Recent advances in on-site mass spectrometry analysis for clinical applications

Abstract

In recent years, mass spectrometry (MS) is increasingly attracting interests for clinical applications, which also calls for technical innovations to make a transfer of MS from conventional analytical laboratories to clinics. The system design and analysis procedure should be friendly for novice users and appliable for on-site clinical diagnosis. In addition, the analysis result should be auto-interpreted and reported in formats much simpler than mass spectra. This motivates new ideas for developments in all the aspects of MS. In this review, we report recent advances of direct sampling ionization and miniature MS system, which have been developed targeting clinical and even point-of-care analysis. We also discuss the trend of the development and provide perspective on the technical challenges raised by diseases such as coronavirus SARS-CoV-2.

Keywords: Ambient ionization; Clinical diagnostics; Direct sampling; Miniature mass spectrometry; Point-of-care testing.

Fig. 1

Surgical MS systems for intraoperative diagnosis. (a) Schematic of an MasSpec Pen MS system. (b) Optical images of a lung adenocarcinoma tissue sample before, during, and after using the MasSpec Pen. The inset shows no observable damage to the tissue sample due to the MasSpec Pen. (c) Negative ion mode mass spectrum of the tissue sample using the MasSpec Pen. Reprinted from Ref. [32] with permission from American Association for the Advancement of Science. (d) Schematic of an iKnife MS system. (e) Classification of the normal and cancerous cervical tissue via univariate analysis of mass spectra collected by the iKnife MS system. Reprinted from Ref. [35] with permission from National Academy of Sciences. (f) Schematic of a PIRL MS system. (g) PIRL direct sampling of normal and cancer tissues for in situ pathological MS analysis. Reprinted from Ref. [36] with permission from The Royal Society of Chemistry.

Fig. 2

(a) Glioma tumor cell concentration (upper) and grade classification (lower) visualized by using segmented preoperative 3D MRI volume reconstruction. Tumor volume is marked in light purple. Reprinted from Ref. [40] with permission from National Academy of Sciences. (b) Chemical predictions of disease state by using principal component analysis. Reprinted from Ref. [41] with permission from National Academy of Sciences. (c) Optical and MS images of skin sections containing miniscule basal cell carcinoma (BCC) aggregates. BCC regions are marked in red. Reprinted from Ref. [44] with permission from National Academy of Sciences. (d) Optical and MS images in heterogeneous ESCC tissue: (i) optical image, (ii) MSI of glutamate, (iii) optical and MSI overlayed, classifications of the cancer (red), epithelial (green) and muscular tissues (blue) in (iv) positive and (v) negative ion modes. Reprinted from Ref. [45] with permission from National Academy of Sciences. (e) Optical and MS images of rat cerebellum: (i) optical image, (ii) MSI of PC 34:1 (LOOH), and MS2I of two CC bond positional isomers, iii) 11Δ/(9Δ+11Δ) and iv) 9Δ/(9Δ+11Δ). Reprinted from Ref. [54] with permission from Wiley-VCH.

Fig. 3

(a) Workflow of a PDA-AR LDI-MS analysis and imaging. LDI-MSI of liver samples from (b) ob/ob mouse and (c) wild-type mouse using the PDA-AR substrate. Reprinted from Ref. [63] with permission from American Chemical Society. (d) Schematic of a water-assisted LDI-MS analysis and imaging system, SpiderMass. MSI of normal and cancer tissues of sarcoma using specific biomarkers, m/z 895.75 (normal, e) and 790.65 (cancer, f). Reprinted from Ref. [64] with permission from Elsevier.

Fig. 4

Instrumentation and analytical performances of state-of-the-art miniature MS systems. (a) Instrumental setup of a dual-LIT miniature mass spectrometer. (b) Tandem MS analysis, MS² to MS⁴, of melezitose in the dual LITs. (c) Multiple reaction monitoring (MRM) analysis of drugs. Reprinted from Ref. [80] with permission from American Chemical Society. (d) Ion mobility spectrum of cytochrome c for charge states between +8 and +12. Reprinted from Ref. [81] with permission from American Chemical Society. (e) Schematic of the Mini 14 system with intelligent adaptability for on-site and POC analysis. Reprinted from Ref. [82] with permission from American Chemical Society. (f) Quantitation analysis of the Met peptide. Reprinted from Ref. [84] with permission from American Chemical Society.

Fig. 5

Application demonstrations of miniature MS systems. (a) Direct analysis of glioma tissues using a sampling probe and Mini 12 MS system. Mass spectra of 2-HG in the (b) glioma tissue and (c) normal brain tissue. (d) Tandem MS spectra of the 2-HG for the glioma tissue. Reprinted from Ref. [87] with permission from American Chemical Society. Box-and-whisker plot of IDH mutation scores in IDH mutant (11 samples, red) and IDH wild-type glioma tissues (16 samples, black). Here, boxes show median, lower, and upper quartiles, and whiskers are at minimum and maximum values. Reprinted from Ref. [88] with permission from Springer Nature. (f) Analysis of ESAT-6 by high-temperature hydrolysis and a miniature dual-LIT MS system. Mass spectra of ESAT-6 (g) before and (h) after the high-temperature hydrolysis. Characteristic peptides of ESAT-6 are marked in dark blue. Reprinted from Ref. [90] with permission from The Royal Society of Chemistry.

Fig. 6

MS platforms for SARS-CoV-2 diagnosis. (a) Scheme for SARS-CoV-2 detection by using MALDI-MS. Characteristic mass spectra of (b) SARS-CoV-2 positive and (c) SARS-CoV-2 negative. Reprinted from Ref. [93] with permission from Springer Nature. (d) Structural analysis of O-glycans on the S protein RBD. Reprinted from Ref. [94] with permission from American Chemical Society. (e) Scheme for SARS-CoV-2 detection by using paper spray MS. Reprinted from Ref. [97] with permission from The Royal Society of Chemistry.