Abstract:
A mass spectrometer is provided herein and is configured to have two ionization sources, in which a first ionization source, such as MALDI, ESI and the like, which is capable of providing in addition to ions a set of normally intractable desorbed neutrals that are ionized by a second EI source coupled with the first source.

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
   This application claims priority to U.S. Provisional Application No. 60/396,693, filed Jul. 18, 2002, the contents of which are fully incorporated herein by reference. 

   BACKGROUND OF THE INVENTION 
   1. Field of the Invention 
   The present invention relates generally to mass spectrometry. More particularly, the present invention is directed to a mass spectrometer configured to handle volatile/non volatile samples, gas and solid phase sample introduction, and ionization methods appropriate to the full spectrum of molecular masses. 
   2. Description of the Related Art 
   Rapid and accurate identification of biological agents is essential in diagnosing diseases, anticipating epidemic outbreaks, monitoring food supplies for contamination, regulating bioprocessing operations. It is highly desirable not only to rapidly distinguish between related biological agents especially pathogenic agents, but also to unmistakably identify species and strains in complex matrices in general and, particularly, for the purpose of risk assessment in field situations. 
   Furthermore, the real threat from biological weapons as tools of modern warfare and urban terrorism is rising. Development of early detection, counter measures, and remediation technology is a high priority in many military, government and private laboratories around the world. Biological warfare (BW) agents such as  Bacillus anthracis  (anthrax),  Clostridium tetani  (tetanus), and  Clostridium botulinum  (botulism) are of critical concern since these spores are non-growing, heat-resistant, dehydrated, and resistant to extremes of temperature, pH, desiccation, radiation, and chemical agents. Due to their high stability, spores are difficult to stain using typical cell biology methods and, consequently, are challenging to detect and enumerate. This stability and difficulty with conventional detection methods, in turn, make them an attractive tool for use in BW weapons. 
   Relatively recently, mass spectrometric techniques have been developed for generating specific protein profiles for various biological agents. Mass spectrometry is an analytical technique in which atoms or molecules from a sample are ionized (usually positively) and separated according to their mass-to-charge ratio (m/z). The resulting mass spectrum is a record of the intensity of the signal as a function of m/z. The instrument used to record a mass spectrum is called a mass spectrometer. Because every compound has a distinct (though not necessarily unique) molecular weight and fragmentation pattern, mass spectrometers have a unique potential for the broadband detection and identification of chemical and/or biological agents. 
   A typical spectrometer has, among others, the following essential parts: the ionizer, detector and mass analyzer frequently provided with data-handling electronics. There are a number of different techniques and solutions for each of these parts. 
   One of the early-developed ionization techniques was Electron Impact Ionization (EI). The principle of the EI source is shown in  FIG. 1  and includes a filament  10 , which serves as a source of electrons  12 . A target or anode  14  is positively charged with respect to the filament  10  and attracts electrons out of it. A repeller  16  is a positively charged electrode which pushes positive ions away from the filament  10  through a lens stack  18  including a series of increasingly more negative electrodes which accelerate the positive ions in such a way that they become focused into a relatively narrow beam. When a sample molecule enters the EI source, it is hit by the electrons  12  and is ionized. 
   Most low molecular weight organic molecules are introduced as neutral volatile samples (generally upon heating) and are charged or ionized by the electron impact (EI) method. EI mass spectra are generally interpretable and can be used to deduce the chemical structure. 
   EI, however, may be limited in its use. As molecules become larger and carry more polar functional groups, they also become less volatile. However, volatility is required for EI, because it is a gas phase ionization technique. Accordingly, while EI is suitable for detection of low molecular weight chemical agents, it may not be sufficiently efficient for the larger toxins and microorganisms that comprise potential biological threat agents. 
   While a number of other ionization techniques have been developed over the last two decades, two new methods: electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI) are now the most commonly used for non-volatile biological samples. 
   ESI is an ionization technique for small amounts of large and/or labile molecules such as peptides, proteins, organometallics, and polymers and forms ions directly from a sprayed solution. A solution of the sample is sprayed though a needle having a certain potential, which causes the spray to be charged as it is nebulized. The droplets evaporate in a region maintained at a vacuum. As any other ionization technique, ESI may have certain limitations. For example, the sample to be analyzed must be soluble, stable in solution, polar, and relatively clean. These conditions can be arranged in a laboratory, but are difficult to set up in a real, field situation. 
   MALDI uses a pulsed laser to form ions from a matrix or substrate that is the initial absorber of the photon energy. MALDI is generally used with solid samples, specifically biological samples dissolved and co-crystallized with a UV-absorbing organic compound (matrix) such as nicotinic acid, 3-OH picolinic acid (HPA), 2, dihydroxybenzoic acid (DHBA) or a-cyano-4-hydroxycinnamic acid (CHCA). The mass spectrum of bacteria, virus and spores are generally quite complex, as these are not pure compounds but mixtures. 
   Because it is not known a priori which compounds from a microorganism will be desorbed, ionized and recorded in the mass spectra, interpretation is not at all straightforward One approach utilizes the different mass spectral patterns observed for different microorganisms in the development of a “library” to which unknown agent can be compared. 
   The MALDI-MS technique is based on the discovery that desorption/ionization of large, nonvolatile molecules such as proteins and the like can be made when a sample of such molecules is irradiated after being co-deposited with a large molar excess of an energy-absorbing “matrix” material, even though the molecule may not strongly absorb at the wavelength of the laser radiation. The abrupt energy absorption initiates a phase change in a microvolume of the absorbing sample from a solid to a gas while also inducing ionization of the molecule of the sample. The ionized molecules are accelerated toward a detector through a flight tube. Since all ions receive the same amount of energy, the time required for ions to travel the length of the flight tube is dependent on their mass. Thus low-mass ions have a shorter time of flight (TOF) than heavier molecules. 
   Accordingly, matrix-assisted laser desorption/ionization (MALDI) is most often used with a time-of-flight mass spectrometer, though interestingly, the earlier TOF instruments had pulsed electron impact source. While initially regarded as low mass range, low mass resolution instruments, time-of-flight (TOF) mass spectrometers now provide excellent mass resolution and mass ranges for proteins that extend into the hundreds of kilodaltons. 
   An exemplary TOF mass spectrometer carrying out MALDI is illustrated in  FIG. 2  and operates in the following manner. Samples are deposited as solid solutions in an organic matrix on a sample plate or probe  20 . The energy from a short (100 ps to 1 ns) pulsed laser  28  is absorbed by the matrix, resulting in desorption and ionization of sample molecules in the source region. The electric potential between the sample plate  20  and extraction grids  22  results in the acceleration of the ions forming an ion beam  26  into a drift region  24  with kinetic energies of eV+½ mv 2 , where V is the total accelerating potential, m is the mass of the ion, e the charge, and v the velocity. The flight time of an ion through the drift region  24  having a length D is:
 
