Surgery – Diagnostic testing – Measuring or detecting nonradioactive constituent of body...
Reexamination Certificate
1999-03-22
2001-02-20
Winakur, Eric F. (Department: 3736)
Surgery
Diagnostic testing
Measuring or detecting nonradioactive constituent of body...
C250S281000
Reexamination Certificate
active
06190316
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method of mass-analyzing a body fluid and an apparatus therefor. More particularly, it relates to a method of mass-analyzing a body fluid and an apparatus therefor which, by mass-analyzing each kind of substances contained in a body fluid of an extremely high or low electrical conductivity, allow component analysis of the body fluid to be performed and can be preferably used for identifying each kind of the substances contained in the body fluid.
2. Description of the Prior Art
As a conventional technique concerning a measuring method for identifying each kind of the substances contained in the body fluid, there is known a method in which the measurement is performed using an electrochemical detection method and employing as the criterion an oxidation-reduction potential characteristic of a substance. Also, as another conventional technique, there is known a component-analyzing method that, with the use of the mass spectrometry, allows a substance to be identified from its mass.
Usually, in the mass spectrometry, an analyte solution such as the body fluid, after being ionized, is introduced into a mass spectrometer so as to detect mass of each kind of the substances contained in the analyte solution. As a conventional technique concerning an ionization method used in the mass analysis of this type, there is known, for example, a technique disclosed in literatures such as USP-5130538. This conventional technique is referred to as an electrospray ionization method. In this method, 2.5 kV or more of high voltage is applied between a metal capillary into which the solution is introduced and a counter electrode, namely, with the high voltage applied to the solution, the solution is sprayed toward the counter electrode over a space to which the electric field is applied. As a result, an electrospray phenomenon occurs, forming a Taylor corn between the metal capillary and the counter electrode. Then, charged droplets, are sprayed from a tip of the Taylor corn.
When an electrical conductivity of the analyte solution falls in the range of 10
−13
to 10
−5
S cm
−1
(S=&OHgr;
−1
), the electrospray ionization method according to the above-described conventional technique enables a stable ionization to be performed.
As another conventional technique regarding the ionization method for the analyte solution, there is known, for example, a technique disclosed in literatures such as JP-A-7-306193. The ionization method according to this conventional technique is referred to as a sonic spray ionization method. In this method, gas is caused to flow outside the capillary coaxially therewith and thus the analyte solution Is forced to be sprayed from a tip of the capillary, thereby generating the charged droplets. Incidentally, it is recognized that quantities of the positive and negative ions thus generated become maximum when velocity of the gas flow at the tip of the capillary is substantially equal to the sonic velocity.
Moreover, in the mass spectrometry in which, after the analyte solution such as the body fluid has been ionized, the ionized particles are Introduced Into the mass spectrometer so as to perform the mass analysis, in the case of mass-analyzing a mixture solution in which many kinds of substances are mixed, it is a common practice to employ the following technique: The substances contained in the mixture solution are separated from each other using a member such as a liquid chromatograph or a capillary electrophoresis system, and after that, the mass analysis is performed using the mass spectrometer.
The conventional technique according to the above-described electrochemical detection method is a method in which the measurement is performed employing as the criterion the oxidation-reduction potential characteristic of a substance. As a result, the conventional technique has a problem that an accurate measurement is impossible regarding a living body and, in particular, regarding a substance such as a neurotransmitter the oxidation-reduction potential of which varies with a lapse of time.
Also, in a conventional technique that uses a non-ion trap mass-analyzing apparatus, no matter which method of the electrospray ionization method and the sonic spray ionization method is employed when performing the ionization, in the case of mass-analyzing the body fluid in which many kinds of substances are mixed, the following process is required: The body fluid is separated for each kind of the substances mixed, and after that, the ionization is carried out and then the mass analysis is carried out using the mass spectrometer. The conventional technique, accordingly, necessitates a considerable time for this separation and, as a result, has a problem that mass analysis cannot be performed accurately toward the analyte solution such as the body fluid in which the substances contained vary with a lapse of time and thus values of the corresponding masses also vary with a lapse of time.
Also, in the conventional technique that uses the electrospray ionization method in association with the mass-analyzing apparatus, as explained already, it is difficult to perform the stable ionization if the electrical conductivity of the analyte solution falls outside the range of 10
−13
to 10
−5
S cm
−1
(S=&OHgr;
−1
). As a result, the conventional technique has a problem that, toward the analyte solution such as the body fluid having an extremely high electrical conductivity, the mass analysis could not be performed.
SUMMARY OF THE INVENTION
It is an object of the present invention to solve the above-described problems in the conventional techniques and thus to provide a configuration embodying a method of mass-analyzing a body fluid and an apparatus therefor which, even toward the analyte solution in which the substances contained vary with a lapse of time and the analyte solution such as the body fluid having an extremely high electrical conductivity, allow the ionization thereof to be performed in a short while, thus making it possible to mass-analyze the analyte solution in a short while.
A new recognition has been obtained that an ionization source using the sonic spray ionization method makes it possible to ionize the analyte solution regardless of how high or low the electrical conductivity of the analyte solution is. In the present invention, the above-described problems have been solved by paying an attention to a combination of this recognition and an ion trap mass spectrometer that allows the mass analysis to be performed in a short while.
Namely, according to the present invention, in a method of mass-analyzing a body fluid, which performs component analysis of the body fluid, an ionization source according to the sonic spray ionization method is employed as an ionization source, and an ion trap three dimensional quadrupole mass spectrometer is employed as a mass spectrometer, and after an analyte solution containing a mixture of living body substances is ionized directly by the above-mentioned ionization source without being separated for each of the substances, the ions are introduced into the mass spectrometer, thereby accomplishing the above-described object.
Also, the above-described living body substances are collected as the analyte solution from a living body with a microdialysis probe, and the mass analysis is performed in real time by immediately introducing the analyte solution into the ionization source from the microdialysis probe through a flowing passage, and also a volatile organic solvent is added to the above-described analyte solution in order to promote the ionization even further, thereby accomplishing the above-described object.
Moreover, in an apparatus for mass-analyzing a body fluid, which performs component analysis of the body fluid, an ionization source using the sonic spray ionization method and an ion trap three dimensional quadrupole mass spectrometer are provided, and after an analyte solution containing a mixture
Hirabayashi Atsumu
Hirabayashi Yukiko
Koizumi Hideaki
Antonelli Terry Stout & Kraus LLP
Hitachi , Ltd.
Winakur Eric F.
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