Radiant energy – Ionic separation or analysis – With sample supply means
Reexamination Certificate
2001-09-17
2004-01-27
Berman, Jack (Department: 2881)
Radiant energy
Ionic separation or analysis
With sample supply means
C250S282000, C250S42300F
Reexamination Certificate
active
06683300
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to mass spectrometry and more specifically to an ionization technique to produce ions in a surrounding gas.
2. Discussion of the Background
In nature and in the laboratory, compounds of biological and biochemical material are frequently present in a liquid form, usually water-based referred to as analyte solutions. In cells of living organisms, protein and DNA molecules are diluted in water which may contain in small quantities other organic and inorganic additives necessary for maintaining electrical and chemical properties required for normal cell functionality and intercellular interaction. Any changes in chemical composition of cell solution can result in corruption of cell processes or even its death. Monitoring of cell processes can also interfere with cell normal operation resulting in some cases in wrong observations and conclusions.
Mass spectrometry is a common method used for detection and identification of separated products. Mass spectroscopy is an informative and powerful method for analyte analysis. Unfortunately, buffer solutions used in separation methods and buffer solutions used in mass spectrometry are not usually compatible with each other. As a result only a limited number of buffer solutions can be used commonly between separation and mass analysis techniques. In matrix assisted laser desorption ionization (MALDI), one of methods used for bioanalyte molecule ionization, special treatments of the sample are required which may include purifying the analyte solution to remove buffer salts, mixing the analyte solution with a matrix solution, depositing and drying the combined mixture on a surface (to be laser irradiated). As a result, MALDI analysis is usually made in an off-line mode and requires special equipment for treatment and handling of samples.
Interfacing of the analyte solutions to the mass spectrometers occurs in the ion sources of the mass spectrometers. More than twenty different types of ion sources are known to date. Of these ion sources, atmospheric pressure (AP) ion sources are playing an increasingly important role for modern analytical applications of mass spectrometry. AP chemical ionization (CI) sources produce ions of volatile analytes with molecular masses within the mass range of 1-150 Da (i.e., atomic mass units). See e.g., the review of Bruins, A. P., in Mass Spectrom. Rev. 1991, vol. 10, pp. 53 and following; the entire contents of which are incorporated herein by reference. Electrospray Ionization (ESI), widely used in modern analytical equipment, can transfer heavy intact molecular ions (with masses of several hundred thousand Dalton) from a liquid analyte solution to a gas phase for subsequent mass analysis. biochemistry See e.g., Yamashita, M., Fenn, J. B. J.Chem.Phys. 1984, vol. 88, pp. 4451-4459 and Fenn, J. B.; Mann, M.; Meng, C. K.; Wong, S. F.; Whitehouse, C. M. Science 1989, vol. 246, pp. 64-71; the entire contents of which are incorporated herein by reference. Meanwhile, AP MALDI sources produce ions of heavy biomolecules under normal atmospheric pressure conditions wherein laser irradiation typically interacts with analyte/matrix solid microcrystals. See e.g., U.S. Pat. No. 5,965,884; the entire contents of which are incorporated herein by reference.
Atmospheric pressure ion sources have several important advantages over “internal” vacuum ion sources.
First, sample ionization takes place in an atmospheric pressure ion source outside the MS instrument itself. Consequently, AP ion sources are interchangeable, and one MS instrument can be adopted to a number of AP sources. Second, gas/liquid/solid sample delivery (or loading) takes place under normal laboratory atmospheric pressure. Third, due to high pressures employed with AP sources, ions produced inside the AP ion source by chemical ionization (CI), electrospray ionization (ESI), or AP MALDI, for example, achieve thermal equilibrium with ambient gas extremely fast. Fast “cooling” of the produced ions favors the production of intact molecular ions rather than non-specific fragmented ions.
Ions produced under atmospheric pressure by an AP ion source are introduced into the vacuum chamber of a mass spectrometer through a special device that is known as an atmospheric pressure interface (API). Typically, an API includes several stages of differential pumping separated by several gas apertures. The pressure on the exterior of the API is at or around atmospheric pressure and can be adjusted by pressurizing or depressurizing the exterior region of the API. Gas from the exterior region is conducted by vacuum into the API, i.e., a conductive limit limiting the amount of gas which can be admitted into the mass spectrometer.
There are two main designs for an inlet gas aperture of an API. One design includes a pinhole orifice in a thin membrane-type flange that separates the atmospheric pressure region and the first vacuum chamber of the MS instrument with the typical pressure of 0.1-5 mTorr. See e.g., the design introduced by Horning et. al., in Anal. Chem. 1973, vol. 455, pp. 936-943; the entire contents of which are incorporated herein by reference. In a second design, the atmospheric pressure region is connected with the intermediate vacuum chamber (i.e., 0.1-5.0 mTorr) through a transport capillary with a typical inner diameter of 0.1-1 mm. See e.g., the design developed by Whitehouse et al. in Anal. Chem. 1985, vol. 57, pp. 675-679; the entire contents of which are incorporated herein by reference. In a third design, a heated capillary delivers atmospheric pressure ions into a vacuum chamber. See e.g., U.S. Pat. Nos. 4,977,320 and 5,245,186; the entire contents of which are incorporated herein by reference. Usually, the transport capillary is heated to a temperature of 80-250° C. for ion desolvation. The heated transport capillary has several advantages over the aforementioned pinhole interface and is used in modern commercial and scientific MS instruments. The process of ion transport by viscous gas flow through capillaries is detailed by B. Lin and J. Sunner in J. Am. Soc. Mass Spectrom. 1994, vol. 5, pp. 873-885; the entire contents of which are incorporated herein by reference.
In one atmospheric pressure ionization technique, electrospray ionization takes place under normal atmospheric pressure conditions. See e.g. Yamashita, M.; Fenn, J. B. J. Chem. Phys. 1984, vol. 88, pp. 4451-4159 and Fenn, J. B.; Mann, M.; Meng, C. K.; Wong, S. F.; Whitehouse, C. M. Science 1989, vol. 246, pp. 64-71; the entire contents of which are incorporated herein by reference. For electrospray ionization, a slightly electroconductive liquid analyte solution is pumped through a thin metal or insulator tube. A high voltage of several hundred volts is applied between the liquid and the counterelectrode. As a result, a Taylor cone is formed at the exit orifice of the capillary tube. The liquid surface at the tip of that cone loses stability, and a cloud of very fine liquid droplets forms. These droplets are electrically charged. After drying, a cloud of molecular analyte ions is formed in an atmospheric pressure region of the exit orifice.
For mass analysis of atmospheric pressure produced ions, mass spectrometers sample through an entrance orifice (i.e. the API) ambient gas along with the atmospheric pressure produced ions and transfer the ions into the high vacuum chamber of a mass analyzer.
By contrast, in vacuum Matrix Assisted Laser Desorption Ionization, laser desorption and ionization takes place inside a vacuum chamber under vacuum conditions. See e.g., Karas, M; Hillenkamp, F.; Anal. Chem. 1988, vol. 60, pp. 2299-2301; the entire contents of which are incorporated herein by reference. A target is prepared by mixing a solution of analyte molecules with a specially chosen material known as a matrix, usually an organic acid in the form of solid crystals. The solution is then dried on a target plate to form a solid analyte and matrix material. The target plate is irradiated in vacuum with a UV or IR laser p
Doroshenko Vladimir M.
Laiko Victor V.
Lee Hyo Sang
Prasad Coorg R.
Yakshin Mikhail
Berman Jack
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Science & Engineering Services Inc.
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