of the cell material by sputtering with 10 keV Ar1500+. Clear localization of silver within the region of the cell is observed. (B) Gives the 3D-reconstruction of the 107 Ag+ signal in an 250  250 μm2 field of view, which reveals that silver is only slightly ablated by the use of the mentioned argon clusters as sputter source. Following, silver is present in each image scan and thus virtually in the whole analysis volume. (Reproduced from A. Henss, S.-K. Otto, K. Schaepe, L. Pauksch, K.S. Lips, M. Rohnke, High resolution imaging and 3D analysis of Ag nanoparticles in cells with ToF-SIMS and delayed extraction, Biointerphases 13 (2018) 03B410. doi: 10.1116/1.5015957, originally published in Biointerphases and licensed under a Creative Commons Attribution (CC BY) license.)

Future developments More accurate and reliable analysis Recent developments in the SIMS community aim at mass range extension by improved cluster ion sources [78–81] and the provision of a more accurate identification of chemical species based on the measured secondary fragment or molecule/quasimolecule ions. Such approaches rely on (a) integration of MS/MS measurement capability to enable identification of chemical species by fragmentation pathways [15,18] and (b) coupling with mass analyzers that provide a substantially increased mass resolving power and accuracy. Another need is to find techniques that are less prone to topography variations. There are other developments that include the integration and facilitation of analysis of frozen-hydrated samples [19] and the combination with complementary techniques such as MALDI [79]. It is crucial to understand why more accurate analyte identification has gained more importance in the last years. This comes with the fact that reliable analyte annotation

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requires a high mass resolving power and mass accuracy (<5 ppm), and this is especially important with respect to organic molecules with higher m/z, which are present when analyzing NPs in complex matrices or engineered nanomaterials with intended or unintended functional organic coatings. The highest mass resolving power and mass accuracy is nowadays obtained with mass spectrometers utilizing Fourier transform ion cyclotron resonance (FTICR) and, second best, by orbital trapping mass spectrometers (Orbitrap, Thermo Fisher Scientific GmbH, Bremen, Germany). To break down complexity at this point, we only mention that mass detection and analysis is in this case performed nondestructively by the determination of the cyclotron frequency of ions trapped in a magnetic field or of the harmonic oscillation frequency of ions trapped in an oscillating electric field, respectively, followed by Fourier transformation. The essential advantage of these analyzers is that the kinetic energy (spread) of the measured ions has no effect on the accuracy of the m/z determination because the measured frequencies are independent of this quantity. So, topography also has no effect on the accuracy and resolution. Furthermore, the primary ion beam does not have to be pulsed anymore. Besides the mentioned advantages, those approaches bring also some disadvantages such as increased cost, reduced transmission, and acquisition speed. In the described context, developments such as the buncher-ToF configuration of the J105 3D Chemical Imager [19], the SIMS FTICR [82,83], and the recently developed 3D OrbiSIMS [15] have to be mentioned. The latter couples an Orbitrap Q Exactive HF (Thermo Fisher Scientific GmbH, Bremen, Germany) to an IONTOF TOF-SIMS 5 instrument [15].

Cluster ion sources Another new development in primary ion beam technology in SIMS involves the development of water cluster ion beams for ToF-SIMS analysis at the Vickerman group in Manchester together with Ionoptika Ltd. [84]. The use of water clusters results in the generation of additional reactive species, for example, protons, on impact on the sample surface. Subsequently, those generated ions can ionize chemicals such as lipids or amino acids present on the sample surface. Therefore, they may significantly enhance ion yields. First results indicate a significant sensitivity gain of the (H2O)+n cluster ion beam over C+60 and Ar+n ion beams especially for biological matrices. Usually, water clusters in the size range n ¼ 2000 to 4000 are used for the analysis. Hereby, the water cluster ion beam seems to significantly reduce matrix effects, which decrease sensitivity and are observed with C+60 and Ar+n cluster ion beams. A possible explanation may be the generation of a specific chemical environment, generated on a microscale after impact on the surface of the analyte, which mimics a frozen-hydrated microenvironment. Another new cluster ion beam development involves the use of CO2 clusters as primary ions proposed by the Winograd group (Penn State University) [85]. Usually, cluster

