Ryan T. Hilger

Purdue University West Lafayette

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Scott A. McLuckey

Purdue University West Lafayette

Robert E. Santini

Northwell Health

Julia Laskin

Purdue University West Lafayette

Hang Hu

Purdue University West Lafayette

Li‐Xue Jiang

Purdue University West Lafayette

Manxi Yang

Purdue University West Lafayette

Lloyd M. Smith

University of Wisconsin–Madison

R. Graham Cooks

Purdue University West Lafayette

Daisy Unsihuay

University of Pennsylvania

Dalton T. Snyder

The Ohio State University

Cooperative Institutions

Purdue University West Lafayette

University of Wisconsin–Madison

State Street (United States)

Center for Cancer Research

Energy Center of Wisconsin

Madison Group (United States)

Purdue University System

Merck & Co., Inc., Rahway, NJ, USA (United States)

Pacific Northwest National Laboratory

Division of Chemistry

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High-Throughput Mass Spectrometry Imaging with Dynamic Sparse Sampling

ACS Measurement Science Au (2022)

Hang Hu David Helminiak Manxi Yang Daisy Unsihuay Ryan T. Hilger

Mass spectrometry imaging (MSI) enables label-free mapping of hundreds of molecules in biological samples with high sensitivity and unprecedented specificity. Conventional MSI experiments are relatively slow, limiting their utility for applications requiring rapid data acquisition, such as intraoperative tissue analysis or 3D imaging. Recent advances in MSI technology focus on improving the spatial resolution and molecular coverage, further increasing the acquisition time. Herein, a deep learning approach for dynamic sampling (DLADS) was employed to reduce the number of required measurements, thereby improving the throughput of MSI experiments in comparison with conventional methods. DLADS trains a deep learning model to dynamically predict molecularly informative tissue locations for active mass spectra sampling and reconstructs high-fidelity molecular images using only the sparsely sampled information. Experimental hardware and software integration of DLADS with nanospray desorption electrospray ionization (nano-DESI) MSI is reported for the first time, which demonstrates a 2.3-fold improvement in throughput for a linewise acquisition mode. Meanwhile, simulations indicate that a 5–10-fold throughput improvement may be achieved using the pointwise acquisition mode.

Mass spectrometry imaging

10.1021/acsmeasuresciau.2c00031

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Citations (19)

Tandem Mass Spectrometry in an Electrostatic Linear Ion Trap Modified for Surface-Induced Dissociation

Analytical Chemistry (2014)

Ryan T. Hilger Robert E. Santini Scott A. McLuckey

A variety of ion traps are used in mass spectrometry. A key feature shared by most of them is the ability to perform tandem mass spectrometry (MS/MS). The Orbitrap is perhaps the most notable ion trap in which MS/MS has yet to be performed. An electrostatic linear ion trap (ELIT) is analogous to an orbitrap in that ions are trapped using solely electrostatic fields. However, the relatively simple ion motion within an ELIT facilitates analysis of fragment ions produced within the device. In this report, we describe an ELIT to which we have added a target for surface induced dissociation (SID). When combined with our previously described method for isolating a precursor ion trapped in an ELIT,1 this apparatus enables MS/MS to be performed. Measurement of product ion m/z is facilitated by the fact that the ELIT is isochronous over the energy range of 1850-2000 eV so that changes to ion energy during SID do not cause major m/z shifts. We demonstrate MS/MS by isolating and dissociating each compound in a four component mixture of tetraalkylphosphonium cations. We also discuss the optimization of collision energy and the length of time that the SID target is available for collision, two parameters that are important in the performance of these experiments.

Orbitrap

Quadrupole ion trap

Collision-induced dissociation

Tandem

Penning trap

10.1021/ac502143p

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Citations (12)

Nondestructive Tandem Mass Spectrometry Using a Linear Quadrupole Ion Trap Coupled to a Linear Electrostatic Ion Trap

Analytical Chemistry (2013)

