Analysis of the State of the Art: ICP-MS

In honor of Spectroscopy's celebration of 30 years covering the latest developments in materials analysis, we asked a panel of experts to assess the current state of the art of inductively coupled plasma–mass spectrometry (ICP-MS) and to try to predict how the technology will develop in the future.

Inductively coupled plasma–mass spectrometry (ICP-MS) and its older sister inductively coupled plasma–optical emission spectroscopy (ICP-OES) have long been a mainstay in fields with little glamour, like geology. Today, however, ICP-MS is also on the forefront of newer, "hot" fields like metallomics and nanoparticles analysis.

In celebration of this 30th year of Spectroscopy, we asked a panel of ICP-MS experts about notable recent advances in the technique, ongoing challenges, and possible future developments. This article is part of a special group of six articles covering the state of the art of key techniques, also including laser-induced breakdown spectroscopy (LIBS), X-ray fluorescence (XRF) spectroscopy, infrared (IR) spectroscopy, near-infrared (NIR) spectroscopy, and Raman spectroscopy.

The Most Significant Advances

We kicked off the discussion among our panelists by asking them what they considered the most important advance in this technique or its instrumentation in the last 5–10 years. Collision–reaction cells, for removing spectral interference in quadrupole instruments, topped the list.

"The use of collision–reaction cell [CRC] technology has taken much (though not all) of the guesswork out for spectral interference removal for most analyses at an instrumentation price point that makes it an affordable option for laboratories," said Craig Westphal, a principal investigator at Chemours Analytical, a subsidiary of DuPont. "In particular, using kinetic energy discrimination as a universal interference removal mode coupled with the advancements in usability (such as improved autotuning and better software interfaces) has established ICP-MS as a routine technique in many labs."

"Until the introduction of the collision–reaction cell, the quality of data obtainable was matrix-limited because online interference removal was not possible," noted Traci A. Hanley, who is a chemist at the United States Food and Drug Administration (US FDA). "The only way to obtain better quality data was through off-line sample pretreatment or mathematical interference correction equations."

Steve Ray, who is currently an associate scientist at Indiana University and will be an assistant professor at the University at Buffalo starting this August, agreed. "The impact that this development has made is difficult to under-estimate," he said.

The triple-quadrupole ICP-MS instrument, which further improves on the interference-removal capabilities of collision–reaction cells, also ranked high on the list.

The ICP–triple-quadrupole MS system eliminates ionized matrix with the first quadrupole. The analyte of interest then enters the CRC, where isobaric and multiply charged interferences can be removed or the analyte can be reacted to a different mass before the second quadrupole filters the mass-to-charge ratio (m/z) corresponding to analyte of interest. The addition of the first quadrupole for matrix removal allows reactions in the CRC to be matrix independent and generate a reproducible and robust reaction. Through this series of events the background signal is greatly reduced (if not removed).

Frank Vanhaecke, who is a senior full professor of analytical chemistry at Ghent University in Belgium, explained the value of this setup. "While it was clear from the start that tandem ICP-MS (also called triple-quadrupole ICP-MS) provides enhanced control over the ion-molecule chemistry proceeding in the reaction cell, it is now realized that the advantage of double mass selection (before and after the reaction cell) can be exploited in quite a different way as well," he said. "Identifying the ions formed upon ion-molecule reaction via product ion scanning is so straightforward that nowadays, quite complex reaction product ions such as Ti(NH₃)₆⁺ (with NH₃ as reaction gas) or ⁴⁸TiF₂(CH₃F)₃⁺ (with CH₃F as reaction gas) can be identified as those ions providing the lowest limits of detection and interference-free conditions." As a result, he said, tandem ICP-MS is more than just an improved form of collision–reaction cell ICP-MS.

