Glenn A. Harris

Mass Spectrometry: Recent Advances in Direct Open Air Surface Sampling/Ionization

1. Scope of this Review 2270 2. Ambient Ionization Techniques 2272 2.1. Solid−Liquid Extraction-Based Techniques 2272 2.1.1. Desorption Electrospray Ionization (DESI) 2272 2.1.2. Desorption Ionization by Charge Exchange (DICE) 2277 2.1.3. Easy Ambient Sonic-Spray Ionization (EASI) 2278 2.1.4. Liquid Micro Junction Surface Sampling Probe (LMJ-SSP) 2279 2.1.5. Liquid Extraction Surface Analysis (LESA) 2279 2.1.6. Nanospray Desorption Electrospray Ionization (nanoDESI) 2280 2.1.7. Desorption Atmospheric Pressure Photoionization (DAPPI) 2280 2.2. Plasma-Based Techniques 2281 2.2.1. Direct Analysis in Real Time (DART) 2282 2.2.2. Flowing Atmospheric-Pressure Afterglow (FAPA) 2286 2.2.3. Low Temperature Plasma (LTP) & Dielectric Barrier Discharge Ionization (DBDI) 2286 2.2.4. Chemical Sputtering/Ionization Techniques 2287 2.3. Two-Step Thermal/Mechanical Desorption/ Ablation (Non-Laser) Techniques 2288 2.3.1. Neutral Desorption Extractive Electrospray Ionization (ND-EESI) 2288 2.3.2. Beta Electron-Assisted Direct Chemical Ionization (BADCI) 2288 2.3.3. Atmospheric Pressure Thermal Desorption-Secondary Ionization (AP-TD/SI) 2289 2.3.4. Probe Electrospray Ionization (PESI) 2289 2.4. Two-Step Laser-Based Desorption Ablation Techniques 2290 2.4.1. Laser-Based Hybrid Techniques Coupled to ESI or Plasma Ionization 2290 2.4.2. Laser Electrospray Mass Spectrometry (LEMS) 2292 2.4.3. Laser Ablation Atmospheric Pressure Photoionization (LAAPPI) 2293 2.4.4. Laser Ablation Sample Transfer 2293 2.5. Acoustic Desorption Techniques 2294 2.5.1. Laser-Induced Acoustic Desorption (LIAD) 2294 2.5.2. Radiofrequency Acoustic Desorption Ionization (RADIO) 2295 2.5.3. Surface Acoustic Wave-Based Techniques 2295 2.6. Multimode Techniques 2296 2.6.1. Desorption Electrospray/Metastable-Induced Ionization (DEMI) 2296 2.7. Other Techniques 2296 2.7.1. Rapid Evaporative Ionization Mass Spectrometry (REIMS) 2296 2.7.2. Laser Desorption Ionization (LDI) 2297 2.7.3. Switched Ferroelectric Plasma Ionizer (SwiFerr) 2297 2.7.4. Laserspray Ionization (LSI) 2297 3. Remote Sampling 2298 3.1. Nonproximate Ambient MS 2298 3.2. Fundamentals of Neutral/Ion Transport 2298 3.3. Transport of Neutrals 2298 3.4. Transport of Ions 2299 4. Future Directions 2300 Author Information 2300 Corresponding Author 2300 Author Contributions 2300 Notes 2300 Biographies 2300 Acknowledgments 2301 References 2301

Simulations and Experimental Investigation of Atmospheric Transport in an Ambient Metastable-Induced Chemical Ionization Source

Since its inception, Direct Analysis in Real Time (DART) has seen utility in a wide range of applications including chemical reaction monitoring, pharmaceutical screening, and forensic mass spectrometry. Despite the growing interest in DART applications, there has been limited research into the fundamental physiochemical phenomena affecting sampling, ionization, and atmospheric ion transport. Presented here are the first experimentally validated finite element method simulations of an ambient DART-type metastable-induced chemical ionization source. It was found that complex coupled fluid dynamics, heat transfer, and electrostatic phenomena within the sampling region determine the variability in ion transmission efficiencies affecting the overall sensitivity of analysis. Particle tracing plots of a circular acetaminophen tablet placed in various positions and orientations yielded insight into optimal sample placement and evidence for sweet spots conducive to better ion transport. Experiments in a wide range of electric field conditions were performed, finding that under optimum sample placement, sensitivity could be improved by as much as 128% if ion mobility contributions were minimized.

