Patent Publication Number: US-6707037-B2

Title: Atmospheric and vacuum pressure MALDI ion source

Description:
This application claims the benefit of provisional application No. 60/293,783 filed May 25, 2001. 
    
    
     BACKGROUND OF THE INVENTION 
     Matrix Assisted Laser Desorption Ionization (MALDI) has become an important ionization technique for use in mass spectrometry. MALDI ion sources are typically configured to produce ions in vacuum pressure that is lower than 10 −4  torr. Ions are produced in MALDI ionization by impinging a pulse of laser light onto a target on which a sample solution has been deposited with an appropriate matrix. The resulting ions produced from a MALDI laser pulse are directed into a mass spectrometer where they are mass to charge analyzed. Time-Of-Flight (TOF) mass analyzers are particularly well suited to mass to charge analyze MALDI generated ions. Ions produced from a MALDI pulse in the TOF vacuum region are accelerated into the TOF flight tube and mass analyzed. Techniques such as delayed extraction or reverse acceleration have been employed to improve the resolution when acquiring low vacuum pressure MALDI TOF mass spectra. TOF mass analyzers are capable of separating and detecting ions over a wide mass to charge range, which is essential when analyzing higher molecular weight compounds. MALDI ion sources have also been interfaced to other mass spectrometer types including Fourier Transform Mass Spectrometers (FTMS) and three dimensional quadrupole ion traps (Ion Traps). 
     Several recipes are available for optimizing a sample and MALDI matrix combination for a given laser wavelength. Typically a nitrogen laser may be used with a DHB matrix. The matrix is chosen to absorb the laser wavelength and transfer the laser power to the matrix to achieve rapid heating of the sample. The rapid heating desorbs and ionizes the sample that was initially dissolved and dried in the matrix solution and a portion of the sample molecules are ionized in the desorption process. To prepare a sample for MALDI ionization, sample solution and matrix solution are combined, deposited on a MALDI probe and dried prior to insertion of the probe into the MALDI ion source. Various conductive and dielectric materials such as glass, metal, silicon and plastics have been configured for use as the MALDI probe substrate. Hydrophobic substrate materials have been used to avoid spreading and thinning of the sample and matrix solution when it is deposited on the probe. It is desirable to concentrate the sample in as small a volume as possible on the MALDI probe to increase the sample ion yield per laser pulse. The MALDI probe substrate should not react with the sample, contribute minimum background peaks in the mass spectrum and allow sufficient binding of sample and matrix to prevent sample loss during MALDI probe handling. When conditioned silicon surfaces are used as MALDI targets, the use of a matrix solution can be eliminated. In some of the embodiments of the invention described below, the additional constraint of using a dielectric MALDI probe material allows the configuration of MALDI probe targets positioned within multipole ion guides or ion funnels causing minimum distortion of Electric fields. 
     Ions produced from MALDI ion sources configured in the low vacuum pressure region of TOF mass analyzers can be pulsed directly into the TOF MS flight tube for mass analysis. This configuration minimizes any constraint on the mass to charge range that can be analyzed but may limit the resolving power and mass measurement accuracy that can be achieved. Ions that are produced from a MALDI matrix have an uncorrelated energy and spatial spread in the pulsing region of a TOF mass analyzer, resulting in reduced resolving power and mass measurement accuracy in TOF ion mass to charge analysis. Although delayed extraction or reverse field extraction of MALDI produced ions has reduced the effects of ion energy and spatial spread, the techniques have a limit as to how much improvement can be achieved. Also delayed extraction must be carefully tuned to minimize distortion of ion signal intensities in the mass to charge range of interest. The kinetic energy spread of MALDI produced ions also reduces the ion transport and capture efficiency in FTMS and ion trap mass analyzers resulting in decreased sensitivity. Mass to charge selection and fragmentation experiments known as MS/MS experiments may be achieved by using MALDI post source decay or by the configuration of gas collision cells in TOF mass analyzer flight tubes. Ion fragmentation and MS/MS TOF experiments have been achieved using these TOF techniques at some sacrifice to resolving power, mass measurement accuracy and, in some configurations, sensitivity. In an effort to improve mass to charge measurement, resolving power, mass to charge selection precision and efficiency and fragmentation efficiency in MS/MS analysis of MALDI produced samples, MALDI ion sources have been configured in atmospheric pressure and in intermediate vacuum pressure regions of mass analyzers. 
     Introducing MALDI samples into an atmospheric (AP) or intermediate vacuum pressure (IP) MALDI ion source facilitates sample handling by eliminating the need to load MALDI samples into low vacuum pressure. Laiko et al. in U.S. Pat. No. 5,965,884 and in Anal. Chem. 2000, 72, 652-657 describe the configuration of an atmospheric pressure MALDI Ion source interfaced to an orthogonal pulsing TOF mass analyzer. Krutchincsky et al. J. Am. Soc. Mass Spectrom 2000, 11, 493-504, describe the configuration of MALDI ion source in the second vacuum pumping stage of a hybrid quadrupole/quadrupole/orthogonal pulsing TOF (QTOF) mass analyzer that includes an atmospheric pressure Electrospray ion source. In the atmospheric and vacuum pressure MALDI mass spectrometers described, the ions traverse at least one multipole ion guide prior to being pulsed into the TOF mass analyzer. The mass to charge range of ions that can be analyzed is limited to the range of mass to charge values that can be transmitted with stable ion trajectories through the downstream ion guides. Ion guides positioned in the first or second vacuum pumping stages have pressures maintained sufficiently high to cause multiple ion to neutral background collisions. Elevated background pressures in multipole ion guides cause damping of ion kinetic energies as the ions traverse an ion guide length. The energy damping creates a primary ion beam with a narrow energy spread and a controlled average kinetic energy. Ion mass to charge selection and collisional induced dissociation fragmentation can be achieved in single or multiple ion guide assemblies prior to TOF mass to charge analysis. The upstream ion kinetic energy damping processes result in improved TOF resolving power and ion mass to charge measurement accuracy in orthogonal pulsing TOF. MALDI ionization at atmospheric and intermediate vacuum pressure may yield differences in ion populations when compared with low vacuum pressure MALDI ionization. Neutral to ion collisions occurring in atmospheric pressure and intermediate vacuum pressure MALDI ion source regions reduce the internal energy of the newly formed ion, minimizing post source decay. Subsequent MS/MS functions can be conducted in downstream multipole ion guides, ion traps, FTMS censor TOF-TOF mass analyzers is user controlled through selected experimental methods. The decoupling of the MALDI ionization, ion mass to charge selection, ion fragmentation and subsequent ion mass to charge analysis steps allows independent optimization of each analytical step. 
     Laiko et al. describe the configuration of a sample MALDI probe positioned near the orifice into vacuum of an API TOF MS instrument so that a portion of the ions produced can be transported into vacuum. A DC field is applied between the MALDI sample target and the orifice into vacuum to direct ions toward the orifice. A gas flow directed over the probe surface was added to push ions produced near the probe surface toward the orifice into vacuum. Laiko reports that substantial sensitivity losses occurred when using the atmospheric pressure MALDI ion source compared with a MALDI ion source configured in the pulsing region of a TOF mass analyzer. Most of the loss of signal was attributed to inefficient ion transport into vacuum. The resulting mass spectrum also included peaks of sample ions clustered with matrix molecules. This clustering may occur due to the condensing of neutral matrix molecules with sample ions in the free jet expansion into vacuum. Krutchinsky et al. describes the configuration of a MALDI probe in the second vacuum stage of a four vacuum stage QTOF where the MALDI target is positioned upstream of the entrance lens orifice to an RF only quadrupole ion guide operating in the second vacuum pumping stage of the QTOF mass analyzer. An additional quadrupole ion guide was added in the second vacuum stage to improve the Electrospray (ES) ion transport efficiency when the MALDI target was removed. Good sensitivities were achieved with MALDI and ES ion sources with the configuration reported. The use of a MALDI ion source operated in vacuum pressure requires that the MALDI target be loaded into vacuum. This constrains the size and shape of the MALDI probe and requires that additional components be added to minimize a decrease in performance of the atmospheric pressure ion sources configured together in the same instrument. Cleaning the vacuum pressure MALDI ion source region requires vacuum venting in the intermediate vacuum pressure stages, causing instrument downtime. 
     One embodiment of the invention, improves the transport efficiency of ions produced in an atmospheric pressure ion source and reduces or eliminates the number of neutral matrix molecules entering vacuum. The elimination of neutral matrix related molecules from entering vacuum prevents condensation of the matrix molecules with the sample ions in the free jet expansion into vacuum. This eliminates cluster matrix related peaks in the acquired mass spectra. The invention improves the ion transport efficiency into vacuum by reducing the initial atmospheric pressure MALDI (AP MALDI) ion energy spread through ion to neutral collisional damping or focusing of the ion trajectories to the centerline of a multipole ion guide or ion funnel operated at atmospheric pressure with RF voltage applied. AP MALDI generated ions are focused along the centerline and directed to the orifice into vacuum in the ion guides or ion funnels operated at atmospheric pressure. Ions can be trapped and some degree of mass to charge selection achieved using mulipole ion guides at atmospheric pressure. Multipole ion guides have been used to efficiently damp the trajectories of ions and transport ions in intermediate vacuum pressures as have been reported in U.S. Pat. No. 5,652,427 (Whitehouse et al &#39;427), U.S. Pat. No. 6,011,259 (Whitehouse et al. &#39;259) and U.S. Pat. No. 4,963,736 (Douglas et al.). RF only Ion Funnels operated in intermediate vacuum pressure regions of 1 to 2 torr in API MS instruments have been reported by Belov et al., J. Am. Soc. Mass Spectrom 2000, 11, 19-23 and U.S. Pat. No. 6,107,628. Although Douglas et al. achieves effective collisional energy damping in intermediate vacuum pressures they report a severe decrease in ion signal for background pressures above 70 millitorr. Miniature quadrupole mass spectrometers configured for use as vacuum pressure gauges as described by R. J. Ferran and S. Boumsellek, J. Vac. Sci. Technol., A 14(3), May/June 1996 exhibit a decrease in ion signal intensity for pressures which have a mean free path longer than the miniature quadrupole rod dimensions. The reported upper practical operating pressure is the point where the ion to neutral collisional mean free path is roughly equal to the length of the quadrupole ion guide described. Whitehouse et. al. &#39;427 report the operation of a multipole ion guide in background pressures of hundreds of millitorr with little or no loss of ion signal intensity over the entire operating background pressure range. The efficiency of ion transmission through multipole ion guides or ion funnels is maximized by moving ions through the ion guide with axial electric fields and/or directed neutral gas flow. In the present invention, ions are transmitted through a multipole ion guide or ion funnel configured in an atmospheric or vacuum pressure region where multiple collisions occur between ions and neutral background gas molecules during transmission. Ion transmission losses are minimized by providing axial DC voltages and/or gas dynamics to move MALDI generated ions through the entrance RF fringing fields and through the ion guide or ion funnel length. In one embodiment of the invention, atmospheric pressure or vacuum pressure MALDI ions are generated directly in the RF ion trapping field of the multipole ion guides or ion funnels thus avoiding ion scattering losses due to entrance fringing fields entirely. 