Secondary ion mass spectrometry

sizes in the range of n ¼ 1000 to 5000 are used for the newly developed (CO2)+n ion beam. A pilot study investigated lipid Langmuir-blodgett films. The results indicate a significant improvement of the lateral resolution of around a factor of 2 in 3D depth profiles by (CO2)+n clusters in comparison with Ar+n clusters. However, all newly developed cluster ion guns need further evaluation and application to a variety of inorganic and organic matrices as well as model systems to systematically evaluate pro and cons of each cluster ion beam in a given analytical application.

Ionization enhancement One of the main problems that remains to be solved is to increase the ionization efficiency to compensate the loss of intensity when going to smaller primary beam sizes needed for single-NP characterization. Besides the mentioned development of cluster ion sources, some approaches to reach higher secondary ion formation probabilities for cations or anions include the application of matrices as in MALDI (matrix-enhanced SIMS) [86], metal NP-enhanced SIMS, and the addition of acids and bases [87,88]. Another approach is the postionization of neutrals [69]. As mentioned earlier, only a small percentage of the emitted particles is charged and directly available for analysis, while the neutrals are lost unless being postionized by help of a laser or otherwise. As already highlighted in section ‘Unpulsed primary beam ToF-SIMS’, it can be observed that the development is directed towards an increasing application of unpulsed primary ion beams (DC beams) instead of pulsed ones to optimize the secondary ion yields.

Multivariate data analysis Data analysis and interpretation of both ToF-SIMS spectra and images are significantly hampered by the sheer complexity of the acquired data sets. Both operation modes generate complex data files that comprise several hundreds of peaks, which need special data interpretation tools to gain meaningful output. Sample complexity is caused by a multitude of additional information, which is generated from the surface analysis and can add significant value to specific topics like the ‘chemical space and environment’ of a single compound on a surface, the surface order, the chemical bonding of compounds to a given surface, or the sample purity. Multivariate data analysis is commonly used to interpret these highly complex data sets [89]. Usually, a PCA in combination with a discriminant analysis methodology is performed to get insights in intergroup variations of the investigated data sets. Usually, the data set is grouped in several a priori defined subgroups, which can result from the experimental study design, for example, controls and groups of specific samples that differ by treatments, as ToF-SIMS data are usually centred, normalized, and subsequently analyzed with the methodology mentioned before. The results reveal whether a group separation can be identified, and the chemical entities, which are responsible for the

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successful group separation, can be derived from the loading coefficients of the analysis [90–93]. The methodology was successfully employed to show significant cell membrane changes within human lung macrophages after exposure to silver NPs [93]. In addition to PCA, also maximum autocorrelation factors (MAF), a scaling independent multivariate analysis method, was successfully used to analyze complex data sets from ToF-SIMS images [93]. MAF was particularly good in identifying subtle underlying chemical features on surfaces, which could not be identified using other multivariate analysis approaches. Recently a new multivariate data interpretation approach, nonnegative matrix factorization, was used for the interpretation of complex hyperspectral images, thereby generating valid information about surface chemistry of otherwise hidden features in combination with multicomponent chemical distribution maps generated directly from the analyzed surface [94]. All multivariate data interpretation clearly shows the need for the use of sophisticated mathematical models to successfully get insights into the complexity of the acquired data sets acquired in ToF-SIMS surface analysis. Not only can the data interpretation tools be used for the evaluation of 2D pictures, they can also be employed for the interpretation of 3D data acquired from ToF-SIMS depth profile analysis.

Acknowledgement The work on this chapter was supported by funding from European Union Horizon 2020 Programme (H2020) through the ACEnano project under grant agreement n° 720952. The authors thank Matthias Kleine-Boymann, Gregory Fisher, Anja M€ uller, Felix Walther, Anja Henss, and Marcus Rohnke whose support has been of great value during the compilation of this book chapter.

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