David Koppenaal, who is the chief technology officer for the Environmental Molecular Sciences Laboratory at the Pacific Northwest National Laboratory, agreed that CRCs and the ICP-triple quadrupole instrument are important advances, but also noted their limitations. "A downside of CRC techniques is they are in many cases element- or isotope-specific and thus are not global or universal across all interferences," he said. "If better, precise control of ion energy and ion energy spreads could be achieved, kinetic energy discrimination approaches might be made more effective and universal (at least for all polyatomic ion interferences)."

Bonner Denton, the Galileo Professor of Chemistry and Professor of Geosciences at the University of Arizona, cited another innovation: new detector technology based on complementary metal oxide–semiconductor (CMOS) circuitry.

"I feel strongly that these new detectors will replace charge coupled devices (CCDs) and charge injection devices (CIDs) in optical spectroscopy and conventional Faraday cups and ion multipliers in mass spectrometry," he said, noting that there are already two commercial instruments that use CMOS detectors, one of which can simultaneously observe all masses from lithium through uranium.

ICP-TOF-MS instrumentation also made the list. "High-speed ICP-TOF-MS also has an important role to play in analytical chemistry, such as in nanoparticle analysis and in imaging-that is, for mapping the distribution of elements over biological tissues or other natural or manmade materials," said Vanhaecke. In addition, it has been essential for the development of mass cytometry. "Mass cytometry is based on ICP-TOF-MS, but serves a totally different field of science, outside the field of analytical chemistry."

The Impact of Microelectronics and Microfluidics

We also asked our panelists to consider the impact of specific advances in this field. One specific advance we asked about was the impact of microelectronics, microfluidics-and other miniaturization-on ICP instrumentation.

"The refinement in electronics has reduced cost and size, and improved efficiency to be certain," said Ray. "The development of fluidics, if not microfluidics, has probably had as significant effect upon ICP instrumentation. Automated and reproducible robotic sample handling significantly improves reproducibility and accuracy, and is becoming an indispensable component in the laboratory.

Plasma source instrumentation has certainly benefited greatly from efforts to downscale and ruggedize the footprint of the instruments, Koppenaal noted. "Part of this was driven by financial drivers, related to manufacturing costs and efficiency, but part was also driven by technical considerations," he said. "Instrument operations and data quality have improved with lower levels of sample and matrix introduction into the instruments." And as chromatographic and fluidic handling techniques have improved, he noted, the need to introduce milliliter-per-minute flow rates has now dropped to microliter-per-minute rates, with consequent improvements in data quality, lower reagent and waste requirements, and smaller instrument footprints. "The advent of microelectronic and detector array technologies has been huge," he concluded.

Advances in electronics are almost always followed by improvements to instrumentation, Hanley said, noting that in particular, nanoparticle and single-cell analysis have benefited from the faster data acquisition and improved data storage capabilities that have been enabled by microelectronics. "Today, the scan time of many ICP-MS instruments on the market is fast enough to resolve events occurring from single nanoparticles," she said, noting that this was not possible even a few years ago. "Improved electronics makes sub-part-per-billion nanoparticle detection possible with ICP-MS, which is not possible with other instrumental techniques."

The growing field of single-cell analysis has also benefited from advances in microfluidics. "The synergistic relationship between microfluidics interfaced with ICP-MS detection allows for the smallest volume of solution to be analyzed with fast and sensitive data acquisition," she said. "This is paramount for many biological applications."

Denton linked advances in microelectronics back to CMOS technology. "Clearly the microelectronic industry has given birth to this CMOS technology," he said. "While the CMOS process itself has been around for many years and even array detectors utilizing CMOS have been available for years, the performance necessary to provide high quality analytical data has not been achieved until recently. These new detectors significantly outperform the CCDs and CIDs that have been utilized for the last 20 some odd years."

Lower Detection Limits Push Advances in Sample Preparation

The panel also commented on the fact that improvements in the detection limits of ICP instruments have pushed developments in sample preparation techniques and equipment. The lower the levels at which target analytes can be detected, the lower the levels at which contaminants can be detected, too. "ICP-MS instrumentation is sensitive enough now that environmental contamination is the limiting factor for most analyses conducted in non-cleanroom environments," Westphal said.

