Abstract:
A system to handle a set of samples for mass spectrometric analysis includes a set of elements that couples to a sample plate containing the set of samples. Each element is integrated with a respective mass analyzer, and includes an ionizer to ionize the respective sample. The set of samples are collected and then ionized simultaneously, and the ionized samples are transferred simultaneously to the respective mass analyzers.

Description:
RELATED APPLICATION  
       [0001]     This application claims the benefit of U.S. Provisional Application No. 60/557,628, filed Mar. 30, 2004, the entire contents of which are incorporated herein by reference. 
     
    
     BACKGROUND  
       [0002]     The present invention generally relates to sample handling for mass spectrometry.  
         [0003]     Mass spectrometers of various types have been used to identify molecules and to determine their molecular structure by mass analysis. The molecules are ionized and then introduced into the mass spectrometer for mass analysis. Typically, the mass analysis is performed using a “single channel”. That is, a sample introduction system collects a single sample and introduces this sample to a single ion source where the sample is ionized. The ion source is connected to a single mass analyzer, or perhaps to a multiple-stage mass analyzer, which in turn is followed by a single detector and a one channel data acquisition system.  
         [0004]     Even though a robotic device may be used to collect the samples from, for example, a 96 well plate, the samples have to be analyzed serially by single channel systems, and, therefore, the throughput capabilities of these systems are quite limited.  
         [0005]     Accordingly, there is a need for a sample handling system for mass spectrometers with significantly higher throughput than conventional single channel systems.  
       SUMMARY  
       [0006]     In general, the present invention is directed to a sample handling system and methods of its operations for performing multichannel analysis of multiple samples. The handling system can be integrated with any type of mass analyzer or any combinations of mass analyzers. Further, the handling system can be integrated with any type of ionizers or any combinations or ionizers.  
         [0007]     In one aspect, a system to handle a set of samples for mass spectrometric analysis includes a set of elements that couples to a sample plate containing the set of samples. Each element is integrated with a respective mass analyzer, and includes an ionizer to ionize the respective sample. The set of samples are collected and then ionized simultaneously, and the ionized samples are transferred simultaneously to the respective mass analyzers. The ionization can be by corona discharge or by electrospray ionization. The headspace of the sample can be analyzed. The sample can be subjected to capillary electrophoresis prior to ionization.  
         [0008]     Further features and advantages will be apparent from the following description, and from the claims. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0009]     The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention. Further, like reference numerals refer to the similar parts throughout the figures.  
         [0010]      FIG. 1A  is a schematic sectional view of a handling system with a set of elements used to perform electrospray ionization (ESI) in accordance with the invention;  
         [0011]      FIG. 1B  is a schematic sectional view of a handling system with a set of elements used to perform atmospheric pressure chemical ionization (APCI) in accordance with the invention;  
         [0012]      FIG. 1C  is a schematic sectional view of a handling system with a set of elements used to perform head space corona discharge analysis (HS-CD) in accordance with the invention;  
         [0013]      FIG. 2A  is a schematic sectional view of an individual element of the set of elements shown in  FIG. 1A ;  
         [0014]      FIG. 2B  is a schematic sectional view of an individual element of the set of elements shown in  FIG. 1B ;  
         [0015]      FIG. 2C  is a schematic sectional view of an individual element of the set of elements shown in  FIG. 1C ; and  
         [0016]      FIG. 2D  is a schematic sectional view of an individual element used to perform capillary electrophoresis (CE) on a large set of samples in parallel prior to their introduction to the corresponding mass analyzers. 
     