 t= ( m/ 2 eV) 1/2   D  
 
   Thus, the flight time is proportional to the square root of the ion&#39;s mass/charge ratio. In actuality, the flight time is more complex, reflecting the different times to, initial energies U 0 , and initial positions s 0  when the ions are formed, and is described as follows:
 
 T =[(2 m) 1/2   /eE ][( U   o   +eE   s ) 1/2   ±U   o   1/2 ]+{[(2 m) 1/2   D]/ 2( U   o   +eE   s ) 1/2   }+t   o  
 
   Because t 0 , U 0  and s 0  are distributions, the peaks representing a particular mass have a finite time width which limits the mass resolution: R=m/Δm=t/2Δt. To somewhat overcome a relatively low resolution in the TOF MS shown in  FIG. 2 , the drift region is configured to have a substantial distance, which increases the overall dimensions of the this device. 
   To improve the mass resolution and to reduce dimensions of the TOF MS shown in  FIG. 2 , a number of means have been developed. One of these is a TOF MS having a reflectron defining a reflecting region or ion mirror  30 , as shown in  FIG. 3 . The reflecting region “d”  30  is a series of lenses that describe a retarding/reflecting electrical field that returns the ions along a path back toward the source. The reflecting voltage V R  is generally slightly higher than the accelerating voltage V so that ions turn around just short of the back of the reflecting region or reflectron. Ions with the same mass but higher kinetic energies have higher velocities and spend less time in the drift region; however, they penetrate the reflecting region  30  more deeply and spend more time there. Thus, the total time spent by ions of different energies in forward L 1  and reverse L 2  directions of the drift region, and the reflecting region “d”  30 , is given by:
 
 t =( m/ 2eV) 1/2   [L   1   +L   2 +4 d] 
 
