Single Particle ICP-MS: From Engineered Nanoparticles to Natural Nanoparticles

Single-particle inductively coupled plasma–mass spectrometry (spICP-MS) is becoming widely used to measure the number of nanoparticles (or other sub-micrometer–sized particles) per mL with a particular elemental chemical composition and the average particle size (diameter) or particle size distribution (1,2). As the use of engineered nanoparticles has grown explosively, the need for rapid measurement of engineered nanoparticle size and number concentration has become critical. The Nanodatabase (3) lists 3901 products that contain nanomaterials, and more than 460 journal articles using spICP-MS were published between 2017 and 2020 (based on a CAS SciFinder literature search).  

Nanoparticles are defined as particles with diameters between 1 and 100 nm. However, many engineered particles have diameters up to 1000 nm and can be measured by spICP-MS, thus the use of the phrase sub-micrometer–sized particles in this article.  

Conversion of sub-micrometer–sized particles to ICP-MS signals. When sub-micrometer–sized particles, suspended in a liquid, are nebulized into a liquid aerosol and introduced into an ICP, first the liquid evaporates, then the remaining particle is vaporized, atomized, and ionized. A spherical cloud of ions is produced in the plasma from each individual particle (Figure 1). If the number of particles entering the plasma per second is small enough, the ion clouds produced from different particles do not overlap in the plasma. A peak in the ICP-MS signal versus time is produced from each particle. The particle suspension must have a small enough particle number concentration so that it is unlikely that ion clouds produced from two different particles will overlap in the ICP. 

As the plasma gas flows from the ICP through the interface and into the mass spectrometer, each ion cloud is detected as a peak (0.2 to ~1 ms wide) (Figure 1b). Millions of aerosol droplets enter the plasma per second, each containing the elements that are dissolved; ion clouds produced from dissolved elements in different droplets overlap extensively, resulting in a “constant” signal (Figure 1b). Therefore, the sharp peaks produced from individual particles can be distinguished from the more constant signal produced from the same element in solution if the signals from the sharp peaks are larger than the variations in signal generated from the element in solution.

The total net ICP-MS signal (counts) at a particular mass/charge across the peak is directly proportional to the amount (in fg) of the measured element in the original, individual particle. The number of detected peaks (“particle events”) (for example, 10 in Figure 1c) is directly proportional to the number of particles/mL in the original suspension. The number of detected peaks also depends on the volume of sample aerosol (typically 20 to 100 μL) that enters the plasma during the duration of continuous ICP-MS signal measurement (typically ~2 to 5 min).

Particles have been detected using peaks in an atomic spectrometry signal versus time as early as 1968 (4). In 2003, Degueldre and coworkers described ICP-MS detection of individual nanoparticles suspended in liquid for the first time (5).

However, spICP-MS should still be considered an emerging technique (1,6) and we have much to learn about variables that can affect the accuracy of measurements of particle size, elemental composition, and number per mL. These variables include the stability of stored particle suspensions, sample preparation, calibration, chemical matrix effects, high backgrounds resulting from elements in solution or ions that cause spectral overlaps, detection limits (in terms of particle size and the minimum detectable amount of analyte elements), and the limited dynamic range of the number of particles/mL and particle size. 

Amount of analyte element in each particle. The technique of spICP-MS directly measures signal from each ion cloud that is proportional to the amount (in fg) of the element measured in each sub-micrometer–sized particle if: (a) the particle is completely vaporized, (b) the fraction of analyte ionized is the same for the sample particles and the calibration solution or calibration particle suspension, and (c) the fraction of ions produced in the ICP that reach the detector is the same for the sample particles and the calibration solution or particles.

The maximum size particle that is completely vaporized and converted to elemental ions prior to entering the ICP-MS interface depends on the chemical composition of the particle and the time that the particle spends in the hot plasma (typically ~1 to 3 ms, depending mainly on the center gas flow rate, injector diameter, and plasma power). While increasing the time that the particles spend in the hot plasma allows larger particles to be vaporized, it also decreases sensitivity (signal/fg of analyte element) because there is more time for diffusion of ions (broadening the ion cloud) (7).

Typically, particles with diameters less than about 1000 nm are completely vaporized in the ICP (7,8). Fluctuations in the time particles spend in the hot plasma (and therefore the extent of diffusion of ions in the ion cloud), in part because of fluctuations in the plasma gas velocity, can result in variations in the relationship between signal intensity (counts) and amount (fg) of analyte element in the particle. 