This development increases demands in terms of purity of reagents and a more general use of cleanrooms. "This has led to the use of highly pure materials, such as quartz and PFA, in digestion vessels," noted Vanhaecke.

Ray agreed. "More that the techniques, the extremely low detection limits of ICP-MS have pushed the purity of the available reagents and consumables," he said. "Plastics, glass, and even disposable sample preparation materials have to be free of trace metal contamination; not to mention the demands placed on solvents like nitric acid."

Hanley said that for ultratrace analysis, it's not just ultraclean reagents that are imperative, but a cleanroom, too-and if the sample preparation can be performed in a closed environment, even better. "In addition to using ultraclean reagents in an ultraclean environment, the automation of sample preparation in a closed environment is a technique that even further reduces the possibility of sample contamination."

A related trend, Koppenaal noted, is toward automated sample preparation and introduction approaches. "With automation, blank levels and reproducibility can be better controlled and maintained," he said. "This in turn allows analysis of smaller sample types and larger sample numbers."

"For common sample preparation techniques such as microwave digestion, sample weight limitations (to minimize pressure buildup in closed vessel digestions) still remain, although there has been growth in using 'self-venting' microwave vessels to increase the sample weight," added Westphal.

Westphal takes this point further. "Ideally we'd like to eliminate sample preparation altogether and analyze the sample directly (such as through laser ablation [LA])," he said. "While there have been advances in this area and overall growth in laser ablation usage, we are still years away from being able to analyze solid samples by LA-ICP-MS on par with standard aqueous analysis by ICP-MS."

Advances in Applications

All of these developments in ICP-MS instrumentation have led to growth in a number of research fields. Key areas where ICP techniques play a critical role include metallomics, speciation, nanoparticles, advanced materials, geochronology, and mass cytometry. Our panelists commented on how these fields are developing and offered some forecasts of how they might continue to develop in the next 10 years.

Nanoparticle Analysis

Method development for the characterization of engineered nanoparticles is receiving considerable attention at atomic spectroscopy conferences, because of concerns about potential health and environmental effects of these particles, and because of interest in characterizing them during manufacturing. ICP-MS is at the forefront of those methods, because of its extremely high detection power. "There are many techniques suitable for measuring particle size, but ICP-MS is unique in its capabilities to measure size and composition (including identifying coated particles) even in very complex matrices," said Westphal.

But even though ICP-MS is a powerful technique, nanoparticle analysis still presents challenges for current instrumentation. As a result, Vanhaecke noted, manufacturers are trying to improve the capabilities of their instruments. For example, he said, efforts have been made to reduce the minimum dwell time to 50 µs, which translate into 20,000 separate measurements per second. This allows for real-time single-particle acquisition, providing information on nanoparticle concentration, size, and size distribution. But, he explained, this improvement in scanning ICP-MS instruments (such as quadrupole-MS systems) only assists with the study of mono-elemental nanoparticles, because the typical millisecond settling time required after selecting another mass-to-charge ratio means that to characterize individual nanoparticles that contain two or more elements is not possible.

"Therefore, I expect a breakthrough for simultaneous or semisimultaneous ICP-MS instrumentation, based on a time-of-flight (TOF) analyzer, distance-of-flight analyzer, or double-focusing sector field mass spectrometer of Mattauch-Herzog geometry," Vanhaecke predicted. "Given that the second type of instrument is not yet commercially available and the third one is currently too slow for this type of application, ICP-TOF-MS seems to be in the pole position for becoming the technique of choice in this context."

Metallomics and Other Biomedical Applications

Metallomics is another field that has benefited from ICP-MS techniques. Metallomics, one of the more recently developed "-omics" fields, focuses on the role of metals in biological systems such as the human body-including both the consequences of an insufficient supply of essential metals such as copper, iron, zinc or molybdenum, as well as the results of an excessive presence such as arsenic, chromium, or nickel.