   Accordingly, the total time in the TOF MS provided with the reflectron is more nearly the same for ions of different kinetic energies than for the simpler linear time-of-flight instrument shown in  FIG. 2 . However, the single-stage reflectron shown in  FIG. 3  provides only first order correction for the kinetic energy. Higher order energy corrections are possible using dual-stage, quadratic and other non-linear reflections. 
   Still a further technique improving mass resolution includes using pulsed extraction. The technique involves a short delay time between ionization and ion extraction that permitted ions to drift in the field-free on source. Upon application of the extraction pulse, the more energetic ions will be closer to the source exit and will move through a shorter portion of the accelerating field. 
   A further approach described to correct the mass dependence includes the TOF instrument, as discussed in reference to  FIGS. 2 and 3  and, in addition, configured to use orthogonal extraction/acceleration of ions, as shown in  FIG. 4 . In this approach, the laser beam  30  irradiates a sample producing ions, which are tightly focused and accelerated along a direction  32  between a pair of electrodes (lens and collimator)  31 , so that the distribution in their velocities (arising from their kinetic energy distribution) lies entirely along this direction. The ions are then directed into a volume from which they can be extracted in a direction  34  orthogonal to their initial direction  32 . 
   To even further improve characteristics of the spectrometer, ions may also be additionally focused using the reflectron, which defines the reflecting region  30 . Further means directed to improvement of mass resolution may include an RF quadruple ion guide diagrammatically shown as  29  in  FIG. 5  and operative to improve focusing of the initial ion beam when a low pressure (1 mTorr) insert gas is used to promote collisional cooling of the ion velocities. The ion guide also makes it possible to utilize high-pressure (1-100 mTorr) sources, or atmospheric pressure sources via a capillary inlet. Because the quadrupole ion guide effectively cools ion kinetic energies, the ions entering the extraction chamber have no memory of their initial kinetic energies. Thus, the orthogonal acceleration mass spectrometer with an R ion guide may be used with almost any ionization source including ESI, MALDI, atmospheric pressure MALDI and EI. A disadvantage of the RF ion guide is that it has a limited mass/charge range. Thus, it has been most successfully used for the low mass ions produced by EI or with high mass multiply-charged ion species produced by ESI. 
   Improvement of the mass resolution is not the only problem associated with mass spectrometers. As briefly mentioned above, the geometry of the mass spectrometer is also very important Commercial time of flight mass spectrometers generally have drift lengths of the order of 1 meter or longer. Time-of-flight instruments have been miniaturized, specifically for the analysis of biological agents. Provided that the instrument dimensions can sustain high voltage, there is no loss of mass range or sensitivity, but the mass resolution is generally considerably less. For example, in the miniature instrument shown in  FIG. 5 , the drift length  40  is 3 inches and is floated at the potential of a dual channel plate detector. The sample plate  42  is pulsed to approximately 10 kV giving ions a total energy at the detector of approximately 11.keV. Mass resolutions of up to one part in 1200 have been obtained on this instrument for purified peptides. Mass resolution is less for the more complex biological mixtures that constitute bacteria, virus, and spores. 
   Thus, many of the known mass spectrometers utilizing various ionization methods may have, among others, the following limitations:
         selective mass resolution ability resulting in efficient detection of only a narrow group of biological and chemical agents; and   substantial geometrical dimensions limiting the practical use of at least some of the mass spectrometers.       