Small Molecule Ambient Mass Spectrometry Imaging by Infrared Laser Ablation Metastable-Induced Chemical Ionization

Presented here is a novel ambient ion source termed infrared laser ablation metastable-induced chemical ionization (IR-LAMICI). IR-LAMICI integrates IR laser ablation and direct analysis in real time (DART)-type metastable-induced chemical ionization for open air mass spectrometry (MS) ionization. The ion generation in the IR-LAMICI source is a two step process. First, IR laser pulses impinge the sample surface ablating surface material. Second, a portion of ablated material reacts with the metastable reactive plume facilitating gas-phase chemical ionization of analyte molecules generating protonated or deprotonated species in positive and negative ion modes, respectively. The successful coupling of IR-laser ablation with metastable-induced chemical ionization resulted in an ambient plasma-based spatially resolved small molecule imaging platform for mass spectrometry (MS). The analytical capabilities of IR-LAMICI are explored by imaging pharmaceutical tablets, screening counterfeit drugs, and probing algal tissue surfaces for natural products. The resolution of a chemical image is determined by the crater size produced with each laser pulse but not by the size of the metastable gas jet. The detection limits for an active pharmaceutical ingredient (acetaminophen) using the IR-LAMICI source is calculated to be low picograms. Furthermore, three-dimensional computational fluid dynamic simulations showed improvements in the IR-LAMICI ion source are possible.

Poor quality vital anti-malarials in Africa - an urgent neglected public health priority

BackgroundPlasmodium falciparum malaria remains a major public health problem. A vital component of malaria control rests on the availability of good quality artemisinin-derivative based combination therapy (ACT) at the correct dose. However, there are increasing reports of poor quality anti-malarials in Africa.MethodsSeven collections of artemisinin derivative monotherapies, ACT and halofantrine anti-malarials of suspicious quality were collected in 2002/10 in eleven African countries and in Asia en route to Africa. Packaging, chemical composition (high performance liquid chromatography, direct ionization mass spectrometry, X-ray diffractometry, stable isotope analysis) and botanical investigations were performed.ResultsCounterfeit artesunate containing chloroquine, counterfeit dihydroartemisinin (DHA) containing paracetamol (acetaminophen), counterfeit DHA-piperaquine containing sildenafil, counterfeit artemether-lumefantrine containing pyrimethamine, counterfeit halofantrine containing artemisinin, and substandard/counterfeit or degraded artesunate and artesunate+amodiaquine in eight countries are described. Pollen analysis was consistent with manufacture of counterfeits in eastern Asia. These data do not allow estimation of the frequency of poor quality anti-malarials in Africa.ConclusionsCriminals are producing diverse harmful anti-malarial counterfeits with important public health consequences. The presence of artesunate monotherapy, substandard and/or degraded and counterfeit medicines containing sub-therapeutic amounts of unexpected anti-malarials will engender drug resistance. With the threatening spread of artemisinin resistance to Africa, much greater investment is required to ensure the quality of ACTs and removal of artemisinin monotherapies. The International Health Regulations may need to be invoked to counter these serious public health problems.

Transmission-mode direct analysis in real time and desorption electrospray ionization mass spectrometry of insecticide-treated bednets for malaria control

Transmission-mode direct analysis in real time (TM-DART) is presented as an alternative sampling strategy to traditional methods of sample introduction for DART MS analysis. A custom-designed sample holder was fabricated to rapidly and reproducibly position insecticide-treated nets normal to the ionizing metastable gas stream, enabling transmission of desorbed analyte ions through the holder cavity and into the MS. Introduction of the sample at this fixed geometry eliminates the need for optimizing sample position and allows spectra based on factors such as metastable gas temperature and flow to be systematically evaluated. The results presented here, supported by computational fluid dynamic simulations, demonstrate the effects of these factors on the resulting mass spectra and the potential of this sampling strategy to be used for qualitative and quantitative analyses. Transmission-mode desorption electrospray ionization (TM-DESI) experiments on similar insecticide-treated nets were performed for comparison purposes.

Comparison of the internal energy deposition of direct analysis in real time and electrospray ionization time-of-flight mass spectrometry.

The internal energy (Eint) distributions of a series of p-substituted benzylpyridinium ions generated by both direct analysis in real time (DART) and electrospray ionization (ESI) were compared using the “survival yield” method. DART mean Eint values at gas flow rates of 2, 4, and 6 L min−1, and at set temperatures of 175, 250, and 325 °C were in the 1.92–2.21 eV range. ESI mean Eint at identical temperatures in aqueous and 50% methanol solutions ranged between 1.71 and 1.96 eV, and 1.53 and 1.63 eV, respectively. Although the results indicated that ESI is a “softer” ionization technique than DART, there was overlap between the two techniques for the particular time-of-flight mass spectrometer used. As a whole, there was an increase in Eint with increasing reactive and drying gas temperatures for DART and ESI, respectively, indicating thermal ion activation. Three dimensional computational fluid dynamic simulations in combination with direct temperature measurements within the DART ionization region revealed complex inversely coupled fluid-thermal phenomena affecting ion Eint values during atmospheric transport. Primarily, that DART gas temperature in the ionization region was appreciably less than the set gas temperature of DART due to the set gas flow rates. There was no evidence of Eint deposition pathways from metastable-stimulated desorption, but fragmentation induced by high-energy helium metastables was observed at the highest gas flow rates and temperatures.

