Ambient desorption ionization mass spectrometry

Trends Trends in Analytical Chemistry, Vol. 27, No. 4, 2008

Ambient desorption ionization massspectrometryAndre Venter, Marcela Nefliu, R. Graham Cooks

Ambient desorption ionization mass spectrometry (MS) allows for the direct

analysis of ordinary objects in the open atmosphere of the laboratory or in

their natural environment. Analyte desorption usually accompanies the io-

nization step and these processes are often concerted, multi-step processes.

Ambient desorption ionization methods typically require little or no sample

preparation, offer a much simplified work flow and deliver unprecedented

ease of use to MS analyses.

Since the introduction of desorption electrospray ionization (DESI

[Z. Takats, J.M. Wiseman, B. Gologan, R.G. Cooks, Science (Washington,

D. C.) 306 (2004) 471]) in 2004 and the direct analysis in real time (DART

[R.B. Cody, J.A. Laramee, H.D. Durst, Anal. Chem. 77 (2005) 2297]) in 2005,

this new field of MS has developed rapidly. Numerous permutations of the

various options for analyte desorption and ionization have been demonstrated.

Desorption steps, such as momentum transfer, dissolution into ricocheting

droplets and thermal desorption, have been combined with ionization steps,

including ESI, atmospheric pressure chemical ionization and photo-ioniza-

tion. The large number of possible combinations of desorption and ionization

components that have already been applied is creating a proliferation of

techniques and acronyms that is becoming ever more complex.

Here, we provide a logical framework for the classification of these related

experiments, based on the desorption and ionization processes involved in each.

ª 2008 Elsevier Ltd. All rights reserved.

Keywords: Ambient ionization; Direct analysis; Electrospray; In situ analysis; Ion

formation; Ionization; Ion transport; Mass spectrometry

Andre Venter, Marcela Nefliu,

R. Graham Cooks*

Department of Chemistry,

Purdue University,

West Lafayette, Indiana 47907,

USA

284

*Corresponding author.

Tel.: +1 765 494 5263;

Fax: +1 765 494 9421;

E-mail: [email protected]

1. Introduction

The invention of electrospray ionizationmass spectrometry (ESI-MS) [3] provided anefficient way to separate analytes from thesolution-phase matrix, and so to transferfree ions from solution at atmosphericpressure into the high-vacuum environ-ment required for analysis by MS. Similarly,matrix-assisted laser desorption ionization(MALDI [4]), which allows for the analysisof analytes dispersed in a condensed-phasematrix, has also been moved out of thevacuum system and into the open envi-ronment. These developments simplifiedthe analysis, increased the ease of use andextended the types of samples that can beinterrogated by MS. However, ESI, MALDIand all the traditional atmospheric pressure

0165-9936/$ - see front matter ª 2008 Elsev

ionization (API) sources, such as atmo-spheric pressure chemical ionization (APCI[5]) and atmospheric pressure photo ioni-zation (APPI [6]), still require extensivesample-preparation steps before the samplecan be dissolved in or coated with a spe-cially selected suitable matrix that is ame-nable to and required by the analyticalsystem. With the introduction of desorptionelectrospray ionization (DESI) and directanalysis in real time (DART), it becamepossible, for the first time, to analyze sam-ples directly in their native condition,bypassing most elements of the analyticalsystem and transferring ions into the massspectrometer without any sample-manipu-lation or sample-preparation steps. Ambi-ent desorption ionization techniques, in asingle operational step, successfully bridgethe gap between the ambient environment,where condensed phase samples are pres-ent, and the vacuum system, where anal-ysis takes place. The development of DESIcreated an awareness of the potential ofopen ambient environment analysis andsparked a new sub-field in MS. The noveltyof this concept is demonstrated by the rapidintroduction of at least 15 new methods inthe past three years, summarized in Table 1.

