U.S. patent application number 14/446771 was filed with the patent office on 2015-11-05 for ionization device, mass spectrometry apparatus, mass spectrometry method, and imaging system.
The applicant listed for this patent is CANON KABUSHIKI KAISHA. Invention is credited to Masafumi Kyogaku, Yoichi Otsuka.
Application Number | 20150318157 14/446771 |
Document ID | / |
Family ID | 52426773 |
Filed Date | 2015-11-05 |
United States Patent
Application |
20150318157 |
Kind Code |
A9 |
Otsuka; Yoichi ; et
al. |
November 5, 2015 |
IONIZATION DEVICE, MASS SPECTROMETRY APPARATUS, MASS SPECTROMETRY
METHOD, AND IMAGING SYSTEM
Abstract
A mass spectrometry apparatus includes a holding table that
holds a specimen to be ionized, a probe that identifies a portion
of the specimen to be ionized, an ion extraction electrode that
extracts ions obtained by ionizing the specimen, a liquid supplying
unit that supplies liquid to between the specimen and the probe to
form a liquid bridge between the specimen and the probe, a
vibrating unit that vibrates one of the probe and the holding
table, an electric field generating unit that generates an electric
field between the probe and the ion extraction electrode, a mass
spectrometry unit that mass analyzes ions extracted by the ion
extraction electrode, and a synchronization unit configured to
synchronize a time at which ions are generated from the portion
with a time at which the mass spectrometry unit measures the
ions.
Inventors: |
Otsuka; Yoichi;
(Kawasaki-shi, JP) ; Kyogaku; Masafumi;
(Yokohama-shi, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CANON KABUSHIKI KAISHA |
Tokyo |
|
JP |
|
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20150034817 A1 |
February 5, 2015 |
|
|
Family ID: |
52426773 |
Appl. No.: |
14/446771 |
Filed: |
July 30, 2014 |
Current U.S.
Class: |
250/282; 250/288;
250/423R; 250/424 |
Current CPC
Class: |
H01J 49/0459 20130101;
H01J 49/0004 20130101; H01J 49/165 20130101; H01J 49/0027 20130101;
H01J 49/26 20130101; H01J 49/24 20130101; H01J 49/10 20130101 |
International
Class: |
H01J 49/10 20060101
H01J049/10; H01J 49/24 20060101 H01J049/24; H01J 49/26 20060101
H01J049/26; H01J 49/00 20060101 H01J049/00 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 2, 2013 |
JP |
2013-161331 |
Sep 5, 2013 |
JP |
2013-183962 |
Claims
1. An ionization device comprising: a holding table configured to
hold a specimen to be ionized; a probe configured to identify a
portion of the specimen to be ionized; an ion extraction electrode
configured to extract ions obtained by ionizing the specimen; a
liquid supplying unit configured to supply liquid to between the
specimen and the probe to form a liquid bridge between the specimen
and the probe; a vibrating unit configured to vibrate one of the
probe and the holding table; an electric field generating unit
configured to generate an electric field between the probe and the
ion extraction electrode; and a synchronization unit configured to
perform at least one of the following two synchronization processes
on the basis of vibration of one of the probe and the holding
table: (i) synchronizing a time at which ions are generated from
the portion with a time at which a mass spectrometry unit for mass
analyzing the ions extracted by the ion extraction electrode
measures the ions, and (ii) synchronizing vibration of the probe
with vibration of the holding table.
2. A mass spectrometry apparatus comprising: a holding table
configured to hold a specimen to be ionized; a probe configured to
identify a portion of the specimen to be ionized; an ion extraction
electrode configured to extract ions obtained by ionizing the
specimen; a liquid supplying unit configured to supply liquid to
between the specimen and the probe to form a liquid bridge between
the specimen and the probe; a vibrating unit configured to vibrate
one of the probe and the holding table; an electric field
generating unit configured to generate an electric field between
the probe and the ion extraction electrode; a mass spectrometry
unit configured to mass analyze ions extracted by the ion
extraction electrode; and a synchronization unit configured to
synchronize a time at which ions are generated from the portion
with a time at which the mass spectrometry unit measures the
ions.
3. The mass spectrometry apparatus according to claim 2, further
comprising: a unit configured to vibrate one of the probe and the
holding table, wherein the synchronization unit synchronizes
vibration caused by the vibrating unit with a time at which the
mass spectrometry unit measures the ions.
4. The mass spectrometry apparatus according to claim 2, wherein
the vibrating unit includes a unit configured to vibrate the probe
and a unit configured to vibrate the holding table, and wherein the
synchronization unit synchronizes the unit configured to vibrate
the probe, the unit configured to vibrate the holding table, and a
time at which the mass spectrometry unit measures the ions with one
another.
5. The mass spectrometry apparatus according to claim 3, wherein
the vibrating unit causes a time period for which the liquid bridge
is formed in the portion of the specimen to be ionized and a time
period for which ions are generated from the portion to alternately
occur.
6. The mass spectrometry apparatus according to claim 3, wherein
the synchronization unit synchronizes the time at which ions are
generated with a time at which one end of the probe that vibrates
moves close to the ion extraction electrode.
7. The mass spectrometry apparatus according to claim 3, wherein
the synchronization unit synchronizes the time at which ions are
generated with a time at which the holding table vibrates.
8. The mass spectrometry apparatus according to claim 3, wherein
the synchronization unit synchronizes the time at which ions are
generated with a time at which the holding table moves close to the
ion extraction electrode.
9. The mass spectrometry apparatus according to claim 3, further
comprising: a measuring unit configured to measure an amplitude and
a frequency of vibration of at least one of the probe and the
holding table.
10. The mass spectrometry apparatus according to claim 9, wherein
the synchronization unit is a unit configured to generate a gate
signal for controlling measurement of ions performed by the mass
spectrometry unit in synchronization with a signal input to the
measuring unit.
11. The mass spectrometry apparatus according to claim 2, further
comprising: a scanning unit configured to scan the probe relative
to a surface of the specimen.
12. An imaging system comprising: the mass spectrometry apparatus
according to claim 2; an image forming unit configured to form
image information used for imaging distribution of a component of a
substance contained in a specimen using mass information analyzed
by the mass spectrometry apparatus and information regarding a
position in the specimen; and an output unit configured to output
the image information.
