Paper spray is a newly developed ambient ionization method that has been applied for direct qualitative and quantitative analysis of biological samples. The properties of the paper substrate and spray solution have a significant impact on the release of chemical compounds from complex sample matrices, the diffusion of the analytes through the substrate, and the formation of ions for mass spectrometry analysis. In this study, a commercially available silica-coated paper was explored in an attempt to improve the analysis of therapeutic drugs in dried blood spots (DBS). The dichloromethane/isopropanol solvent has been identified as an optimal spray solvent for the analysis. The comparison was made with paper spray using chromatography paper as substrate with methanol/water as solvent for the analysis of verapamil, citalopram, amitriptyline, lidocaine and sunitinib in dried blood spots. It has been demonstrated the efficiency of recovery of the analytes was notably improved with the silica coated paper and the limit of quantitation (LOQ) for the drug analysis was 0.1 ng mL−1 using a commercial triple quadrupole mass spectrometer. The use of silica paper substrate also resulted in a sensitivity improvement of 5-50 fold in comparison with chromatography papers, including the Whatmann ET31 paper used for blood card. Analysis using a handheld miniature mass spectrometer Mini 11 gave LOQs of 10~20 ng mL−1 for the tested drugs, which is sufficient to cover the therapeutic ranges of these drugs.

We had developed pulsed direct current electrospray ionization mass spectrometry (pulsed-dc-ESI-MS) for systematically profiling and determining components in small volume sample. Pulsed-dc-ESI utilized constant high voltage to induce the generation of single polarity pulsed electrospray remotely. This method had significantly boosted the sample economy, so as to obtain several minutes MS signal duration from merely picoliter volume sample. The elongated MS signal duration enable us to collect abundant MS(2) information on interested components in a small volume sample for systematical analysis. This method had been successfully applied for single cell metabolomics analysis. We had obtained 2-D profile of metabolites (including exact mass and MS(2) data) from single plant and mammalian cell, concerning 1034 components and 656 components for Allium cepa and HeLa cells, respectively. Further identification had found 162 compounds and 28 different modification groups of 141 saccharides in a single Allium cepa cell, indicating pulsed-dc-ESI a powerful tool for small volume sample systematical analysis.

The demand for on-the-spot analysis is met by a miniature mass spectrometer which is preferred to be robust, stable, as small as possible and capable of analyzing different samples by coupling with various ionization methods. However, largely constrained by the atmospheric pressure interface (API), these aspects are difficult to be realized in one system. Herein, we describe the development of a new miniature mass spectrometer with balanced performance. The miniature mass spectrometer is small in size (30 × 30 × 18 cm) but has a continuous API, which was achieved by high-pressure ion trap operation and maximized ion transfer efficiency with the utilization of a differential pumping system. The miniature mass spectrometer was characterized and optimized in terms of stability, sensitivity, mass range, mass resolution and scan speed. Rapid analysis of mixtures was demonstrated by coupling the miniature mass spectrometer with the ambient ionization technique of paper spray. This is the smallest miniature mass spectrometer to date, which has a continuous API.

A low temperature plasma ambient ionization source, coupled to a portable mass spectrometer (Mini 10.5), is used for the determination of melamine contamination in whole milk and related materials. Thermally assisted desorption and ionization of the analyte was achieved with the plasma probe. The small size, low power consumption and capability for direct sampling without pretreatment makes plasma ionization an appropriate ionization method for use with a handheld mass spectrometer. The standard discontinuous atmospheric pressure interface used to connect atmospheric pressure ion sources to mass spectrometers (Gao et al., Anal. Chem., 2008, 80, 4026-4032) was modified by using supplementary pumping to increase the ion transfer efficiency. Whole milk, fish, milk powder and other complex matrices spiked with melamine were placed on glass slides close to the vacuum inlet and analyzed without sample pretreatment. Quantitation in complex matrices was achieved using MS/MS of protonated melamine m/z 127 to yield the characteristic fragment ion of m/z 85. Analysis rates of two samples per minute, levels of melamine as low as 250 ng/mL in whole milk (below the regulatory level in the US of 1 ppm (1 microg/mL) or the European level of 2.5 ppm (microg/mL)), a linear dynamic range of 0.5-50 microg/mL and a relative standard deviation of ca. 7.6-16.2% were achieved. The importance of melamine to public health and the prior lack of a rapid, sensitive and yet highly specific field analysis method add to the relevance of this study.

The discontinuous atmospheric pressure interface (DAPI) has allowed the transfer of ions from atmospheric pressure ionization sources to an ion trap mass analyzer in hand-held mass spectrometers with miniature pumping systems at transfer efficiencies high enough for proper chemical analysis. The DAPI potentially would allow a significant enhancement to the mass analysis efficiency of laboratory-scale mass spectrometers, which have pumping systems of much larger capacities. A laboratory-scale mass spectrometer with a DAPI-RIT (rectilinear ion trap)-DAPI configuration has been developed to explore this possibility. The gas dynamic effects on ion trapping and mass analysis have been studied at various conditions. A pulsed nanoelectrospray ionization source synchronized with the DAPI has been implemented to improve the sample usage efficiency as well as to adjust the number of ions to be trapped for MS analysis, so that space charge effects can be avoided. Single-scan spectra of peptides were recorded with an ionization time as short as 1 mus, corresponding to an analyte consumption of several attomoles. The simplicity of application of the DAPI for performing ion/molecule and ion/ion reactions has also been demonstrated with proton transfer and electron transfer dissociation reactions with peptides.

The mass-selective manipulation of ions at elevated pressure, including mass analysis, ion isolation, or excitation, is of great interest for the development of mass spectrometry instrumentation, particularly for systems in which ion traps are employed as mass analyzers or storage devices. While experimental exploration of high-pressure mass analysis is limited by various difficulties, such as ion detection or electrical discharge at high-pressure, theoretical methods have been developed in this work to study ion/neutral collision effects within quadrupole ion traps and to explore their performance at pressures up to 1 Torr. Ion trapping, isolation, excitation, and resonance ejection were investigated over a wide pressure range. The theoretically calculated data were compared with available experimental data for pressures up to 50 mTorr, allowing the prediction of ion trap performance at pressures more than 10 times higher. (J Am Soc Mass

Methods and devices that use gas flows to collect ions and transfer them over long distances for mass spectrometric analysis have been developed. Gas flows derived from the ionization source itself or provided by means of additional pumping were used to generate a laminar flow inside cylindrical tube. Hydrodynamic simulations and experimental tests demonstrate that laminar flow can transfer ions over long distance. The typical angular discrimination effects encountered when sampling ions from ambient ionization sources are minimized, and the sampling of relatively large surface areas is demonstrated with desorption electrospray ionization (DESI). Ion transfer over 6 m has been achieved and its application to multiplexed chemical analysis is demonstrated on samples at locations remote from the mass spectrometer.

The key concepts and technologies developed in our laboratories in Purdue University for the miniaturization of mass spectrometry analysis systems are introduced. Mass analyzers of simple geometries with a novel atmospheric pressure interface were used to allow reduction in the size of the ion trap mass spectrometer. Ambient ionization methods were developed and coupled to miniature mass spectrometers to allow direct MS analysis of complex samples without sample preparation and chemical separation. The performance of desorption electrospray ionization, low temperature plasma probe, paper spray, and two handheld MS systems, Mini 10 and Mini 11, are described with demonstrations of capabilities for chemical analysis.