1.1. Finding your way with ambientionizationAmbient ionization techniques (Fig. 1) canbe organized according to the traditionaltechnique that plays the central role in theoverall ionization process and as such alsogoverns the nature of the resulting massspectra. In this way, they can be separatedinto classes, such as those closely relatedto ESI, including DESI, and those resem-bling APCI, such as DART, desorptionatmospheric pressure chemical ionization(DAPCI), or ambient solid analysis probe(ASAP).

ier Ltd. All rights reserved. doi:10.1016/j.trac.2008.01.010

mailto:[email protected]

Table 1. Ambient desorption ionization techniques listed in orderof publication

Technique Acronym Date

Desorption Electrospray Ionization DESI [1] 2004Surface Sampling Probe SSP [26] 2004Direct Analysis in Real Time DART [2] 2005Ambient Solid Analysis Probe ASAP [27] 2005Electrospray Laser Desorption/Ionization ELDI [28] 2005Fused Droplet Electrospray Ionization FD-ESI [29] 2005Desorption AtmosphericPressure Chemical Ionization

DAPCI [21] 2005

MALDI Assisted Electrospray Ionization MALDESI [30] 2006Extractive Electrospray Ionization EESI [31] 2006Desorption Sonic Spray Ionization DeSSI [32] 2006Plasma-Assisted Desorption/Ionization PADI [33] 2007Dielectric Discharge Barrier Ionization DBDI [24] 2007Helium Atmospheric PressureGlow Discharge Ionization

HAPGDI [34] 2007

Neutral Desorption ExtractiveElectrospray Ionization

ND-EESI [35] 2007

Laser Ablation Electrospray Ionization LAESI [36] 2007Atmospheric Pressure ThermalDesorption Ionization

APTDI [25] 2007

Desorption AtmosphericPressure Photo Ionization

DAPPI [37] 2007

Figure 1. Techniques used in ambient desorption ionization.

Trends in Analytical Chemistry, Vol. 27, No. 4, 2008 Trends

Conceptually, separating the desorption step from theionization step helps to rationalize the contribution of theindividual techniques in the overall process when acombination of techniques is used. For example, electro-spray laser desorption/ionization (ELDI), MALDI-assistedESI (MALDESI), and laser ablation ESI (LAESI) combinelaser desorption (LD) to liberate ions, neutrals and clus-ters of material from the sample surface with a secondarydesorption and/or collection step where the heteroge-neous plume of liberated material is intercepted by apneumatically-assisted electrospray. These combinedmethods produce spectra that predominantly resemblethose observed in ESI. It is not always possible to separatethe desorption and the ionization steps, as in the cases

where plasmas are employed for sample interrogation –helium atmospheric pressure glow discharge ionization(HAPGDI), dielectric discharge barrier ionization (DBDI)or plasma-assisted desorption/ionization (PADI). In otherinstances, it is not clear that a desorption step is involvedat all, as in the case of the techniques where liquid orgaseous samples are analyzed by pneumatically-assistedelectrospray – fused droplet ESI (FD-ESI) and extractiveESI (EESI). In the following paragraphs, we briefly de-scribe the various techniques and their interrelationshipsby grouping them into ESI-related techniques (DESI,DESSI, SSP, ELDI, MALDESI and LAESI) and APCI-relatedtechniques (DAPCI, ASAP, DART, DBDI, HAPGDI, andPADI) (see Table 1 for acronyms).

2. ESI-related techniques

ESI is successful with moderately polar to polar mole-cules that can be dissolved in aqueous solvents. Ioniza-tion occurs predominately through:� adduct formation in both positive-ion and negative-

ion modes (e.g., [M + H]+, [M + Cl]�);� direct release of intact cations and anions from salts;

and,� deprotonation in the negative-ion mode.

The mass spectra are often complex due to theformation of solvent clusters and multiple-ionizationproducts, such as multiply-charged ions and alkali-metal-cation adducts. In the ESI-related ambient techniques,analyte molecules are first desorbed or sampled from solidor liquid samples, and then transported into themass spectrometer in evaporating charged solventdroplets.

The desorption mechanisms vary greatly frommomentum desorption by a solvent spray (DESI and closevariant DeSSI) or a nitrogen-gas stream (ND-EESI), toenergy-sudden activation when lasers are employed(ELDI and LAESI). Pneumatically-assisted electrospraysare also used to sample liquids directly, as in EESI and FD-ESI. In these cases, a sample is pneumatically nebulizedand then intercepted by an ionizing electrospray. Ana-lytes are extracted from the neutral sample droplets intothe charged droplets mainly due to differences in theirsolubility in the two solvent systems. Moreover, selectiveextraction of the analytes in preference to matrix com-ponents occurs due to differences in their spatial distri-bution in the sample droplets (e.g., analyte molecules arepreferentially located on the droplet surface while thesalts prefer the droplet interior [7]). When using thesolid sampling probe (SSP), a liquid junction is createdbetween the probe and the solid surface. Solublecompounds are collected by solvent flow, which issubsequently delivered into an electrospray emitter.