13. A mass spectrometry method for ionizing a specimen and
performing mass spectrometry, comprising: causing a probe to move
closer to, or be in contact with, a portion of a specimen to be
ionized and forming a liquid bridge between the specimen and the
probe; generating ions from liquid deposited to the probe and
directing the ions to a mass spectrometry unit that performs mass
spectrometry; and mass analyzing the ions, wherein a time at which
ions are generated from the portion of the specimen identified by
the probe is synchronized with a time at which the mass
spectrometry unit measures the ions.
14. The mass spectrometry method according to claim 12, wherein
vibration of one of the probe and the holding table causes a time
period for which the ions are generated and a time period for which
the liquid bridge is formed to occur.
15. An ionization device comprising: a holding table configured to
hold a specimen; a probe configured to identify a portion of the
specimen to be ionized; an ion extraction electrode configured to
extract ions obtained by ionizing the specimen; a liquid supplying
unit configured to supply liquid to between the specimen and the
probe so as to form a liquid bridge between the specimen and the
probe; and a voltage applying unit configured to apply a voltage
between a portion of the probe in contact with the liquid bridge
and the ion extraction electrode, wherein at least the probe has a
vibrating unit that repeatedly moves the probe close to the holding
table and moves the probe away from the holding table, and wherein
the vibrating unit vibrates the probe at least at two different
frequencies, one of which is a frequency for forming the liquid
bridge and the other of which is a frequency that is greater than
the frequency for forming the liquid bridge.
16. The ionization device according to claim 15, wherein the
vibrating unit includes a probe vibrating unit configured to
vibrate the probe and a holding table vibrating unit configured to
vibrate the holding table, and wherein a frequency of vibration of
the probe is an integral multiple of a frequency of vibration of
the holding table, where the integral multiple is 2 or more.
17. The ionization device according to claim 16, wherein the
vibrating unit is a probe vibrating unit for vibrating the probe,
and wherein a frequency for forming the liquid bridge is set to an
integer fraction of the frequency of vibration of the probe by
modulating an amplitude of the vibration of the probe.
18. A mass spectrometry apparatus comprising: the ionization device
according to claim 15; and a mass spectrometry unit configured to
analyze the mass-to-charge ratio of the ions.
19. An imaging system comprising: the mass spectrometry apparatus
according to claim 18; and an image information generating unit
configured to generate, as image information, a distribution of a
component of a substance contained in a specimen using information
regarding a signal intensity of a mass spectrum obtained by the
mass spectrometry apparatus and information regarding a position in
the specimen.
20. An ionization method comprising: causing a probe to move closer
to a surface of a specimen held by the holding table and
identifying a portion of the specimen to be ionized; supplying
liquid to form a liquid bridge between the specimen and the probe;
and directing ions to a mass spectrometry unit by applying a
voltage between a portion of the probe in contact with the liquid
bridge and an ion extraction electrode, wherein vibration that
repeatedly moves the probe closer to the holding table and away
from the holding table occurs, and wherein the vibration has at
least two different frequencies, one of which is a frequency for
forming the liquid bridge and the other of which is a frequency for
vibrating the probe that is higher than the frequency for forming
the liquid bridge.
Description
BACKGROUND
[0001] 1. Field
[0002] The present invention relates to an ionization device and a
mass spectrometry apparatus for ionizing a specimen and mass
analyzing a specimen.
[0003] 2. Description of the Related Art
[0004] For analysis of component in a surface of a solid specimen,
a technology for ionizing a solid substance in an atmospheric
pressure environment has been developed.
[0005] For example, such a technique is described in the following
non-patent literature: Yoichi Otsuka et al., "Scanning probe
electrospray ionization for ambient mass spectrometry" Rapid
Communications in mass spectrometry, 26, 2725 (2012). In the
technique, a small volume of the solvent is deposited onto a
microregion of a surface of a solid specimen, and a component of
the specimen is dissolved in the solvent. Thereafter, the component
is ionized by electrospray ionization. Generated ions are
introduced into a mass spectrometry apparatus, which measures the
mass-to-charge ratio of the ion. Thus, the component can be
analyzed. To deposit the solvent onto the microregion of the
surface of the solid specimen, a probe formed from a needle-like
capillary is used. The solvent is continuously fed to the probe. A
liquid bridge is formed between the probe and the surface of the
solid specimen that is located in close proximity to the probe. The
component contained in the surface of the solid specimen is
dissolved into the liquid bridge. The solvent having the component
dissolved therein is ionized by applying a voltage to the solvent.
The probe is vibrated and, thus, the solvent that is continuously
supplied to the surface of the solid specimen is ionized. Such a
technique is referred to as Tapping-mode Scanning Probe
Electrospray Ionization (Tapping-mode SPESI). In contrast, a
technique for ionizing the solvent with the probe remaining in
close proximity to the surface of the solid specimen is referred to
as Contact-mode Scanning Probe Electrospray Ionization
(Contact-mode SPESI).
[0006] In the Tapping-mode SPESI described in non-patent literature
above, a liquid bridge is alternately formed and disrupted. In the
technique, dissolution of a component into the liquid bridge and
ionization of the component are alternately and continuously
performed. The frequency of the formation of the liquid bridge and
the ionization is determined by the frequency of vibration of the
probe. In addition, the mass spectrometry apparatus is electrically
separated from an ionization device. The mass spectrometry
apparatus and the ionization device are independently driven. The
ions introduced into the mass spectrometry apparatus are measured
within a predetermined measurement period of time.
[0007] In the technique, measurement using mass spectrometry is
performed even during a period of time during which ionization is
not performed, that is, during a period of time during which a
liquid bridge is being formed and during a period of time during
which ions are being generated after the liquid bridge is
formed.
[0008] As a result, a noise signal generated when ionization is not
performed is mixed with measurement data, which makes mass spectral
analysis of the data difficult.
[0009] In addition, it is difficult to finely control the number of
ionization processes performed within the measurement time of
ionization, the quantitative capability of measurement is low and,
thus, the quantitative capability when the measurement values each
measured in one measurement process are compared with one another
is low.