     Ion mobility analyzers have been interfaced with mass spectrometers to allow separation of ions due to differences in ion mobility prior to conducting ion mass to charge analysis. Such a hybrid instrument allows the separation of ions having the same mass to charge value but different collisional cross sections to be analytically separated in mass spectrometric measurements. Coupling ion mobility separation with mass to charge analysis of ions provides additional information regarding the tertiary structure of a molecule or ion. U.S. Pat. No. 5,905,258 (Klemmer) and U.S. Pat. No. 5,936,242 (De La Mora) describe ion mobility analyzers interfaced to mass spectrometers. Klemmer describes a mobility analyzer interfaced to an orthogonal pulsing TOF mass analyzer. De La Mora and Klemmer describe ion mobility analyzers that employ DC electric fields and gas flow to separate ions by their mobility. Unlike the prior art which uses DC only electric fields in a background gas to separate ions due to different ion mobility, the invention enables ion mobility separation from AP MALDI generated ions to occur within a multipole ion guide prior to conducting mass to charge analysis. In the invention, ions are exposed to RF as well as DC electric fields as they traverse the ion guide length. Ion collisions with neutral background gas causes translational energy damping of ion trajectories to the centerline and spatial separation of ions with different ion mobility along the ion guide axis. By radially trapping ions with RF fields and directing the ions in the axial direction with DC fields, the sampling efficiency into the orifice to vacuum after ion mobility separation is improved compared with the ion focusing that can be achieved with DC only electric fields applied in atmospheric pressure as described in the prior. 
     To facilitate interfacing with higher throughput automated sample preparation and separation systems, the MALDI ion sources must be configured to accommodate a wide range of probe geometries and automated MALDI target sample introduction means. On-line integration of a MALDI ion source with capillary electrophoresis separation systems has been achieved as described by Karger et. al. in U.S. Pat. No. 6,175,112 B1. Sample preparation and separation is being conducted in smaller scale using integrated devices. The current invention is configured to facilitate and optimize the interfacing of an AP MALDI ion source with such integrated sample preparation and sample handing devices and automated MALDI sample target introduction. In one embodiment of the invention, MALDI ionization is conducted from sample deposited on a moving belt positioned to move through a multipole ion guide operated in an atmospheric or vacuum pressure region. The invention allows multiplexed MALDI ionization across parallel sample tracks synchronized with ion pulsing into TOF mass analyzers to increase sample throughput. Improvements in on-line MALDI TOF MS and MS/MS n  performance can be achieved according to the invention by conducting MALDI ionization at atmospheric or vacuum pressures from moving belts traversing laterally through a multipole ion guide from which ions can be subsequently mass to charge selected or fragmented prior to a last mass to charge analysis step. 
     SUMMARY OF THE INVENTION 
     In one embodiment of the invention a multipole ion guide with RF and DC electric fields applied to the poles is operated at atmospheric pressure. A MALDI ion source is configured to operate at atmospheric pressure and deliver ions into the multipole ion guide configured to operate at atmospheric pressure. The transfer of AP MALDI ions into and through the multipole ion guide is aided by directed gas flow and DC electric fields. Ion collisions with the background gas damp the stable ion trajectories toward centerline as the ions traverse the length of the multipole ion guide toward an orifice into vacuum. Axial DC electric fields can also be configured to move the ions through the length of the multipole ion guide toward the orifice into vacuum. Ions focused along the centerline are directed with gas flow and DC electric fields into an orifice into vacuum where the ions are mass to charge analyzed or undergo mass to charge selection and fragmentation steps prior to a final mass to charge analysis step (MS/MS n ). Gas flow at the ion guide entrance end is directed along the ion guide axis toward the orifice into vacuum to aid in ion transfer into and through the ion guide along the multipole ion guide centerline. In one embodiment of the invention, a second gas flow is introduced at the ion guide exit end directed axially toward the multipole ion guide entrance end, countercurrent to the first gas flow. Ions move in the axial direction against the second gas flow due to the axial DC electric fields. The second gas flow prevents neutral matrix related molecules from entering vacuum with the MALDI produced ions. Reduction or elimination of neutral contamination molecules avoids recondensation of such molecules with sample ions in the free jet expansion into vacuum. 
     The orifice into vacuum can be configured as a sharp edged orifice, a nozzle, a dielectric capillary or a conductive capillary. The countercurrent gas and/or the capillary tubes may be heated. The face of the orifice into vacuum comprises a conductive material and can be configured as the exit lens of the multipole ion guide operated at atmospheric pressure. The potential of the orifice into vacuum can be increased higher than the multipole ion guide DC offset or bias potential to trap ions in the ion guide. Ions from several MALDI pulses can be accumulated in the multipole ion guide before release into vacuum in this manner. RF, +/−DC and resonant frequency potentials can be applied to the multipole ion guide to reduce the mass to charge range of stable ion trajectories through the ion guide. Using this method, unwanted contamination or matrix related ions can be eliminated before entering vacuum. In non-trapping mode, the multipole ion guide can be operated as a mobility analyzer where ions generated in an Atmospheric Pressure MALDI pulse separate spatially along the ion guide axis due to different ion mobilities as they traverse the multipole ion guide length. In an alternative embodiment of the invention, one or more additional electrostatic lens can be configured between the multipole ion guide exit and the orifice into vacuum. One of these electrostatic lenses can be split to allow steering of selected ions away from the orifice into vacuum. By timing the switching of voltage levels applied to the steering lens elements while conducting ion mobility separation, selected ions can be allowed to enter the orifice into vacuum. Using this technique, different conformations of the same molecule can be isolated and mass to charge analyzed with MS or MS/MS n  experiments to study compound structure. 
     In an alternative embodiment of the invention, the MALDI probe is configured to place the sample target inside the volume described by the poles of the multipole ion guide operated in atmospheric or vacuum pressure. The MALDI probe and target material may be conductive or dielectric, however, dielectric materials cause minimum distortion of the multipole ion guide RF and DC fields during operation. MALDI ions generated inside the multipole ion guide are trapped in the RF field avoiding the need to transfer ions through RF and DC fringing fields at the ion guide entrance. High capture and transport efficiency can be achieved using this in-multipole ion guide MALDI ion production technique. The MALDI probe can be configured with an array of target samples or be configured as a moving belt to conduct on-line experiments. A moving belt MALDI target can be interfaced on-line or off-line to the outlet of one or more Capillary Electrophoresis (CE) or Liquid Chromatography (LC) columns. The moving belt with the deposited sample and MALDI matrix solution is configured to traverse laterally through the multipole ion guide volume and the sample is ionized near the multipole ion guide centerline as it passes through. The laser beam can be rastered from one sample line to another on the moving belt synchronized with the TOF mass analyzer pulsing to allow multiplexed parallel analysis of several samples with one mass analyzer. This multiple sample analysis technique improves off-line or on-line sample throughput. 
     In an alternative embodiment of the invention, the MALDI target is configured in an intermediate vacuum pressure region and MALDI produced ions are swept into a multipole ion guide by gas dynamics and applied DC fields. The local gas pressure at the multipole ion guide entrance is maintained higher than the vacuum chamber background gas to aid in sweeping ions into the ion guide entrance minimizing transmission losses due to the ion guide fringing fields. Ions continue to traverse the ion guide length moved by gas dynamics and/or DC fields. Ion to neutral collisions occur as the ions traverse the ion guide length damping the internal and kinetic energies. In one embodiment of the invention the multipole ion guide is configured to extend continuously from one vacuum pumping stage into a subsequent vacuum stage to maximize ion transmission efficiency. The multipole ion guide may be segmented to allow the conducting of ion mass to charge selection and fragmentation analytical functions in the same ion guide volume. This embodiment of the invention improves the ion transfer efficiency of MALDI ions produced in a vacuum pressure region into a mass analyzer. Similar to the atmospheric pressure MALDI ion source embodiment, ion mobility analysis can be conducted on MALDI generated ions in the multipole ion guide configured in an intermediate vacuum pressure region. 
     MALDI ionization generates positive and negative ions simultaneously. In one embodiment of the invention, a MALDI probe, is configured with the MALDI sample target positioned inside the multipole ion guide. The multipole ion guide may be operated in RF only mode with a DC gradient applied along its axis. The DC gradient is achieved by any number of techniques including but not limited to, configuring the multipole ion guide with segmented, conical or non parallel rods or adding DC electrostatic lens elements external to the multipole rod set which establishes an external axially asymmetric DC field which penetrates to the multipole ion guide centerline. Two mass analyzers are configured to simultaneously accept opposite polarity MALDI generated ions leaving opposite ends of the multipole ion guide. In one embodiment of the invention, the first mass analyzer is operated in positive ion mode and the second analyzer is operated in negative ions mode. Positive MALDI generated ions move along the multipole ion guide axis and exit through one end of the ion guide. The simultaneously produced negative MALDI generated ions move in the opposite direction along the multipole ion guide axis and exit through the opposite end of the ion guide. The positive ions are transferred from the ion guide operated in atmospheric or vacuum pressure and mass to charge analyzed in the first mass to charge analyzer. The negative ions are directed to and mass to charge analyzed in the second mass to charge analyzer. 