   These problems were addressed by utilizing interchangeable ionization sources in commercial mass spectrometers. Commercial magnetic and multiple sector instruments have generally been offered with interchangeable electron impact (EI), chemical ionization (CI), field desorption (FD) and fast atom bombardment (FAB) sources. The quadruple-based gas chromatography/mass spectrometer (GCMS) is generally equipped with EI and CI sources. Combination EI/CI sources have also been available, with the ability to select the ionization mode without physically changing the source. Examples of the above may be found in U.S. Pat. No. 5,668,370 which discloses a plurality of ion EI and CI sources, which operate in a mutually exclusive manner and U.S. Pat. No. 6,326,615 which discloses glow discharge and photo ionization sources functioning only simultaneously. 
   More recently, interchangeable (alternately operating) MALDI and ESI sources have become available for the time-of-flight, Fourier transform mass spectrometer (FTMS), the ion trap (ITMS) and hybrid instruments using combinations of quadruples or ion traps with a time-of-flight mass analyzer. Some of the known structures are configured to have these sources placed in different locations: the electrospray at the atmospheric side of the vacuum chamber, and the MALDI at an intermediate (milliTorr) region. However, both of these ionization techniques are utilized with non-volatile samples and would therefore not address the needs of combined chemical/biological agent detection. In addition, they have not offered the opportunity, or any perceived advantage, for simultaneous operation. 
   Furthermore, attempts to incorporate EI and Infrared laser desorption (IRLD) ionization sources in a single instrument were undertaken in the past. As disclosed by Dr. Robert J. Cotter, one of the inventors of the present invention, in “Time Resolved Laser Desorption Mass spectrometry”, In. J. Mass Spectrom. Ion Phys. and Ion Processes, pages 49 and 54, respectively (1983), a combination of EI and IRLD was used to resolve some ionization and fragmentation mechanisms, but not analytically. 
   Furthermore, the mass range and resolution of the instrument, as disclosed in these publications, was limited for the following reasons. First, as is known, since there is no matrix in IRLD, very large ions remained undetected. Second, the IRLD and EI sources were used alternately. As a result, if used to detect biological agents, each of these sources would exhibit specific limitations, as discussed in detail above. 
   A need, therefore, exists for a single mass spectrometer addressing the full breadth of chemical and biological agents including volatile/non volatile samples, gas and solid phase samples, and configured to carry out a combination of EI and MALDI ionization methods appropriate to the full spectrum of molecular masses. 
   SUMMARY OF THE INVENTION 
   The objectives of the present invention can be attained by a TOF mass spectrometer for combined chemical/biological agent detection and identification that comprises a combined electron impact and MALDI ionization source for volatile and non-volatile sample analyses, respectively. Particularly, the inventive mass spectrometer operates in a mode, in which both EI and MALDI sources function simultaneously for the detection of marginally volatile chemical and biological markers, or for increasing fragmentation. 
   Accordingly, one of the advantages of the mass spectrometer of the present invention is its ability to compete favorably with most existing detectors specific for a small group of agents. However, in contrast to the existing detectors, mass spectrometer of the present invention is capable of handling the wide range of molecular weights, chemical properties (such as volatility) and complexity of both chemical and biological agents. In other words, using the inventive instrument to detect bioagents and some other compounds and mixtures, one gains access to additional diagnostic or structural information. 
   In accordance with another aspect of the invention, the TOF mass spectrometer of the present invention is configured to have the orthogonal acceleration geometry. With the orthogonal pulsing technique, any kinetic energy distribution in the primary ion beam is not coupled to the ion velocity component oriented in the direction of ion acceleration into the TOF tube drift region. The primary ion beam kinetic energy spread oriented along the beam axis only affects the location of ion impact on the planar detector surface, not the ion arrival time at the detector surface. 
   In accordance with another embodiment of the present invention, a MALD/EI TOF mass spectrometer is provided with a reflectron. Both the orthogonal and reflectron configurations do not negatively affect the ability of the inventive MALDI TOF mass spectrometer to detect a wide spectrum of chemical and biological agents. 
   It is, therefore, an object of the present invention to provide a TOF mass spectrometer configured to detect a wide spectrum of chemical and biological agents. 
   A further object of the present invention is to provide a TOF mass spectrometer incorporating MALDI and EI ionization sources capable of operating simultaneously. 
   Still another object of the present invention is to provide a TOF mass spectrometer with combined MALDI and EI sources and having a miniaturized geometry without detrimentally affecting the detection ability of the TOF mass spectrometer. 