The last stage of the ionization process resembles theESI mechanism, with ions being transferred from small

http://www.elsevier.com/locate/trac 285


charged solvent droplets into the gas phase by charge-residue or ion-evaporation mechanisms.

2.1. DESI2.1.1. Mechanistic description. DESI is the process whereaqueous droplets with diameters less than 10 lm impacton a sample surface at velocities typically in excess of100 m/s. Measurements of droplet size and velocity dis-tributions, as well as simulations and anecdotal evidencebased on spectral characteristics, indicate that a droplet-pick-up mechanism probably operates under most cir-cumstances. This mechanism probably does not dependon quasi-elastic droplet-surface impact events or thesurvival of intact droplets after surface collision. Instead,it is believed that the surface is pre-wetted by initialdroplets. Surface analytes dissolve or otherwise collect inthis localized solvent layer. Later-arriving dropletsimpact this surface solvent-layer and break it up,creating numerous off-spring droplets containing thematerial originating from the solvent layer including thedissolved analytes. Thus, analyte desorption occurs bymomentum transfer in the form of charged sub-lmdroplets that are then ionized by ESI mechanisms.

DeSSI is a version of DESI where no voltage is appliedto the spray emitter, therefore producing solvent dropletsof lower charge density. Differences between DESI andDeSSI spectra are similar to those differences observedbetween ESSI [8] and SSI [9] and arise mostly from theionization step. Although charge build-up on the surfacehas been shown to affect the charge transfer andtherefore the ion currents in DESI [10], simulations ofthe DESI process [11] show that hydrodynamic forcesplay the major role in analyte desorption from surfaces.Further investigation is needed to elucidate the chargingeffects in the desorption process.

2.1.2. Instrumental considerations. DESI sources can beas simple as a ring stand holding an electrospray emitter atan angle relative to the surface and the mass spectrometerinlet. However, the signal intensity observed in the massspectrometer strongly depends on the various geometricalfactors, including the angle and the distance between theelectrospray emitter and the surface and between thesurface and the MS inlet. These geometrical factors oftenhave to be re-optimized to obtain a good signal, so theyhave been a major influence in DESI-source development.Micrometer translational control in the x,y,z dimensionsfor the sample and for the sprayer together with angularcontrol of the spray direction greatly improve reproduc-ibility and ease of use of the DESI set-up and make it muchmore robust. Positional control is also the basis for thedevelopment of 2D imaging [12].

The latest DESI-source configurations aim to reducefurther the dependence of the ion signal on the variousgeometrical factors and feature a small, pressure-tightenclosure with fixed spatial relationships between the

286 http://www.elsevier.com/locate/trac

sprayer, surface and sampling capillary [13]. This con-figuration provides improved ionization efficiency, safetyand ease of use; performance is largely independent of thegeometrical configuration of the spray and the inlet, sothe arrangement has been called geometry-independentDESI. Irrespective of the combination of sprayer andcollection-capillary angles, comparable results to thetraditional DESI set-up are obtained in most cases forproteins, peptides and small molecules. Moreover, withthe sprayer and the collection capillary set parallel toeach other and perpendicular to the surface, the newDESI source allows easy, direct, high-throughput anal-ysis of the contents of standard 96-well plates [13].

DESI has been implemented using various mass spec-trometers, including triple quadrupoles [14], linear iontraps [15], the Orbitrap [16], quadrupole-time-of-flight(QTOF) [17] instruments, ion-mobility/TOF and ion-mobility/QTOF [18] hybrids, and Fourier transform ioncyclotron resonance instruments [19]. As samples areusually analyzed without any pre-separation from theirnatural matrices, high resolution, accurate mass and theability to perform tandem MS (MS2) are valuable char-acteristics to help address the complexity of these mix-tures [20].

