Laser Ablation Inductively Coupled Plasma Time-of-flight Mass Spectrometry Research Articles

LA-ICP-TOFMS ImagingReveals Significant Influenceof Cancer Cell Resistance on Oxaliplatin Compartmentalization in theTumor Microenvironment

Chemoresistance incancer cells, particularly in refractorytypes,such as colorectal cancer, poses a major challenge to effective treatment.In particular, the interaction between cancer cells and the tumormicroenvironment (TME) has been shown to exert substantial influenceon the efficacy of therapeutic agents. This study investigated whetheran intrinsic resistance phenotype alters drug distribution in theTME using xenograft models derived from HCT116 colorectal cancer cells,including oxaliplatin (OxPt)-sensitive and OxPt-resistant (OxR) variants.Tumors were prepared as formalin-fixed paraffin-embedded (FFPE) sections,followed by single-cell analysis with laser ablation inductively coupledplasma time-of-flight mass spectrometry (LA-ICP-TOFMS). Based on histologicalevaluations, a panel of metal-conjugated antibodies was designed totarget tissue architecture and distinct cell states within the TME.A dedicated calibration strategy was applied to accurately measureplatinum (Pt) uptake in phenotypically defined single cells acrossboth the tumor and its microenvironment. The results revealed substantialstructural differences: HCT116/OxR tumors exhibited robust growthfollowing drug administration, while parental tumors displayed extensivedegradation. Notably, OxPt accumulated significantly in necrotic regionsspecific to HCT116/OxR, indicating resistance-dependent changes indrug compartmentalization. These findings suggest that an intrinsicallyresistant cancer cell phenotype is capable of markedly altering metaldistributions within the TME.

Evaluating the feasibility of LA-ICP-TOF-MS for the analysis of environmental particle collections

Laser ablation-inductively coupled plasma-time-of-flight-mass spectrometry (LA-ICP-TOF-MS) was employed to rapidly analyze environmental particle samples collected using aerosol contaminate extractors (ACE).

Detection of Li in synthetic slags of Li-ion batteries by laser ablation inductively coupled plasma time of flight mass spectrometry (LA-ICP-ToF-MS)

Accurate phase determination of Li-containing compounds by a combination of X-ray and mass spectrometry.

Occurrence and enrichment of critical metals in ferromanganese deposits in the western Pacific

Occurrence and enrichment of critical metals in ferromanganese deposits in the western Pacific

Advancing elemental analysis by collision/reaction cell technology and micro-droplet calibration for bioimaging applications by LA-ICP-TOFMS

BackgroundBioimaging applications by laser ablation inductively coupled plasma time-of-flight mass spectrometry (LA-ICP-TOFMS) require comprehensive elemental analysis spanning the entire mass range. Within biological systems, endogenous elements are critical for maintaining metal homeostasis in cells, a fundamental aspect in disease progression when disrupted. Additionally, elements from the higher mass range may originate from various sources such as metal-tags for immuno-mass spectrometry, nanoparticles, or metal-based anticancer drugs. This study assesses the efficacy of collision/reacton cell (CCT) mode for simultaneously analysing elements across the complete mass spectrum. Furthermore, we demonstrate the accuracy of the LA-ICP-TOFMS methodology through the analysis of serum reference material. ResultsOur findings demonstrate that the CCT mode outperforms the standard/no gas mode for LA-ICP-TOFMS measurements, particularly in quantifying endogenous elements susceptible to interferences. Through the analysis of picolitre-volume micro-droplet standards and serum reference material (deposited as micro-droplets), we observed accurate quantification of elements such as iron and selenium, with isotope ratios closely resembling natural compositions. As key advantage, the utilization of the CCT mode eliminated the need for labor-intensive post-data processing, streamlining analytical procedures. Additionally, the CCT mode also provided enhanced sensitivity (factor of 1.5–2) for elements in the higher mass range compared to the standard mode, without compromising the sensitivity for endogenous elements. SignificanceWe successfully integrated Seronorm serum reference material-containing micro-droplets into LA-ICPMS bioimaging workflows for quality control, enabling validated measurements of key biological elements. The use of the CCT mode is highly recommended for bioimaging applications that address the analysis of elements across the entire mass range.

