About

David C Muddiman is the Jacob and Betty Belin Distinguished Professor of Chemistry and serves as the Associate Head for Research at NC State University. His research group focuses on developing innovative mass spectrometry measurements to address important biological problems. His projects include the development of an ambient ionization method called IR-MALDESI, which is applied to a diverse range of materials such as soft tissue, plants, textiles, and bone. Additionally, his group works on advanced separation techniques to enable detailed characterization of complex biological samples. Dr. Muddiman's expertise lies in analytical chemical biology, with a particular emphasis on applying mass spectrometry to solve biological questions.

Research topics

• Chemistry
• Internal medicine
• Biochemistry
• Biology
• Medicine
• Optics
• Physics
• Endocrinology
• Chromatography
• Genetics
• Botany

Selected publications

• Spatially resolved lipids in a mouse brain model of globoid cell leukodystrophy via IR-MALDESI MSI and parallel reaction monitoring MSI

  Analytical and Bioanalytical Chemistry · 2026-01-23

  articleOpen accessSenior author

  Globoid cell leukodystrophy (GLD) is a genetic neurodegenerative disease caused by mutations in galactosylceramide β-galactosidase (GALC) that results in the accumulation of the cytotoxic sphingolipid, psychosine. As psychosine is a biomarker specific to GLD, identifying the most afflicted regions of the nervous system can assist in better understanding the disease mechanism. Infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) mass spectrometry imaging (MSI) and parallel reaction monitoring were utilized to elucidate the spatial distribution of the psychosine analyte and confirm the identity of the ion in a sagittal section of a GALC-deficient mouse brain. The presence of the psychosine was increased in specific anatomical regions of the brain responsible for the bodily functions that are impaired by GLD (cerebellum and brain stem). Several electrospray solvent additives (dopants) have enhanced the detection of various analyte types but with little success in enhancing the detection of sphingolipids. This study investigates the usefulness of ammonium fluoride electrospray doping in the positive ion mode for lipidomic IR-MALDESI MSI analysis.

  PublisherOA PDFDOI

• High‐Throughput <i>N</i> ‐Glycan Analysis by IR‐MALDESI With a 1.5‐kHz Pulsed Mid‐IR Laser

  Journal of Mass Spectrometry · 2026-04-07

  articleOpen accessSenior authorCorresponding

  Infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) is a laser-based, hybrid ionization source for mass spectrometry, enabling both mass spectrometry imaging (MSI) and high-throughput screening (HTS). In this work, a 2.2-ns, 2.72-μm laser, operating at 1.5 kHz, was integrated into the IR-MALDESI platform to evaluate its performance for robust HTS and glycan profiling. The system produced robust HTS performance, achieving a relative standard deviation (RSD) of 9.1% with no detectable carryover between wells and consistent ion abundances in multiwell screening experiments. Using this configuration, 29 glycans were detected from a solution of cleaved N-glycans derived from bovine fetuin, with multiple charge states observed for several species. These results demonstrate rapid, high-throughput analysis and expanded glycan detection enabled by desorption using a low-power mid-IR laser operating at kHz repetition rates, highlighting its potential for advanced biochemical screening and characterization.

  PublisherDOI

• Glycan signal enhancement by ammonium fluoride doping and electrospray diverting

  The Analyst · 2026-01-01

  articleOpen accessSenior author

  , adduct, or specific monosaccharides, suggesting that this technique is highly robust and agnostic to analyte characteristics.

  PublisherOA PDFDOI

• Demonstrating Voxel‐by‐Voxel (V × V) Single‐Point Calibration in Whole‐Body Zebrafish by IR‐MALDESI Quantitative MSI

  Journal of Mass Spectrometry · 2026-01-12

  articleOpen accessSenior authorCorresponding

  This work describes a quantitative mass spectrometry imaging (qMSI) method comparison for the absolute quantification of arachidonic acid (AA) in whole-body zebrafish using infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI). Whole-body zebrafish are structurally heterogeneous samples that are complex to analyze by many qMSI methods largely due to practical sample preparation limitations. However, the multi-organ quantification is valuable in zebrafish, especially for lipid-related investigations. In the standard workflow, the ion abundance of AA was normalized to a structural analogue that was sprayed on the slide before mounting the tissue. A series of calibration spots of stable isotope label (SIL) deuterated AA were spotted onto tissue to construct a calibration curve and subsequently calculate the concentration of endogenous AA in the tissue sections. The calculated values of AA using this method provided values significantly lower than the literature. In the subsequent workflow, the structural analogue was considered in a voxel-by-voxel (V × V) calculation of the concentration of AA in the tissues resulting in an AA concentration similar to the literature within whole-body zebrafish. The V × V method proved simpler in sample preparation, and more accurately quantified AA. This implies the potential utility of single-point V × V calibration for the qMSI of highly heterogeneous tissues.