2.1.3. Analytical figures of merit. Limits of detection(LODs) in DESI are typically an order of magnitudegreater than those in the corresponding ESI experiments.A typical LOD for small molecules, such as explosives, islow femtomole [21], and biopolymers, such as peptidesand proteins [1], approach similar levels. Greatimprovements have been made in the reproducibility ofquantitative results and relative standard deviationsbelow 5% have been reported. This is facilitated by usinga particularly suitable surface, a porous polytetrafluo-roethylene (PTFE) surface, which shows minimal crosscontamination between samples and improved sensitiv-ity and signal stability when compared to other surfacesreported in the literature. Good day-to-day accuracy ofbetter than ±7% (relative error) suggests that DESI-MScan be successfully employed for routine quantitativeanalysis [22]. Analytical figures of merit for DESI arecompared to those of other ambient desorption ioniza-tion techniques in Table 2. Since its introduction in2004, DESI has been used in numerous areas of appli-cation, including forensics, imaging, metabolomics,pharmaceuticals, characterization of natural products,bacteria, polymers, proteins, and explosives detection.

2.2. Laser desorption/spray ionization hybridtechniquesAmbient ionization techniques ELDI and LAESI combinelaser desorption with ESI. Unlike ambient desorptionionization methods, MALDESI requires the addition of amatrix to the sample before analysis. In ELDI andMALDESI, a UV laser is used to desorb analytes from the

Table 2. Demonstrated analytical figures of merit for ambient desorption ionization methods

Technique Highest mass LODa Dynamic range Imaging capability Lateral resolution

DESI [1,21,22] 66 kDa 1–10 fmol 103 Yes 200 lmDART [2,38] �1 kDa 7 fmol �20 N/A <3 mmELDI [28,39] 66 kDa 20 fmolb N/A N/A N/ASSP [40] 15 kDa 1 fmol 102 N/A 635 lmDBDI [24] <200 Da 3.5 pmol N/A N/A N/ALAESI [36] 66 kDa 8 fmol 104 Yes 300–400 lmDAPPI [37] <500 Da 56–670 fmol N/A N/A N/A

aAmount of sample on the surface.bAmount sampled by the laser beam.


sample surface, while, in LAESI, an IR laser is used. Thetype of laser provides a degree of selectivity in the natureof the target analytes due to the specific modes andpower used for excitation. These methods producespectra that predominantly resemble ESI results.

In a first step, a laser is used to produce ions and lib-erate neutrals and larger solid particles from the samplesurface through a process called energy-sudden activa-tion. In a second step, the heterogeneous plume ofmaterial is intercepted by an electrospray. The neutralmolecules and particles, which are the dominant fractionof the desorbed plume, are engulfed by the chargeddroplets, similar to what happens in EESI and FD-ESIexperiments, prior to the production of free ions throughESI mechanisms, which dominate. The spectra resemblethose produced by traditional ESI. As a consequence, theaccessible range of analytes is limited to polar andmoderately polar compounds, although both polar andnon-polar compounds can be desorbed.

3. APCI-related techniques

In addition to the ESI-related methods, gas-phase chemi-cal reactions have also been used together with adesorption step to ionize condensed-phase analytes di-rectly from surfaces. Chemi-ionization refers to the for-mation of ions through reaction between neutralmolecules at collision energies below the ionizationenergies of the reacting species [23], while chemical ion-ization involves reactions between ions and analyte mol-ecules. In Penning ionization, the most common chemi-ionization reaction encountered in MS, an excited atom ormolecule transfers energy to a target molecule producinga molecular radical cation. Penning ionization can beused directly to produce radical cations from analytemolecules. Alternatively, an intermediate molecule, suchas ambient O2, N2, water or intentionally added solventvapor, may first react with the excited state gas moleculeto produce a charge-transfer reagent, which then reactswith the analyte molecule to produce adduct ions that aretypically protonated molecules.

3.1. Ionization methods3.1.1. Ionization by electrical discharge. In the tech-niques of DART, PADI, HAPGDI, DAPCI, DBDI andASAP, neutral metastable species are formed by electri-cal discharge in a gas. These species react with waterand air molecules to produce the reactive ionic species.The gas-phase ions used as reagents in chemical ioni-zation can also be produced directly in the discharge byvirtue of the high voltages involved.