[0010] In contrast, in terms of Contact-mode SPESI, a technique for
steadily vibrating a substrate having a solid specimen placed
thereon is proposed. In such a technique, vibration of the
substrate makes ionization stable. However, measurement of ions is
performed during an entire period of vibration time of the
substrate, a noise signal generated during a period of time during
which ionization is not actually performed is mixed in measurement
data. In addition, when the substrate is steadily vibrated for a
long time, a device for generating the vibration is heated. The
heat may cause the amplitude and the frequency of the vibration to
fluctuate.
SUMMARY
[0011] The present disclosure provides an ionization device and the
mass spectrometry apparatus capable of measuring the component
distribution in a microregion of a surface of a specimen in an
atmospheric pressure environment with a high sensitivity.
[0012] According to an aspect of the present disclosure, an
ionization device includes a holding table configured to hold a
specimen to be ionized, a probe configured to identify a portion of
the specimen to be ionized, an ion extraction electrode configured
to extract ions obtained by ionizing the specimen, a liquid
supplying unit configured to supply liquid to between the specimen
and the probe to form a liquid bridge between the specimen and the
probe, a vibrating unit configured to vibrate one of the probe and
the holding table, an electric field generating unit configured to
generate an electric field between the probe and the ion extraction
electrode, and a synchronization unit configured to performing at
least one of the following two synchronization processes on the
basis of vibration of the probe or the holding table:
[0013] (i) synchronizing a time at which ions are generated from
the portion with a time at which a mass spectrometry unit for mass
analyzing the ions extracted by the ion extraction electrode
measures the ions, and
[0014] (ii) synchronizing vibration of the probe with vibration of
the holding table.
[0015] According to another aspect disclosed herein, a mass
spectrometry apparatus includes a holding table configured to hold
a specimen to be ionized, a probe configured to identify a portion
of the specimen to be ionized, an ion extraction electrode
configured to extract ions obtained by ionizing the specimen, a
liquid supplying unit configured to supply liquid to between the
specimen and the probe to form a liquid bridge between the specimen
and the probe, a vibrating unit configured to vibrate one of the
probe and the holding table, an electric field generating unit
configured to generate an electric field between the probe and the
ion extraction electrode, a mass spectrometry unit configured to
mass analyze ions extracted by the ion extraction electrode, and a
synchronization unit configured to synchronize a time at which ions
are generated from the portion with a time at which the mass
spectrometry unit measures the ions.
[0016] According to the present disclosure, an ionization device
capable of measuring the component distribution of a microregion of
a surface of a specimen in an atmospheric pressure environment with
a high sensitivity and a mass spectrometry apparatus or an imaging
system including the ionization device are provided.
[0017] Further features of the present invention will become
apparent from the following description of exemplary embodiments
with reference to the attached drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 is a schematic illustration of an imaging system
including an ionization device according to a first exemplary
embodiment
[0019] FIG. 2 is a timing diagram illustrating the operation timing
of each of apparatuses in a first drive mode of the ionization
device according to the first exemplary embodiment.
[0020] FIG. 3 is a timing diagram illustrating the operation timing
of each of apparatuses in a second drive mode of the ionization
device according to the first exemplary embodiment.
[0021] FIG. 4 is a timing diagram illustrating the operation timing
of each of apparatuses in a third drive mode of the ionization
device according to the first exemplary embodiment.
[0022] FIG. 5 is a schematic illustration of a synchronization
circuit and apparatuses controlled by the synchronization circuit
in a third drive mode of an ionization device according to a second
exemplary embodiment.
[0023] FIG. 6 is a schematic illustration of an imaging system
including the ionization device according to the third exemplary
embodiment.
[0024] FIGS. 7A and 7B are timing diagrams of the operation timing
of apparatuses in first and second drive modes of the ionization
device according to the third exemplary embodiment.
[0025] FIG. 8 is a timing diagram of the operation timing of
apparatuses in a third drive mode of the ionization device
according to the third exemplary embodiment.
[0026] FIG. 9 is a timing diagram of the operation timing of
apparatuses in the first to third drive modes of the ionization
device according to the third exemplary embodiment.
DESCRIPTION OF THE EMBODIMENTS
First Exemplary Embodiment
[0027] FIG. 1 is a schematic illustration of an imaging system
including an ionization device according to the first exemplary
embodiment of the present invention. The imaging system includes a
probe 1 having a flow passage therein, where the flow passage
allows liquid to flow through, a vibration providing unit 2 that
vibrates the probe 1, a solid specimen 3, a liquid bridge 4 formed
between the probe 1 and the solid specimen 3, a Taylor cone 5,
charged fine liquid droplets 6, an ion entrapment unit 7 including
an ion extraction electrode for entrapping ions into a mass
spectrometry apparatus, an XY stage 8 serving as a holding table
that holds the solid specimen 3, a Z stage 9 for moving the solid
specimen 3 in a Z direction (the vertical direction in FIG. 1),
specimen stage control devices 10 and 11, a voltage applying
apparatus 12, a liquid supply unit 13 that supplies liquid to the
probe 1, a voltage applying apparatus 14, light sources 15 and 19,
displacement sensors 16 and 20 serving as measurement units that
measure displacement, a mass spectrometry unit 17, a voltage
applying apparatus 18, an ion counter 21, an image forming unit 22,
a displacement calculation device 23, and a display unit 24.
[0028] The ion counter 21 is incorporated into the mass
spectrometry unit 17 and be used. Alternatively, instead of being
incorporated into the mass spectrometry unit 17, the ion counter 21
may be externally connected to the mass spectrometry unit 17 and be
used. In either case, the number of ions entrapped in the mass
spectrometry unit 17 can be measured. In addition, the ion counter
21 includes an input terminal of a gate signal. By inputting an
appropriate signal to the input terminal of a gate signal, driving
of the ion counter 21 can be controlled.
[0029] An ion detector (e.g., a microchannel plate detector) and an
electric signal measuring device (e.g., an analog-to-digital
converter (ADC) or a time-to-digital converter (TDC)) can be used
as the ion counter 21. In addition, a device for adjusting the
waveform of the electric signal (e.g., a discriminator or an
amplifier circuit) may be provided between the ion detector and a
measuring instrument of the electric signal. The input terminal of
a gate signal is incorporated into the measuring instrument of the
electric signal.