Ryan T. Hilger Robert E. Santini Scott A. McLuckey

A novel hybrid tandem mass spectrometer is presented that combines a linear quadrupole ion trap (QLIT) with a linear electrostatic ion trap (ELIT), which is composed of opposing ion mirrors. The QLIT is used both as an accumulation device for the pulsed injection of ions into the ELIT and as a collision cell for ions released from the ELIT and back into the QLIT. Ions are subjected to mass analysis in the ELIT via Fourier transformation of the time-domain signal obtained from an image current measurement using a pick-up electrode in the field-free region of the ELIT. The nondestructive nature of ion detection and the relatively straightforward axial entrance and exit of ions into and from the ELIT allow for the execution of nondestructive tandem mass spectrometry experiments whereby both the initial mass spectrum and the product ion spectrum are obtained on the same initial ion population. The timed pulsing of a deflection electrode, in conjunction with the release of ions from the ELIT, allows for the selection of precursor ions for recapture by the QLIT. The transfer of ions back and forth between the QLIT and ELIT is illustrated with Cs ions, the selection of precursor ions is demonstrated with isotopes of tetraoctylammonium cations, and complete nondestructive tandem mass spectrometry experiments are demonstrated with a mixture of angiotensin II and bradykinin cations. With the current apparatus, the efficiency for the process of recapturing ions and then reinjecting them into the ELIT is 35%-40%. The instrument is capable of isolating an ion from a neighbor with a mass as close as 1 part in 500, with negligible loss of the desired species.

Quadrupole ion trap

Tandem

Trap (plumbing)

Top-down proteomics

10.1021/ac4007182

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Citations (27)

The effect of reagent charge state on the charge inversion efficiency of singly charged polyatomic ions in the gas phase

Physical Chemistry Chemical Physics (2011)

Kerry M. Hassell Ryan T. Hilger Scott A. McLuckey

A variety of combinations of oppositely charged ions have been reacted to examine the role of the charge state from a multiply protonated or multiply deprotonated reagent ion on the efficiency of conversion of a singly charged ion of opposite polarity to a singly charged ion of the same polarity as the reagent. Maximum efficiencies on the order of tens of percent were observed. A threshold for charge inversion was noted in all cases and, with one exception, a clear decrease in efficiency was also noted at high charge states. A model was developed to predict charge inversion efficiency based on charge states, cross-sections of the reactants, and relevant thermodynamic ion affinity values for the reactants and products. The model predicts a threshold for charge inversion, although the prediction does not match the observed threshold quantitatively. This discrepancy is likely due to a simplifying assumption that is not justified on a quantitative basis but which does reproduce the qualitative trend. The model does not predict the major decrease in efficiency at high charge states. However, calculations show that the kinetic energies of the charge inversion products can lead to significant scattering losses at high charge states of the ion-ion collision complex.

Polyatomic ion

10.1039/c1cp21581g

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Citations (5)

Nanospray desorption electrospray ionization (nano-DESI) mass spectrometry imaging with high ion mobility resolution

Li‐Xue Jiang Emerson L. Hernly Hang Hu Ryan T. Hilger Heiko Neuweger

Untargeted separation of isomeric and isobaric species in mass spectrometry imaging (MSI) is challenging. The combination of ion mobility spectrometry (IMS) with MSI has emerged as an effective strategy for differentiating isomeric and isobaric species, which substantially enhances the molecular coverage and specificity of MSI experiments. In this study, we have implemented nanospray desorption electrospray ionization (nano-DESI) MSI on a trapped ion mobility spectrometry (TIMS) mass spectrometer. A new nano-DESI source was constructed, and a specially designed inlet extension was fabricated to accommodate the new source. The nano-DESI-TIMS-MSI platform was evaluated by imaging mouse brain tissue sections. We achieved high ion mobility resolution by utilizing three narrow mobility scan windows that cover the majority of the lipid molecules. Notably, the mobility resolution reaching up to 300 in this study is much higher than the resolution obtained in our previous study using drift tube IMS. High-resolution TIMS successfully separated lipid isomers and isobars revealing their distinct localizations in tissue samples. Our results further demonstrate the power of high mobility resolution IMS for unraveling the complexity of biomolecular mixtures analyzed in MSI experiments.

Ion-mobility spectrometry

Desorption electrospray ionization

Mass spectrometry imaging

Isobar

MALDI imaging

10.26434/chemrxiv-2023-73g9n

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Citations (1)

Nanospray Desorption Electrospray Ionization (Nano-DESI) Mass Spectrometry Imaging with High Ion Mobility Resolution

Journal of the American Society for Mass Spectrometry (2023)

Li‐Xue Jiang Emerson Hernly Hang Hu Ryan T. Hilger Heiko Neuweger

Untargeted separation of isomeric and isobaric species in mass spectrometry imaging (MSI) is challenging. The combination of ion mobility spectrometry (IMS) with MSI has emerged as an effective strategy for differentiating isomeric and isobaric species, which substantially enhances the molecular coverage and specificity of MSI experiments. In this study, we have implemented nanospray desorption electrospray ionization (nano-DESI) MSI on a trapped ion mobility spectrometry (TIMS) mass spectrometer. A new nano-DESI source was constructed, and a specially designed inlet extension was fabricated to accommodate the new source. The nano-DESI-TIMS-MSI platform was evaluated by imaging mouse brain tissue sections. We achieved high ion mobility resolution by utilizing three narrow mobility scan windows that covered the majority of the lipid molecules. Notably, the mobility resolution reaching up to 300 in this study is much higher than the resolution obtained in our previous study using drift tube IMS. High-resolution TIMS successfully separated lipid isomers and isobars, revealing their distinct localizations in tissue samples. Our results further demonstrate the power of high-mobility-resolution IMS for unraveling the complexity of biomolecular mixtures analyzed in MSI experiments.