Direct analysis in real time coupled to multiplexed drift tube ion mobility spectrometry for detecting toxic chemicals.

Current and future chemical threats to homeland security motivate the need for new chemical detection systems to provide border, transportation, and workplace security. We present the first successful coupling of a commercial direct analysis in real time (DART) ion source to a resistive glass monolithic drift tube ion mobility spectrometer (DTIMS) as the basis for a low maintenance, versatile, and robust chemical monitoring system. in situ ionization within the electric field gradient of the instrument enhances sensitivity and provides a safe sampling strategy. The instrument uses nitrogen as both the DART discharge and DTIMS drift gases, allowing for a high electric field to be used for ion separation while keeping cost-of-use low. With the use of a traditional signal averaging acquisition mode, the 95% probability of detection (POD) for analytes sampled from melting point capillary tubes was 11.81% v/v for DMMP, 1.13% v/v for 2-CEES, and 10.61 mM for methamidophos. Sensitivity was improved via a prototype transmission-mode geometry interface, resulting in an almost 2 orders of magnitude decrease in the POD level for DMMP (0.28% v/v). As an alternative to transmission mode operation, digital multiplexing of the DTIMS ion injection step was also implemented, finding a 3-fold improvement in signal-to-noise ratios for 200 μs gate injections and a 4.5-fold for 400 μs gate injections.

MALDI Imaging and in Situ Identification of Integral Membrane Proteins from Rat Brain Tissue Sections

Transmembrane proteins are greatly underrepresented in data generated by imaging mass spectrometry (IMS) because of analytical challenges related to their size and solubility. Here, we present the first example of MALDI IMS of two highly modified multitransmembrane domain proteins, myelin proteolipid protein (PLP, 30 kDa) and DM-20 (26 kDa), from various regions of rat brain, namely, the cerebrum, cerebellum, and medulla. We utilize a novel tissue pretreatment aimed at transmembrane protein enrichment to show the in situ distribution of fatty acylation of these proteins, particularly of post-translational palmitoylation. Additionally, we demonstrate the utility of protease-encapsulated hydrogels for spatially localized on-tissue protein digestion and peptide extraction for subsequent direct coupling to LC-MS/MS for protein identification.

Localized in situ hydrogel-mediated protein digestion and extraction technique for on-tissue analysis.

A simultaneous on-tissue proteolytic digestion and extraction method is described for the in situ analysis of proteins from spatially distinct areas of a tissue section. The digestion occurs on-tissue within a hydrogel network, and peptides extracted from this gel are identified with liquid chromatography tandem MS (LC-MS/MS). The hydrogels are compatible with solubility agents (e.g., chaotropes and detergents) known to improve enzymatic digestion of proteins. Additionally, digestions and extractions are compatible with imaging mass spectrometry (IMS) experiments. As an example application, an initial IMS experiment was conducted to profile lipid species using a traveling wave ion mobility mass spectrometer. On-tissue MS/MS was also performed on the same tissue section to identify lipid ions that showed spatial differences. Subsequently, the section underwent an on-tissue hydrogel digestion to reveal 96 proteins that colocalized to the rat brain cerebellum. Hematoxylin and eosin (H & E) staining was then performed to provide additional histological information about the tissue structure. This technology provides a versatile workflow that can be used to correlate multiple complementary analytical approaches in the analysis of a single tissue section.

Medications for sexual health available from non-medical sources: a need for increased access to healthcare and education among immigrant Latinos in the rural southeastern USA.

This study documented the types and quality of sexual health medications obtained by immigrant Latinos from non-medical sources. Samples of the medications were purchased from non-medical sources in the rural Southeast by trained native Spanish-speaking “buyers”. Medications were screened the presence of active pharmaceutical ingredients using mass spectrometry. Eleven medications were purchased from tiendas and community members. Six were suggested to treat sexually transmitted diseases, one was to treat sexual dysfunction, one was to prevent pregnancy, and two were to assist in male-to-female transgender transition or maintenance. All medications contained the stated active ingredients. Findings suggest that medications are available from non-medical sources and may not be used as indicated. Interventions that target immigrant Latinos within their communities and rely on existing structures may be effective in reducing barriers to medical and healthcare services and increasing the proper use of medications to reduce potential harm.