[0030] The liquid supply unit 13 supplies the solvent for
dissolving a component to be analyzed contained in the solid
specimen 3 or mixed solution of a component to be analyzed and the
solvent (hereinafter, the solvent and the mixed solution are
collectively and simply referred to as "liquid"). The liquid
supplied from the liquid supply unit 13 is led to the flow passage
in the probe 1. At that time, a voltage is applied to the liquid by
the voltage applying apparatus 14. The voltage applied to the
liquid is one of a DC voltage, an AC voltage, a pulse voltage, and
a zero volt.
[0031] According to the present exemplary embodiment, the liquid
supplied from the liquid supply unit 13 forms the liquid bridge 4
between the solid specimen 3 and the probe 1. At that time, the
solid specimen 3 is an object formed from an object to be measured
that is placed on one of a metal substrate, an electrically
insulating material substrate, and a semiconductor substrate, and
the object to be measured requires that the component distribution
in the microregion of the object is measured. Examples of the
object include a biological tissue and bodily fluid. However, the
object may be an object other than a biological tissue and bodily
fluid.
[0032] In addition, the liquid that forms the liquid bridge 4 is
turned into the fine liquid droplets 6 by the vibration of the
probe 1, and the fine liquid droplets 6 are charged by the electric
field generated by the voltage applying apparatus 14 and the
voltage applying apparatus 18. Thus, the component of the object to
be measured can be entrapped in the ion entrapment unit 7 in the
form of ions. That is, according to the present exemplary
embodiment, the probe 1 functions as a supply unit for supplying
the liquid onto the substrate, a substance acquiring unit, a
transport unit for transporting the liquid to a position that is
suitable for ionization, and a forming unit for forming a Taylor
cone for ionization.
[0033] Note that according to the present exemplary embodiment, an
electrically conductive probe has such a configuration that
provides electrical conductivity to the flow passage and a
connection pipe in the probe 1 and that allows a voltage to be
applied to the liquid contained in the probe 1. To achieve such a
structure, it is desirable that an electrically conductive member
be disposed in the entire or part of the flow passage that is in
contact with the liquid.
[0034] However, the electrically conductive member is not
necessarily disposed in the flow passage and the connection pipe
inside the probe 1. It is only required that the structure allows
the liquid contained in the top end portion of the probe 1 to be
charged before the liquid reaches the top end of the probe, that
is, the electrically conductive member can be located in a mid-top
end portion.
[0035] To achieve the suitable configuration of the probe 1, at
least part of the material of the probe 1 has electrical
conductivity. Examples of such a material include a metal and a
semiconductor. However, any material that has a property generating
a reproducible constant voltage can be used. That is, according to
the present exemplary embodiment, a voltage is applied to the
liquid by applying a voltage to a conductive portion of the probe
1.
[0036] As used herein, the term "application of voltage to a probe"
is used to denote a process to apply an electric potential that
differs from the electric potential of an ion extraction electrode
(described in more detail below) to a conductive portion that
constitutes at least part of the probe and generate an electric
field between the conductive portion and the ion extraction
electrode. As long as the electric field is generated, the applied
voltage may be zero volt. The material of at least part of the
probe 1 should be electrically conductive. For example, a stainless
steel, gold, or platinum can be used as the material.
[0037] For example, a tubule, such as a silica capillary or a metal
capillary, capable of supplying a small volume of liquid can be
used as each of the probe 1 and the connection pipe that connects
the probe 1 to the liquid supply unit 13. The tubule may have the
same electric conductivity as any one of an insulating material, a
conductor, and a semiconductor. Note that the electrically
conductive flow passage should be at least part of the flow passage
that allows the liquid supplied from the liquid supply unit 13 to
pass through inside of the probe 1 and reach the top end of the
probe 1 on the opposite side of the liquid supply unit 13. The
position of the electrically conductive flow passage is not limited
to any particular position of the probe 1. For example, the entire
or part of the electrically conductive flow passage may be included
in the flow passage or the connection pipe inside the probe 1.
[0038] If the probe 1 itself is electrically conductive, the
voltage applied by the voltage applying apparatus 14 propagates
through the probe 1 and is applied to the liquid in the flow
passage inside the probe 1. In contrast, if the probe 1 is made of
an electrically insulating material, the voltage applied to the
electrically conductive flow passage does not propagate to the
probe 1. At that time, the voltage is applied to the liquid flowing
in the electrically conductive flow passage, and the liquid enters
the probe 1. Accordingly, even when the voltage is not propagated
to the probe 1, the voltage can be applied to the liquid. Thus, the
liquid is charged.
[0039] The liquid supplied from the liquid supply unit 13 is
provided from the top end of the probe 1 onto the solid specimen 3.
In this manner, a minutely small amount of the substance contained
in the solid specimen 3 can be dissolved into the liquid and be
ionized in an atmospheric pressure environment.
[0040] In the above-described configuration according to the
present exemplary embodiment, the probe 1 can be vibrated.
According to the present exemplary embodiment, the vibration of the
probe 1 is the periodic motion of the probe 1 such that the
position of the top end of the probe 1 adjacent to the solid
specimen 3 is spatially displaced. In particular, it is desirable
that the probe 1 be bending-vibrated in a direction crossing the
axis direction of the probe 1. To vibrate the probe 1, mechanical
vibration is provided from the vibration providing unit 2 to the
probe 1. In addition, by stopping supply of vibration from the
vibration providing unit 2, the vibration of the probe 1 can be
stopped.
[0041] In general, the natural resonance frequency in a primary
mode of a cantilevered object can be expressed by using the length,
the density, the cross sectional area, the Young's modulus, and the
second moment of area of the cantilever. Since the needle-like
probe 1 according to the present exemplary embodiment is similar to
a cantilevered probe, the natural resonance frequency of the probe
1 can be controlled by controlling the material and the size of the
probe 1, the type and volume of the liquid supplied to the probe 1,
and the magnitude of the electric field generated between the probe
1 and the ion entrapment unit 7. Examples of the material of the
probe 1 include, but not limited to, silica, silicon, a polymer
material, and a metal material. Alternatively, a probe formed by
joining two or more materials having different densities and
Young's moduli may be used. In addition, any device that generates
vibration can be used as the vibration providing unit 2. For
example, a piezoelectric device or a vibration motor may be used as
the vibration providing unit 2. Vibration of the probe 1 may be
either continuous vibration or intermittent vibration. The timing
at which the voltage is applied to the liquid and the timing at
which vibration is provided to the probe 1 may be determined as
needed.
