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1. An overview of biological applications and fundamentals of new inlet and vacuum ionization technologies

   https://doi.org/10.1002/rcm.8829  

   Trimpin, Sarah; Marshall, Darrell_D; Karki, Santosh; Madarshahian, Sara; Hoang, Khoa; Meher, Anil_K; Pophristic, Milan; Richards, Alicia_L; Lietz, Christopher_B; Fischer, Joshua_L; et al (November 2020, Rapid Communications in Mass Spectrometry)

   RationaleThe developments of new ionization technologies based on processes previously unknown to mass spectrometry (MS) have gained significant momentum. Herein we address the importance of understanding these unique ionization processes, demonstrate the new capabilities currently unmet by other methods, and outline their considerable analytical potential. MethodsTheinletandvacuumionization methods of solvent‐assisted ionization (SAI), matrix‐assisted ionization (MAI), and laserspray ionization can be used with commercial and dedicated ion sources producing ions from atmospheric or vacuum conditions for analyses of a variety of materials including drugs, lipids, and proteins introduced from well plates, pipet tips and plate surfaces with and without a laser using solid or solvent matrices. Mass spectrometers from various vendors are employed. ResultsResults are presented highlighting strengths relative to ionization methods of electrospray ionization (ESI) and matrix‐assisted laser desorption/ionization. We demonstrate the utility of multi‐ionization platforms encompassing MAI, SAI, and ESI and enabling detection of what otherwise is missed, especially when directly analyzing mixtures. Unmatched robustness is achieved with dedicated vacuum MAI sources with mechanical introduction of the sample to the sub‐atmospheric pressure (vacuumMAI). Simplicity and use of a wide array of matrices are attained using a conduit (inletionization), preferably heated, with sample introduction from atmospheric pressure. Tissue, whole blood, urine (including mouse, chicken, and human origin), bacteria strains and chemical on‐probe reactions are analyzed directly and, especially in the case ofvacuumionization, without concern of carryover or instrument contamination. ConclusionsExamples are provided highlighting the exceptional analytical capabilities associated with the novel ionization processes in MS that reduce operational complexity while increasing speed and robustness, achieving mass spectra with low background for improved sensitivity, suggesting the potential of this simple ionization technology to drive MS into areas currently underserved, such as clinical and medical applications. 

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2. A Combination MAI and MALDI Vacuum Source Operational from Atmospheric Pressure for Fast, Robust, and Sensitive Analyses

   https://doi.org/10.1021/jasms.0c00298  

   Hoang, Khoa.; Trimpin, Sarah; McEwen, Charles N.; Pophristic, Milan (January 2020, Journal of the American Society for Mass Spectrometry)

   Previously, vacuum matrix-assisted ionization (vMAI) was employed with matrix:analyte sample introduction into the vacuum of the mass spectrometer on a probe sample introduction device. Low attomole detection was achieved while no carryover was observed even for concentrated samples. Here, we report a new vacuum ionization source designed to duplicate the sensitivity and robustness of probe device while providing fast multi-sample introduction to vacuum and rapid sequential ionization. Exposure of a sample to the vacuum of the mass spectrometer provides spontaneous ionization of volatile as well as nonvolatile analytes without the need of external energy input. However, the novel source design described herein, in addition to vMAI, can employ a laser to obtain vacuum matrix-assisted laser desorption/ionization (vMALDI). In particular, ionization by vMAI or vMALDI is achieved by using the appropriate matrix. Switching between ionization modes is accomplished in a few seconds. We present results demonstrating the utility of the two ionization methods in combination to improve molecular analyses of sample composition. In both ionization modes, multiple samples can be sequentially and rapidly acquired to increase throughput in MS. With the prototype source, samples were acquired in as little as 1 second per sample. Exchanging multi-sample plates can be accomplished in as little as 2 seconds suggesting low-cost high throughput automation when properly developed. 

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3. Resolving Isomers of Star-Branched Poly(Ethylene Glycols) by IMS-MS Using Multiply Charged Ions

   https://doi.org/10.1021/jasms.0c00045  

   Austin, Calvin A.; Inutan, Ellen D.; Bohrer, Brian C.; Li, Jing; Fischer, Joshua L.; Wijerathne, Kanchana; Foley, Casey D.; Lietz, Christopher B.; Woodall, Daniel W.; Imperial, Lorelie F.; et al (January 2020, Journal of the American Society for Mass Spectrometry)

   null (Ed.)