"I see the best opportunities for ICP-OES and ICP-MS in the metallomics and nanoparticle effects research areas," said Koppenaal. "Biology is where the research funds are these days and these technologies must follow the research trend and apply themselves to unfolding new scientific frontiers involving metal and isotope biochemistry."

Our panelists noted several further developments in ICP-MS instrumentation that could help these fields continue to advance.

Vanhaecke came back to the need for simultaneous or semisimultaneous detection. "For elemental mapping or bioimaging with LA-ICP-MS, simultaneous or semisimultaneous instrumentation provides important benefits, because information on a large collection of target elements-in theory the entire elemental mass spectrum-can be obtained for exactly the same position, thus avoiding skew in the maps obtained and providing a higher spatial resolution, not affected by the number of target elements selected," he explained.

Another way that ICP-MS research is advancing biomedical fields such as metallomics, Hanley noted, is through efforts to combine the elemental features of ICP-MS and the molecular features of electrospray ionization mass spectrometry (ESI-MS) into a single instrument. "Also, biomedical applications are emerging where liquid chromatography (LC)–ICP-MS can be used to identify metallic-based tags and replace traditional methods that rely on radioactive isotopic labeling," she said.

Koppenaal also considered the broader question of how researchers need to think about metallomics. Metallomics research today is still too much like speciation research of the past, he said, in that there is lots of research on a metal in a particular biosystem. "Metals do not act on their own, but rather-much like proteins-act in concert with each other," he said. "Thus metallomics research has to become more multi-metal and multi-omics in nature." Researchers need to consider what all the metals in a biosystem are doing and how their concentrations, fluxes, and protein or enzyme associations are related, he concluded.

Mass Cytometry

Mass cytometry, which uses ICP-TOF-MS instrumentation, has become an important tool for cell biology and its applications in cancer research. In mass cytometry, reporter molecules, usually antibodies, are tagged with isotopically pure rare earth elements (REEs). The tagged reporter molecules then bind with specific components of cells, and the mass cytometer measures the expression of these reporter molecules in each individual cell. Developments in ICP and TOF-MS have been essential in making mass cytometry possible.

"Mass cytometry has advantages over traditional flow cytometry because the heavy metal-tags can be detected at much lower concentrations than the fluorochromes used in flow cytometry," Hanley said. "The metallic tags are generally easier to detect with certainty in a quantitative manner using the ICP-TOF-MS in comparison to the fluorochromes used with flow cytometry."

The development of mass cytometry, Ray said, is an excellent example of great insight into the future needs of community-before the users of the existing technology appreciated that the solution existed. "It's true that development of the instrument would have been impossible without prior work in plasma-source TOF-MS and 20 years of ICP-MS development that came before," he said. "With that said, the inventors of this technology are incredibly gifted and should be lauded for their insight, fortitude, and talent."

Vanhaecke agreed. "In my personal view, we owe mass cytometry to the intellect and guts of Scott Tanner and coworkers," he said. "When the established company they were working for did not support their plans, they took a giant leap and started their own company," he continued. "I can only admire this type of audacity."

"It is really good to see the success and impact this technology is having in single-cell measurements and the improved understanding of biological heterogeneity at the single-cell level," added Koppenaal. "This development has really put the use of metal and isotope tags for specific proteins on the map, showing much improved analytical performance over more traditional fluorescence tag techniques."

"Without doubt, the improvements in single-cell cytometry realized by this application are profound and will increase in popularity," Ray concluded.

Geochronology

Geoscience is another field that has advanced as a result of improvements in ICP-MS technology.

"Geochronology has driven progressively more accurate and precise isotope ratio precision measurements for quite some time," said Ray. "In turn, these improvements have allowed new geochronological systems, not previously conceived, to be developed. I see that cycle continuing for some time."

Specifically, these advances result from the introduction of multicollector ICP-MS (MC-ICP-MS), which is a great advance over to thermal ionization mass spectrometry (TIMS). "MC-ICP-MS has revolutionized the fields of geochemistry and cosmochemistry," said Vanhaecke.