In DAPPI, these primary metastable species are formedby photoionization. The electrical discharge can be pro-duced by corona discharge, as in DART, DAPCI andASAP, glow discharge in HAPGDI and PADI, anddielectric barrier discharge (DBD) in DBDI. In all cases,diffuse, low-temperature (close to room temperature)plasmas are sustained by high voltages and low currents.Corona discharges are created by applying DC voltagesto sharp electrically conductive needles.

Atmospheric pressure glow discharges require that theglow-to-arc transition be avoided. In HAPGDI and PADI,stable glow discharges are obtained at atmosphericpressure by applying direct or alternating currents,respectively, to electrodes in a continuous gas flow,usually helium. In DBDI, an alternating voltage is ap-plied between two electrodes separated by a dielectriclayer to produce a stable, diffuse plasma at atmosphericpressure.

In DART and DAPCI, the discharge occurs far awayfrom the sample surface, and a stream of heated gas isused to carry the active species towards the sample. InDART, during transit, metastable helium atoms origi-nating in the plasma react with ambient water, oxygen,or other atmospheric components to produce the reac-tive ionizing species. In DAPCI, solvent ions or clusterions are produced through ionization of gaseous solventvapor in close proximity to the tapered electrode tip dueto the high voltage applied to it. In the positive-ion mode,analytes with high proton affinity are ionized by proton-transfer reactions while non-polar molecules with ioni-zation energies lower than the excited states of He or N2

are observed as radical cations. In the negative-ionmode, the dominant reactions are deprotonation or



adduct formation with various anions, including chlo-ride, acetate, and nitrate anions. Radical anions areobserved for species having high electron affinity. InHAPGDI minimal fragmentation is typically due to col-lisional relaxation of the ionizing species.

In PADI, HAPGDI and DBDI, the sample is exposed tothe plasma directly. Plasmas are complex mixtures ofmetastable atoms and/or molecules, ions, radicals andelectrons, including secondary ions. Their composition isdetermined by the type of gas used to sustain the plasmaand by the chemical environment in which they arecreated. Both chemi-ionization and chemical-ionizationmechanisms are likely to occur simultaneously. Theanalysis of only a limited number of analytes by thesethree methods has been reported. The extent of frag-mentation is expected to be higher than in the case ofDART and DAPCI due to the highly energetic speciesresiding in the plasma. In some cases, redox reactionsoccur in concert with simple molecular ionization. In theanalysis of amino acids by DBDI, protonated molecularions and fragments were observed [24].

3.1.2. Photoionization. In DAPPI, dopant-assisted pho-toionization is combined with thermal and momentumdesorption to ionize compounds on a surface. The use oftoluene and acetone as dopants has been demonstratedfor the ionization of neutral non-polar compounds andcompounds with high proton affinities, respectively.Dopant vapors are exposed to UV radiation by a kryptonlamp producing metastable molecules. Chemi-ionizationand chemical ionization occur as explained above,directly through the neutral metastables and secondaryions, respectively.

3.1.3. Ionization by ion evaporation. Reagents forchemical ionization can also be produced simply byheating organic or inorganic salts through a methodcalled atmospheric pressure thermal desorption ioniza-tion (APTDI [25]). In APTDI, the gas-phase ions are di-rected towards the sample surface by a heated inert gasstream. The ionizing mixture is selected as a function ofthe analyte and is less complex than plasma since itcontains only positive and negative ions of the heatedsalt. As a result, the ionization can be very selective aswell as very sensitive. The ability to manipulate thechemistry of the system by using specific reagents inorder to increase the sensitivity and the selectivity ofionization is a feature of reactive DESI, APTDI, DAPCI,and, to some extent, DART.

3.2. Desorption mechanisms in APCI-related methodsCombined thermal desorption and momentum desorp-tion with a heated gas stream is used in most of theAPCI-related ambient desorption ionization methods.Usually, the metastable molecules or atoms and ions areproduced upstream from the sample surface. However,


in the ASAP technique, the sample is vaporized byheating the sample (solid or liquid) with a stream of hotnitrogen and subsequently ionized by corona discharge.Where the sample is directly exposed to the plasma,electrical desorption effects may also be involved. Closecoupling between desorption and ionization steps in thedirect plasma techniques makes it difficult to determinethe sequence of events in these methods.

