Matrix-assisted laser desorption electrospray ionization

Matrix-assisted laser desorption electrospray ionization (MALDESI) is an ambient ionization technique which combines the benefits of electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI). MALDESI was introduced in 2006 as the first hybrid ionization source combining laser ablation and electrospray post-ionization using a resonantly excited matrix (endogenous or exogenous).[1] An infrared (IR) or ultraviolet (UV) laser can be utilized in MALDESI in order to resonantly excite an endogenous or exogenous matrix. The term ‘matrix’ refers to any molecule that is present in large excess and absorbs the energy of the laser, facilitating desorption of analyte molecules. The original MALDESI design was implemented using organic matrices, similar to those used in MALDI, along with a UV laser.[1] The more recent MALDESI source uses a thin layer of ice as the energy-absorbing matrix that is resonantly excited using a mid-infrared (IR) laser.[2]

The IR-MALDESI source can be used for mass spectrometry imaging (MSI), a technique using MS data collected over the sample area to visualize the spatial distribution of specific analyte molecules. A versatile IR-MALDESI MSI source was designed and implemented,[3] which is currently coupled to a high resolving power hybrid Quadrupole-Orbitrap mass spectrometer. The source has single- or multi-shot capabilities with adjustable laser fluence, repetition rate, as well as the delay between the laser trigger and MS ion accumulation. The sample plate and moving components are enclosed in a nitrogen purged enclosure where ambient ions and relative humidity can be regulated. A water cooled Peltier thermoelectric plate is used to control the sample temperature (−10 °C to 80 °C).

The IR-MALDESI source is currently used to investigate the fundamentals of the ionization process, in addition to being routinely employed for visualizing analyte distributions in biological, forensic, and pharmaceutical samples.

Principles of operation

In IR-MALDESI imaging experiments, a thin layer of ice is deposited/formed on the sample as the energy-absorbing matrix. A mid-IR laser pulse (λ=2940 nm) is then absorbed by exciting the O-H stretching mode of water causing rapid phase change leading to an ablation event, which facilitates desorption of neutral material from surface. The plume of desorbed material interacts with an orthogonal electrospray plume where desorbed compounds partition into charged electrospray droplets and ions are generated by an ESI-like process that are sampled by a mass spectrometer.[2] The ESI-like ionization mechanism was experimentally demonstrated by Muddiman et al.[4]

Using ice as the matrix has been reported in IR-MALDI experiments; however, the ion yields for such experiments have been very low. The electrospray post-ionization employed in IR-MALDESI helps alleviate issues associated with low ionization yield. Using an exogenous ice matrix was shown to improve the detected ion abundance by a factor of approximately 15 for selected small molecules.[5] By employing the method of oversampling,[6] spatial resolutions of ~100 micrometer can be readily achieved. In a recent study, oversampling was used to achieve cellular-level MSI of epithelial cells using a step size of 10 micrometer.[7]


The IR-MALDESI source has been employed in variety of different applications. The most common application of the source has been assessing the distribution of endogenous and exogenous species in tissue specimens. One example of such studies is mapping distribution of antiretrovirals in human cervical tissues.[5] In a subsequent study, the imaging source was used to quantify the amount of an antiretroviral drug in the cervical tissues incubated with the drug of interest.[8]

Another application of the IR-MALDESI source is in the field of forensic analysis of textile fibers. In contrast to the traditional MS methods, where the dye must be extracted from the fabric and the dye components are separated by chromatography prior to mass spectrometric analysis, the IR-MALDESI source allows for direct analysis of the dye from the fabric. Using the IR-MALDESI imaging source, a variety of dye classes were analyzed from various fabrics with little to no sample preparation allowing for the identification of the dye mass and in some cases the fiber polymer.[9]

Samples could be desorbed from the surface without using matrices. The technique called electrospray-assisted laser desorption/ionization (ELDI) uses an ultraviolet laser to form ions by irradiating the sample directly, without using any matrices, for ion formation through interaction with the electrospray plume.[10] The infrared laser version of ELDI has been called laser ablation electrospray ionization (LAESI).[11] IR-MALDESI differs from ELDI since the laser is used to resonantly excite the endogenous or exogenous matrix in order to enhance the desorption of sample from the surface.

