Emerging trends in paper spray mass spectrometry: Microsampling, storage, direct analysis, and applications

Abstract

Recent advancements in the sensitivity of chemical instrumentation have led to increased interest in the use of microsamples for translational and biomedical research. Paper substrates are by far the most widely used media for biofluid collection, and mass spectrometry is the preferred method of analysis of the resultant dried blood spot (DBS) samples. Although there have been a variety of review papers published on DBS, there has been no attempt to unify the century old DBS methodology with modern applications utilizing modified paper and paper-based microfluidics for sampling, storage, processing, and analysis. This critical review will discuss how mass spectrometry has expanded the utility of paper substrates from sample collection and storage, to direct complex mixture analysis to on-surface reaction monitoring.

Keywords: ambient ionization; direct analysis; direct reaction monitoring by paper spray; dried blood spot (DBS); mass spectrometry; microfluidic devices; microsampling; paper spray (PS); solid-phase extraction.

Figure 1.

Summary of current applications of paper including the impact with respect to microsampling, sample storage, and analysis.

Figure 2.

Schematic for paper spray. Experiments show that when solvent is first applied to the paper and readily available, ESI mode results in large droplets and lower spray currents. As time progresses, APCI mode results in smaller diameter droplets and larger spray currents, possibly accessing alternative ionization routes.

Figure 3.

(A) Ion intensity of vapor-phase electron capture agent 1,4-Benzoquinone when a voltage of −4 kV is applied. (B) Spray current as a function of increasing voltage. Stable spray plumes were unable to form at higher voltages for PS. (Reprinted with permission from Wang et al., 2010, copyright 2010 John Wiley and Sons).

Figure 4.

(Left) Hematocrit effect: various blood samples containing different hematocrit levels spotted on the same type of paper substrate exhibit different drying properties. (Reprinted with permission from Wilhelm et. al, 2014, copyright 2014 Wilhelm et. al, 2014) (Right) Chromatographic effect: Top: Whole blood spiked with ¹⁴C radiolabeled Compound A from Isotope Chemistry and Metabolite Synthesis, sanofi-aventis, spotted on various types of paper substrate storage cards. Bottom: Autoradiogram of ¹⁴C distribution in each DBS. (Reprinted with permission from Ren et al., 2010, copyright 2010 Future Science Ltd.)

Figure 5.

Comparison of three basic workflows typically used in dried blood spot analysis: offline, online, and direct in-source MS strategies. The various acronyms are explained in Table 1 below. (Adapted and modified from Wagner M. et. al., 2016, copyright 2014 Wiley Periodicals, Inc).

Figure 6.

(Left column) Reflective-mode geometry configuration for desorption electrospray ionization (Reprinted with permission from Ifa et al., 2010, copyright 2010 The Royal Society of Chemistry), direct analysis in real time (Adapted and modified with permission from Hajslova et al., 2011, copyright 2010 Elsevier Ltd.), and low-temperature plasma ionization sources (Reprinted with permission from Harper et al., 2008, copyright 2008 American Chemical Society). (Right column) Transmission-mode geometry configurations for desorption electrospray ionization (Reprinted with permission from Chipuk et al., 2010b, copyright 2009 American Chemical Society), direct analysis in real time (Reprinted with permission from Gómez-Ríos et al., 2017b, copyright 2017 The Royal Society of Chemistry), and low-temperature plasma ionization sources (Reprinted with permission from Zhao et al., 2016, copyright 2016 American Chemical Society).

Figure 7.

(a) Plasma extraction card device for rapid extraction of plasma from blood for subsequent analysis by MS (Adapted and modified with permission from Kim et al., 2013, copyright 2013 American Chemical Society); (b) volumetric absorptive device for acquiring fixed micro-volumes of biofluid sample (Adapted and modified with permission from Denniff and Spooner, 2014 copyright 2014 American Chemical Society); and (c) capillary microsampling of blood in EDTA-coated tubes containing thixotropic gel for plasma separation (Reprinted with permission from Bowen et al., 2013, copyright 2013 Future Science Ltd.).

Figure 8.

Chemical structures of common metabolite biomarkers for disease monitoring.

Figure 9.

Unmodified chemical structures of common drugs of abuse.

Figure 10.

Chemical structures of molecules monitored in food, beverages, and the environment.

Figure 11.

Online derivatization of metaldehyde simultaneously analyzed via reactive PS MS which gives rise to an additional unique m/z transition. Reprinted with permission from Maher et al., 2016, with no modifications to the figure, copyright 2016 Maher et. al., 2016). Licensing: https://creativecommons.org/licenses/by/4.0/

Figure 12.

(A) Paper spray schematic for the detection of derivatized quinones. (B) In-situ reaction for derivatization of polycyclic aromatic hydrocarbons in the presence of cysteamine. (Reprinted with permission from Zhou et al., 2015, copyright 2014 John Wiley and Sons, Ltd.)

Figure 13.

Katritzky reactions between 2,4,6-triphenyl pyrylium cation and mono-, di-amines monitored by PS MS. (Reprinted with permission from Yan et al., 2013, copyright 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Figure 14.

Summary of several modification methods used during paper spray.

Figure 15.

Summary of several non-paper substrates used for spray ionization during ambient analysis.

Figure 16.

Coated Blade Spray workflow and schematic (Reprinted with permission from Gómez-Rios et. al, 2014, copyright 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.).