3.3. Spectral characteristicsThe APCI-related techniques are able to ionize smallpolar and non-polar molecules. The mass range can beextended by heating the sample with a stream of gas, asdemonstrated for ASAP and DART. The spectra aregenerally simple, dominated by the molecular ions thatare mostly the singly-charged protonated or deproto-nated molecules or the radical cations (through Penningionization of the molecules with low ionization poten-tials). Alkali-metal-cation adducts and multiply-chargedions are generally not observed. The analytical figures ofmerit are compared in Table 2.

4. Prognosis

Table 1 lists a large number of ambient desorption ion-ization techniques, which we have described in the text.There is significant overlap between the different tech-niques, as they are permutations of only a small numberof possible desorption steps and ionization mechanisms.New instrumental configurations or approaches attain-ing the same combination of desorption and ionizationsteps are typically given a unique acronym. The acro-nym is often chosen for its ability to perform as a mar-keting tool more than for describing the processes bywhich desorption and ionization occur or for relating thesmall differences in the instrumental set-up to similartechniques.

A logical approach to describe the different types ofexperiments can be achieved by conceptually separatingthe overall process into desorption and ionization steps.Table 3 is an attempt to fit the current methods into sucha scheme. Set-ups are arranged according to thedesorption step and then further separated by the vari-ous ionization possibilities. Although it involves signifi-cant simplifications, the desorption steps can be reducedto three different types: momentum (MD); energy-suddenactivation (LD); and, thermal desorption (TD). Ionizationsteps reduce to ESI, chemi-ionization and chemical ion-ization (CI) mechanisms.

It is also possible to classify the methods using theprimary ionization mechanism as the starting point. Thisis attempted with the flowergrams presented in Fig. 2.The ionization mechanism forms the center of eachdiagram. In ESI-like mechanisms (Fig. 2a), two desorp-tion steps have been applied to date (i.e. laser desorption

Figure 2. Flowergrams summarizing ambient desorption ionization methods. (a) The techniques (Red) where ESI mechanisms (Yellow) are pre-dominantly responsible for ionization. Both laser and momentum desorption (Green) have been demonstrated. (b) The methods where chemicalionization (Yellow) is responsible for ionization. The chemical reagents are produced by various methods (Green), such as photoionization (PI),ion evaporation (IE) and electrical discharge.

Table 3. Classification of ambient desorption ionization techniques by desorption and ionization methods used

Desorption Ionization Mechanism Example Classification

Mechanism Agent

Momentum desorption Droplet projectiles ESI DESI, DeSSI MD-ESIGas flow ESI ND-EESI MD-ESI

Chemi- and chemical ionization DBDI, HAPGDI MD-CIEnergy-sudden activation Laser ESI ELDI, LAESI LD-ESIThermal desorption Heated gas flow Chemi- and chemical ionization ASAP, DART, DAPCI, PADI TD-CI

Chemical ionization APTDI TD-CIPI DAPPI TD-CI


and momentum desorption). Where APCI mechanismsare applied for ionization (Fig. 2b), thermal desorptionwith gas transport was used in all cases. In Fig. 2b, thecommon desorption step was omitted. Instead, the sec-ond tier shows the various options for producing thechemical reagents used in the ionization step.

Additional permutations of desorption and ionizationmethods described in this text are possible, although notall are practical due to the low efficiencies (or crosssections) produced by the order and choice of desorptionand ionizations agents. There are additional ionizationmethods that have not yet been used in ambient ioni-zation methods (e.g., radioactive ionization sources);however, these are not immediately amenable to open-source analysis in the ambient environment.

In time, it will become clear which of the various ap-proaches are superior; however, it is clear that spray andplasma techniques are complementary. The spray tech-niques have access to molecules with much highermolecular masses, but are limited to moderately polar tohighly polar compounds. Spectra are often complex dueto adduct formation, and partially solvated and multiply-charged ions. They are advantageous in biochemicalapplications. The plasma techniques can also accessnon-polar compounds, and their mass spectra are simple

(no solvent clusters, multiply-charged or alkali-metaladducts), but the mass range is more limited.

Acknowledgements

This work was supported by funding from the Office ofNavel Research (Grant number: N00014-05-1-0405)and by the National Science Foundation (Grant number:CHE-0412782).

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Ambient desorption ionization mass spectrometry