bettmer_thermo_2019When you think of what techniques might be useful for analyzing single cells, ICP-MS is not an immediately obvious choice. However, with its sensitivity, versatile sample introduction capability and selectivity for measuring a wide range of elements, including biologically important ones such as phosphorus and sulphur, it turns out to be very useful indeed. This technique is particularly suitable for analysing the interaction of potentially toxic metal based nanomaterials with biological systems and for the study and development of metal-ion based drugs for treating diseases such as cancer, where the take up of drug molecules into individual cells can be clearly detected. By tagging antibodies with metal ions and then culturing cells with these antibodies, ICP-MS can also be used to track cells which the tagged antibodies have bound to.

In this interview, Professor Jörg Bettmer describes how ICP-MS can complement and help to advance research and development in the fast growing field of single cell analysis.

Could you introduce yourself and where you work please?

My name is Jörg Bettmer and since 2007 I have been working at the University of Oviedo in Northern Spain. In my professional life, I have experienced great luck to work with some ICP-MS gurus, namely with Professor Klaus Heumann at the University of Mainz, Germany, from the year 2000 to 2007 and afterwards with Professor Alfredo Sanz-Medel in Oviedo. However, my very first “physical” contact with ICP-MS dated back to the year 1996, right after defending my PhD, when I spent a few months in the laboratory of Professor Ryszard Lobinski, another ICP-MS and metallomics guru, at that time at the University of Bordeaux, France. Until my arrival at his laboratory, I had been working on the development of analytical techniques applying atomic emission spectrometry with a microwave-induced plasma based on the famous Beenakker cavity and, due to my ignorance, I was really amazed that a plasma could sustain more than traces of water. Since then, ICP-MS has played an utmost important role in my research activities.

What are your main research areas?

Within our research group “Mass Spectrometry and Biomedical Analysis” at the University of Oviedo, we are developing analytical methods based on mass spectrometry useful for interdisciplinary studies in areas related to medicine, pharmacology and microbiology, among others. During the last few years, we have focused our research work on the analysis of small objects like nanomaterials and individual cells. Our interest here is to study the interaction of nanomaterials with biological systems and the use of different nanomaterials for drug delivery. For this purpose, ICP-MS based approaches are under development to track these materials in biological species.

Could you tell me more about what single cell analysis is?

Thanks to the development of more and more sensitive analytical techniques, the chemical analysis of individual cells has become feasible and popular. The idea behind it is to characterise each small object in terms of its chemical composition. The analytes of interest can be proteins, metabolites or elements among others. The analysis of larger cell populations result in an average concentration of the sought species without taking into account the individual biological variability and exactly this important information can be given by the analysis of individual cells. Therefore, single cell analysis can provide data on the concentration of one or more chemical compounds, so that their mass distribution can be correlated to a specific cell physiology.

Another disadvantage of bulk analyses, at least for elemental determinations, is that the analytical results can be easily biased due to potential contamination from cell media. This risk is minimised in the case of single cell ICP-MS. The reason can be found in the basic principle of this technique. In single cell ICP-MS, a highly diluted cell suspension is introduced into the ionisation source in order to guarantee that only one cell enters the plasma at a given moment. This cell forms an ion cloud (with a duration of approximately 500 µs), resulting in a short detector signal called an event (see Figures 1 and 2).

Figure 1.  Schematic showing individual cell entry into the plasma and the corresponding transient signal.

Figure 2.  Typical time resolved signal trace generated with single cell ICP-MS analysis.

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In combination with short detector integration times (≤ 10 ms) individual signals can be easily distinguished. The resulting time-resolved measurements show that: i) the signal background is related to dissolved species of the sought element not attached to the cells, ii) the number of signals (events) can be correlated to the cell number concentration, and iii) the net signal intensity of the event can be associated to the elemental mass in each individual cell.

What benefits do you see with triple quadrupole compared to single quadrupole ICP-MS?

Triple quadrupole ICP-MS does provide two main advantages over traditional single quadrupole instruments equipped with a reaction/collision cell: selectivity and sensitivity. First of all, spectral interferences (e.g. 40Ar40Ar+ on 80Se+) can be much better controlled as the first quadrupole (Q1) allows all ionic species generated in the plasma source other than the target mass (or a narrow range of masses close to the target mass) to be eliminated prior to the ion beam entering the reaction cell (second quadrupole, Q2). Then, the reaction/collision cell gives – in a better controlled way than with single quadrupole instruments – a number of possibilities for eliminating the spectral interference prior to transmitting the target analyte into the mass analyser quadrupole (Q3). In the case of selenium, you might choose a selective reaction with pure oxygen in order to form 80Se16O+ (m/z = 96 Da). Amazingly, with the latest instrumentation available, ion transmission is maintained at a very high level, enabling excellent detection limits to be achieved. The high sensitivity achievable is the second main advantage, especially for critical ICP-MS elements like phosphorous, titanium, arsenic, and selenium, among others. In my opinion, triple quadrupole ICP-MS is nowadays the ultimate choice for trace and ultratrace analysis of elements that are strongly hampered by spectral interferences.

How does triple quadrupole ICP-MS meet your analytical demands?

As I mentioned before, the high sensitivity and selectivity of the triple quadrupole ICP-MS offers us the ability to analyse elements that are traditionally difficult in ICP-MS. In our laboratory, we routinely determine elements like phosphorous, iron, copper, selenium, etc. in the context of single cell analysis. The gain in sensitivity, for instance, allows us to now use phosphorous as an excellent ICP-MS cell marker. Moreover, nanomaterials that can be found in many consumer products, such as titanium dioxide (TiO2, known as food additive E171), are under debate due to a lack of scientific data over its harmfulness. Thanks to the triple quadrupole ICP-MS, we were able to develop an analytical method that can support the characterisation of these nanomaterials in food products.

How do you see single cell analysis using ICP-MS evolving in the future?

In recent years, single cell ICP-MS has already made some important improvements in order to be considered relatively soon as a routine analytical technique. Fit for purpose sample introduction systems are under development that might guarantee analyses of the highest quality. Although enormous progress has been seen on the instrumental market, even more sensitivity would be welcome, together with fast-scanning or simultaneous detection systems that can provide multi-element determinations in individual cells. In my opinion, a critical point will be to convince scientists from other disciplines (microbiology, pharmaceutics, medicine, etc.) of the usefulness of this technique. The added value such a technique can give needs to be projected by us, the analytical chemists developing these techniques. I think that a similar technique called mass cytometry developed some ten years ago has shown the way how such a technique can enter disciplines that were not necessarily associated with ICP-MS analysis. Another potential market for single cell analysis might be the pharmaceutical and nutrition industries. Yeast cells, for instance, serve as nutritional supplements, in which essential elements like calcium or selenium are enriched. Here, single cell ICP-MS serves as an excellent tool to monitor these enrichment procedures and the intracellular accumulation. For the pharmaceutical industry, it might be very interesting to investigate to which extent drugs (containing any hetero-element that can be detected by ICP-MS) enter different cells. Single cell ICP-MS can provide an answer to this question and many more.

Thank you Jörg for your illuminating insight into single cell analysis and how ICP-MS technology can benefit this rapidly evolving area of analytical science.

To learn more about our complete ICP-MS instrument portfolio, visit our ICP-MS resource page here.  If you have any questions about how to set up nanoparticle or single cell analysis in your laboratory, or you’d like advice on how to solve your ICP-MS interference challenges, let us know via the comments box below!

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