Applications of Mass Spectrometry for Clinical Diagnostics: The Influence of Turnaround Time

Abstract

This critical review discusses how the need for reduced clinical turnaround times has influenced chemical instrumentation. We focus on the development of modern mass spectrometry (MS) and its application in clinical diagnosis. With increased functionality that takes advantage of novel front-end modifications and computational capabilities, MS can now be used for non-traditional clinical analyses, including applications in clinical microbiology for bacteria differentiation and in surgical operation rooms. We summarize here recent developments in the field that have enabled such capabilities, which include miniaturization for point-of-care testing, direct complex mixture analysis via ambient ionization, chemical imaging and profiling, and systems integration.

Figure 1.

Current methodology for analyzing clinical samples for diagnostic testing, comparing point-of-care (POC) testing with centralized laboratory analysis.

Figure 2.

Dispersive-SPE workflow for liver samples. Reprinted and modified with permission from Springer Nature: Springer Japan. FORENSIC TOXICOLOGY. Application of modified QuEChERS method to liver samples for forensic toxicological analysis, K. Usui, M. Hashiyada, Y. Hayashizaki, Y. Igari, T. Hosoya, J. Sakai, M. Funayama, Forensic Toxicol. 2014, 1, 139–147, (ref 52). Copyright 2013.

Figure 3.

Recent work in clinical diagnostics using traditional separation techniques with mass spectrometry. (A) Immunocapture methodology for the detection of hIgG1 using streptavidin coated tips with liquid chromatography. Reproduced from C. Lanshoeft, S. Cianférani, O. Heudi, Anal. Chem. 2017, 89, 2628–2635 (ref 62). Copyright 2017 American Chemical Society.; (B) SEC-MS method for enriching and studying extracellular vesicles from biological fluid samples. Reproduced and modified from Optimizing Size Exclusion Chromatography for Extracellular Vesicle Enrichment and Proteomic Analysis from Clinically Relevant Samples, Lane, R.E.; Korbie, D.; Trau, M.; Hill, M.M., Proteomics, Vol. 19, Issue 8 (ref 64). Copyright 2019 Wiley.

Figure 4.

Clinical turnaround time phases. Abbreviations: HIS, Hospital information system.

Figure 5.

Comparison of thermal protection between a 2D DBS and a 3D dried blood spheroid as a function of time. Reproduced from D. E. Damon, M. Yin, D. M. Allen, Y. S. Maher, C. J. Tanny, S. Oyola-Reynoso, B. L. Smith, S. Maher, M. M. Thuo, A. K. Badu-Tawiah, Anal. Chem. 2018, 90, 9353–9358 (ref 82). Copyright 2018 American Chemical Society.

Figure 6.

(A) Summary of ambient ionization methods (outer circle) and their use for studying various clinical samples (middle circle) from different patient types (inner circle). (B) Comparison of a traditional method (LC) with an ambient ionization technique (DESI) for analysis of clinical samples.

Figure 7.

Representative data for ambient ionization methods applied for diagnostic testing. (A) Paper spray-MS workflow for detecting mass spectrometric profiles of bacteria strains from cell and cell lysate samples. Reproduced from C. A. Chamberlain, V. Y. Rubio, T. J. Garrett, Anal. Chem. 2019, 91, 4964–4968 (ref 150). Copyright 2019 American Chemical Society; (B) VAMS-Touch Spray schematic for detecting drugs of abuse from oral fluids. Reproduced from N. M. Morato, V. Pirro, P. W. Fedick, R. G. Cooks, Anal. Chem. 2019, 91, 7450–7457 (ref 165). Copyright 2019 American Chemical Society.

Figure 8.

(A) Metal and blade substrate-based ambient ionization techniques: i) Coated Blade Spray schematic for biofluid analysis. Reprinted with permission from G. A. Gómez-Ríos, M. Tascon, N. Reyes-Garcés, E. Boyacı, J. Poole, J. Pawliszyn, Sci. Rep. 2017, 7, 16104 (ref 151). Copyright 2017. Springer Nature. Creative Commons Attribution 4.0 International License. http://creativecommons.org/licenses/by/4.0/ ; ii) Conventional Touch Spray schematic for liquid and solid sample analysis.; iii) Probe Electrospray Ionization schematic for liquid sample analysis. Reproduced from Development of probe electrospray using a solid needle, Hiraoka, K., Nishidate, K., Mori, K., Asakawa, D., Suzuki, S., Rapid Communications in Mass Spectrometry, Vol. 21, Issue 18 (ref 160). Copyright 2007 Wiley; (B) Cellulose-based materials (paper and thread) utilized for analyzing clinical samples with MS.

Figure 9.

Integrative-MS platforms using traditional biological assays. (A) BEARS-MALDI platform for high throughput analysis using immunoprecipitation to detect renin activity levels. Reproduced from H. Li, R. Popp, M. Chen, E. M. MacNamara, D. Juncker, C. H. Borchers, Anal. Chem. 2017, 89, 3834–3839 (ref 178). Copyright 2017 American Chemical Society; (B) Ambient ionization immunoassay platform utilizing cleavable, rhodamine-based mass tags for multiplexed analysis for various cancer antigens. Reproduced from S. Xu, W. Ma, Y. Bai, H. Liu, J. Am. Chem. Soc. 2019, 141, 72–75 (ref 181). Copyright 2019 American Chemical Society. (C) Summary workflow for the analysis of breast cancer stem cells using a DSN-mediated amplification strategy with streptavidin-bound agarose beads for signal enhancement. Reproduced from Y. Kuang, J. Cao, F. Xu, Y. Chen, Anal. Chem. 2019, 91, 8820–8826 (ref 193). Copyright 2019 American Chemical Society.

Figure 10.

Ambient ionization techniques used for tissue profiling studies. (A) Rapid evaporative ionization mass spectrometry or iKnife, (B) MasSpec Pen, and (C) SpiderMass.

Figure 11.

Mass Spectrometry Imaging Studies. (A) Glycoprotein capture methodology coupled to MALDI for the detection of N-glycans from biological fluid samples. Reproduced from A. P. Black, H. Liang, C. A. West, M. Wang, H. P. Herrera, B. B. Haab, P. M. Angel, R. R. Drake, A. S. Mehta, Anal. Chem. 2019, 91, 8429–8435 (ref 214). Copyright 2019 American Chemical Society. (B) SIMS imaging profiles for various anionic lipid species in brain tissues. Reproduced from H. Tian, L. J. Sparvero, A. A. Amoscato, A. Bloom, H. Bayır, V. E. Kagan, N. Winograd, Anal. Chem. 2017, 89, 4611–4619 (ref 226). Copyright 2017 American Chemical Society.

Figure 12.

Clinical diagnostics using microfluidic platforms. (A) Microfluidic chip coupled to a cylindrical mini-MS for the detection of amino acids and peptides via CE. Reproduced from W. M. Gilliland, J. S. Mellors, J. M. Ramsey, Anal. Chem. 2017, 89, 13320–13325 (ref 236). Copyright 2017 American Chemical Society; (B) Schematic of a laser desorption ionization method using plasmonic gold chips for early stage lung cancer diagnostics. Reproduced from X. Sun, L. Huang, R. Zhang, W. Xu, J. Huang, D. D. Gurav, V. Vedarethinam, R. Chen, J. Lou, Q. Wang, et al, ACS Cent. Sci. 2018, 4, 223–229 (ref 238). Copyright 2018 American Chemical Society.