Semi-quantitative elemental imaging of corrosion products from bioabsorbable Mg vascular implants in vivo

Semi-quantitative elemental imaging of corrosion products from bioabsorbable Mg vascular implants in vivo

Abstract 4949: Multimodal analysis of metals, spatial transcriptomics, and histological structures in colorectal cancer

Abstract Colorectal Cancer (CRC) accounts for nearly 10% of all cancer cases and is the second-leading cause of cancer-related deaths worldwide. The increased incidence of CRC in younger demographics underscores the need for improved screening and prognostication. These enhancements are crucial to augment staging practices which focus on accurate evaluation of local lymph node involvement and distant metastasis. Essential trace elements such as copper and iron within the tumor microenvironment (TME) present novel therapeutic strategies- e.g., copper in cell proliferation/signaling and iron in pro-tumorigenic pathways, amongst other multifaceted roles. Despite advancements in spatial imaging/sequencing for detailed mapping of elemental abundance and gene expression profiles at near-subcellular resolution, the understanding of metal signaling and transport pathways in tumors is limited. This gap highlights the need for sophisticated informatics software for data integration and analysis. We developed a computational workflow for spatial multimodal analysis of elements, genes, cell-types, and histological features, applied to a unique CRC case (pT3) as proof-of-concept. Elemental imaging at 5-micron resolution was performed using laser ablation inductively coupled plasma time-of-flight mass spectrometry (LA-ICPTOF-MS). The 10x Genomics Visium spatial transcriptomic (ST) CytAssist assay captured spatial variation in gene expression within 55-micron spots, with 40X H&E-stained whole slide imaging (Leica Aperio GT450). Cell type proportions within spots were determined through integration of single cell RNASeq. Regions within, around and away from tumor were annotated by a pathologist. ST and LA-ICPTOF-MS were integrated through co-registration software developed at Biomedical National Elemental Imaging Resource. Local Getis-Ord spatial statistics defined hotspots with high elemental concentration. Wilcoxon tests were used to perform differential expression analysis based on metal hotspots, followed by identification of associated biological pathways through Enrichr with Bonferroni adjustment. Preliminary findings revealed distinct trace element distributions in the TME. For instance, Copper was localized within tumor, correlating with pathways related to immune response and activation (overlap=10/89, p<0.0001). Iron was found concentrated at the proliferative front of the tumor, associated with the epithelial to mesenchymal transition pathway and extracellular matrix remodeling (overlap=25/291, p<0.0001), as well as with a mesenchymal phenotype (W=11.7, p<0.0001), identified through cell type deconvolution. Future work will expand on these findings across multiple tissue contexts as means to capture biological processes governing tumor metastasis, recurrence and survival for biomarker discovery and therapeutics development. Citation Format: Aruesha Srivastava, Neha Shaik, Yunrui Lu, Matthew Chan, Alos Diallo, Serin Han, Ramsey Steiner, Tracy Punshon, Brian Jackson, Linda Vahdat, Louis Vaickus, Jack Hoopes, Fred Kolling, Jonathan Marotti, Joshua Levy. Multimodal analysis of metals, spatial transcriptomics, and histological structures in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4949.

Multimodal analytical tools for the molecular and elemental characterisation of lesions in brain tissue of multiple sclerosis patients

Multimodal analytical tools for the molecular and elemental characterisation of lesions in brain tissue of multiple sclerosis patients

Improving spatially-resolved lithium quantification in drill core samples of spodumene pegmatite by using laser-induced breakdown spectroscopy and pixel-matched reference areas

Improving spatially-resolved lithium quantification in drill core samples of spodumene pegmatite by using laser-induced breakdown spectroscopy and pixel-matched reference areas

Fluid-rock interaction, skarn genesis, and hydrothermal alteration within an upper crustal fault zone (Island of Elba, Italy)

Fluid-rock interaction, skarn genesis, and hydrothermal alteration within an upper crustal fault zone (Island of Elba, Italy)

Quantitative elemental mapping of chondritic meteorites using laser ablation-inductively coupled plasma-time of flight-mass spectrometry (LA-ICP-TOF-MS)

Fast-(semi)quantitative elemental mapping using state-of-the-art laser ablation-inductively coupled plasma-time of flight-mass spectrometry (LA-ICP-TOF-MS) was applied to a set of chondritic meteorite samples.

The copper transporter CTR1 and cisplatin accumulation at the single-cell level by LA-ICP-TOFMS.