   
     BRIEF DESCRIPTION OF THE DRAWINGS 
     The above and other objects, features and advantages will become more readily apparent from the following description accompanied by a group of drawings, in which: 
       FIG. 1  illustrates schematics of an EI technique; 
       FIG. 2  illustrates a typical MALDI TOF mass spectrometer; 
       FIG. 3  illustrates a known TOF mass spectrometer provided with a reflectron; 
       FIG. 4  illustrates a TOF mass spectrometer having the orthogonal acceleration geometry and a reflection, as known in the prior art; 
       FIG. 5  illustrates another TOF mass spectrometer for biological detection configured in accordance with the prior art; 
       FIG. 6  illustrates an inventive TOF mass spectrometer provided with a combined MALDI/EI ionization sources; 
       FIG. 7  illustrates mass regions detectable by the inventive MALD/EI TOF mass spectrometer of  FIG. 6 ; 
       FIG. 8  illustrates one of embodiments of the inventive MALD/EI TOF mass spectrometer of  FIG. 6 ; 
       FIG. 9  illustrates a further embodiment of the inventive MALD/EI TOF mass spectrometer of  FIG. 6 ; 
       FIG. 10  illustrates still another embodiment of the inventive MALD/EI TOF mass spectrometer featuring the orthogonal acceleration geometry; and, 
       FIG. 11  is a diagram illustrating EI orthogonal acceleration TOF mass spectrum of DMMP obtained by utilizing the inventive TOF mass spectrometer of  FIGS. 5 and 6 . 
   

   DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
   Referring to  FIG. 6 , mass spectrometer  50  of the present invention is configured to have a MALDI ionization source  52  and an EI ionization source  54  used together to gain access to additional biological and chemical compounds not accessible by electron impact (i.e. not volatile) or desorbed by MALDI source  52 . Thus, the mass spectrometer  50  is configured to carry out a method that increases specificity for correct bioagent identification either directly or by detecting additional biomarkers for biological agents. Although the following discussion relates mainly to a TOF mass spectrometer, it is understood that the TOF configuration is given only for the illustrative purposes of the inventive concept. Other configurations of the inventive instrument can include, but not limited to the quadrupole or triple quadrupole ion trap mass spectrometer, or hybrids such as quadrupole/time-of-flight QTOF, or a Fourier transform mass spectrometer (FTMS). 
   As illustrated in  FIG. 7 , mass spectrometer  50  is based on the inventive MALD/EI mode of operation capable of handling a broad spectrum of mass regions including chemical or matrix regions A, middle mass region B peptides, glycans and etc., as well as high mass region C proteins. 
   Specifically, the inventive TOF mass spectrometer  50 , as illustrated in  FIG. 6 , is configured to have a sample backing plate  72 , on which a solid or liquid sample  66 , including microorganisms or non-volatile chemicals and toxins, is deposited with an appropriate organic matrix. The sample  66  is placed so that a laser beam  56 , generated by the MALDI source  52 , impacts upon the sample plate  72  to treat the sample  66  so that ionized particles and neutral particles are adsorbed from the sample  66  in correspondence with the MALDI technique. The MALDI or laser source  52  is not limited to any particular type or model and is subject to only one condition—it must work in combination with an electron beam source  54  to meet the objective of the invention. Thus, the laser source  52  can be a UV or IR laser; the most common lasers used in the MALDI technique are pulsed nitrogen lasers, with a wavelength of 337 mm, a pulse width of 600 ps to 1 ns, and pulse energies of 10 uJ to 1 mJ. Also common are Nd:YAG lasers with wavelengths of 256 or 353 nm, Er:YAG lasers with 2.94 micron wavelength, all having similar pulse widths and energies. Overall, there are no restrictions on sizes of the inventive spectrometer that can be both portable and stationary to meet the specific requirements. 
   At least three mechanisms may be simultaneously at work in mass spectrometer  50  configured to process the sample  66 . First, the sample  66  is bombarded by the laser beam  56  causing the desorption of ionized particles  64 , which are further accelerated into a drift region  80  toward a detector  100  ( FIG. 8 ). Ions formed using this MALDI mode are generally even-electron protonated molecular species MH +  undergoing comparatively little fragmentation as they are accelerated between multiple extraction grids or lenses  68 ,  70 . 
   Second, gaseous samples  60  including volatile chemical agents from a gas chromatograph, adsorbant column or direct inlet and those volatile chemicals emitted from the sample  60  condense to the sample backing plate  72 , are ionized by an electron beam  58  emitted by the electron beam source  54 . Ions formed in this EI mode
 
 e   −   +M→M   + +2 e   − 
 
are generally odd-electron (radical) species with high internal energy that leads to fragmentation  74  as these ions are extracted along a path between the grids  68 ,  70 .
 