[0042] In addition, the solvent may be supplied from the liquid
supply unit 13 through a flow passage formed in the surface of the
probe 1. For example, a minutely small groove may be formed in the
surface of the probe 1. By using capillarity, the solvent
introduced from the liquid supply unit 13 may flow in the surface
of the probe 1 and reach the top end portion of the probe 1.
[0043] Although the configuration in which the liquid supply unit
13 is physically connected to the probe 1 is illustrated in FIG. 1,
the liquid supply unit 13 may be spatially separated from the probe
1. For example, by using an inkjet technique, the solvent may be
ejected from the liquid supply unit 13 spatially separated from the
probe 1 to the probe 1 and be deposited onto the probe 1.
[0044] The frequency and amplitude of the vibration of the probe 1
may be set to desired values. The values may be constant values or
modulated values. For example, by varying a voltage value or a
frequency value output from the voltage applying apparatus 12 that
is electrically connected to the vibration providing unit 2, the
amplitude and frequency of the vibration of the probe 1 can be
adjusted to the desired values.
[0045] The Z stage 9 is physically connected to the XY stage 8 and
the solid specimen 3. The Z stage 9 is used to vibrate the solid
specimen 3 in the vertical direction. The Z stage 9 can vibrate a
specimen on the basis of a control signal output from the specimen
stage control devices 11 connected to the Z stage 9. The frequency
and amplitude of the vibration may be set to desired values. The
values may be constant values or modulated values. In such a case,
by varying the voltage value or the frequency value output from the
specimen stage control devices 11, the frequency and amplitude of
the vibration can be adjusted to the desired values.
[0046] At that time, the XY stage 8 may be fixed onto the Z stage
9. Alternatively, the Z stage 9 may be fixed onto the XY stage
8.
[0047] The light source 15 and the displacement sensor 16 are used
to measure the vibration of the probe 1. The light source 15 and
the displacement sensor 16 are disposed so that a spot light ray
formed by collecting the light emitted from the light source 15 is
reflected by the probe 1 and is led to the displacement sensor 16.
By detecting the position of the reflected spot light ray using the
displacement sensor 16, the frequency and amplitude of the
vibration of the probe 1 can be measured. Examples of the light
source 15 include a laser light source, a halogen light source, and
a light emitting diode (LED) light source. In addition, one of a
lens and a pinhole that collects light or one of a cylindrical lens
and a slit that collect light into a line shape may be disposed in
front of the light source 15. Like the light source 15 and the
displacement sensor 16, the light source 19 and the displacement
sensor 20 are used to measure the vibration of the XY stage 8 and
the vibration of the Z stage 9.
[0048] In this example, a light source and a displacement sensor
are used to measure the vibration of the probe 1, the XY stage 8,
and the Z stage 9. However, instead of the light source and the
displacement sensor, another type of displacement sensor may be
used. Examples of another type of displacement sensor include an
electrostatic capacitance displacement sensor, an eddy current
displacement sensor, a laser Doppler displacement sensor, and a
piezoelectric displacement sensor. In the case of an electrostatic
capacitance displacement sensor, a portion having electric
conductivity can be formed in each of the probe 1, the XY stage 8,
and the Z stage 9. The vibration can be measured by detecting the
variation of the electrostatic capacitance between the portion and
the sensor. In the case of an eddy current displacement sensor, an
eddy current generated in a metal which is part of each of the
probe 1, the XY stage 8, and the Z stage 9 is measured from a
variation of the inductance of a coil of the sensor that generates
an alternating-current magnetic field. Since the variation of the
inductance depends on the distance between the sensor and the
metal, the vibration can be measured. In the case of a laser
Doppler displacement sensor, the vibration can be measured by
detecting the frequency of reflected light when a laser beam is
emitted to the probe 1, the XY stage 8, and the Z stage 9. In the
case of a piezoelectric displacement sensor, the vibration can be
measured by detecting the pressure applied to a piezoelectric
device in contact with each of the probe 1, the XY stage 8, and the
Z stage 9 in the form of a voltage signal.
[0049] The electric signals output from the displacement sensor 16
and the displacement sensor 20 are input to the displacement
calculation device 23. The frequency, amplitude, and phase of the
vibration of the probe and the stage can be measured using the
electric signals.
[0050] According to the present exemplary embodiment, a vibration
unit that vibrates the probe is independent from a vibration unit
that vibrates the specimen. Accordingly, the following three
vibratory modes can be provided as a drive mode. That is, the three
vibratory modes are (A) a mode for vibrating the probe, (B) a mode
for vibrating the solid specimen, and (C) a mode for independently
vibrating the probe and the solid specimen at the same time.
[0051] FIG. 1 is a schematic illustration when the drive mode (A)
or (C) is selected. In the drive mode (B), provision of a signal
from the voltage applying apparatus 12 to the vibration providing
unit 2 is stopped, and the probe 1 is located in close proximity to
a solid specimen or is in contact with the solid specimen.
[0052] In the drive mode (A) in which the probe 1 is vibrated, a
signal is input to the vibration providing unit 2, and provision of
a signal to the specimen stage control device 11 is stopped. As a
result, the probe 1 vibrates, and the vibration of the Z stage 9 is
stopped.
[0053] In the drive mode (B) in which the solid specimen is
vibrated, provision of a signal to the vibration providing unit 2
is stopped, and a signal is input to the specimen stage control
device 11. As a result, the probe 1 is stopped, and the Z stage 9
vibrates. If the probe 1 is in contact with a surface of the solid
specimen 3, vibration of the Z stage 9 propagates to the probe 1.
Accordingly, the probe 1 can be vibrated. Even in such a case, the
drive mode (B) is applied.
[0054] In the drive mode (C) in which the probe 1 and the solid
specimen 3 are independently vibrated, a signal is input to the
vibration providing unit 2. At the same time, a signal is input to
the specimen stage control device 11. As a result, the probe 1 and
the Z stage 9 independently vibrate.