     In an alternative embodiment of the invention, an ion funnel operated with RF and an axial DC fields is configured in place of the multipole ion guide in a MALDI ion source operated in atmospheric or vacuum pressure. The MALDI probe can be configured with the MALDI target positioned inside or outside the ion funnel volume. MALDI produced ions are directed to move axially along the ion funnel using DC fields and directed gas flow. Ion motion in the ion funnel guide is damped due to collisions with background gas resulting in higher ion transport efficiency through the ion funnel exit orifice. 
     MALDI ion sources operated in atmospheric or vacuum pressure interfaced to multipole ion guides or ion funnels can be configured with but not limited to TOF, TOF-TOF, Ion Trap, Quadrupole, FTMS, hybrid Quadrupole-TOF, magnetic sector, hybrid magnetic sector TOF mass analyzers and other hybrid mass analyzers types. 
     Other objects, advantages and features of this invention will become more apparent hereinafter. 
    
    
     LIST OF FIGURES 
     FIG. 1 is one embodiment of the invention where an AP MALDI probe operated at atmospheric pressure is configured to position the MALDI sample target inside a multipole ion guide operated at or near atmospheric pressure. 
     FIG. 2 is a side view of the AP MALDI target region of the embodiment shown in FIG.  1 . 
     FIG. 3 is a top view of the AP MALDI target region of the embodiment shown in FIG. 1 with a disk shaped MALDI target. 
     FIG. 4A is a cross section of the hexapole ion guide shown in FIG. 1 configured with one embodiment of the electrical connections to RF and DC power supplies and with the AP MALDI target positioned near the hexapole ion guide centerline. 
     FIG. 4B is a cross section of a quadrupole ion guide configured with one embodiment of the electrical connections to RF and DC power supplies and with a MALDI target located in atmospheric or vacuum pressure positioned near the quadrupole ion guide centerline. 
     FIG. 5 is the side view of an embodiment of an AP MALDI source configured to conduct ion mobility in the multipole ion guide as ion traverse the ion guide length. 
     FIG. 6 shows a linear MALDI target with sample spots positioned inside the volume of an ion guide in an AP MALDI ion source. 
     FIG. 7 is the top view of a MALDI target configured with individual sample spot fingers positioned inside the volume of a hexapole ion guide. 
     FIG. 8 shows a moving belt MALDI target with sample laid down in lines on the belt surface configured to move through the volume of a multipole ion guide where MALDI sample ionization is conducted. 
     FIG. 9 shows an AP MALDI target positioned to produced ions inside the volume of a consecutive ring RF ion guide assembly operated at atmospheric pressure. 
     FIG. 10 shows a disk shaped AP MALDI target configured with a MALDI target sample spot inside an ion funnel operated at atmospheric pressure. 
     FIG. 11 shows an AP MALDI target mounted outside a multipole ion guide with gas flow directed around the MALDI spot to sweep ions into said multipole ion guide operated at atmospheric pressure. 
     FIG. 12A shows cross section A—A of FIG.  11 . 
     FIG. 12B shows a face view of the MALDI target sample spot positioned at the Multipole ion guide entrance region as configured in FIG.  11 . 
     FIG. 13 shows an AP MALDI source configured with the MALDI target surface positioned external to but parallel with the multipole ion guide centerline. 
     FIG. 14 shows an embodiment of a MALDI target that is configured with individually movable MALDI sample spots. 
     FIG. 15 shows a MALDI target configured so that the MALDI sample spot is positioned inside an multipole ion guide operated at low or intermediate vacuum pressures. 
     FIG. 16 shows an enlargement of the MALDI sample target, multipole ion guide and vacuum pumping stage region of the embodiment shown in FIG.  15 . 
     FIG. 17 shows a MALDI ion source operated in low or intermediate vacuum pressure configured with the sample spot positioned inside a multipole ion guide with a higher vacuum pressure multipole ion guide collision cell configured in a second vacuum pumping stage. 
     FIG. 18 shows a vacuum pressure MALDI ion source configured with the sample spot positioned inside a multipole ion guide with a higher pressure multipole ion guide collision cell configured a third vacuum pumping stage. 
     FIG. 19 shows a vacuum pressure MALDI ion source configured with the sample spot positioned inside a multipole ion guide that extends continuously through multiplevacuum pumping states. 
     FIG. 20 shows a vacuum MALDI ion source where the MALDI target assembly is configured outside a multipole ion guide where gas flow s gas flow sweeps over the sample spot to help move MALDI produced ions into the multiple ion guide. 
     FIG. 21 shows a vacuum MALDI ion source with the MALDI target positioned outside a multipole ion guide that extends continuously into multiple vacuum pumping states. 
     FIG. 22 shows a combination Electrospray ion source and vacuum MALDI ion source configured on the same mass analyzer with MALDI ions produced inside the volume of a multipole ion guide. 
     FIG. 23 shows a retractable MALDI probe assembly and target mounted in the gap between the capillary and skimmer of an Electrospray ion source with gas flow introduced through the probe assembly. 
     FIG. 24 shows a retractable MALDI target assembly mounted in the gap between the capillary and skimmer of an Electrospray ion source with gas flow introduced through the capillary or through and independent gas feedthrough. 
     FIG. 25 shows a linear MALDI target configured to position sample spots inside a multipole ion guide which extends into multiple vacuum stages in a combination Electrospray and MALDI ion source. 
     FIG. 26 shows a retractable MALDI target configured to position sample spots inside a multipole ion guide volume located in the first vacuum pumping stage of an Electrospray ion source. 
     FIG. 27 Shows a MALDI target configured to position a sample spot inside a multipole ion guide operated with an axial electric field. Positive MALDI ions exit one end while simultaneously produced negative ions exit the opposite end of the multipole ion guide. Two mass analyzers are positioned to simultaneously detect positive and negative MALDI generated ions. 
     FIG. 28 shows two Time-of-Flight mass analyzers one operated in positive ion mode and one operated in negative ion mode configured to simultaneously mass to charge analyze MALDI ions produced inside the volume of a multipole ion guide. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     In one embodiment of the invention, ions are produced at atmospheric pressure by impinging a laser pulse on a MALDI target mounted in a multipole ion guide operated in atmospheric pressure. Alternating current (AC or RF radio frequency) and direct current (DC) potentials are applied to the poles of the multipole ion guide to radially trap ions in the multipole ion guide. Collisions between the ions and the atmospheric pressure neutral background gas damp the ion trajectories toward the centerline as the ions traverse the length of the multipole ion guide toward an orifice into vacuum. The ion trajectory in the axial direction is aided by an axially directed gas flow and a DC electric field applied in the axial direction. One preferred embodiment of the invention is diagrammed in FIG.  1 . Referring to FIG. 1, atmospheric pressure MALDI ion source  1  is interfaced to Time-Of-Flight mass to charge analyzer  3  through the multiple vacuum stage ion transport region  2 . MALDI target  4  with multiple sample spots  5  is configured so that each MALDI sample spot  5  on MALDI target  4  can be positioned near the centerline and inside the poles of multipole ion guide  8 . FIG. 2 shows a side view of the MALDI sample target and ion guide entrance region shown in FIG.  1  and FIG. 3 shows a top view of the MALDI sample target configuration of MALDI ion source  1 . Laser beam  10  is pulsed onto sample spot  11  deposited on MALDI target  4 . In the preferred embodiment, MALDI target  4  comprises a dielectric material including but not limited to glass, silica, ceramic or a polymer material. MALDI target  4  may comprise a hydrophobic material or be coated with a hydrophobic material to minimize the spreading of the sample solution when it is deposited on the probe surface. It is preferred to have smaller and more concentrated MALDI sample spots so that a maximum number of ions from the sample material are produced per laser pulse and a minimum number of laser pulses are required to produced a mass spectrum with sufficient analyte signal to noise. 
     Laser pulse  10  generated from laser  10  is directed to impinge on sample spot  11  releasing ions and neutral molecules. The MALDI generated ions and neutral molecules collide with the atmospheric pressure background gas present in multipole ion guide  8  internal volume  12 . Gas flow  14  is introduced into MALDI ion source  1  through flow control valve  6  and channel  15  whose exit end  16  is oriented to direct gas flow  14  over MALDI sample spot  11  along axis  17  of multipole ion guide  8  in the forward direction. Gas flow  14  may comprise a non-reactive gas such as helium, nitrogen or argon to avoid chemical interaction with MALDI generate sample ions. Alternatively, reactive gaseous components can be used if it is desirable to cause ion molecule reactions. Collisions occurring between neutral gas flow  14  and MALDI generated ions and neutral molecules released from MALDI sample spot  11  serve to damp the ion and MALDI produced molecule trajectories inside multipole ion guide  11 . Gas flow  14  moves MALDI generated ions and neutral molecules in the forward axial direction as the applied RF field traps the MALDI generated ions that fall within the operating stability region on the ion guide. The motion of the mass to charge ions that fall within the stability region is damped toward centerline  17  of ion guide  8  by ion collisions with neutral gas molecules. The MALDI generated neutral molecules are free to follow the streamlines of gas flow  14  as it moves through volume  12  of ion guide  8  and out through gaps  89  between poles  7  of ion guide  8 . 
     An axial DC electric field can be applied to aid in moving MALDI generated ions through volume  12  of multipole ion guide  8 . One means of achieving an axial DC electric field is to apply decreasing voltages to a set of concentric rings  18  surrounding multipole ion guide assembly  8 . As shown in FIG. 2, concentric rings  19  through  22  are connected to resistors  23  through  26  respectively forming a resistive voltage divider between DC electrical power supplies  27  and  28  labeled DC  2 A and DC  2 B respectively. The DC voltages applied to conductive rings of  19  through  22  penetrate to centerline  17  through gaps  89  of multipole ion guide  8  providing an axial force component to aid in moving ions through ion guide volume  12 . For positive ions, power supply  27  is set at a higher positive electrical potential than the potential set on power supply  28  forming a voltage gradient that aids in moving positive ions from entrance end  30  to exit end  31  of multipole ion guide  8 . Multipole ion guide  8  may comprise four (quadrupole), six (hexapole) or eight (octopole) rods or poles as the preferred embodiment. Alternatively, multipole ion guide  8  may comprise more than 8 poles or an odd number of poles. The poles may be configured in a parallel arrangment or may be angled to create an axial electric field. The poles may be cylindrical in profile or alternatively tapered to create an axial electric field as is described in U.S. Pat. No. 5,847,386. 