    
     DETAILED DESCRIPTION  
       [0017]     Referring now to the drawings, a handling system embodying the principles of the present invention is illustrated therein and designated at  10 . As its primary components, the system  10  includes a set of individual electrospray ionization (ESI) elements  12  coupled to respective mass analyzers  14  arranged as an array. Each mass analyzer may function as a mass spectrometer or may be combined as a multiplexed mass spectrometer.  
         [0018]     Each of the ESI elements  12  collects a sample from a well in a microtiter plate  16  and performs a set of operations on the sample. The microtiter plate  16  can be a conventional  96  well plate arranged as a 12 by 8 array. The samples may be arranged in sets or groups, such that a group of samples may be collected from the microtiter plate  16  and treated simultaneously by respective ESI elements  12  in a parallel manner. A group may contain a single sample, more than one sample, or all the samples in the microtiter plate  16 . The operations performed in each ESI element  12  include but are not limited to standard unit operations in analytical chemistry, such as operations used to prepare samples for analysis by mass spectrometry. These include filtration, automated chemical reactions, such as derivativation, pre-analysis quality control steps, such as absorbance measurements, sample pretreatments, such as buffering, and separation methods including liquid and gas chromatography and capillary electrophoresis. After each sample is ionized, although not necessarily from the solution state, and it can be subjected to mass spectrometry and, optionally, tandem mass spectrometry and ion mobility separation.  
         [0019]     As shown in  FIG. 2A , each ESI element  12  includes a shield plate  20 , a nebulizer plate  22  with a capillary  24  extending through an aperture  26 , a capillary plate  28  with a bottom conductor  30 , a top conductor  32  and an aperture  33 , a lens plate  34  with an aperture  35 , and a skimmer plate  36  with an aperture  38 .  
         [0020]     When the ESI elements  12  are in use, each well in the microtiter plate  16  contains a sample  40  in solution form, such as a protein, drug, or amino acid. The nebulizer plate  22  couples to the microtiter plate  16  in a sealed manner, so that as a nebulizing gas, such as N 2 , is pumped in the region between the microtitier plate  16  and the nebulizer plate  22 , this region is pressurized above atmospheric pressure (i.e., &gt;1 bar), while the region on the other side of the nebulizer plate  22  is at about atmospheric pressure (i.e., about 1 bar). Thus, the nebulizer plate  22  acts as a restrictor between the atmospheric region on one side of the nebulizer plate and the higher pressure region between the nebulizer plate  22  and the microtiter plate  16 . The capillary  24  extends from the sample  40  through though the aperture  26  of the nebulizer plate  22  and draws the sample  40  to the tip  42  of the capillary  24 . In a particular embodiment, each capillary  24  has a diameter of about 254 μm and has a length of about 20 cm.  
         [0021]     The bottom conductor  30  of the capillary plate  28  can be any suitable conductive material, such as a metal. A potential difference of about 2 to 5 KV is generated between the tip  42  and the bottom conductor  3   o  to produce an electrospray  44 . The shield plate  20  minimizes cross contamination with other elements on either side of the ESI element  12 .  
         [0022]     The capillary plate  28  may be heated to desolvate the ions, that is, to separate the solvent molecules from the ions, as the spray sample progresses through the aperture  33  in the capillary plate  28 . A voltage in the range between about 0 and 50 v is applied to the top conductor  32  which is made from any suitable conductive material, such as metal. In addition, a voltage in the range between about 0 and 200 V is applied to the lens plate  34  while the skimmer plate  36  is grounded. A vacuum of about 1 to 2 Torrs is maintained, for example, by a two-stage rotary vane pump, in the region between the capillary plate  28  and the skimmer plate  36 , with the pressure between the lens plate  34  and the capillary plate  28  at a slightly higher pressure than the region between the lens plate  34  and the skimmer plate  36 . A higher vacuum of about 10 −4  Torr is maintained, for example, by a turbomolecular drag pump, on the other side of the skimmer plate  36 . After the ions are guided through the capillary plate  26 , the lens plate  34  and the skimmer plate  36  focus the ions through the aperture  38 , which has a diameter of about 500 μm into the high vacuum side of the mass analyzer  14 .  
         [0023]     Other implementations are also considered. For example, as shown in  FIG. 1B , a sample handling system  110  includes a set of atmospheric pressure ionization (APCI) elements  112 , which may also be coupled to respective mass analyzers  14  similar to those shown in  FIG. 1A . Although some of the components of the APCI element  112  are similar to those of the ESI element  12  and are identified by like reference numerals, indicating that they perform similar functions, the APCI element  112  includes a plate  114  with a discharge needle  116 . As such, a potential of about 2 to 5 KV is generated between the tip  118  of the discharge needle  116  and the conductor  30  of the capillary plate  28 , and not between the tip  42  of the capillary  24  and the conductor  30 . The potential between the tip  118  and the conductor  30  creates a corona discharge to produce the ionized spray  44 . Optionally, the APCI elements  112  can be provided shield plates  20 .  
         [0024]     In another implementation shown in  FIG. 1C , a sample handling system  210  includes a set of headspace analysis elements  212 , which may be coupled to respective mass analyzers like those discussed above with reference to  FIG. 1A . Referring also to  FIG. 2C , the headspace analysis element  212  is similar in many respects to the APCI element  112  shown in  FIG. 2B . However, the headspace analysis element  212  includes a sample tube  214  rather than the capillary  34  of the APCI element  112 . Rather than extending into the sample, the tube  214  enables sampling the headspace of the sample  40  contained in the microtiter plate  16 , so that the gas stream through the tube  214  can be used to transport the sample vapor. The spray  44  is emitted from the tube  214 , and is ionized in the same manner as described above with reference to  FIG. 2B . The headspace anlaysis elements  212  may or may not include shield plates  20 .  
         [0025]     In yet another implementation, a capillary electrophoresis element  312  shown in  FIG. 2D  includes a high voltage supply plate  314  to create the electrospray bias with the conductor  30  of the capillary plate  28 . This bias generates the ionized spray  44  as the sample is emitted from a capillary column  316  extending through the high voltage supply plate  314 . The supply plate  314  is also provides a sheath liquid  320  to the capillary column  316 , since the flow rate of the sample through the column  316  for capillary electrophoresis may be too low for the electrospray process.  
         [0026]     A set of capillary electrophoresis elements  312  may be combined to form a handling system coupled to respective mass analyzers  14  like those shown in  FIGS. 1A, 1B , and  1 C.  
         [0027]     Other embodiments are within the scope of the following claims.