More than a decade ago, studies on cellular cisplatin accumulation via active membrane transport established the role of the high affinity copper uptake protein 1 (CTR1) as a main uptake route besides passive diffusion. In this work, CTR1 expression, cisplatin accumulation and intracellular copper concentration was assessed for single cells revisiting the case of CTR1 in the context of acquired cisplatin resistance. The single-cell workflow designed for in vitro experiments enabled quantitative imaging at resolutions down to 1µm by laser ablation-inductively coupled plasma-time-of-flight mass spectrometry (LA-ICP-TOFMS). Cisplatin-sensitive ovarian carcinoma cells A2780 as compared to the cisplatin-resistant subline A2780cis were investigated. Intracellular cisplatin and copper levels were absolutely quantified for thousands of individual cells, while for CTR1, relative differences of total CTR1 versus plasma membrane-bound CTR1 were determined. A markedly decreased intracellular cisplatin concentration accompanied by reduced copper concentrations was observed for single A2780cis cells, along with a distinctly reduced (total) CTR1 level as compared to the parental cell model. Interestingly, a significantly different proportion of plasma membrane-bound versus total CTR1 in untreated A2780 as compared to A2780cis cells was observed. This proportion changed in both models upon cisplatin exposure. Statistical analysis revealed a significant correlation between total and plasma membrane-bound CTR1 expression and cisplatin accumulation at the single-cell level in both A2780 and A2780cis cells. Thus, our study recapitulates the crosstalk of copper homeostasis and cisplatin uptake, and also indicates a complex interplay between subcellular CTR1 localization and cellular cisplatin accumulation as a driver for acquired resistance development.

Quantification in bioimaging by LA-ICPMS - Evaluation of isotope dilution and standard addition enabled by micro-droplets

Quantification in bioimaging by LA-ICPMS - Evaluation of isotope dilution and standard addition enabled by micro-droplets

Accumulation of molybdenum in major organs following repeated oral administration of bis-choline tetrathiomolybdate in the Sprague Dawley rat.

Molybdenum is an essential dietary trace element required for several critical enzyme systems. High intake is associated with toxicity in ruminants and animal studies. The proposed therapeutic use of molybdenum-based drugs poses a potential risk for accumulation through chronic administration of therapeutic doses of this element. The current experiment was designed to study the effect of daily dosing of a molybdenum compound, bis-choline tetrathiomolybdate (TTM), in Sprague Dawley rats using laser ablation inductively coupled plasma time-of-flight mass spectrometry (LA-ICP-ToF-MS) and two dosing levels of TTM for up to 3months. To investigate if molybdenum accumulation was associated with tissue toxicity, histopathology, haematology and clinical biochemistry markers of toxicity were incorporated into the study design. There were no behavioural signs of toxicity to the rats, and no clinical or anatomic pathology was associated with treatment. The current data did show a progressive accumulation of molybdenum within the adrenal gland, kidneys, liver, spleen, brain and testes. Although this was not associated with tissue toxicity within the 3-month study design, greater exposure over a longer period of time has the potential for producing adverse pathophysiological cellular function. Tissue toxicity, as a result of local excessive accumulation of molybdenum over time, has clear implications for the therapeutic use of molybdenum in humans and demands sensitive monitoring of tissue molybdenum levels to avoid toxicity. The current study highlights the shortcomings of conventional biomonitoring approaches to detect molybdenum accumulation with the goal of avoiding molybdenum-associated toxicity.

Elemental Mapping of Human Malignant Mesothelioma Tissue Samples Using High-Speed LA-ICP-TOFMS Imaging.

This is the first report of the use of laser ablation–inductively coupled plasma time-of-flight mass spectrometry (LA–ICP–TOFMS) to analyze human malignant pleural mesothelioma (MPM) samples at the cellular level. MPM is an aggressive, incurable cancer associated with asbestos exposure, with a long latency and poor overall survival. Following careful optimization of the laser fluence, the simultaneous ablation of soft biological tissue and hard mineral fibers was possible, allowing the spatial detection of elements such as Si, Mg, Ca, and Fe, which are also present in the glass substrate. A low-dispersion LA setup was employed, which provided the high spatial resolution necessary to identify the asbestos fibers and fiber fragments in the tissue and to characterize the metallome at the cellular level (a pixel size of 2 μm), with a high speed (at 250 Hz). The multielement LA–ICP–TOFMS imaging approach enabled (i) the detection of asbestos fibers/mineral impurities within the MPM tissue samples of patients, (ii) the visualization of the tissue structure with the endogenous elemental pattern at high spatial resolution, and (iii) obtaining insights into the metallome of MPM patients with different pathologies in a single analysis run. Asbestos and other mineral fibers were detected in the lung and pleura tissue of MPM patients, respectively, based on their multielement pattern (Si, Mg, Ca, Fe, and Sr). Interestingly, strontium was detected in asbestos fibers, suggesting a link between this potential toxic element and MPM pathogenesis. Furthermore, monitoring the metallome around the talc deposit regions (characterized by elevated levels of Al, Mg, and Si) revealed significant tissue damage and inflammation caused by talc pleurodesis. LA–ICP–TOFMS results correlated to Perls’ Prussian blue and histological staining of the corresponding serial sections. Ultimately, the ultra-high-speed and high-spatial-resolution capabilities of this novel LA–ICP–TOFMS setup may become an important clinical tool for simultaneous asbestos detection, metallome monitoring, and biomarker identification.