     A top view of radially symmetric MALDI sample target  4  is shown in FIG.  3 . MALDI sample target  4  can be rotated to align a each sample spot with MALDI laser pulse  10  and can be translated in the x an z directions to allow any portion of sample spot to be impinged by laser shot  10  even if the laser beam is focused to a small area at the surface of sample spot  11 . Several laser pulses can be taken of sample spot  11  during a TOF mass to charge or MS/MS n  analysis. When the mass analysis of sample spot  11  is complete, MALDI sample target  4  is rotated to move sample spot  88  into the position formally occupied by sample spot  11 . MALDI sample target  4 , positioned in the gap between poles  7  of ion guide  8  can rotate without touching ion guide  8 . Gas flow channel  15  and ion guide entrance entrance lens  90  remain in a fixed position during rotation and x and z movement of MALDI sample target  4 . MALDI sample target  4  can be manually or automatically removed and replaced without adjusting the position of gas chennel  15 , ion guide entrance lens  90  or ion guide assembly  8 . 
     The cross section of two embodiments of multipole ion guide  8  are shown in FIGS. 4A and 4B. The poles have a round cross section shown in FIGS. 4A and 4B but alternatively may have a more ideal hyperbolic cross section. FIG. 4A shows the electrical connection configuration for RF only operation of hexapole ion guide  34 . FIG. 4B show the electrical connection configured for RF operation of quadrupole ion guide  40 . In FIG. 4A, AC or RF electric fields are applied to poles  32  and  33  of hexapole  34 . Three poles  33  of hexapole ion guide  34  are connected to output  35  of RF power supply  41  through capacitor  37  and three poles  32  are connected to output  36  of RF power supply  41  through capacitor  38 . The RF electrical potentials applied to outputs  35  and  36  have common amplitude but opposite phase. A common DC offset potential is applied to all poles  32  and  33  of hexapole  24  through DC  1  power supply  42  and resistors  39  and  40  respectively. The outputs of RF power supply  41  and DC  1  supply  42  are decoupled through capaciters  37  and  38  and resistors  39  and  40 . The RF potential amplitude and frequency output of RF power supply  41  and the DC potential output of DC  1  power supply  42  may be adjusted manually or through computer control using controller  44 . The value of capacitors  37  and  38  and resistors  39  and  40  respectively may be adjusted to balance or tune the potentials applied to poles  32  and  33  of hexapole ion guide  34 . An axial DC field can be achieved along the internal length of multipole ion guide by configuring a series of ring electrodes externally along the ion guide length as was described for FIGS. 1 and 2. Ring  19  is connected to DC  2 A power supply  27  as the first lens connected to a resistor divider series. As described above, DC field penetration from the ring electrodes creates an axial DC electric field gradient along the length of ion guide volume  12 . 
     In an alternative embodiment for ion guide  8  of FIG. 1, a cross section of quadrupole ion guide  45  is shown in FIG.  4 B. RF power supply  48  is connected to poles  46  and  47  through outputs  50  and  51  and capacitors  52  and  53  respectively. An offset DC electrical potential is applied to all poles from DC  1  power supply  49  through resistors  54  and  55  configured for RF only quadrupole ion guide operation. Alternatively, quadrupole  45  can be configured for ion mass to charge range selection by supplying +/−DC to rods  46  and  47  or by adding resonant or secular frequency electrical potentials to the RF electrical potentials applied to poles  46  and  47 . 
     MALDI sample target  4  is configured to extend into internal volume  12  of multipole ion guide  8  as shown in FIGS. 1 through 4. In the preferred embodiment, sample target  4  comprises a dielectric material so that its positioning in multipole ion guide volume  12  causes minimum distortion to the RF and DC electrical fields present in ion guide volume  12 . Ions produced from sample spot  11  by laser pulse  10  are immediately subjected to the radial trapping imposed by the RF fields minimizing ion loss. The ions produced by laser pulse  10  will be swept away from the sample spot by gas flow  14  and moved toward ion guide exit end  31 . The trajectories of MALDI ions whose m/z values fall within the operating multipole ion guide stability region will be collisionally damped toward ion guide centerline  17  as they traverse the length of multipole ion guide  8 . Ions exiting multipole ion guide  8  at exit end  31  near centerline  17  are swept into capillary orifice  60 . The relative DC potentials applied to capillary entrance electrode  81  and the ion guide offset potential are set to a value that aids in directing ions into capillary orifice  60 . A neutral gas flow  80  is directed countercurrent to gas flow  14  to sweep any neutral MALDI produced contamination molecules away from orifice  60 . This prevents recombining or condensing of such MALDI generated neutral molecules with the MALDI generated ions in the free jet expansion as the ions enter vacuum. If desired countercurrent gas flow  80  and gas flow  14  may be heated by heater elements  84  and  85  respectively. 
     Referring again to FIGS. 1 through 4, ions and neutral molecules produced from impinging laser pulse  10  are swept in the forward direction in volume  12  of multipole ion guide  8  by gas flow  14 . The ion forward movement is aided by the presence of the axial DC field created by lens elements  19  through  22 , resistor divider  23  through  26  and DC power supplies  27  and  28 . Collision damping of ion energy coupled with the RF field cause the ion trajectories to move towards multipole ion guide centerline  17  as the ions traverse the ion guide length in the forward direction. The neutral molecules produced from laser pulse  10  are not confined by the RF fields and move with gas flow  14 . A second gas flow  80  is introduced through heater  84  and is directed to flow around capillary  82  and exit as countercurrent a gas flow. Typically gas  80  is a non reactive substance such nitrogen, helium or argon. Countercurrent gas flow  80  is directed in the reverse or backward direction, entering from multipole ion guide exit end  31  and flowing toward entrance end  30 . Gas flow  14  encounters the counter current gas flow forming a gas flow stagnation point or gas mixing region in volume  12  of multipole ion guide  8 . The opposing gas flows result in both gas flows exiting multipole ion guide  8  through the gaps  89  in the rods or poles  7 . The combined gas flows exit source chamber  33  through gas channel  24  as shown in FIG.  2 . Ions traversing the length of multipole ion guide  8  are driven through the stagnation point and against the countercurrent gas flow by the axial DC field near centerline  17  and by DC formed by the relative potentials applied between capillary entrance lens  81  and the ion guide  8  DC offset potential. The DC potential applied to capillary entrance electrode  81  is set to direct ions from multipole ion guide  8  into capillary entrance orifice  60 . Ions approaching capillary entrance electrode  81  are swept into orifice  60  by the gas flow into and through capillary bore  48 . Ions are swept along by the gas flow through capillary bore  48  and expand into vacuum through capillary exit end  83 . The potential energy of the ions traversing capillary bore  48  can be changed as described in U.S. Pat. No. 4,542,293 and included herein by reference. 
     Neutral molecules are swept out of multipole ion guide  8  by forward gas flow  14  and countercurrent gas flow  80  before they reach capillary entrance orifice  60  preventing contamination molecules from entering vacuum with the MALDI generated ions. This avoids condensation of neutral molecules with ions in the free jet expansion region, minimizing any distortion in subsequent ion mass to charge selection and measurement. The heating of countercurrent gas flow  80  serves to aid in the evaporation of any remaining neutral molecules such as solvent or MALDI matrix related molecules condensed on MALDI generated ions as they traverse the length of multipole ion guide  8 . Ion movement driven by the axial DC field through countercurrent gas flow  80  may also serve to separate ions along the ion guide length due to differences in ion mobility. Ions produced from a MALDI laser pulse with different ion mobility will arrive at capillary entrance orifice  60  at different times. Switching of the potential applied to capillary entrance electrode  81  can gate ions arriving at different times into or away from capillary entrance orifice  60 . As will be described in alternative embodiments of the invention, ions separated spatially by differences in ion mobility can also be electrically gated or steered away from entering capillary entrance orifice  60  by changing the potential applied to additional electrostatic lenses configured between exit end  31  of multipole ion guide  8  and capillary entrance electrode  81 . Although some degree of ion mass to charge selection can be achieved with hexapole ion guides, multipole ion guide  8  may be configured as a quadrupole for conducting mass to charge selection at atmospheric pressure with higher resolving power. 
     Referring to FIG. 1, ions entering orifice  60  of capillary  82  are swept into the first vacuum pumping stage  61  through a supersonic free jet in capillary exit region  83 . Ions are focused through the opening of skimmer  65  and move into multiple ion guide assembly  68  comprising rod or pole sections  69  through  74 . Ions traversing the length of ion guide assembly  68  move through a background gas with decreasing pressure. Multipole ion guide  74  extends continuously from second vacuum stage  62  into third vacuum stage  63 . The neutral gas pressure at the entrance of ion guide assembly  68  may be as high as a few hundred millitorr. The vacuum pressure at the exit end of ion guide assembly  68  may be a low as 10 −6  torr. Ions traversing ion guide assembly  68  whose mass to charge values fall in the multipole ion guide stability regions are captured by the applied RF fields and transported efficiently through several orders of magnitude of background pressure gradient. Multipole ion guide assembly  68  located in vacuum region  2  of FIG. 1 can be operated in a number of trapping and non-trapping modes with combinations of ion mass to charge selection and fragmentation as is described in U.S. patent application Ser. No. 09/235,946. One or more ion mass to charge selection and fragmentation steps followed by product ion mass to charge analysis will be referred to as MS/MS n  mass analysis functions. MS/MS n  mass analysis functions can be performed with one or more steps of ion mass to charge selection and fragmentation conducted in multipole ion guide assembly  68  followed by Time-Of-Flight (TOF) mass to charge analysis. Ions exiting multipole ion guide  74  enter TOF pulsing region  84  and are pulsed into TOF flight tube  64  in a direction substantially orthogonal to the axis of multipole ion guide assembly  68 . The ions proceed through the TOF flight tube  64  and ion mirror  85  and are detected on electron multiplier detector  86 . Other ion mass to charge analyzer types may be configured replacing the ion guide assembly  68  and TOF mass analyzer shown in FIG.  1 . Such ion mass to charge analyzer types may include but are not limited to a quadrupole, three dimensional ion trap, two dimensional ion trap, in line Time-Of-Flight (TOF), TOF-TOF, Fourier Transform (FTMS) or Ion-cyclotron Resonance (ICR) MS, magnetic sector or hybrid mass analyzers. 