   Third, in the MALDI mode, some of desorbed particles  62 , which are released from the sample  66 , including the biological or toxin sample, are neutral. To process these neutral particles, the MS operates in the MALD/EI mode in which desorbed neutral molecules will be subsequently ionized in the gas phase by the electron beam  58  and further fragmented at  76 . 
   Thus, the inventive mass spectrometer  50  has at least the following advantages over known instruments:
         for some protein and peptide biomarkers, the desorption of neutral molecular species may exceed that of ionized species, so that this mode may produce additional sensitivity,   additional peptide and protein biomarkers that do not easily form ions in the desorption process may be observed,   additional fragmentation will be observed from these radical ion species, and   the MALD/EI mode may be utilized to bridge the region between the easily volatilized chemical agents and high molecular weight toxins.       

   In order to provide analytical coverage of the wide mass range that comprises chemical agents and the complex mixtures from microorganism the instrument must be able to transmit ions with high mass/charge ratio. In accordance with one embodiment of the invention shown in  FIG. 8 , the inventive mass spectrometer  50  has the linear geometry characterized by a linear one-way path of a focused ion beam of stream  78  composed of the molecules ionized at  64 ,  74  and  76 . In operation, the EI source generates the electron beam  58  focused between the sample plate  72  and the extraction optics (grids or lenses)  68 ,  70  differently charged to have a potential difference therebetween. The laser source  52  generates the laser beam  56  impinging upon the sample  66  to cause the adsorption of initially ionized particles  64  forming along with gases  60  and neutrals  62  ( FIG. 6 ), which are subsequently ionized by the EI beam  58 , the ion beam  78  ( FIG. 8 ). Upon acceleration between the extraction grids  68 ,  70 , wherein the upstream grid  68  is charged and the downstream one  70  is grounded, the ionized particles and fragments thereof enter a drift vacuum region  80  as the focused ion beam of the stream  78  to be detected by the detector  100 . 
   The corresponding mass spectrum output by the detector  100  is analyzed to determine if the biological or chemical agent of interest is present. The mass spectra may be analyzed in a traditional manner, for example, by an expert analyst viewing an oscilloscope (not shown) connected to the detector of the mass spectrometer  50 . Alternatively, a controller (CPU)  82  may contain software that automatically identifies the threat by receiving the mass spectral data from the detector  100 . 
   In the embodiment shown in  FIG. 8 , both the electron  58  and laser  56  beams are pulsed in response to synchronous control signals from the controller  82 . Alternatively, the controller  82  may be configured to provide delayed extraction by any of the known time-dependent extraction techniques that can be used to improve mass resolution. 
     FIG. 9  illustrates the mass spectrometer  50  incorporating a reflectron  84 , which is located along a downstream path of the drift region  80 . In use, the reflectron applies a voltage that increases with distance that the ion penetrates a reflecting region  86 . Structurally, the reflectron  84  commonly comprises a series of equally spaced conducting rings  88  that form a retarding/reflecting field in which the ions penetrate, slow down gradually, and reverse direction, as illustrated by arrow S, thereby reflecting the ion&#39;s trajectory back along the incoming path. At the downstream end of the reverse ion beam path S, the detector  100  detects the ions and generates an output signal received and analyzed by the controller  82 . 
   As is known, the variation in energy causes a spread in the measured mass for any one kind of ion. Ions with higher energy travel further into the reflecting region  86  before they are reflected by a downstream ring  90  (higher voltage), and so take longer to travel through the reflecting region. Of course, they travel faster outside the reflectron in the drift region along the reverse ion path S. Concomitantly, ions with lower energy but the same mass travel at a smaller distance in the reflecting region  86  and spend less time there before turning back. Thus, instead of continuing to disperse through the drift region (as in the linear TOF mass spectrometer), the reflectron imparts a focusing effect on the ions traveling in the drift region. 