[0055] FIG. 2 is a timing diagram illustrating the operation timing
of each of the apparatuses in the drive mode (A) of the ionization
device according to the first exemplary embodiment. In the timing
diagram, a waveform chart (a) illustrates the voltage value of a
trigger signal for measurement performed by the ion counter 21, a
waveform chart (b) illustrates the voltage value of a vibration
signal for the probe 1, and a waveform chart (c) illustrates the
gate voltage value input to the ion counter 21. In general, the ion
counter 21 operates so as to intermittently receive the trigger
signal for the mass spectrometry unit 17 and, after receiving the
trigger signal, count the number of ions. The type of trigger
signal differs in accordance with the configuration of an ion
separation unit of the mass spectrometry unit 17. According to the
present exemplary embodiment, for example, a quadrupole mass
spectrometer, a time-of-flight mass spectrometer, a magnetic sector
mass spectrometer, or an ion-trap mass spectrometer can be used as
the mass spectrometry unit 17. In addition, the trigger signal may
be generated at a particular timing for each of the types of mass
spectrometer.
[0056] For example, in quadrupole mass spectrometers, a signal
indicating a point in time at which application of a high-frequency
voltage to the quadrupole is started may be used as the trigger
signal. In time-of-flight mass spectrometers, a signal indicating a
point in time at which a pulse voltage for accelerating the speed
of ions in a device for measuring the flight time of the ions is
applied may be used as the trigger signal. In magnetic sector mass
spectrometers, a signal indicating a point in time at which
application of a magnetic field to a sector electrode is started
may be used as the trigger signal. In ion-trap mass spectrometers,
a signal indicating a point in time at which ions are entrapped in
an ion trap may be used as the trigger signal. In general, the
frequency of the pulse voltage of a time-of-flight mass
spectrometer is in the range of several KHz to several tens of kHz.
In addition, the frequency of ion entrapment performed by an
ion-trap mass spectrometer is in the range of several tens Hz to
several kHz. That is, in general, the frequencies are higher than
the frequency of vibration of a probe.
[0057] The probe 1 vibrates, and formation of a liquid bridge and
ionization are alternately performed. The frequency of vibration of
the probe 1 is in the range of hundred Hz to tens of KHz. In FIG.
2, the frequency of the trigger signal of the mass spectrometry
unit 17 is 20 times the frequency of vibration of the probe 1. At a
time 1, the probe 1 is located so as to be in close proximity to or
in contact with the solid specimen 3 and, thus, a liquid bridge is
formed between the probe 1 and the surface of the solid specimen 3.
In addition, at a time 2, the probe 1 is moved away from the solid
specimen 3 and comes close to the ion entrapment unit 7, where
ionization is performed. A gate voltage value (c) input to the ion
counter 21 is synchronized with the voltage value (b) of the signal
for vibrating the probe 1. The output gate voltage value (c) is set
so as to be turned ON in a given time window around the time 2 of
the voltage value (b) of the signal for vibrating the probe 1. At
that time, a duration 3 is defined as a period of time during which
ions are generated. The duration 3 can be set to a desired value.
The gate voltage value (c) that is output is input to the input
terminal of a gate signal of the ion counter 21. The ion counter 21
is operated only when the gate voltage value (c) is being output.
As a result, only for the period of time indicated by the "duration
3", during which ions are generated by the probe 1, the ion counter
21 can be operated. Accordingly, during a period of time during
which the liquid bridge is formed and during a period of time from
the time the liquid bridge is formed to the time ions are
generated, a noise signal is not measured. In this manner, a noise
signal included in a measurement data signal can be reduced.
[0058] In the above-described example, when the duration 3 is set,
the voltage value (b) of a vibration signal for the probe 1 is
defined as a reference signal for regulating a period of time
during which electrospray ionization is performed, and the gate
voltage value (c) that is synchronized with the reference signal is
used. Note that if a signal indicating the displacement of the top
end portion of the probe 1 is synchronized with the probe vibration
signal, the signal output from the displacement sensor 16 may be
used as the reference signal instead of the voltage value (b) of
the signal for vibrating the probe 1. Alternatively, if a phase
difference exists between the signal for vibrating the probe 1 and
the signal indicating the displacement of the top end portion of
the probe 1, either the probe vibration signal or the displacement
signal may be selected as the reference signal. Thereafter, by
adjusting the rise time and the fall time of the gate voltage value
(c) that is synchronized with the reference signal, the phase
difference may be compensated for.
[0059] FIG. 3 is a timing diagram illustrating the operation timing
of each of the apparatuses in the drive mode (B) of the ionization
device according to the first exemplary embodiment. In the timing
diagram, a trigger signal (a) for measurement performed by the ion
counter 21 connected to the mass spectrometry unit 17, a vibration
signal (b) for the Z stage 9, and the gate voltage signal (c) input
to the ion counter 21 are illustrated. The vibration signal input
to the Z stage 9 is modulated so as to be alternately turned ON and
OFF for a predetermined period of time. Ions are more stably
generated in a duration 2 than in a duration 1 for which the Z
stage 9 is not vibrated. By modulating the vibration of the Z stage
9 in this manner, heat generated when the Z stage 9 is vibrated at
high speed (at 1 KHz or higher) can be advantageously reduced. If
the Z stage 9 is continuously vibrated, the Z stage 9 is overheated
and, thus, the amplitude of the vibration may be decreased or
malfunction of the Z stage 9 may occur. Accordingly, it is
desirable that a modulating operation be performed to reduce the
vibration time. In this manner, a cooling time period of the Z
stage 9 can be provided. If the Z stage 9 is continuously vibrated,
it is desirable that an additional cooling mechanism of the Z stage
9 be provided. Note that if a signal that is not modulated is used,
setting should be performed so that the duration 1 is not present
and the duration 3 in which ions are stably generated is considered
as a duration in which ions are generated.
[0060] The gate voltage signal (c) is set so as to be output in
synchronization with the duration 2 in which the vibration signal
(b) for the Z stage 9 is generated. The gate voltage signal (c) is
input to the input terminal of a gate signal of the ion counter 21.
As a result, only for the period of time for which ions are stably
generated by the probe 1, the ion counter 21 can be operated.
Accordingly, a noise signal generated during a period of time until
ionization is performed is not measured. In this manner, a noise
signal included in a measurement data signal can be reduced.
[0061] In FIG. 3, a single pulse having a duration 2 is
illustrated. However, the gate signal may be modulated in
synchronization with the vibration signal (b). That is, pulse
signals each having a duration that is less than the duration 2 and
synchronizing with the positive or negative peak of the vibration
signal (b) may be used.