     In an alternative embodiment of the invention, shown in FIG. 5, two electrostatic lenses  110  and  111  are positioned between multipole ion guide  8  exit end  31  and capillary  82  entrance orifice  60 . Lens  111  is split into halves  112  and  113 . As was described previously, MALDI generated ions are directed against countercurrent gas flow  80  by the electric fields applied to lenses  19  through  22 . The DC potential applied to electrostatic lenses  110 ,  111  and capillary entrance lens  81  direct ions from ion guide exit  31  into capillary entrance orifice  60 . Ions entering capillary bore  48  are swept into vacuum by the expanding gas flow and subsequently mass to charge analyzed. Different ion species or ions with different folding patterns produced from a MALDI laser pulse will begin to separate due to differences in their mobility as they are driven through countercurrent gas flow  80 . Ions of different mobility can be directed to enter capillary entrance orifice  60  or steered away from orifice  60  by adjusting the relative DC voltages applied to lens elements  112  and  113  of electrostatic lens  111 . Ions with different ion mobility can be selected or rejected from entering vacuum by pulsing a voltage difference between lens elements  112  and  113 . Controlling timing of the differential voltage pulse applied to lens elements  112  and  113  relative to laser pulse  10  allows ions of specific ion mobility to be consistently rejected from or selected to enter capillary entrance orifice  60  for subsequent mass to charge analysis. Lens element  110  prevents the steering voltage electric field to penetrate into entrance region  31  of ion guide  8  minimizing any loss of ions present in this region. The addition of electrostatic lenses  110  and  111  allows more precise control when selecting ions based on their mobility a atmospheric pressure compared with changing the DC potential applied to capillary entrance lens  81 . 
     The invention can be configured with MALDI targets of different shapes, sizes and sample spot patterns. These alternate MALDI target shapes can be configured to position the sample spot inside a multiple ion guide volume. As shown in FIG. 6, a linear MALDI target  120  is positioned in gaps  89  between rods  7  of multipole ion guide  8 . Linear shaped sample targets have the advantage of requiring less volume then a round shaped target as shown in FIGS. 1 through 3. Positioning a sample spot on a linear target relative to a laser pulse location is simplified with only x and z axis of movement required. A rotation movement is not needed. Sample spot  121  is located inside ion guide volume  122  where MALDI laser pulse  10  from laser  7  impinges on sample spot  121  to produce MALDI generated ions  123 . Gas flow  14  from gas channel  15  move MALDI generated ions  123  toward exit end  31  of ion guide  8 . The DC potential applied to ion guide entrance lens  90  relative to the offset potential applied to rods  7  of ion guide  8  and gas flow  14  prevent MALDI generated ions from moving toward the entrance end of ion guide  8 . Different sample spots can be selected for analysis by moving MALDI sample target  120  in the x direction. MALDI sample target can be manually or automatically loaded into position in MALDI ion source  125 . Each sample spot can be positioned inside ion guide  8  by manual or automated manipulation of a MALDI target position translation assembly. 
     An alternative MALDI target  130  shape is shown in FIG. 7 where sample spot  131  is positioned at the end of MALDI target finger  132 . Laser pulse  134  is directed through a gap in poles  137  of multipole ion guide  138  to impinge on sample spot  131  positioned within ion guide volume  145 . Configuring MALDI target  130  with individual fingers allows the insertion of sample spot  131  without requiring MALDI target  130  to be positioned in the gaps between poles  137  as was shown using the round MALDI target shape diagrammed in FIG.  3 . Translating MALDI target  130  in the z direction removes or inserts finger  132  and sample spot  131  into ion guide volume  145  through the entrance end of ion guide  138  while maintaining a distance from ion guide poles  137 . A thicker MALDI target geometry can be used if the target is not positioned in the gap of ion guide poles  137 . To change sample spots, MALDI target  130  is moved in the negative z direction, away from entrance end  148  of ion guide  138  removing sample spot  131  from ion guide volume  145 . MALDI target  130  is then rotated to align finger  143  with ion guide axis  147  and moved in the positive z direction until sample spot  144  is inserted into ion guide entrance end  148  for analysis. MALDI target  130  can be moved in the z and x direction to allow a fixed position laser pulse to impinge on different regions of sample spot  144 . Alternatively the position of laser pulse  134  can be directed to different regions on sample spot  144  by moving mirror  106  as shown in FIG.  2 . MALDI target  130  may comprise conductive or dielectric material. Less distortion to the RF field in ion guide  138  will occur during operation if MALDI target  130  comprises a dielectric material. 
     In the embodiment shown in FIG. 7, multipole ion guide  138  is configured as a hexapole. Alternatively, ion guide  138  may be configured as a quadrupole, octapole or with any number of odd or even pole sets comprising at least four poles. MALDI generated ions produced by impinging laser pulse  134  on sample spot  131  are directed along ion guide axis  147  by gas flow  142  exiting from gas channel  133  similar to that shown in FIGS. 1 through 3. MALDI generated ions are radially trapped by the RF field applied to poles  137  of ion guide  138  as previously described. Gas flow  142  and the repelling voltage applied to entrance lens  141  relative to the common DC offset potential applied to poles  137  of ion guide  138  prevents MALDI generated ions from moving toward entrance end  148  of ion guide  138 . The MALDI ion source embodiment shown in FIG. 7 comprises angled rods  135  positioned in the gaps between ion guide poles  137 . A common DC potential is applied to angled rods  135  forming a DC electric field in the axial direction along the length of ion guide volume  145 . This DC field serves to move ions that fall within the operating stability region of ion guide  138  towards exit end  136  of ion guide  138 . Similar to the configuration shown in FIGS. 1 through 3, ions exiting ion guide  138  are directed into vacuum through an orifice and subsequently mass to charge analyzed. 
     Alternatively, a moving belt MALDI target can be positioned to extend through the internal volume of an ion guide configured at atmospheric pressure or in a vacuum pressure region. FIG. 8 shows moving belt MALDI target  152  with three sample tracks  169  through  171  deposited from individual capillary electrophoresis (CE) or liquid chromatography (LC) separation systems. The output sample flow  158  from separation system  155  is continuously deposited on moving belt  174 . Deposited sample solution  158  is mixed with a MALDI matrix solution  160  delivered from fluid delivery system  157 . The sample and MALDI matrix mixture is dried as it passes under heater  163  prior to entering volume  151  of multipole ion guide  150 . Controlled rotation of delivery spool  161  and take up spool  162  determines the speed of belt movement. Moving belt  152  passes through gap  164  between ion guide poles  154  and gap  165  between ion guide poles  175 . Moving belt  152  may comprise a conductive or dielectric material. Configuring moving belt  152  with a dielectric material, minimizes the distortion of the electric fields within multipole ion guide  150  during operation. 
     As the dried sample and MALDI matrix track pass through the region of ion guide centerline  175 , it is subjected to one or more laser pulses  153 . Laser pulse  153  impinging on sample track  170  at location  173  produces MALDI generated ions inside multipole ion guide  150  internal volume  151 . Gas flow  167  passes over sample track location  173  sweeping MALDI generated ions away from ion guide entrance  177 . Maintaining a potential difference between entrance lens  168  and the common DC offset potential applied to the rods of multipole ion guide  150  during operation prevents MALDI generated ions of the desired polarity from moving in the direction of ion guide entrance  177 . MALDI generated ions of a selected polarity that fall within the stability region of ion guide  150  operation are directed to traverse the length of ion guide  150  toward exit end  178  moved by gas flow and DC electric fields penetrating into ion guide volume  151  as was previously described. The MALDI generated ions are directed toward and through an orifice into vacuum where they are subsequently mass to charge analyzed. Ions can be generated from multiple sample tracks  169  through  171  by shifting laser beam  153  to impinge on each track in a controlled manner. Ions generated from different sample tracks can be separately mass analyzed sequentially in time by synchronizing the laser pulse and position timing with the subsequent mass to charge analysis spectrum acquisition. Running multiple sample tracks can increase sample throughput by allowing parallel sample separation systems to operate simultaneously. MALDI generated ion populations from different tracks can be trapped in ion guide  150  to delay their entrance into vacuum or can be trapped in ion guides located in vacuum prior to TOF mass analysis in a hybrid quadrupole TOF mass analyzer as diagrammed in Figure 
     In alternative embodiments of the invention, atmospheric pressure MALDI ion sources may comprise different type of ion guides to trap and direct MALDI generated ions into an orifice into vacuum. One such alternative ion guide is shown in FIG. 9 where a multiple ring ion guide  180  replaces multipole ion guide  8  of FIGS. 1 through 5. As is known in the art, RF voltage is applied to ring electrodes  180  with opposite phase RF applied to adjacent ring electrodes. Each ring electrode  181  has a different DC potential applied forming a DC field in the axial direction along the length of ion guide  180 . MALDI generated ions produced by impinging laser pulse  183  on sample spot  182  are swept toward ion guide exit end by gas flow  184 . Ions are driven against countercurrent gas flow  186  by the axial DC field applied to ring electrodes  181  of ion guide  180 . As was previously described, the potentials applied to electrode  187  and split electrode  188  can be controlled to select ions for mass analysis that are separated while traversing the length of ion guide  180  due to differences in ion mobility. 
     Alternatively, as shown in FIG. 10, ion funnel  190  can be configured in place of multipole ion guide  8  in atmospheric pressure MALDI ion source  191 . Operation of an ion funnel, as known in the art, is similar to that of a ring electrode ion guide. RF potential is applied to electrodes  192  with opposite phase RF applied to adjacent electrodes. The aperture size in each ion funnel electrode  192  can vary in size along the length of ion funnel  190 . Ions are generated inside ion funnel volume  197  by impinging laser pulse  194  onto sample spot  193 . MALDI generated ions are swept away from MALDI sample target  200  by gas flow  195  and a DC electric field maintained along the length of ion funnel  190 . the DC field is formed by applying different DC voltages to entrance electrode  204  and each electrode  192  along the length of ion funnel  190 . The DC field directs ions against countercurrent gas flow  201  and into capillary entrance orifice  202 . The MALDI generated ions are swept into vacuum by the gas expanding through capillary bore  103  where the MALDI generated ions are subsequently mass to charge analyzed. 