   Ion mobility spectrometry (IMS) mass spectrometry (MS) centers on the ability to separate gaseous structures by size, charge, shape, and followed by mass-to-charge (m/z). For oligomeric structures, improved separation is hypothesized to be related to the ability to extend structures through repulsive forces between cations electrostatically bonded to the oligomers. Here we show the ability to separate differently branched multiply charged ions of star-branched poly(ethylene glycol) oligomers (up to 2000 Da) regardless of whether formed by electrospray ionization (ESI) charged solution droplets or from charged solid particles produced directly from a surface by matrix-assisted ionization. Detailed structural characterization of isomers of the star-branched compositions was first established using a home-built high-resolution ESI IMS-MS instrument. The doubly charged ions have well-resolved drift times, achieving separation of isomers and also allowing differentiation of star-branched versus linear oligomers. An IMS-MS “snapshot” approach allows visualization of architectural dispersity and (im)purity of samples in a straightforward manner. Analyses capabilities are shown for different cations and ionization methods using commercially available traveling wave IMS-MS instruments. Analyses directly from surfaces using the new ionization processes are, because of the multiply charging, not only associated with the benefits of improved gas-phase separations, relative to that of ions produced by matrix-assisted laser desorption/ionization, but also provide the potential for spatially resolved measurements relative to ESI and other ionization methods. 

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4. New Ionization Processes for Ionizing Nonvolatile Compounds in Mass Spectrometry: The Road of Discovery to Current State-of-the-Art

   https://doi.org/10.1021/jasms.0c00312  

   Trimpin, Sarah; Moreno-Pedraza, Abigail; Yenchick, Frank S.; Hoang, Khoa; Pophristic, Milan; Karki, Santosh; Marshall, Darrell D.; Lee, Chuping; Lu, I-Chung; El-Baba, Tarick J.; et al (January 2020, Journal of the American Society for Mass Spectrometry)

   null (Ed.)

   This Perspective covers discovery and mechanistic aspects as well as initial applications of novel ioni-zation processes for use in mass spectrometry that guided us in a series of subsequent discoveries, in-strument developments, and commercialization. With all likelihood, vacuum matrix-assisted ionization on an intermediate pressure matrix-assisted laser desorption/ionization source without the use of a laser, high voltages, or any other added energy was the defining turning point from which key developments grew that were at the time unimaginable, and continue to surprise us in its simplistic preeminence, and is therefore a special focus here. We, and others, have demonstrated exceptional analytical utility with-out a complete understanding of the underlying mechanism. Our current research is focused on how best to understand, improve, and use these novel ionization processes through dedicated platform and source developments which convert volatile and nonvolatile compounds from solid or liquid matrices into gas-phase ions for analysis by mass spectrometry using e.g., mass-selected fragmentation and ion mobility spectrometry to provide reproducible, accurate, and sometimes improved mass and drift time resolution. The combination of research and discoveries demonstrated multiple advantages of the new ionization processes and established the basis of the successes that lead to the Biemann Medal and this Perspective. How the new ionization processes relate to traditional ionization is also presented, as well as how these technologies can be utilized in tandem through instrument modification and implementa-tion to increase coverage of complex materials through complementary strengths. 

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5. Multi-functional Vacuum Ionization Source for MAI, LSI, and MALDI: Operational from AP for Comprehensive, Low-Cost Data-Mining in Mass Spectrometry

   Trimpin, Sarah; Moreno-Pedraza, Abigail; Hoang, Khoa; Pophristic, Milan; Inutan, Ellen D; Marshall, Darrell D; Karki, Santosh; Meher, Anil; Yenchick, Frank S; Lee, Chupiong; et al (January 2020, 68th Annual ASMS Conference on Mass Spectrometry and Allied Topics)

   null (Ed.)

   Unprecedented ionization processes developed into powerful methods have attributes highly desirable for MS and include high sensitivity, low cost, simplicity, ability to directly analyze biological and synthetic materials, potential for high throughput, automation, exceptional robustness, and wide applicability, especially in environments outside analytical laboratories. Initial matrix-assisted ionization (MAI) results showed different selectivity relative to ESI or MALDI providing information not readily obtained with current methodologies. Here, we demonstrate the first vacuum ionization source with multi-ionization capabilities on the same high-resolution API-mass spectrometer for a range of analytical problems with sensitivity in low fmol and detection limit in low amol ranges. The potential for achieving MS and MS/MS analysis speeds of ca. 4 seconds/sample in a simple low-cost fashion is demonstrated. 

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