[0062] In addition, when the duration 2 is set, the voltage value
of the vibration signal (b) for vibrating the Z stage 9 is defined
as the reference signal for determining the period of time during
which electrospray ionization is performed, and the gate voltage
signal (c) that is synchronized with the reference signal is used.
However, the signal output from the displacement sensor 20 may be
used as the reference signal instead of the voltage value of the
vibration signal (b).
[0063] FIG. 4 is a timing diagram illustrating the operation timing
of each of the apparatuses in the drive mode (C) of the ionization
device according to the first exemplary embodiment. In the timing
diagram, a trigger signal (a) for measurement performed by the ion
counter 21 connected to the mass spectrometry unit 17, a vibration
signal (b) for the probe 1, a vibration signal (c) for the Z stage
9, and a gate signal "d" input to the ion counter 21 are
illustrated. The frequency of vibration of the Z stage 9 is set so
as to be one fifth of the frequency of vibration of the probe 1. As
described above, it is desirable that one of the two frequencies of
vibration be an integer multiple of the other frequency and, in
addition, the phase difference between the vibrations be 0 or 180
degrees. At the time 1, the probe 1 is in close proximity to or in
contact with the solid specimen 3, and a liquid bridge is formed
between the probe 1 and a surface of the solid specimen 3. At the
time 2, the probe 1 is located so as to be the farthest from the
solid specimen 3. After the liquid bridge is formed at the time 1
and before the next liquid bridge is formed, ionization is
performed. The gate signal (d) is synchronized with the vibration
signal (b) or the vibration signal (c). The gate signal (d) is set
so as to be turned ON within a predetermined period of time
immediately before the time 1. The duration 3 for which the gate
signal (d) is ON is defined as a time period during which ions are
generated. The duration 3 can be set to any value. As a result, the
ion counter 21 is operated only when ions are stably generated from
the probe 1. Thus, a noise signal generated during a period of time
during which a desired component is not ionized is not measured. In
this manner, a noise signal included in a measurement data signal
can be reduced.
[0064] According to the present exemplary embodiment, in addition
to advantages that are the same as in the above-described drive
modes (A) and (B), an advantage that the absolute value of the
distance between the probe 1 and the Z stage 9 is increased due to
vibrations of both the probe 1 and Z stage 9 can be provided. Note
that when the irregularity of the surface profile of the solid
specimen 3 is significant and, thus, the vibration amplitude of the
probe 1 needs to be increased so that formation of the liquid
bridge and ionization are stably performed, it is desirable that
the present exemplary embodiment be applied. While the present
exemplary embodiment has been described with reference to the
control signals of the specimen stage control device 11 and the
voltage applying apparatus 12 being a triangle wave, a sine wave,
or a square wave, the waveform is not limited thereto. For example,
the waveform may be a sawtooth waveform or a waveform obtained by
combining a triangle wave, a sine wave, a square wave, and a
sawtooth wave illustrated in FIG. 2.
[0065] According to the present exemplary embodiment, when the
duration 3 is set, the voltage value (b) of a vibration signal for
the probe 1 is defined as a reference signal for regulating a
period of time during which electrospray ionization is performed,
and the gate voltage value (c) that is synchronized with the
reference signal is used. However, instead of the voltage value (b)
of the vibration signal, the signal output from the displacement
sensor 16 or the displacement sensor 20 may be used as the
reference signal.
[0066] In each of the drive modes (A), (B), and (C), the vibration
state is measured by using the displacement calculation device 23.
Thereafter, control signals are output from the displacement
calculation device 23 to the specimen stage control device 11 and
the voltage applying apparatus 12 so that a desired vibration state
is obtained. The vibration state corresponds to an ion generation
period for which electrospray ionization is performed and a non-ion
generation period. Accordingly, the displacement calculation device
23 can be used to measure a period of time during which ions are
generated through electrospray ionization.
[0067] For example, a period of time for which each of the voltages
of the AC signals output from the displacement sensor 16 and the
displacement sensor 20 is higher than a threshold voltage is
measured as a period of time for which ionization is well
performed. The measurement can be performed by measuring the
signals output from the sensors using an oscilloscope or a circuit
for generating a vibration control signal of a probe and a circuit
for generating a vibration control signal of a solid specimen. Note
that such circuits are included in a gate signal generation circuit
(described in more detail below).
[0068] The threshold voltage can be set to any value. The threshold
voltage is set to detect a period of time for which the probe 1 is
located in close proximity to the ion entrapment unit 7 or a period
of time for which the XY stage 8 and the Z stage 9 are vibrating. A
voltage pulse is output from a waveform generator or the gate
signal generation circuit (described in more detail below) in
synchronization with a period of time for which ionization is well
performed. The voltage pulse is input to the input terminal of a
gate signal of the ion counter 21.
[0069] If a feedback circuit is provided in the displacement
calculation device 23, the displacement calculation device 23 can
automatically maintain stable vibration. When the probe 1 scans the
solid specimen 3, a slight variation of the frequency or the
amplitude may occur. At that time, by measuring a shift of a signal
output from each of the displacement sensor 16 and the displacement
sensor 20 from a reference signal that can be set in the
displacement calculation device 23, generating a signal that
corrects the shift, and outputting the signal to the specimen stage
control device 11 and the voltage applying apparatus 12, stable
scan can be performed. Note that the reference signal is a signal
having a desired waveform used to determine the frequency and the
amplitude of vibration of each of the probe 1 and the Z stage
9.
[0070] In addition, a slight timing shift may occur between the
vibration of the probe 1 and the vibration of the Z stage 9 due to,
for example, electrical wiring between the components and the
electric capacitances of the components illustrated in FIG. 1. In
such a case, by providing a delay circuit that controls the timing
in the displacement calculation device 23, the timing shift between
the vibration of the probe 1 and a control signal and the timing
shift between the vibration of the Z stage 9 and a control signal
can be compensated for.
[0071] According to the present exemplary embodiment, by selecting
one of the drive modes (A), (B), and (C), the following processes
are alternately performed: (i) a process to supply liquid from a
probe onto a solid specimen and form a liquid bridge between the
probe and the solid specimen, and (ii) a process to generate an
electric field for generating ions between the conductive portion
of the probe in contact with the liquid and an ion extraction
electrode. That is, by changing the position of one end of the
probe that vibrates, the position of the probe can be set to the
position optimum for performing each of the processes (i) and
(ii).