     If the MALDI target is not positioned within a multipole ion guide or ion funnel, the constraints imposed by the ion guide geometry or electric fields on the MALDI target materials and shape are eliminated. Any loss in ion capture or transport efficiency may be compensated by increased flexibility in MALDI sample target configuration and manipulation. An alternative embodiment of the invention is shown in FIGS. 11 and 12 where MALDI sample target  210  is positioned at entrance end  212  of multipole ion guide  211 . MALDI sample target  210  is configured to align sample spot  213  with entrance end  212  of ion guide  211  such that the sample spot surface is facing ion guide centerline  220 . MALDI sample target  210 , mounted on X-Y-Z translation stage  230  is located in chamber  221 . Gas flow  223  enters chamber  221  through flow control valve  234  and gas flow channel  222  and exits through aperture  224  in ion guide entrance lens  217 . Exiting gas flow  223  sweeps MALDI generated ions  228  formed from sample spot  213  into multipole ion guide volume  225 . In the embodiment shown in FIG. 11, gas flow  223  pushes MALDI generated ions  228  through the length of ion guide  211  while the RF field applied to rods  231  of ion guide  211  trap ions in the radial direction whose mass to charge values fall within the ion guide operating stability region. Due to collisions with neutral gas molecules, the trajectories of MALDI generated ions damp to center of ion guide volume  225  as they traverse the length of ion guide  211 . MALDI generated ions  228  traversing the length of multipole ion guide  211  to ion guide exit end  226  enter capillary bore  229  where they are swept into vacuum through capillary  232  and subsequently mass to charge analyzed. 
     The gap between multipole ion guide entrance electrode  217  and MALDI target  210  may be adjusted to optimize performance using the Z translation direction of MALDI target X-Y-Z translator  230 . A smaller gap allows a higher gas velocity near the surface of sample spot  213 , to sweep ions away from sample spot  213  for a given rate of gas flow  223 . If increased gas flow  223  is desired to more effectively sweep the volume of ion guide  211 , the gap between entrance lens  217  and MALDI target  210  can be increased to optimize the gas velocity passing over sample spot  213 . The flow rate of gas flow  223  is changed by adjusting the setting of gas flow valve  234 . When MALDI sample target  210  comprises a conductive material, a DC potential difference can be applied between MALDI sample target  210  and ion guide entrance electrode  217 . MALDI generated ions  228  of the desired polarity can be directed into volume  225  of multipole ion guide  211  by gas flow  223  and the electric field applied between MALDI sample target  210  and ion guide entrance lens  217 . Closed chamber  221  is electrically isolated from ion guide entrance lens  217  through insulators  218 . If MALDI target  210  comprises a dielectric material, it can be backed by a conductive element to establish an electric field at sample spot  213 . Section A—A of FIG. 12A shows a face-on view of sample spot  213 , lens aperture  224 , entrance lens  217  and insulator  218 . Different sample spots on MALDI sample target  210  can be aligned with aperture  224  in ion guide entrance lens  217  by moving MALDI sample target  210  in the x and/or y direction. Laser pulse  214  delivered from laser  215  can be directed to hit a specific location on sample spot  213  by moving MALDI sample target  210  or by moving mirror  216  manually or using computer control. MALDI sample target  210  can be automatically or manually loaded into chamber  221  and moved manually or automatically through computer control. MALDI target  210  can be configured with a standard plate dimension and with standard sample spot locations or be configured with a custom shape and custom sample spot locations. 
     FIG. 13 shows an alternative embodiment of the invention where MALDI generated ions are formed from sample spot  240  positioned outside ion guide volume  241 . In the embodiment shown in FIG. 13, MALDI target  243  is configured to position sample spot  240  near multipole ion guide centerline  244 . Gas flow  245  from gas channel  246  sweeps MALDI generated ions through ion guide entrance lens aperture  247  in ion guide entrance lens  248  into ion guide volume  241  of multipole ion guide  242 . Ions of the desired polarity, generated when laser pulse  251  impinges on sample spot  240 , are directed through ion guide entrance lens aperture  247  by gas flow  245  and the appropriate electrical potentials applied to lens  252 , MALDI target  243 , electrostatic entrance lens  248  and the DC offset potential applied to the poles of ion guide  242 . MALDI generated ions are directed through the length of ion guide  242  by applying different DC potentials along ring electrodes  249 . The DC potential gradient formed along ring electrodes  249  penetrates into volume  241  of ion guide  242  as was previously described. Selection of ion species based on their mobility can be conducted by applying the appropriate steering potentials across lens half sections  251  and  252  of lens  250 . Selected ions are directed into capillary entrance orifice  253  where gas flow sweeps the MALDI generated ions through bore  255  of capillary  254  and into vacuum where they are subsequently mass to charge analyzed. MALDI target  243  is shown circular in shape with sample spots along the outer diameter, however, for the embodiment shown in FIG. 13, MALDI target  243  can be configured in a variety of shapes and with a variety of sample spot patterns. 
     FIG. 14 shows an alternative embodiment for a MALDI target that allows MALDI generated ions to be formed inside or outside of the volume of a multipole ion guide at atmospheric pressure or in vacuum. MALDI target  260  comprises individual sample spot holders  261  and  262  that can be retracted as shown with sample spot holder  262  or moved forward as shown with sample spot holder  261 . Similar to the embodiment shown in FIGS. 11 and 12, MALDI target  260  is configured in chamber  263  and is moved by X-Y-Z translator  264  to line up a sample spot with chamber opening channel  265 . Adjustable gas flow  267  enters chamber  263  through gas flow channel  266  and exits through opening channel  265  sweeping around sample spot  268 . Laser pulse  271  delivered from laser  272  impinges on sample spot  268  generating ions that are swept into segmented multipole ion guide  269  by gas flow  273 . Sample spot holder  261  and opening channel  265  may comprise dielectric or conductive materials. Dielectric materials allow MALDI generated ions to be created directly in the relatively unperturbed RF field of ion guide  269  providing radial trapping of ions during collisional damping of initial ion translational energies. When conductive materials are used for sample spot holder  261  and opening channel  265 , MALDI generated ions can be directed away from sample spot  268  toward exit end  276  of ion guide  269  by applying the appropriate electrical potentials to sample spot holder  261 , opening channel  265  and segmented rods  275  of ion guide  269 . In the embodiment shown, multipole ion guide  269  comprises segment rods where a different DC potential can be applied to each segment  270  to create an axial DC field along the length of ion guide  269 . The axial DC field directs ions through ion guide volume  277  toward capillary entrance orifice  278  where they are swept into vacuum for mass to charge analysis. MALDI target  260  with moveable individual sample spots allows the optimal placement of a sample spot relative to the entrance or internal volume of multipole ion guide  269  to maximize MALDI generated ion transfer efficiency into vacuum. Ion mass to charge selection and ion mobility selection can be conducted in the MALDI ion source embodiment shown in FIG. 14 as has been previously described. 
     An alternative embodiment of the invention configured for MALDI ionization in intermediate and low vacuum pressures is shown in FIGS. 15 and 16. Improvements in ion transport efficiency can be gained by operating a MALDI ion source configured according to the invention in vacuum when compared with atmospheric pressure MALDI ion source operation. Ions generated with MALDI ionization in vacuum are not required to pass through a small orifice leading into vacuum as is the case with ion generated with MALDI ionization at atmospheric pressure. It may not be possible to focus all MALDI generated ions through an orifice into vacuum that typically have diameters of less than 600 um resulting in ion losses with atmospheric pressure MALDI ion sources. Ion guide volumes, orifices or lenses between vacuum pumping stages are considerably larger and electrostatic fields have greater focusing effect in vacuum pressures improving overall ion transmission from intermediate or low vacuum pressure MALDI ion sources. A second advantage of an intermediate or low vacuum pressure MALDI ion source configured according to the invention is that the number of ion to neutral collisions experienced by MALDI generated ions can be controlled by adjusting the vacuum pressure in the MALDI ion source region. The number of collisions an ion experiences will affect its internal and translational energy. Controlling the number and location of ion to neutral collisions can be used to promote or suppress MALDI generated ion fragmentation and clustering and to damp translational energies and ion energy spread. These functional capabilities result in increased ion transport efficiency and signal sensitivity and increased analytical capability. 
     MALDI target  280  and multipole ion guide  284  are configured in vacuum chamber  285  that is evacuated through vacuum pumping port  286 . MALDI ion source  291  located in vacuum chamber  285 , is interfaced to a hybrid quadrupole ion guide TOF instrument whose function is similar to that described in FIG.  1 . The pressure in vacuum stage  285  can be varied by adjusting gas flow  305  through gas channel  287  with gas flow valve  288 . The background pressure in chamber  285  can be maintained sufficiently low to minimize or eliminate collisions between MALDI generated ions and neutral background gas molecules. Alternatively, the background pressure in chamber  285  can be maintained at a level where multiple collisions occur between MALDI generated ions and neutral background gas. Depending on the analysis being conducted either vacuum pressure range may have advantages. Ion collisions with background gas can reduce ion internal energy and reduce fragmentation. Multiple collisions with background gas can damp ion kinetic energies and increase ion capture and transport efficiency. Ion to neutral collisions can be used to study ion to neutral reactions when reactant gas is introduced into vacuum chamber  285 . The flow rate of gas flow  305  can be adjusted by changing the gas flow rate setting of gas flow valve manually or automatically through programmed control to achieve optimal analytical performance. 