In early versions of thermospray, an infrared laser was directed at a liquid spray tip to heat the sample and aid in ionization.[12] Desorption atmospheric pressure photoionization (DAPPI) uses a jet of heated solvent for desorption and ultraviolet light for photoionization.[13]


  1. Sampson, J. S.; Hawkridge, A. M.; Muddiman, D.C. (2006). "Generation and Detection of Multiply-Charged Peptides and Proteins by Matrix-Assisted Laser Desorption Electrospray Ionization (MALDESI) Fourier Transform Ion Cyclotron Resonance Mass Spectrometry". J. Am. Soc. Mass Spectrom. 17 (12): 1712–16. doi:10.1016/j.jasms.2006.08.003. PMID 16952462.
  2. Robichaud, G.; Barry, J.A.; Muddiman, D.C. (2014). "IR-MALDESI Mass Spectrometry Imaging of Biological Tissue Sections Using Ice as a Matrix". J. Am. Soc. Mass Spectrom. 25 (3): 319–28. doi:10.1007/s13361-013-0787-6. PMC 3950934. PMID 24385399.
  3. Robichaud, G.; Barry, J.A.; Garrard, K. P.; Muddiman, D.C. (2013). "Infrared Matrix-Assisted Laser Desorption Electrospray Ionization (IR-MALDESI) Imaging Source Coupled to a FT-ICR Mass Spectrometer". J. Am. Soc. Mass Spectrom. 24 (1): 92–100. doi:10.1007/s13361-012-0505-9. PMC 3689149. PMID 23208743.
  4. Dixon, R. B., Muddiman, D.C. (2010) "Study of the ionization mechanism in hybrid laser based desorption techinques" Analyst. 135, 880-2 .
  5. Barry, J.A.; Robichaud, G.; Bokhart, M. T.; Thompson, C.; Sykes, C.; Kashuba, A. D. M.; Muddiman, D.C. (2014). "Mapping antiretroviral Drugs in Tissue by IR-MALDESI MSI Coupled to the Q Exactive and Comparison with LC-MS/MS SRM Assay". J. Am. Soc. Mass Spectrom. 25 (12): 2038–47. doi:10.1007/s13361-014-0884-1. PMC 4201889. PMID 24744212.
  6. Jurchen, J. C.; Rubakhin, S. S.; Sweedler, J. V. (2005). "MALDI-MS Imaging of Features Smaller than the Size of the Laser Beam". J. Am. Soc. Mass Spectrom. 16 (10): 1654–59. doi:10.1016/j.jasms.2005.06.006.
  7. Nazari, M.; Muddiman, D.C. (2014). "Cellular-level mass spectrometry imaging using infrared matrix-assisted desorption electrospray ionization (IR-MALDESI) by oversampling". Anal. Bioanal. Chem. 407 (8): 2265–2271. doi:10.1007/s00216-014-8376-5. PMC 4359048.
  8. Bokhart, M. T.; Rosen, E.; Thompson, C.; Sykes, C.; Kashuba, A. D. M.; Muddiman, D.C. (2014). "Quantitative mass spectrometry imaging of emtricitabine in cervical tissue model using infrared matrix-assisted laser desorption electrospray ionization". Anal. Bioanal. Chem. 407 (8): 2073–2084. doi:10.1007/s00216-014-8220-y. PMC 4495968.
  9. Cochran, K. H.; Barry, J. A.; Muddiman, D.C.; Hinks, D. (2013). "Direct Analysis of Textile Fabrics and Dyes Using Infrared Matrix-Assisted Laser Desorption Electrospray Ionization Mass Spectrometry". Anal. Chem. 85 (2): 831–836. doi:10.1021/ac302519n. PMC 3654692. PMID 23237031.
  10. Shiea J, Huang MZ, Hsu HJ, Lee CY, Yuan CH, Beech I, Sunner J (2005). "Electrospray-assisted laser desorption/ionization mass spectrometry for direct ambient analysis of solids". Rapid Commun. Mass Spectrom. 19 (24): 3701–4. doi:10.1002/rcm.2243. PMID 16299699.
  11. Nemes P, Vertes A (2007). "Laser Ablation Electrospray Ionization for Atmospheric Pressure, in Vivo, and Imaging Mass Spectrometry". Analytical Chemistry. 79 (21): 8098–106. doi:10.1021/ac071181r. PMID 17900146.
  12. Blakley, C. R.; Carmody, J. J.; Vestal, M. L. (1980). "Liquid Chromatograph-Mass Spectrometer for Analysis of Nonvolatile Samples". Analytical Chemistry. 52 (11): 1636–1641. doi:10.1021/ac50061a025.
  13. Haapala M, Pól J, Saarela V, et al. (2007). "Desorption Atmospheric Pressure Photoionization". Analytical Chemistry. 79 (20): 7867–7872. doi:10.1021/ac071152g. PMID 17803282.
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