  PublisherOA PDFDOI

• Integrating Remote Sensing and Metabolomics to Assess Synergistic Effects of Phosphate Deficiency, Drought, and <scp>AMF</scp> Symbiosis in Soybean

  Physiologia Plantarum · 2026-01-01 · 1 citations

  articleOpen access

  ABSTRACT Soybean growth and yield are susceptible to abiotic stresses such as phosphate (P) deficiency and drought. Symbiotic association of plant roots with arbuscular mycorrhizal fungi (AMF) can improve water uptake, thereby increasing stress resilience. This study evaluates the interactive effects of P availability, drought, and AMF symbiosis on physiology, reflectance traits, roots, and metabolite responses in two soybean genotypes during the early reproductive stages. Under P deficiency (P−), AMF colonization significantly ( p &lt; 0.05) increased, enhancing root hair development and maintaining ~30% lower leaf water potential (Ψ) under drought stress. Drought significantly ( p &lt; 0.05) negatively impacted photosynthesis as well as triggered shifts in metabolite accumulation and reflectance‐based vegetation indices in both P treatments. P− sufficient (P+) plants developed significantly higher biomass. Chlorophyll‐related vegetation indices were more responsive to P during drought, showing 45%–60% reductions in P− plants compared with only 25%–35% in P + plants. The ratio of red‐to‐far‐red chlorophyll fluorescence also significantly decreased (10%) under drought, indicating altered canopy spectral balance and stress‐induced pigment changes. Carbohydrates, jasmonic acid, and amino acids exhibited significant variations ( p &lt; 0.05) among genotypes and P treatment under drought. Interestingly, a metabolite involved in phylloquinone biosynthesis (C 11 H 12 O 6 ) was strongly upregulated under drought in P− plants with a strong correlation ( r = 0.72) to Ψ. These findings highlight the critical role of P in AMF symbiosis for drought resistance. The integration of remote sensing and mass spectrometry‐based metabolite profiling provides a comprehensive multiscale approach to link physiological and molecular responses, facilitating rapid and informed breeding decisions under diverse environmental stresses.

  PublisherDOI

• Resolving the glycosaminoglycan signature of ischemic stroke brain using PRM-based IR-MALDESI mass spectrometry imaging

  Analytical and Bioanalytical Chemistry · 2026-01-23

  articleOpen accessSenior author

  Stroke is the second most common cause of death in the world and a leading cause of disability. Ischemic stroke is the most common type of stroke (~87%), necessitating research into effective treatments. Chondroitin sulfate (CS) is a sulfated glycosaminoglycan (GAG) found in the central nervous system (CNS) that contains labile sulfate groups which, upon loss, leads to inaccurate structural annotations. Variable sulfation patterns have been implicated in several neurological diseases. Additionally, CS-GAG analysis is challenging due to labile sulfate groups and the presence of positional isomers. These isomers must be distinguished to develop effective targeted therapies. Currently, glycan mass spectrometry imaging (MSI) lacks soft ionization sources which impedes intact analysis of the labile sulfate modifications. Infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) is a soft ambient ionization technique capable of preserving labile species without chemical derivatization. In this work, IR-MALDESI with parallel reaction monitoring (PRM) was used to energetically resolve and characterize intact mono-sulfated CS-GAG positional isomers in healthy and ischemic stroke brain. Our results revealed that both positional isomers were upregulated in the stroke brain and their relative abundance remained constant across the tissue.

  PublisherOA PDFDOI

• A Strategy to Achieve Sub‐Parts‐per‐Million Mass Measurement Accuracy of <i>N</i>‐Linked Glycans Using Infrared Matrix‐Assisted Laser Desorption Electrospray Ionization

  Journal of Mass Spectrometry · 2025-09-29 · 2 citations

  articleOpen accessSenior author

  Mass calibration techniques are vital in achieving high mass measurement accuracy (MMA) of large biomolecules. Variable ion populations that shift the axial frequencies due to space charge effects have been a significant challenge in achieving sub-parts-per-million (sub-ppm) MMA of glycans on a high-resolution accurate mass (HRAM) orbitrap instrument without the activation of automatic gain control. As the role of glycans is critical to our understanding of diverse biological processes, accurate identification of glycans using sub-ppm MMA is critical for biological interpretations. Hence, this study aims to achieve sub-ppm MMA of glycans by exploring the impact of different ion accumulation times, data collection modes, in addition to custom calibration strategies and external mass correction to optimize accurate mass measurements. Using infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI), direct analysis was performed on N-linked glycans cleaved from bovine fetuin in negative polarity, where 17 N-linked glycans were detected and annotated. Our results indicate the significance of implementing a custom calibration external lock mass and other techniques, including the effect of external mass correction in achieving sub-ppm MMA of large biomolecules. Implementing such approaches in mass spectrometry imaging (MSI) of biological tissue will enhance the confidence of glycan annotation and enable more accurate biological conclusions.