     In the embodiment shown in FIGS. 15 and 16, ions are generated by impinging laser pulse  282  from laser  283  on sample spot  281  mounted on movable MALDI target  280 . Sample spot  281  is positioned inside multipole ion guide volume  283  where MALDI generated ions are directly subjected to the RF trapping fields in volume  283  of multipole ion guide  284  during ion guide operation. Gas flow  289  can be added through gas channel  287  with gas flow rate adjusted by valve  288 . Gas flow  289  can be heated using heater  304  to reduce condensation of molecules released from sample spot  281  due to cooling as gas flow  289  expands into vacuum. The vacuum pumping speed through vacuum pumping port  286  is typically fixed, so the vacuum pressure in vacuum chamber  285  will increase by increasing the rate of gas flow  289 . Increased gas pressure locally at sample spot  281  and in ion guide volume  283  causes collisional damping of ion kinetic and internal energies, minimizing ion fragmentation due to post source decay and maximizing ion capture and transport efficiency through multipole ion guide  284 . MALDI generated ions whose mass to charge values fall within the operating stability region of multipole ion guide  284  are directed toward ion guide exit end  298  by gas flow  289 , an axial DC field formed by different DC potentials applied to lens elements  302  as has been previously described and DC potentials applied to ion guide entrance lens  304 , exit lens  301  and conical lens or skimmer  303 . Ions exiting ion guide  284  are directed through orifice  300  of lens  303  and into multiple ion guide assembly  292 . Ion mass to charge selection and fragmentation steps may be conducted in multipole ion guide assembly  292  prior to mass to charge analysis of ions in orthogonal pulsing Time-Of-Flight mass analyzer  296 . Multipole ion guide  284 , shown as a hexapole in FIGS. 15 and 16 can be alternatively comprise a quadrupole, an octapole or other odd or even numbers of poles. If ion guide  284  is configured as a quadrupole, ion mass to charge selection and fragmentation can be conducted in ion guide volume  283 . By adjusting the electrical potentials applied to lenses  301  and  300 , ions can be selectively trapped in or axially released from ion guide volume  283 . 
     In an alternative embodiment of the invention, downstream lenses and ion guides are reconfigured to allow an increased range of pressure in the vacuum MALDI ion source region and to increase the range of analytical capabilities in ion mass to charge analysis. FIGS. 17 through 19 show three alternative ion guide assembly embodiments interfaced to a vacuum MALDI ion source and a TOF ion mass to charge analyzer. A vacuum MALDI ion source embodiment according to the invention is shown in FIG. 17 where MALDI sample spot  310  is positioned in volume  312  of multipole ion guide  311 . MALDI generated ions move through volume  312  of ion guide  311  toward ion guide exit end  313  as has been previously described. Electrostatic lens  319  forms a vacuum partition between vacuum chambers  314  and  315 . Multipole ion guide  317 , located in vacuum chamber  315 , is positioned between lens  313  and collision chamber  320 . Multipole ion guide  318  is configured in collision chamber  318 . As is known in the art, additional vacuum pumping stages and/or ion guides can be added between collision chamber  320  and TOF mass analyzer  316  to reduce gas flow into TOF mass analyzer  316 . MALDI generated ions traversing multipole ion guide  311  are directed through lens orifice  324  into ion guide  317 . Ions can then pass through ion guide  317  and move into ion guide  318 . Ions leaving collision chamber  320  are directed into TOF mass analyzer  316  where they are mass to charge analyzed. As was previously described in FIGS. 15 and 16, the vacuum pressure in vacuum chamber  314  can be adjusted by varying the rate of gas flow  325 . The pressure in collision chamber  320  can be independently adjusted by controlling gas flow  321  through gas channel  323  with gas flow valve  322 . The vacuum pressure in chamber  315  will be affected by the pressure in vacuum chamber  314  and collision chamber  320  but sufficient vacuum pumping speed can be applied through vacuum pumping port  326  in chamber  315  to minimize ion to neutral collisions over a wide range of operating pressures in chambers  315  and  320 . 
     Multipole ion guide  311 , configured as a quadrupole, can be used to trap and axially release ions and conduct ion mass to charge selection and ion fragmentation. The vacuum pressure in vacuum chamber  314  can be adjusted allowing a wide range of ion mass to charge selection and fragmentation functions to be conducted in multipole ion guide  311 . For example conducting ion mass to charge selection using +/−DC and RF applied to the poles of quadrupole  311  as is know in the art achieves improved performance at vacuum pressures where collisional scattering affects are minimized. Multipole ion guides  317  and  318  individually in tandem can be used to mass select and fragment ions. Ions can be trapped in and axially released from ion guides  317  and  318 . The MALDI ion source and multiple ion guide embodiment shown in FIG. 17 can be operated to achieve MS and MS/MS n  functions with TOF ion mass to charge analysis. Additional vacuum pumping stages and multipole ion guides can be added to increase the operating pressure ranges of the vacuum MALDI ion source and increase analytical capability. One such embodiment is shown in FIG. 18 where multipole ion guide  330  has been added in vacuum pumping chamber  331 . MALDI ion source  332  can be operated with increased pressure in this embodiment without compromising the vacuum pressure in vacuum stage  333 . Multipole ion guide  330  can be used to conduct additional ion mass to charge selection and/or fragmentation steps if the vacuum pressure in chamber  331  is maintained at appropriate levels. 
     Multipole ion guides that extend through multiple vacuum pumping stages can be configured with a vacuum MALDI ion source according the invention to improve ion transmission efficiency and sensitivity. A single ion guide extending through multiple vacuum stages can be configured to reduce instrument size and cost compared with multiple ion guide configurations. FIG. 19 shows an alternative embodiment of the invention where MALDI sample spot  334  is positioned inside multipole ion guide volume  336 . Ion guide  335  is configured to extend contiguously into multiple vacuum stages  337 ,  338  and  339 . As is known in the art, multipole ion guides that extend into multiple vacuum stages can efficiently transport ions through large vacuum pressure gradients. Ion guides that extend into multiple vacuum pumping stages can be used to conduct ion mass to charge separation and fragmentation. As has been previously described, MALDI ions generated from sample spot  334  are radially trapped by the RF field present in ion guide volume  336  during operation. MALDI generated ions transverse the length of multipole ion guide  335  and are directed into TOF mass analyzer  340  where they are mass to charge analyzed. 
     An alternative embodiment of a vacuum MALDI ion source configured according to the invention is shown in FIG.  20 . Similar to the embodiment shown in FIGS. 11 and 12 for an atmospheric pressure MALDI ion source, MALDI target  345  is configured so that sample spots are positioned outside multipole ion guide volume  358 . Gas flow  349  enters chamber  346  through flow control valve  347  and gas channel  348 . Gas flow  353  exits chamber  346  through lens aperture  350  in electrostatic lens  354 . The vacuum pressure in vacuum chamber  351  evacuated through vacuum pumping port  355  is set by the flow rate of gas flow  353  and the vacuum pumping speed through vacuum pumping port  355 . Setting the flow rate of gas flow  349  through flow control valve  347  adjusts the vacuum pressure in vacuum chamber  351 . Different vacuum pressures can be set in vacuum chamber  351  to achieve optimal performance for a given mass spectrometric analysis with MALDI ionization. The number of collisions a MALDI generated ion experiences near sample spot  357  can be adjusted to optimize ion internal energy and translational energy cooling. The gas flow  353  sweeping past sample spot  357  through lens aperture  350  helps to direct MALDI generated ions  361  into ion guide volume  358  where they are trapped radially by the RF fields during operation of multipole ion guide  352 . MALDI generated ion transmission efficiency into ion guide  352  is aided by optimizing the gap between MALDI target  357  and electrostatic lens  354  by moving the MALDI target in the z direction with x-y-z translator  359 . Electrostatic potentials applied to conductive MALDI target  357  and electrostatic lens  354  and the common DC offset potential applied to the poles of ion guide  352  can be optimized to improve the transfer efficiency of MALDI generated ions  361  into multipole ion guide  352  for any flow rate of gas flow  353 . MALDI generated ions  361  traversing the length of multipole ion guide  352  and are directed through lens aperture  362  in electrostatic lens  363  and into multipole ion guide assembly  360  for MS or MS/MS n  mass to charge analysis as previously described. MALDI generated ions  361  move through multipole ion guide  352  due to collisions with gas flow  353  and due to the presence of axial DC fields. Ion collisions with neutral background molecules in ion guide volume  358  aid in damping ion trajectories toward ion guide centerline  364  and reducing the kinetic energy spread of MALDI generated ions  361  whose mass to charge values fall within the stability region of ion guide  352  during operation. This improves ion transmission efficiency of MALDI generated ions into downstream vacuum chambers, ion guides and mass to charge analyzers. 
     Multipole ion guide  352  is replaced with multipole ion guide  370  in an alternative embodiment of the invention shown in FIG.  21 . Multipole ion guide  370  extends from vacuum chamber  371  into vacuum chamber  372  providing efficient transfer of MALDI generated ions  373  through a wide range of vacuum pressure gradients. Multipole ion  370  may be operated in ion mass to charge selection mode. If the vacuum pressure is sufficiently high along a portion of the length of multipole ion guide  370 , ion fragmentation may be conducted in multipole ion guide  370  using resonant frequency excitation collisional induced dissociation fragmentation. 
     Combining Electrospray ionization and MALDI ionization in the same mass spectrometer instrument with the ability to switch rapidly and automatically to either ionization mode has advantages in cost, flexibility ionization modes and increased analytical capability. FIG. 22 shows an alternative embodiment of the invention in which MALDI target  380  is configured in mass spectrometer  381  requiring minimum change to the configuration of Electrospray ion source  382 . The operation of Electrospray ion source  382  at atmospheric pressure is known in the art. Dielectric MALDI target  380  is inserted through vacuum lock  384  into ion guide volume  385  by passing through the gap between poles  402  of multipole ion guide  387 . The Electrospray ion source may be turned off or operated during MALDI ionization and in either mode gas flow  388  continues to enter vacuum through bore  383  of capillary  389 . Gas flow  388  forms a supersonic free jet expansion when it enters vacuum pumping stage  390  and a portion of gas flow  388  passes through orifice  391  of skimmer  392 . Gas flow  393  flowing into vacuum pumping stage  394  through skimmer orifice  391  sweeps past MALDI target  380  and sample spot  395 . Laser pulse  396  from laser  397  impinging on sample spot  395  produces ions that are radially trapped by the RF fields applied to multipole ion guide  387 . 
