Radiant energy – Ionic separation or analysis – With sample supply means
Reexamination Certificate
2001-06-18
2004-09-21
Wells, Nikita (Department: 2881)
Radiant energy
Ionic separation or analysis
With sample supply means
C250S281000, C250S285000, C250S287000, C250S42300F
Reexamination Certificate
active
06794644
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates generally to mass spectrometry and the analysis of chemical samples, and more particularly to the apparatuses and methods for the automated preparation and introduction of samples into an atmospheric pressure ionization (API) mass spectrometer. Described herein is a system utilizing a multiple part capillary device with a robot for use in mass spectrometry (particularly with ionization sources) to transport ions to the mass spectrometer for analysis therein.
BACKGROUND OF THE PRESENT INVENTION
The present invention relates to a means of delivering ions to a mass spectrometer. Mass spectrometry is an important tool in the analysis of a wide range of chemical compounds. Specifically, mass spectrometers can be used to determine the molecular weight of sample compounds. The analysis of samples by mass spectrometry consists of three main steps—formation of ions from sample material, mass analysis of the ions to separate the ions from one another according to ion mass, and detection of the ions. A variety of means exist in the field of mass spectrometry to perform each of these three functions. The particular combination of means used in a given spectrometer determine the characteristics of that spectrometer.
To mass analyze ions, for example, one might use a magnetic (B) or electrostatic (E) analyzer. Ions passing through a magnetic or electrostatic field will follow a curved path. In a magnetic field the curvature of the path will be indicative of the momentum-to-charge ratio of the ion. In an electrostatic field, the curvature of the path will be indicative of the energy-to-charge ratio of the ion. If magnetic and electrostatic analyzers are used consecutively, then both the momentum-to-charge and energy-to-charge ratios of the ions will be known and the mass of the ion will thereby be determined. Other mass analyzers are the quadrupole (Q), the ion cyclotron resonance (ICR), the time-of-flight (TOF), and the quadrupole ion trap analyzers.
Before mass analysis can begin, however, gas phase ions must be formed from sample material. If the sample material is sufficiently volatile, ions may be formed by electron ionization (EI) or chemical ionization (CI) of the gas phase sample molecules. For solid samples (e.g. semiconductors, or crystallized materials), ions can be formed by desorption and ionization of sample molecules by bombardment with high energy particles. Secondary ion mass spectrometry (SIMS), for example, uses keV ions to desorb and ionize sample material. In the SIMS process a large amount of energy is deposited in the analyte molecules. As a result, fragile molecules will be fragmented. This fragmentation is undesirable in that information regarding the original composition of the sample—e.g., the molecular weight of sample molecules—will be impossible to determine.
For more labile, fragile molecules, other ionization methods now exist. The plasma desorption (PD) technique was introduced by Macfarlane et al. in 1974 (Macfarlane, R. D.; Skowronski, R. P.; Torgerson, D. F.,
Biochem. Biophys. Res Commoun.
60 (1974) 616). Macfarlane et al. discovered that the impact of high energy (MeV) ions on a surface, like SIMS would cause desorption and ionization of small analyte molecules, however, unlike SIMS, the PD process also results in the desorption of larger, more labile species—e.g., insulin and other protein molecules.
Lasers have been used in a similar manner to induce desorption of biological or other labile molecules. See, for example, VanBreeman, R. B.: Snow, M.: Cotter, R. J.,
Int. J. Mass Spectrom. Ion Phys.
49 (1983) 35; Tabet, J. C.; Cotter, R. J.,
Anal. Chem.
56 (1984) 1662; or Olthoff, J. K.; Lys, I.: Demirev, P.: Cotter, R. J.,
Anal. Instrument.
16 (1987) 93. Cotter et al. modified a CVC 2000 TOF mass spectrometer for infrared laser desorption of involatile biomolecules, using a Tachisto (Needham, Mass.) model 215G pulsed carbon dioxide laser. The plasma or laser desorption and ionization of labile molecules relies on the deposition of little or no energy in the analyte molecules of interest. The use of lasers to desorb and ionize labile molecules intact was enhanced by the introduction of matrix assisted laser desorption ionization (MALDI) (Tanaka, K.; Waki, H.; Ido, Y.; Akita, S.; Yoshida, Y.; Yoshica, T.,
Rapid Commun. Mass Spectrom.
2 (1988) 151 and Karas, M.; Hillenkamp, F.,
Anal. Chem.
60 (1988) 2299). In the MALDI process, an analyte is dissolved in a solid, organic matrix. Laser light having a wavelength that is absorbed by the solid matrix but not by the analyte is used to excite the sample. Thus, the matrix is excited directly by the laser, and the excited matrix sublimes into the gas phase carrying with it the analyte molecules. The analyte molecules are then ionized by proton, electron, or cation transfer from the matrix molecules to the analyte molecules. This process, MALDI, is typically used in conjunction with time-of-flight mass spectrometry (TOFMS) and can be used to measure the molecular weights of proteins in excess of 100,000 daltons.
Recently, MALDI has been especially gaining acceptance as a way to ionize large molecules such as proteins. MALDI requires that samples applied to the surface of a sample support must be introduced into the vacuum system of the mass spectrometer. According to the prior art, a relatively large number of sample are introduced together on a support, and the sample support is moved within the vacuum system in such a way that the required sample is situated specifically in the focus of the laser's lens system. The analyte samples are placed on a sample support in the form of small drops of a solution, which dry very quickly and leave a sample spot suitable for MALDI. Normally a matrix substance is added to the solution for the MALDI process and the sample substances are encased in the crystals when the matrix substance crystallizes while drying. There are other methods known in the prior art, such as the application of sample substances to an already applied and dried matrix layer.
Current methods use visual control of the sample spots via microscopic observation. Thus, these are not truly automated. True automation opens up the possibility of processing large numbers of samples. It is well established within the art that microtiter plates are used for parallel processing of many samples. The body size of these plates is 80 by 125 millimeters, with a usable surface of 72 by 108 millimeters. There are commercially available sample processing systems which work with microtiter plates of this size. These originally contained 96 small exchangeable reaction vials in a 9 mm grid on a usable surface of 72 by 108 millimeters. Today, plates of the same size with 384 reaction wells imbedded solidly in plastic in a 4.5 mm grid have become standard.
The use of Atmospheric pressure ionization (API) is also well known in the prior art. Typically, analyte ions are produced from liquid solution at atmospheric pressure. One of the more widely used methods, known as electrospray ionization (ESI), was first suggested by Dole et al. (M. Dole, L. L. Mack, R. L. Hines, R. C. Mobley, L. D. Ferguson, M. B. Alice,
J. Chem. Phys.
49, 2240, 1968). In the electrospray technique, analyte is dissolved in a liquid solution and sprayed from a needle. The spray is induced by the application of a potential difference between the needle (where the liquid emerges) and a counter electrode. By subjecting the sample liquid to a strong electric field, it becomes charged, and as a result, it “breaks up” into smaller particles if the charge imposed on the liquid's surface is strong enough to overcome the surface tension of the liquid (i.e., as the particles attempt to disperse the charge and return to a lower energy state). This results in the formation of finely charged droplets of solution containing analyte molecules. These droplets further evaporate leaving behind bare charged analyte ions.
Electrospray mass spectrometry (ESMS) was introduced by Yamashita and Fein (M
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