A key reason, he explained, is that MC-ICP-MS offers more efficient ionization than TIMS, including for elements characterized by a high ionization potential. "In TIMS, M⁺ ions can be generated with sufficient efficiency only for elements with an ionization energy ≤7.5 eV," he said. "With MC-ICP-MS, even nonmetals such as sulfur and bromine isotope ratios are characterized based on the M⁺ ions of their constituting isotopes."

Of particular importance, the isotopic composition of mercury-which is an important element in environmental studies because of its toxicity and transport over long distances-can now be measured. That was not possible with TIMS. "Now, it is known that the isotopic composition of mercury is affected by both mass-dependent and mass-independent fractionation effects, which opens interesting possibilities for provenance determination of mercury pollution and for studying its biogeochemistry," Vanhaecke said.

Moreover, the ICP is operated at atmospheric pressure-unlike TIMS where ionization takes place in vacuum. That means that in ICP-MS, straightforward sample introduction into the ion source is possible. "Solution nebulization is the standard approach, but also laser ablation, vapor generation and chromatographic separation techniques (such as high performance liquid chromatography and gas chromatography) have been used," Vanhaecke said.

"The widespread adoption of MC-ICP-MS in the geological fields is astounding," said Koppenaal. He recalls suggesting this development to an instrument manufacturer many years ago, and being met with the incredulous query of 'Why would we do that?' "I was incredulous myself that they could not see why," he said. "It appears they have now answered that question."

Further Advances: Speeding Up Isotope Analysis

Given the advances in high-precision isotope analysis-such as in geochronology-that have been enabled by stable multicollector sector-field MS instrumentation, we asked our panelists what instrument advances might come down the line to improve the speed of this type of analysis and to reduce the sample preparation efforts involved.

While excited about the tremendous boost in isotopic analysis that has resulted from the introduction of multicollector ICP-MS instruments, Vanhaecke still has a considerable wish list of desired improvements. "The technique would benefit, for example, from higher sensitivity and from Faraday collectors with a faster response," he noted.

But the most important problem, Vanhaecke said, is still mass discrimination, which causes a bias between the measured isotope ratio and the corresponding true value that is orders of magnitude higher than the precision attainable. "The underlying phenomena are not fully understood yet and there is still some debate as to the best approach for mass bias correction," he noted. "A better understanding of the origin of mass discrimination is desirable, as perhaps this would permit the manufacturers to adapt the instrument design to reduce mass discrimination to the largest possible extent."

Such a development could make it possible to avoid target element isolation altogether, and that would increase sample throughput immensely and benefit many types of research. "It would also allow a more general use of laser ablation as a means of sample introduction, boosting sample throughput even more and enabling reliable spatially resolved isotopic analysis," he said.

Ray noted that time-of-flight MS and distance-of-flight MS have the potential to compete with MC-ICP-MS for applications in which sample aliquots are very limited (such as biological applications) or when a transient signal is important (such as in chromatography, laser ablation, or the analysis of single nanoparticles).

But in terms of improving speed, the focus needs to be on sample preparation, he said- particularly robotic or automated sample preparation. "As R. Browner said, 'sample introduction remains the Achilles heel of atomic spectrometry'-and many other techniques as well," Ray quipped.

Koppenaal agreed that automated and on-line sample preparation approaches are key. "We have to move away from the tedium of isolating single elements or isotopes using traditional manual, wet chemical approaches," he said. "Getting analyte–matrix separation accomplished using automated, instrumental approaches is again the wave of the future here."

Denton felt the question completely missed the point. "Stable multicollector sector-field MS instruments do not provide for simultaneous measurement of all isotope ratios or the ensuing flexibility that the new CMOS detector technology provides," he said. Faraday cup detectors have very limited sensitivity and the multiplier detectors have a very limited dynamic range, he explained, which means that both technologies depend on the ion flux of a particular isotope.