   Still another embodiment of the inventive TOF mass spectrometer utilizing an orthogonal acceleration system is illustrated in  FIG. 10 . In accordance with the cardinal concept of the invention, irradiation of the sample  66  by the laser beam  56  will form the adsorbed ionized and neutral particles. The neutral particles or molecules as well as volatiles will be ionized in the central region of the initial portion of the focused ion beam of the stream  78  by focusing the electron beam  58  during the EI or MALD/EI mode. All the ions will be focused equally, since the orthogonal acceleration design is relatively insensitive to distributions in initial kinetic energies and space. As a result, the initially focused ion beam is accelerated along the upstream through a guide  94  towards the extraction chamber in which an orthogonal extraction system  92  is configured to apply the field so that the stream  78  changes its direction at a substantially 90° angle. Once the direction is changed, the stream  78  including all ionized particles and fragments thereof further flows along its downstream stretch  96  through the drift region  80  towards the reflecting region  86 . 
   The “orthogonal” geometry is used to minimize effects of the kinetic energy distribution of the initial focused ion beam of the stream  78 . With the orthogonal technique, any kinetic energy distribution in the initial focused ion beam is not coupled to the ion velocity component oriented in the direction of ion acceleration into the TOF tube drift region. The primary ion beam kinetic energy spread oriented along the beam axis only affects the location of ion impact on the planar detector surface, not the ion arrival time at the detector surface. 
   The guide  94  may contain electrostatic lenses including, but are not limited to, Einsel, accelerating/decelerating or steering lenses; thus the mass range is not limited. In a second configuration, the guide  94  may include an RF ion guide including a quadrupole one for ions with mass/charge below a cutoff value and higher mass ions focused electrostatically through the guide. In this embodiment, it is preferred that the electron beam  58  need not be pulsed. 
   Though samples  66  may be introduced both on the sample plate (or probe)  72  and in the gas phase, the TOF mass spectrometer  50  is envisioned primarily for use in analyzing chemical and biological samples presented in a single specific format in the location of the sample plate. In one configuration, the sample plate  72  is attached to an XY translatable sample stage  102  ( FIG. 10 ) and supports an array of sample locations carrying high binding affinity to a range of chemical and/or biological agents. The combined EI, MALDI and MALD/EI source interrogates all of the volatile and nonvolatile species that are present and can be ionized. 
   In use, the controller  82  (which may be any digital control device, including a processor, microprocessor, PC, computer, microcomputer, etc.) provides control signals to the electron beam and laser sources  54 ,  52  and mass spectrometer  50  via signal conduits (for example, electrical wires). However, although the simultaneous operation of the MALDI and EI sources is critical for the purposes of this invention, it is envisioned that the TOF mass spectrometer can operate in either of the MALDI and EI modes or in a mode where these sources alternate to meet the specific requirements. 
   The controller  82  may include software that analyzes the agents of interest. Alternatively, the mass spectral output itself may be displayed to the user, who may be a mass spectral analyst trained to determine the presence or absence of compounds based on spectral lines. 
   A plot made of m/z vs. the relative abundance is shown in  FIG. 11 . Quite frequently, the peak with the highest m/z represents the molecular ion, giving the molar mass of the compound. Since each compound has its own unique fragmentation pattern, by comparison to literature spectra, the identity of a compound can be determined. 
   The combined chemical/biological agent mass spectrometry detector can be miniaturized for portable use and retain excellent high mass resolution and mass range. Thus,  FIG. 11  shows a mass spectrum of the simulant DMMP using a 40 cm orthogonal acceleration TOF mass spectrometer with an RF guide. Peak widths as narrow as 1.6 ns have been observed for ions in this mass range using a fast digitizer in the interleaving mode, and correspond to a mass resolution of 5,000 to 6,000. 
   Although illustrative embodiments of the present invention have been described herein with reference to the accompanying drawings, it is to be understood that the invention is not limited to those precise embodiments and can include, for example a structure configured to operate with a combined EI and ESI sources. Still another obvious modification includes the use of any type of mass spectrometer capable of utilizing MALDI and/or ESI techniques in combination with an EI source. Therefore, those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.