  PublisherOA PDFDOI

• Exploring ammonium salt doping to enhance ion abundance for quantitative mass spectrometry imaging

  Analytical and Bioanalytical Chemistry · 2025-11-04 · 1 citations

  articleOpen accessSenior author

  Abstract Increasing ion abundance in mass spectrometry is essential for enhancing detection, quantification, and understanding of biomolecules involved in key cellular processes. Infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI), MALDI, and nano-DESI have shown improved ion abundance when integrating specific concentrations of ammonium fluoride into the sample preparation and/or ionization steps. Herein, the importance of electronegativity and atomic size for the proposed mechanism of increased ion abundance is evaluated by testing a variety of ammonium halide salts. Ammonium fluoride was confirmed to result in the largest increase in ion abundance and was subsequently used to perform quantitative mass spectrometry imaging (qMSI) of glutathione (GSH) in healthy mouse liver tissue. Using ~70 µM NH 4 F as an ESI dopant, up to a ~ two-fold increase in ion abundance was observed for these biomolecules, as well as an improvement in the limit of detection, detection frequency, and quantification of endogenous GSH in tissue. Graphical Abstract

  PublisherOA PDFDOI

• Three-Dimensional (3D) Topographic Mass Spectrometry Imaging of <i>Artemisia annua</i> by UV-MALDESI

  Journal of the American Society for Mass Spectrometry · 2025-12-01

  articleSenior authorCorresponding

  Matrix-assisted laser desorption electrospray ionization (MALDESI) enables mass spectrometry imaging (MSI) capabilities to reveal the localization of a wide range of biomolecules across an organism. Three-dimensional (3D) MSI of biological tissues is typically accomplished by imaging two-dimensional sections followed by the creation of a 3D image informatically. In contrast to this sectioning-based approach, we employ an ablation-based 3D MSI technique to image Artemisia annua, a medicinal herb that naturally produces the antimalarial drug artemisinin. We incorporated a novel high-energy burst-mode ultraviolet (UV) laser, and a chromatic confocal aberration (CA) probe with automatic z-axis correction (AzC) to measure the depth of ablation (i.e., z-resolution). The combination of these techniques allowed the visualization of the artemisinin metabolic pathway along with other secondary metabolites beneath the tissue surface, as supported by the resulting data. This approach enabled detailed molecular mapping in 3D, providing a comprehensive view of the plant’s molecular landscape layer by layer, offering new insights into its biosynthetic pathways in three dimensions.

  PublisherDOI

• Glycosaminoglycan Mass Spectrometry Imaging by Infrared Matrix-Assisted Laser Desorption Electrospray Ionization

  Journal of the American Society for Mass Spectrometry · 2025-03-04 · 5 citations

  articleSenior authorCorresponding

  Chondroitin sulfate (CS) is a type of glycosaminoglycan (GAG) that is abundant in cartilage and perineural networks (PNNs). Changes in the CS signature of PNNs have been implicated in several neurological diseases. Most CS-GAGs contain labile sulfate groups, which can be lost during ionization events that deposit large amounts of internal energy. Infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) is a soft ionization technique used for mass spectrometry imaging. In this work, we determine the spatial distribution of CS-GAG disaccharides within rodent brain using IR-MALDESI MSI. Non-, mono-, and disulfated disaccharides were detected with various adducts. All disaccharides colocalized to the PNNs, which are most abundant in the cortex and hippocampus regions of the brain. This is the first MSI study to spatially resolve CS-GAG disaccharides within brain, paving the way for IR-MALDESI to measure GAGs in neurological diseases.

  PublisherDOI

Recent grants

• NIH Grant R33CA147988

  NIH · $1.1M · 2015

• NIH Grant R21CA134250

  NIH · $347k · 2011

• NIH Grant R21GM134219

  NIH · $403k · 2023

• NIH Grant R01HG002159

  NIH · $967k · 2004

• Development and Application of New Ionization Methods for Biological Mass Spectrometry

  NIH · $4.7M · 2009–2026

Frequent coauthors

• Peter J. Stang

  University of Utah

  87 shared

• Adam M. Hawkridge

  Virginia Commonwealth University

  80 shared

• Richard Smith

  Pacific Northwest National Laboratory

  65 shared

• Hai‐Bo Yang

  East China Normal University

  49 shared

• Angelito I. Nepomuceno

  North Carolina State University

  27 shared

• H. Robert Bergen

  26 shared

• Kenneth P. Garrard

  North Carolina State University

  25 shared

• Quanzi Li

  Chinese Academy of Forestry

  24 shared

Labs

• The Muddiman GroupPI

Awards & honors

• AAAS Fellow