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Final Report Summary - FIRST (Fundamental investigations of high-resolution LA-ICPMS: Fast Imaging – Resolution, Sensitivity, and Time (FIRST))

Laser-ablation inductively coupled plasma mass spectrometry (LA-ICPMS) is a powerful analytical method for the quantitative and semi-quantitative determination of elemental concentrations in solid materials. Initially, this method was used for bulk- or micro-analysis of targeted domains in solid materials. In recent years, LA-ICPMS has increasingly been used to measure the spatial distribution of elements across a sample surface, i.e. for measuring elemental images of samples. In fact, elemental imaging of specimens such as biological tissues or thin rock sections with LA-ICPMS is quickly becoming a routine method in many research labs; however, advancements in the basic hardware and methodologies used for LA-ICPMS imaging are still required to meet the demands of many challenging applications. For example, elemental images with high lateral resolution (i.e. <~5 µm) remain challenging to achieve, but are required to measure elemental distributions at a sub-cellular level or to visualize some micro-domains or heterogeneities in geological specimens. In this research, we aimed to overcome the fundamental limitations of conventional LA-ICPMS instrumental setups and imaging methodologies by establishing a new imaging system that combines LA cells designed for low-dispersion aerosol transport with next-generation ICP-time-of-flight mass spectrometry (ICP-TOFMS) instrumentation.

In LA-ICPMS, a pulsed laser beam is focused onto a surface with enough energy to cause the ejection (ablation) of minute quantities of material. The ablated aerosol particles then are transferred online into an ICPMS for mass analysis. To construct a two-dimensional elemental image, the solid sample is scanned beneath a pulsed laser beam and resultant time-dependent ICPMS signals are correlated with laser-spot position. In conventional LA-ICPMS imaging approaches, a high-repetition-rate laser is used to create a continuous stream of ablated aerosol that is measured with a scanning-type mass analyzer, such as a quadrupole-MS (QMS). With ICP-QMS, only one mass-to-charge (m/z) value can be measured at a time, so pseudo steady-state signal from the laser-ablation sampling provides the most representative measurement. This need for quasi-steady-state LA aerosol delivery fundamentally limits the lateral resolution achievable because aerosols from adjacent LA positions mix together and cause an image smearing effect. On the other hand, if the signals from each LA event are measured individually, lateral resolution of the resultant LA-ICPMS image depends directly on the area sampled with each laser shot. Importantly, pulse-resolved LA-ICPMS imaging is not well suited for scanning-based mass analyzer types because these instruments require aerosol cloud durations that are relatively long to ensure representative sampling across the mass-scan period.

In this research project, we demonstrate that low-dispersion LA aerosol transport combined with ICP-TOFMS overcomes many of the limitations of conventional LA-ICPMS imaging approaches in order to provide high-resolution quantitative LA-ICPMS images while also improving the image-collection speed. The specific objectives of this research project were to 1. develop a low-dispersion LA-ICP-TOFMS imaging setup, 2. characterize the performance of this setup for single-shot LA analysis, 3. establish LA-ICP-TOFMS imaging methodologies and characterize its performance, and 4. to apply this elemental imaging approach for the analysis of real geological samples. The development of LA-ICP-TOFMS instrumentation and methodologies was quite successful, and initial results have been recently published (A. Gundlach-Graham, Anal. Chem. 2015. DOI: 10.1021/acs.analchem.5b01196; Burger, M. Anal. Chem. 2015. DOI: 10.1021/acs.analchem.5b01977). Application of this imaging approach to help understand geological processes through visualization of element and isotope distributions in thin rock sections was also performed and a manuscript is in preparation. Below, we briefly summarize critical results and evaluate these results in terms of extant technologies to highlight the potential impacts of the technology developed here.

Low-dispersion LA combined with newly developed higher-sensitivity ICP-TOFMS instrumentation offers a unique pathway to improve detection limits for single-shot LA analysis and elemental imaging. The most recent low-dispersion LA cell developed in the Günther lab delivers laser-ablation aerosols to the ICPMS in packet widths less than 10 ms in duration. Compared to conventional LA cells, which usually deliver aerosols with 0.5-10 s peak durations, the low-dispersion LA cell provides higher instantaneous concentration of analyte into the ICP. This higher instantaneous concentration increases the signal-to-noise (S/N) ratio and thus improves detection limits. Moreover, because TOFMS simultaneously measures all elements within each LA transient, detection limits are improved for all elements without sacrificing multi-element detection capabilities. With the current LA-ICP-TOFMS setup, single-LA shot detection limits down to 0.9 µg/g are possible for a 5-µm LA spot diameter, which translates to absolute detection limits in the 10s of attograms from the ablation of only 10s of picograms of material. This extremely low absolute LOD is especially important for the analysis of precious samples, and emphasizes how LA can be considered a quasi-non-destructive sampling method.

In addition to enhancing detection capabilities, the short duration of signals generated with low-dispersion LA allows for the baseline separation of signals from all LA events at laser frequencies approaching 100 Hz. The ability to use high-repetition-rate LA without sacrificing elemental image resolution or quality dramatically improves the speed of elemental image acquisition and also makes it feasible to collect high-pixel-density and large-area LA-ICP-TOFMS elemental images. For comparison, our current LA-ICP-TOFMS imaging approach can generate full-spectrum elemental images at 100 pixels/s. On the other hand, a reasonable pixel generation rate for conventional LA-ICP-QMS setups is about 4 pixels/s if a limited number of m/z values are measured. A 25x improvement in time-of-analysis is substantial; for instance, a 1 square millimeter sample area imaged at a lateral resolution of 5 µm would take 6.7 min with the LA-ICP-TOFMS setup, but 2.8 hours with a more conventional system.

With ICP-TOFMS, complete elemental spectra are recorded simultaneously and continuously at a spectral generation rate up to 1000 Hz, so that the intensity profiles from each LA event are recorded accurately. This high-speed detection enables excellent pixel registration during image assembly and quantification on a pixel-by-pixel basis. To this end, we have used LA-ICP-TOFMS to demonstrate the possibility of high-speed, quantitative three-dimensional elemental imaging, as well as high-resolution imaging down to a lateral resolution 1.5 µm. In addition to the hardware, significant advancements in data reduction and data processing software were made to generate these elemental images. This initial time investment in software development created a workflow that enables simple application of our methodology to study samples of interest.

In this research, we investigated how low-dispersion LA cell technology combined with LA-ICP-TOFMS can offer substantial improvements and new measurement capabilities for LA-ICPMS imaging. It is our opinion that the development and demonstration of this technology will enable its transfer into multiple disciplines, such as biology and geology, in which elemental imaging is critical to understanding processes of metal and element transport and accumulation. Here, the resolution and speed-of-analysis improvements obtained with low-dispersion LA-ICP-TOFMS imaging are paramount because they allow for improved elemental distribution visualization, dramatically improved sample throughput, and cost savings due to reduced analysis time. The socio-economic impact of this research will be realized as, for example, biologists and geologists employ the technology developed here to better characterize and understand the systems they study.

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Life Sciences
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