Strain-induced trace element mobility in a quartz-sulphide vein system: An example from the ONKALO™ spent nuclear fuel repository (Olkiluoto, SW Finland)

Strain-induced trace element mobility in a quartz-sulphide vein system: An example from the ONKALO™ spent nuclear fuel repository (Olkiluoto, SW Finland)

Micro-droplet-based calibration for quantitative elemental bioimaging by LA-ICPMS

In this work, a novel standardization strategy for quantitative elemental bioimaging is evaluated. More specifically, multi-element quantification by laser ablation-inductively coupled plasma-time-of-flight mass spectrometry (LA-ICP-TOFMS) is performed by multi-point calibration using gelatin-based micro-droplet standards and validated using in-house produced reference materials. Fully automated deposition of micro-droplets by micro-spotting ensured precise standard volumes of 400 ± 5 pL resulting in droplet sizes of around 200 μm in diameter. The small dimensions of the micro-droplet standards and the use of a low-dispersion laser ablation setup reduced the analysis time required for calibration by LA-ICPMS significantly. Therefore, as a key advance, high-throughput analysis (pixel acquisition rates of more than 200 Hz) enabled to establish imaging measurement sequences with quality control- and standardization samples comparable to solution-based quantification exercises by ICP-MS. Analytical figures of merit such as limit of detection, precision, and accuracy of the calibration approach were assessed for platinum and for elements with biological key functions from the lower mass range (phosphorus, copper, and zinc). As a proof-of-concept application, the tool-set was employed to investigate the accumulation of metal-based anticancer drugs in multicellular tumor spheroid models at clinically relevant concentrations.Graphical abstract

Identification of growth mechanisms in metamorphic garnet by high-resolution trace element mapping with LA-ICP-TOFMS

Garnet is one of the most robust and ubiquitous minerals that record element zoning during crustal metamorphism. In addition to major elements, zoning in trace elements can provide a wealth of information to document the changing conditions of garnet growth and modification. However, mapping trace elements at low concentrations, over large areas and with high resolution has remained a major challenge. We present a comprehensive investigation of the TE distribution in garnet from three Alpine samples that underwent a complex evolution at different metamorphic conditions. The TE distribution in garnet grains is mapped in 2D in thin section with a novel approach using laser ablation inductively coupled plasma time of flight mass spectrometry (LA-ICP-TOFMS) to achieve a lateral resolution of 5 µm and limits of detection for the heavy rare earth elements (REE) down to 0.2 µg/g. Comparison with major element zoning measured by electron probe microanalysis and trace elements measured by conventional LA-ICPMS spot analysis testifies to the accuracy of the measurements. Garnet in an amphibolite-facies metapelite from Campolungo, Central Alps, that recorded metamorphism to 600 °C preserves Y + REE trace element zoning that closely matches that of Ca. In this sample, there is no notable diffusive modification for trace elements. Y + REE zoning is dominated by Rayleigh fractionation in the core and by the sporadic breakdown of accessory phases producing annuli in the rim of the garnet. A granulite-facies garnet from Malenco, Eastern Central Alps, formed during subsolidus heating, followed by peritectic melting reactions up to temperatures of 800–850 °C. Major and trace element zoning are decoupled indicating diffusional resetting of major elements, whereas trace elements still largely document the growth history. Enrichment of trace elements in the garnet mantle may be related to the consumption of biotite (V, Cr) and the dissolution of zircon (Zr) and monazite (Y + REE) in the melt. Diffusion of Y + HREE at the core–mantle boundary occurred over a length scale of ~ 200 µm. Garnet in an eclogite from the Sesia Zone, Western Alps (P ~ 2 GPa, T ~ 600 °C), displays pronounced fluid-related veinlets, visible in FeO, MgO and MnO, which cross-cut the primary growth zoning. Surprisingly, complex Y + REE and Cr zoning is not affected by the veinlets, indicating that they did not form by a crack-seal mechanism but are rather related to a selective replacement process. The trace element maps provide a detailed insight into the growth and modification of garnet and thus allow assessment of equilibrium versus disequilibrium processes, and assist in determination of P–T conditions, garnet dating, diffusion modelling as well as documenting fluid-induced modifications.