"The CMOS detectors have been demonstrated to provide the sensitivity of the multipliers and a dynamic range of over 10¹⁰, overlapping the dynamic range of both historic detector technologies while providing the ability to observe all masses of all isotopes simultaneously," he said. "I feel I can safely predict that this new ion array detector technology will have the same revolutionary impact that optical arrays have already had on OES."

The Future of Speciation

Speciation analysis is an important application area for ICP-MS, and it has been gaining more and more attention, particularly as regulatory expectations for monitoring toxic species of metals (like arsenic in food and chromium in water) are increasing. For complete speciation analysis of unknown compounds, ICP-MS techniques require supplementary structural information provided, for example, by electrospray ionization (ESI)-MS. ESI-MS has long been used for identifying the formulas and structures of organic molecules. And because ESI is a soft ionization source, molecular ions are produced that lead to conclusive structure identification. So we asked our experts, would ESI-MS soon replace hyphenated ICP-MS for quantitative speciation analysis?

The consensus was that it would not, because ICP-MS has some key advantages over ESI-MS for this type of work. ESI-MS is limited by the fact that its ionization efficiency is analyte-dependent, necessitating the use of internal standards for many quantitative analyses. By contrast, atomic ionization sources, such as the ICP, produce ions with almost uniform efficiency and with little or no regard to the initial chemical structure of an element. "This last attribute is incredibly valuable when quantitative analysis is required, particularly if the analyte target of the analysis is unknown or unexpected," said Ray.

Another strength of ICP-MS for speciation analysis, Westphal pointed out, is the ease of combining it with other separation techniques. "The latest improvements in interfaces and software for coupling LC, GC, and ion chromatography (IC) with ICP-MS, together with the comparative ease in quantitation and spectral interpretation using ICP-MS, make it unlikely ESI-MS will replace hyphenated ICP-MS, especially for very low level analyses," he said.

Hanley elaborated on the importance of this factor. Speciation of metallic or metalloid compounds commonly requires some form of ion chromatography, or sometimes ion-pairing reversed-phase chromatography, she noted. To achieve speciation separations with ion chromatography, mobile phases with salts are often used. "Salts, to a certain degree, are easily tolerated when chromatography is coupled with ICP-MS detection," she said. "Resulting LC–ICP-MS speciation methods are robust, reproducible, and have sub-part-per-billion detection limits." In contrast, salts are incompatible with many ESI-MS applications, and their use affects the detection limits and overall robustness of the method.

In addition, ICP-MS has other strengths for speciation, Hanley noted. When speciation is performed with LC–ICP-MS, the detector only generates signal relating to the metallic component corresponding with that particular species-eliminating purely organic compounds with no metallic component from the generated spectra. "This allows for easy analysis of complex samples that can range from biological materials like urine and blood to foods like rice and seafood," she said. In contrast, in LC–ESI-MS, organic components are coeluted with the inorganic species and the inorganic species commonly have m/z values that are too low to be easily detected with ESI-MS. "If LC–ESI-MS were used on the same complex matrices mentioned above, prepared as they typically are for elemental speciation applications, the resulting LC–ESI-MS chromatograms would be too complex to obtain meaningful data because the detector generates a signal for anything that is ionizable."

Given all these factors, several panelists continue to see the techniques as complementary. "I expect that splitting of the column effluent for introduction of one fraction into an ICP-MS unit and the other into an ESI-MS one will become more common," said Vanhaecke.

Koppenaal agreed. "Combined ESI-MS and ICP-MS approaches will continue to be used and applied to effect better speciation analysis," he said. "The benefit of such an approach will be better definition of both elemental and molecular composition."

Tackling Unresolved Problems

We also asked our expert panel what unresolved problems exist-especially with samples in complex matrices-and how ICP-MS methods or technologies can be developed to attack them.

Ray responded with a wise reminder: "Very rarely is there ever a silver bullet solution to complex analytical problems."