Ion-mobility spectrometry

Desorption electrospray ionization

Mass spectrometry imaging

Isobar

MALDI imaging

Isobaric process

10.1021/jasms.3c00199

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Citations (23)

Hardware and software solutions for implementing nanospray desorption electrospray ionization (nano-DESI) sources on commercial mass spectrometers

Li‐Xue Jiang Ryan T. Hilger Julia Laskin

Nanospray desorption electrospray ionization (nano-DESI) is an ambient ionization mass spectrometry imaging (MSI) approach that has been used for imaging of biological and environmental samples with high spatial resolution and throughput. Because nano-DESI has not yet been commercialized, researchers develop their own sources and interface them with different commercial mass spectrometers. Previously, several protocols focusing on the fabrication of nano-DESI probes have been reported. In this tutorial, we discuss different hardware requirements for coupling the nano-DESI source to commercial mass spectrometers, such as the safety interlock, inlet extension, and contact closure. In addition, we describe the structure of our custom software for controlling the nano-DESI MSI platform and provide detailed instructions for its usage. With this tutorial, interested researchers should be able to implement nano-DESI experiments in their own labs.

Desorption electrospray ionization

10.26434/chemrxiv-2024-rxtmz

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Citations (1)

Hardware and software solutions for implementing nanospray desorption electrospray ionization (nano‐DESI) sources on commercial mass spectrometers

Journal of Mass Spectrometry (2024)

Li‐Xue Jiang Ryan T. Hilger Julia Laskin

Nanospray desorption electrospray ionization (nano-DESI) is an ambient ionization mass spectrometry imaging (MSI) approach that enables spatial mapping of biological and environmental samples with high spatial resolution and throughput. Because nano-DESI has not yet been commercialized, researchers develop their own sources and interface them with different commercial mass spectrometers. Previously, several protocols focusing on the fabrication of nano-DESI probes have been reported. In this tutorial, we discuss different hardware requirements for coupling the nano-DESI source to commercial mass spectrometers, such as the safety interlock, inlet extension, and contact closure. In addition, we describe the structure of our custom software for controlling the nano-DESI MSI platform and provide detailed instructions for its usage. With this tutorial, interested researchers should be able to implement nano-DESI experiments in their labs.

Desorption electrospray ionization

Ambient ionization

10.1002/jms.5065

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Citations (3)

Square wave modulation of a mirror lens for ion isolation in a Fourier transform electrostatic linear ion trap mass spectrometer

International Journal of Mass Spectrometry (2014)

Ryan T. Hilger Robert E. Santini Scott A. McLuckey

Quadrupole ion trap

10.1016/j.ijms.2014.02.003

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Citations (16)

Electroosmotically driven solution mixing in borosilicate theta glass nESI emitters

Journal of Mass Spectrometry (2015)

Christine M. Fisher Ryan T. Hilger Feifei Zhao Scott A. McLuckey

The use of borosilicate theta glass capillaries as nanoelectrospray ionization emitters has recently been demonstrated as a method for mixing two solutions as they are sprayed into the mass spectrometer for analysis. All previous experiments resulted in a solution mixing timescale limited to the time the analytes spend in the Taylor cone and subsequent droplets (i.e. sub-millisecond timescale). In an effort to extend the solution mixing timescale to the milliseconds regime, we demonstrate that solution can be moved from one channel of the theta tip to the opposite channel via electroosmosis by applying a potential difference between the two wire electrodes inserted into each channel of the theta tip. First, we establish that electroosmosis is responsible for solution movement using fluorescence microscopy to track fluorescent tracer dyes. We then demonstrate the utility of this technique in varying the extent of denaturation of holomyoglobin to apomyoglobin on the millisecond timescale just prior to analysis by mass spectrometry. Finally, we induce additional turbulence for better mixing by applying a square wave potential to one of the wire electrodes while holding the opposite wire at a constant voltage between the low and high potentials of the square wave. This experiment was found to provide nearly complete mixing after a single cycle of the square wave. The use of electroosmosis significantly expands the flexibility of theta tips for altering solutions prior to nESI without the need for off-line sample manipulation. Copyright © 2015 John Wiley & Sons, Ltd.

Borosilicate glass

Square wave

Millisecond

10.1002/jms.3620

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Citations (11)