Number of particles/mL. With spICP-MS, we directly measure the number of particles that enter the ICP per second if each particle produces a detectable ion cloud. As the detection limit is approached, the percentage of particles that produces a detectable ion cloud decreases. To quantitatively relate the number of “particle events” measured to the number of particles/mL in the original suspension, two different calibration methods can be used (1,9): (a) a particle suspension with a known number of particles/mL can be measured, or (b) a solution standard with a known concentration of the analyte element and nanoparticles with a known amount (fg) of analyte are separately measured. For (b) the ratio:  

 determines the fraction of nanoparticles delivered to the nebulizer that enter the plasma and are detected. In order to know the amount of analyte element in the nanoparticle the elemental composition of the particle, the nanoparticle size (typically diameter), and the density (g/cm³) must be known. Sometimes, the two different calibration techniques lead to different results. There is some evidence that the sensitivity-ratio–based calibration is more stable over time; that suggests that the number of nanoparticles per volume in a suspension may not be as stable over time.

Particle size. Single-particle ICP-MS can be used to measure sub-micrometer particle diameters of spherical particles because spICP-MS determines the amount of analyte element (fg) in each particle. To convert amount of analyte to particle size (for example, diameter) the shape of the particle (for example, spherical), the chemical composition of the particle and the density (g/cm³) of the particle must be known.

Application of spICP-MS to engineered sub-micrometer–sized particles. Many widely used engineered nanoparticles are elemental (for example, Au or Ag) or oxides (ZnO, TiO₂, SiO₂). In addition, many engineered nanoparticles contain elements that are not abundant in nature (for example, Au or Ag). The vast majority of publications to date have focused on measurement of these engineered nanoparticles (or sub-micrometer–sized particles), typically in samples that would not be expected to contain these elements in high abundance in natural sub-micrometer–sized particles. 

ICP-MS with a quadrupole mass spectrometer can monitor just one element continuously. This provides element-selective detection of sub-micrometer–sized particles such as engineered nanoparticles. Element-selective detection allows specific particles (such as Au, Ag, ZnO, and TiO₂ engineered nanoparticles) to be measured independently from many other particles that do not contain detectable amounts of the same element as the particle of interest (for example, carbon-based particles like soot). This is one of the advantages of spICP-MS compared to other particle-measurement techniques, such as dynamic light scattering or a Coulter counter, that are not element-specific. 

Application of spICP-MS to mixtures of sub-micrometer–sized particles including natural particles. Natural particles and anthropogenic particles can have a wide variety of chemical compositions, including combinations of different elements. Some engineered particles have layers or coatings of different materials. Using spICP-MS with a quadrupole MS that measures one element at a time, it would be impossible to distinguish small single element or oxide particles from larger particles that contained a small portion (but same number of fg) of the same element.

Single-particle ICP-MS with a time-of-flight mass (TOF) spectrometer can provide a complete elemental mass spectrum (for the elements detectable by ICP-MS) for each sub-micrometer–sized particle (for example, Figure 2). By calibrating the signal/fg, the amount of each detectable element in each individual particle can be measured.

Single-particle ICP-TOF–MS can also measure the number of particles per mL (all particles with detectable elements or for each type of particle, based on its chemical composition). Single-particle ICP-TOF–MS does have some limitations compared to currently sold ICP-quadrupole-MS instruments, including poorer abundance sensitivity, poorer sensitivity, and limitations in use of gases in collision–reaction cells that may also react with some elemental ions.

Conclusion  

Single-particle ICP-MS is uniquely capable of rapidly measuring the number of sub-micrometer–sized particles/mL with either element-selective detection (using quadrupole or sector field mass spectrometers) or elemental chemical composition of individual sub-micrometer–sized particles (using time-of-flight mass spectrometers). At this point, far more care and expertise are needed to obtain accurate results with spICP-MS than for solution analysis with ICP-MS. Detection limits in the best case scenario (single element nanoparticles in suspensions that contain little if any of the element of interest in solution and with no spectral overlaps) are typically around 6 to 10 nm in diameter. The analyte element mass depends on the cube of the particle diameter; to reduce the diameter detection limit by 2x, the detection limit in the amount of analyte element (fg) would need to be reduced by 8x. 

Acknowledgments  

Thanks to Paolo Gabrielli (Ohio State University Byrd Polar Climate and Research Center) for comments on this manuscript. Thanks to Luke Monroe, Garret Bland, and Ryan Sullivan for the mass spectrum shown in Figure 2, acquired using the ICP-TOF–MS instrument at Carnegie Mellon University. The mass spectrum was acquired from a particle entrapped in an ice core from Mt. Ortles; the sample was prepared for analysis by Paolo Gabrielli and Aja Ellis. The Mt. Ortles project was supported from NSF awards no. 1060115 and no. 1461422 and from the Ripartizione Opere idrauliche e Ripartizione Foreste of the autonomous province of Bolzano and the Stelvio National Park as well as The Ohio State University, the OSU Institute for Materials Research, The Byrd Polar Research Center, and the Ohio Third Frontier Research Scholar program.  

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John W. Olesik is a Research Scientist, an Adjunct Associate Professor, and the Director of the Trace Element Research Laboratory in the School of Earth Sciences at The Ohio State University, in Columbus, Ohio. Direct correspondence to olesik.2@osu.edu