Collision cell technology has helped immensely, he said, but as certain problems are solved, the remaining problems become progressively more difficult and less tractable. "Oddly, the solution to many problems with ICP-MS likely falls not on the MS portion, but in the source itself," he said. "More study of ICP-MS as an ionization source is required, particularly as it will be applied in laser-ablation and nanoparticle applications."

Westphal pointed back to sample handling. "It's now possible to use ICP-MS to analyze high total dissolved solids samples directly at levels on par with ICP-OES, but carryover and subsequent raised instrument background levels mean we can't analyze percent and low parts-per-trillion levels easily on the same instrument, even with dedicated sample introduction systems," he said. Nevertheless, he feels that for most applications in his industrial R&D environment, existing instrumentation has sufficient detection limits. "Although I'd always want it to be faster, better, and cheaper," he added.

The majority of remaining unresolved problems relate to interference removal, Hanley said, with multiply charged interferences remaining an inherent problem of ICP. Although the introduction of the collision–reaction cell greatly enhanced the ability to reduce isobaric interferences, interference removal with the CRC is matrix-dependent in single-quadrupole ICP-MS instruments, she noted-anything ionized that enters the CRC will affect the reproducibility and robustness of the cell reaction.

"As a result, the introduction of the triple-quadrupole ICP-MS system has been revolutionary in combating doubly charged, isobaric, and background noise interferences without losing sensitivity," she said. In a triple-quadrupole ICP-MS instrument, she explained, ionized matrix is removed in the first quadrupole, and isobaric and multiply charged interferences can be removed or reduced in the CRC, leaving the second quadrupole as a mass filter.

Triple-quadrupole ICP-MS instrumentation has its place, said Koppenaal, but it likely won't be the ultimate panacea. "New, integrated methods for sample preparation and instrumental analysis must be developed," he said. "For too long, instrument manufacturers have approached this issue as two separate problems, and have treated them as such-letting smaller, independent companies handle the sample handling issues while they focus only on the instrumentation itself."

The Future

So, we asked our panelists, what other developments in this technique, its instrumentation, or application areas are we likely to see in the near future?

"Some aspects of development are side effects of iterative improvement: faster analysis, cheaper instrumentation, more accurate analytical results on smaller aliquots of sample," noted Ray. "These, and other, capabilities will continue to improve."

Still, he agreed with Denton and Vanhaecke on the need for one key development: a simultaneous multielemental ICP-MS instrument. "This is true for much the same reasons that polychromators have virtually taken over ICP-OES," he said. "In the future, a true multielemental, multi-isotopic simultaneous MS platform will catch the current offerings, and exceed their capabilities," he predicted.

Vanhaecke agreed. In bioimaging, he noted, two-dimensional tissue scanning has improved because laser ablation cells have improved, accelerating sample throughput and improving spatial resolution. This means that what is hindering research in this field, he said, is the limitations of scanning-type ICP-MS instruments. "Together with the demands of those involved in nanoparticle analysis, this need in bioimaging should be a strong incentive for instrument manufacturers to invest in the further development of simultaneous or semisimultaneous ICP-MS instrumentation," he said.

Westphal also joined the call for instruments capable of simultaneous detection. Currently, he said, sequential MS systems typically force the user to select certain isotopes to measure in advance before a sample has even been analyzed. This means that if an unexpected interference arises, the analyst has to go back and repeat the entire analysis.

"With the faster MS systems now, it will be interesting to see if this situation can be reversed for fully quantitative (not semiquant) analyses for routine samples-where the analyst could collect all of the data upfront and determine afterwards which elements and isotopes to report," he said. "At the very least, it would be nice to have 'smart software' that takes advantage of information that is currently available about known interferences and proposes changes during an analysis when interferences are found."

Koppenaal agreed that simultaneous multielement detection is needed. He feels that systems using CMOS array detectors still need some time to be fully successful, but that they will develop as analysts realize the significant advantages they provide. He pointed to other developments, such as distance-of-flight mass spectrometry (DOF-MS), that also offer near simultaneous detection across small mass ranges and offer other advantages relative to the more familiar TOF-MS. "I think this is also an exciting new technology that needs to be further developed and applied," he said. "It also offers ability to collect isolated amounts of separated analytes at a preparative (milligram) level."