Coal Discrimination Analysis Using Tandem Laser-Induced Breakdown Spectroscopy and Laser Ablation Inductively Coupled Plasma Time-of-Flight Mass Spectrometry.

The contribution and impact of combined laser ablation inductively coupled plasma time-of-flight mass spectrometry (LA-ICP-TOF-MS) and laser-induced breakdown spectroscopy (LIBS) were evaluated for the discrimination analysis of different coal samples. This tandem approach allows simultaneous determination of major and minor elements (C, H, Si, Ca, Al, Mg, etc.) and trace elements (V, Ba, Pb, U, etc.) in the coal. The research focused on coal-classification strategies based on principle component analysis (PCA) combined with K-means clustering, partial least-squares discrimination analysis (PLS-DA), and support vector machine (SVM) for analytical performance. Correlation analyses performed from TOF mass and LIBS emission spectra from the coal samples showed that most major, minor, and trace element emissions had negative correlation with the volatile content. Suitable variables for the classification models were determined from these data. The individual TOF data, LIBS data, and combined data of TOF and LIBS as the inputs for different models were analyzed and compared. In all cases, the results obtained with the combined TOF and LIBS data were found to be superior to those obtained with the individual TOF or LIBS data. The nonlinear SVM model combined with TOF and LIBS data provided the best coal-classification performance, with a classification accuracy of up to 98%.

U–Pb Dating of Zircon and Zirconolite Inclusions in Marble-Hosted Gem-Quality Ruby and Spinel from Mogok, Myanmar

The Mogok area in Myanmar (Burma) is known since historic times as a source for some of the finest rubies and spinels in the world. In this study, we focus on in-situ U–Pb geochronological analyses of zircon and zirconolite, either present as inclusions in gem-quality ruby and spinel or as accessory minerals in ruby- and spinel-bearing marble and adjacent granulite facies gneisses. The age determination was carried out using both laser ablation inductively coupled plasma time-of-flight mass spectrometry (LA-ICP-TOF-MS) and sector-field mass spectrometry (LA-ICP-SF-MS). In addition, we present multi-element data (REE) of zircon and zirconolite collected with LA-ICP-TOF-MS to further characterize these inclusions. Most of the studied zircon grains display growth zoning (core/rim) regardless if as inclusion in gemstones, or as accessory mineral in host rock samples. U–Pb dating was conducted on both core and rim of zircon grains and revealed most ages ranging from ~200 Ma in the core to ~17 Ma in the rim. The youngest U–Pb ages determined from the rim of zircon inclusions in gem-quality ruby and spinel are 22.26 ± 0.36 Ma and 22.88 ± 0.72 Ma, respectively. This agreement in U–Pb ages is interpreted to indicate a simultaneous formation of ruby and spinel in the Mogok area. In ruby- and spinel-bearing marble from Bawlongyi, the youngest zircon age was determined as 17.11 ± 0.22 Ma. Furthermore, U–Pb age measured on the rim of zircon grains in a biotite-garnet gneiss reveals a Late Oligocene age (26.13 ± 1.24 Ma), however older ages up to Precambrian age were also recorded in the cores of zircon as accessory minerals from this gneiss. These old ages point to a detrital origin of the analysed zircon cores. Although non-matrix matched standard was applied, zirconolite U–Pb age results are narrower in distribution from ~35 Ma to ~17 Ma, falling within the range of zircon ages. Based on results which are well in accordance with previous geochronological data from the Mogok Metamorphic Belt (MMB), we deduce that gem-quality ruby and spinel from Mogok probably formed during a granulite-facies regional metamorphic event in Oligocene to Early Miocene, related to post collision tectonics of the Eurasian and Indian plates. Our data not only provide key information to understand the formation of gem-quality ruby and spinel in the so-called Mogok Stone Tract, but also provide assisting evidence when determining the country of origin of gemstones in gemmological laboratories.