     The movement of MALDI generated ions  400  toward exit end  398  of ion guide  387  is aided by gas flow  393  and an axial DC field applied along the length of ion guide  387 . An axial DC field is formed by DC voltages applied to skimmer  392 , ion guide exit lens  401  and the DC offset potential applied to rods  402  of ion guide  387 . Additional electrostatic lens assemblies can be configured to created an axial DC field in ion guide  387  as has been previously described. Gas flow  393  provides sufficient pressure in vacuum stage  394  to cause collisional cooling of internal energies and translational energy damping of MALDI generated ions  400  in multipole ion guide  387 . The MALDI generated ion population with reduced energy spread and reduced internal energy is directed from ion guide  387  through lens aperture  403  into ion guide  405  positioned in vacuum pumping stage  404  by applied the appropriate DC potentials to the poles of ion guide  387 , electrostatic lens  401  and ion guide  405 . MALDI generated ions  400  are subsequently mass to charge analyzed or subjected to mass selection and fragmentation steps prior to mass to charge analysis. Alternatively, MALDI generated ions  400  can be trapped in multipole ion guide  387  and selectively released into downstream ion guides and mass analyzers. MALDI target  380  can be removed through vacuum lock  384 . Vacuum lock  384  can be configured, as is known in the art, to avoid venting vacuum when inserting or removing MALDI target  380 . When MALDI target  380  is removed, the Electrospray ion source can be run in its normal operating mode. The insertion and removal of MALDI target  380  can be controlled manually or automated through computer control. Generating ions using Electrospray and/or MALDI ionization individually or simultaneously can be automated to maximize sample throughput and to provide optimal and complimentary analytical information. 
     An alternative embodiment of a combined Electrospray and MALDI ion source is shown in FIG.  23 . MALDI target probe assembly  410  comprising MALDI target  412  is inserted into first vacuum stage  411  through vacuum lock  413  without venting vacuum. Probe assembly  410  blocks capillary exit  427  when inserted into vacuum stage  411  stopping gas flow from atmospheric pressure through capillary  414 . MALDI target  412  can move within probe assembly  410  aligning sample spot  416  with probe assembly orifice  417  and skimmer orifice  418 . Gas flow  419  controlled by gas flow valve  420  enters probe assembly  410  through gas channel  421 . Gas flow  422  sweeps over sample spot  416  and exits orifice  417  in probe assembly  410 . A portion of gas flow  419  enters vacuum stage  411  and is pumped away. The remainder of gas flow  422  enters vacuum stage  415  through skimmer orifice  418 . MALDI generated ions  422  are formed when laser pulse  420  from laser  421  impinges on sample spot  416 . MALDI generated ions  426  are directed into ion guide volume  423  by gas flow  422  and the relative DC potentials applied to MALDI target  412 , probe assembly  410 , skimmer  425  and the poles of multipole ion guide  424 . Gas flow  422  provides collisional damping of MALDI generated ion trajectories near sample spot  416  and in multipole ion guide volume  423  creating a population of ions  426  with a low energy spread and with trajectories that damp toward ion guide centerline  428  as the ions traverse the length of ion guide  424 . MALDI generated ions  426  pass through multipole ion guide  424  and are subsequently mass to charge analyzed. Alternatively, MALDI generated ions  426  may be trapped and axially released from multipole ion guide  424 . Ion mass to charge selection and/or fragmentation of MALDI generated ions  426  may be conducted in multipole ion guide  424  prior to ion mass to charge analysis. MALDI target  412  can be moved inside probe assembly  410  to align each sample spot with probe assembly orifice  417  for sample ionization. Sample probe  410  can be retracted through vacuum lock  413  without venting vacuum in vacuum stage  411 . Electrospray ionization can be conducted when MALDI probe assembly  410  has been retracted from blocking the Electrospray ion beam. MALDI probe assembly  410  can be inserted and retraction manually or automated using programmed control. 
     MALDI target probe assembly  410  is simplified in the alternative embodiment of the invention shown in FIG.  24 . MALDI target  430  is inserted into vacuum pumping stage  432  through vacuum lock  431  without venting vacuum in vacuum stage  432 . Gas flow  433  from atmospheric pressure expanding through capillary bore  434  continues to flow with MALDI target  431  inserted. This MALDI target configuration retains the operating vacuum pressure in vacuum stage  432  similar to the vacuum pressure maintained during Electrospray operation. Neutral gas in vacuum stage  432  sweeps across sample spot  436  and through skimmer orifice  435  into vacuum stage  438 . Similar to the embodiment shown in FIG. 23, MALDI generated ions  442  are directed into ion guide volume  441  by gas flow  437  and the DC potentials applied to MALDI target  430 , skimmer  449  and the poles of multipole ion guide  440 . Laser pulse  443  from laser  444  is directed through a gap between poles of multipole ion guide  440  and through skimmer orifice  435  to impinge on sample spot  436 . MALDI generated ions  442  entering multipole ion guide volume  441  are radially trapped by the RF field applied to the poles of ion guide  440  and their trajectories are collisionally damped toward centerline  445  of ion guide  440  as they traverse the length of ion guide  440 . 
     The gas flow rate into vacuum stage  432  can be controlled to provide different pressures and gas flow rates across sample spot  436 . In an alternative embodiment of the invention, capillary bore  434  can be blocked at its entrance by a plug or valve or at its exit by the inserted MALDI probe assembly. With gas flow through capillary bore  434  blocked, gas flow  446  can enter vacuum stage  432  through gas flow control valve  447  and gas channel  448  by opening gas flow control valve  447 . Gas flow control valve  447  can be adjusted to establish the desired pressure in vacuum stage  432  to optimize performance for a given MALDI mass analysis experiment. Ions can be generated from different sample spots by manually or automatically moving MALDI target  430  to align different sample spots with skimmer orifice  435 . MALDI target  430  can be manually or automatically retracted and removed through vacuum lock  431  without venting vacuum in vacuum stage  432 . Electrospray ionization can be continued when MALDI target  430  is retracted from centerline  445 . 
     Alternative embodiments of the invention are shown in FIGS. 25 and 26 wherein MALDI targets are inserted into ion guide volumes positioned in the first vacuum stage of an Electrospray ion source. In FIG. 25, multipole ion guide  450  extends into three vacuum stages  451 ,  452  and  453  of a mass to charge analyzer interfaced with Electrospray ion source  454 . Multipole ion guide  450  provides high ion transfer efficiency to a mass analyzer through a wide range of vacuum pressures. Similar to the embodiment of the invention shown in FIG. 19, MALDI ions are generated in ion guide volume  455  by impinging laser pulse  456  on sample spot  457 . Gas flow  458  exiting bore  460  of capillary  461  aids in sweeping MALDI generated ions away from sample spot  457  and toward exit end  462  of multipole ion guide  455 . Dielectric MALDI target  460  can be manually or automatically moved or inserted and removed from vacuum lock  460  without venting vacuum in vacuum stage  451 . When MALDI target  460  is removed, Electrospray ionization with mass to charge analysis can be conducted as a single ionization source. In an alternative embodiment of the invention shown in FIG. 26, vacuum stage  465  comprises a separate multipole ion guide positioned between capillary exit end  468  and electrostatic lens and vacuum partition  467 . Different RF and DC potentials can be applied to the poles of multipole ion guides  466  and  469  to optimize performance during MALDI or Electrospray ionization. MALDI target  470  is inserted into ion guide volume  472  with sample spot  471  being swept by gas flow  473  through bore  475  of capillary  474  as has been described previously. Matrix assisted laser desorption ionization simultaneously generates positive and negative ions. Electrospray ionization can be conducted while simultaneously producing MALDI generated positive and negative ions to study ion to ion reactions in the embodiments shown in FIGS. 22,  25  and  26 . Electrospray ions entrained in the gas exiting capillary bore  475  flow over MALDI sample spot  471  while MALDI ions are being produced allowing ion to ion reactions to occur. MALDI target probe  470  can be manually or automatically inserted, moved or retracted without venting vacuum in vacuum stage  465 . 
     A MALDI ion source can be configured according to the invention to deliver positive and negative ions to two separate mass to charge analyzers as shown in FIGS. 27 and 28. Positive and negative ions may be produced when laser pulse  485  impinges on MALDI sample spot  480  in FIG.  27 . An axial DC potential gradient is maintained along ion guide volume  487  by applying different DC potentials to ring electrodes  482  as previously described. Positive MALDI generated ions  486  created in ion guide volume  487  move toward ion guide exit end  488  and into MS  2  mass analyzer  484  for mass to charge analysis. Negative MALDI generated ions  490  created in ion guide volume  487  simultaneously move toward ion guide exit end  489  and into MS  1  mass analyzer  483  for mass to charge analysis. MALDI generated ions  486  and  490  are radially trapped in ion guide volume  487  as they traverse the length of ion guide  481  by the RF fields applied to the poles of multipole ion guide  481  during operation. The vacuum gas pressure in ion guide volume  487  can be maintained sufficiently high to provide multiple ion to neutral collisions between MALDI generated ions and background gas. Collisional damping of MALDI generated ions improves ion capture and transfer efficiency in multipole ion guide  481 . 
     FIG. 28 shows one embodiment of the dual mass analyzer instrument diagrammed in FIG.  27 . MS  1  comprises quadrupole TOF hybrid mass to charge analyser  500  and MS  2  comprises quadrupole TOF mass to charge analyzer  501 . Positive  509  and negative  508  ions generated from sample spot  505  positioned in ion guide volume  504  are directed into multipole ion guides  507  and  506  respectively. Ion mass to charge selection and/or fragmentation can be conducted in ion guides  507  and  506  prior to directing ions into TOF mass analyzers  501  and  502  respectively for mass to charge analysis. Different parallel MS or MS/MS n  analysis may be conducted with the different but simultaneously generated positive and negative MALDI ion populations. Mass spectra data acquired by conducting mass to charge analysis of both positive and negative MALDI generated ion populations can be combined and compared or evaluated independently. 
     In many embodiments of the invention described the multipole ion guides described can be substituted with other ion guide types including but limited to multiple ring electrode ion guides or ion funnels. Capillary orifices into vacuum as described in alternative embodiments of the invention can be substituted with other orifice types including but not limited to heated capillaries and aperture orifices. Additional or fewer vacuum pumping stages can be configured for the embodiments of the invention described. Alternative mass to charge analyzers can be configured with the invention including but not limited to quadrupoles, three dimensional in traps, TOF-TOF, magnetic sectors, Fourier Transform Mass Spectrometers, hybrid trap TOFs, orbitraps and two dimensional or linear ion traps. 
     It should be understood that the preferred embodiment was described to provide the best illustration of the principles of the invention and its practical application to thereby enable one of ordinary skill in the art to utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated. All such modifications and variations are within the scope of the invention as determined by the appended claims when interpreted in accordance with the breadth to which they are fairly legally and equitably entitled.