Hanley reiterated her desire to see an instrument with twin MS detectors, one for elemental and one for molecular MS detection. "Prototypes have been made, and such an instrument is likely to be a competitor in commercial markets," she said.

She also thinks that the use of hyphenated ICP-MS techniques for metallic nanoparticle characterization will transition from being a research tool into routine analysis. "Various peer-reviewed publications show how ICP-MS, hyphenated with techniques such as field-flow fractionation, high performance liquid chromatography, and capillary electrophoresis, can achieve nanoparticle characterization at detection limits not achievable by spectroscopic methods like UV–vis or dynamic light scattering," she said. "And sample introduction devices for single-particle detection have been developed in research applications."

Vanhaecke foresees advances in another area of biomedical analysis. "A few labs (including mine) are currently exploring the use of high-precision isotopic analysis of mineral elements in a medical context," he said. It is now known, he said, that some diseases measurably affect the isotopic composition of some of these elements in human biofluids. Research in this area could lead to diagnosis of diseases that can otherwise only be established at a later stage or via a more invasive method. "I am undoubtedly biased, but see important novel applications in this field," he concluded.

Westphal hopes we will see more advances in software and data processing tools. He is pleased to see that a lot of improvement has been made with software and interfaces for hyphenated techniques, and more recently, software modules for nanoparticle analysis. He would like to see the same for laser ablation. "Laser ablation is an area where similar improvements would be welcome, as data processing and analysis is the current bottleneck," he said. "The ability to obtain quantitative data by LA-ICP-MS for 2D and 3D chemical imaging is an exciting area of research with a broad range of application areas, and is a complementary technique to LA-ESI-MS and TOF-SIMS."

Hanley foresees another development in laser-ablation techniques: internal and quantification standards for LA-ICP-MS techniques. "New LA-ICP-MS standards have been beta-tested to determine their effectiveness as internal and quantitation standards," she said.

Conclusion

Significant advances in ICP-MS instrumentation have been made in recent years. Collision–reaction cells and triple-quadrupole instruments have significantly reduced spectral interference. More advanced detectors based on CMOS technology have been developed. Microfluidics has improved plasma source instrumentation, lowering the levels of sample and matrix introduced into the instruments, and has advanced single-cell analysis. Microelectronics has enabled faster data acquisition and improved data storage, making trace levels of detection possible and leading to the development of high-performance CMOS detectors. Indeed, with the ultratrace capabilities of today's instruments, sample preparation becomes the limiting factor in many types of analysis, driving improvements in reagents and vessels and increased use of cleanrooms, closed vessel sample preparation systems, and automation.

Developments in ICP-MS technology are also advancing key applications. Powerful ICP-MS techniques are enabling parts-per-billion analysis of nanoparticle concentration, size, and size distribution, which is essential as researchers, regulators, and consumers seek to understand the fate of nanoparticles in the environment and in food, and the potential impact of biological exposure. ICP-MS is also critical in metallomics and in the advanced study of single cells, through mass cytometry. Geochronology, meanwhile, has also moved forward as a result of developments in ICP-MS systems, in this case multicollector sector-field MS instruments that have enabled more accurate and precise isotope ratio precision measurements. Speciation also continues to advance, with ESI-MS providing some complementary information to ICP-MS data.

For the future, a much desired future development is instrumentation that can simultaneously detect a wide range of elements. Detectors using CMOS technology are already in the process of moving this concept from dream to reality, but distance-of-flight or time-of-flight detectors may reach that goal first. There is also a desire to see instrumentation that includes twin MS detectors, one for elemental and one for molecular detection.

Acknowledgments

I would like to thank Ramon Barnes for his excellent guidance and advice throughout the process of preparing this article.

Laura Bush is the editorial director of Spectroscopy.