[0072] By intermittently or continuously providing the liquid from
the probe 1, the liquid bridge 4 is formed. When the liquid bridge
4 is formed, the probe 1 may or may not be in contact with the
solid specimen 3. If the probe 1 is in contact with the solid
specimen 3, the liquid bridge 4 can be formed more reliably. The
liquid bridge 4 is formed from liquid that bridges between 1 and
the solid specimen 3. The liquid bridge 4 is formed by using, for
example, the surface tension. A substance contained in the solid
specimen 3 is dissolved in the liquid bridge 4. The liquid bridge 4
is formed in an atmospheric pressure environment. The volume of the
liquid bridge 4 is minutely small and is approximately
1.times.10-12 mL. The liquid bridge 4 is located in part of the
surface of the solid specimen 3. The dimensions of the part of the
surface of the solid specimen 3 is approximately 1.times.10-8
m2.
[0073] When the probe 1 moves away from the solid specimen 3 due to
the vibration, liquid that forms the liquid bridge 4 moves closer
to the ion entrapment unit 7 including the ion extraction electrode
electrically connected to the voltage applying apparatus 18. At
that time, the liquid moves to the side surface of the probe 1
adjacent to the ion entrapment unit 7 to form the Taylor cone 5 due
to the potential difference between the electric potential of the
liquid having the voltage applied thereto and the electric
potential of the ion extraction electrode having the voltage
applied by the voltage applying apparatus 18 (preferably 0.1 kV or
higher and 10 kV or lower and, more preferably, 3 kV or higher and
5 kV or lower). As used herein, the term "side surface" refers to a
portion of the probe 1 in which the electrospray occurs. In FIG. 1,
the Taylor cone 5 is formed on a continuous surface that forms the
long axis direction of the probe 1. However, since this location is
influenced by, for example, the electric field generated between
the ion entrapment unit 7 and the liquid and the wettability of the
probe 1 with the liquid, the Taylor cone 5 may be formed at a
location that includes a surface other than the above-described
surface.
[0074] The magnitude of the electric field increases in the top end
portion of the Taylor cone 5 and, thus, electrospray is generated
from the mixed solution. Accordingly, fine charged liquid droplets
6 are generated. By setting the magnitude of the electric field to
an appropriate value, Rayleigh breakup of the charged liquid
droplets occurs and, thus, ions of a particular component can be
generated. The charged liquid droplets and the ions are led to the
ion entrapment unit 7 by the airflow and the electric field. At
that time, in order to increase the electric field in the vicinity
of the solvent that forms the Taylor cone, it is desirable that
vibration of the probe 1 include the motion to move close to the
ion entrapment unit 7.
[0075] Note that the term "Rayleigh breakup" refers to a phenomenon
that when the fine liquid droplets 6 reach the Rayleigh limit,
excessive charge in the charged liquid droplets are released in the
form of secondary liquid droplets. It is known that liquid forms a
Taylor cone. Electrospray including charged liquid droplets is
generated from the top end portion of the Taylor cone. For a period
of time for which Rayleigh breakup occurs, a component contained in
the charged liquid droplets turns into gas-phase ions. In addition,
a threshold voltage Vc for the occurrence of the electrospray is
given as follows:
Vc=0.863(.gamma.d/.epsilon.0).sup.0.5
where .gamma. denotes the surface tension of the liquid, d denotes
the distance between the liquid and the ion extraction electrode,
and .epsilon.0 denotes the permittivity of vacuum (refer to J. Mass
Spectrom. Soc. Jpn. Vol. 58, 139-154, 2010).
[0076] To evaporate the solvent from the charged liquid droplets
generated through the electrospray and generate ions, the ion
entrapment unit 7 is heated at a particular temperature between a
room temperature and several hundred degrees. In addition, a
voltage is applied to the ion entrapment unit 7. At that time, to
generate an appropriate electric field that generates ions, it is
necessary to adjust the voltage that is applied to the liquid by
the voltage applying apparatus 18 serving as an electric field
generating unit and the voltage that is applied to the ion
extraction electrode by the voltage applying apparatus 18. Examples
of the voltage applied by the voltage applying apparatus 12 include
a DC voltage, an AC voltage, a pulse voltage, zero volt, and any
desired combinations thereof. Note that the electric field for
generating ions is determined by the electric potential applied to
the electrically conductive portion of the probe 1, the electric
potential of the ion entrapment unit 7, and the distance between
the liquid and the ion entrapment unit 7. Accordingly, these
electric potentials and distance need to be set so that an
appropriate electric field is generated in accordance with the type
of substance to be ionized and the type of solvent.
[0077] Subsequently, the ions are introduced into the mass
spectrometry unit 17 connected to the ion entrapment unit 7 through
a differential exhaust system, and the mass-to-charge ratio of the
ions is measured in the mass spectrometry unit 17. Any one of a
quadrupole mass spectrometer, a time-of-flight mass spectrometer, a
magnetic sector mass spectrometer, an ion-trap mass spectrometer,
and an ion-cyclotron mass spectrometer can be used as the mass
spectrometry unit 17. In addition, by measuring a correlation
between the mass-to-charge ratio (mass number/charge number)
(hereinafter, referred to as "m/z") of the ions and the amount of
generated ions, the mass spectrum can be obtained.
[0078] Furthermore, to fix the specimen onto the substrate and
ionize the specimen, the coordinates of the position of a portion
of the specimen to be ionized can be controlled by changing the
position of the XY stage 8 using the specimen stage control device
10. Still furthermore, by associating the coordinates of the
ionized positions (positional information) with the obtained mass
spectra, the two-dimensional distribution of the mass spectrum can
be obtained. Data obtained using this technique is
three-dimensional data containing the coordinates (an X coordinate
and a Y coordinate) of the ionized position and the mass spectrum.
After the ionization and the mass spectrum acquisition are
performed at different positions, the amount of ions having a
desired mass-to-charge ratio is selected, and the distribution
thereof is displayed. In this manner, a mass image can be obtained
for each of the components, and the distribution of a particular
component across the surface of the specimen can be captured. The
specimen can be moved so that the liquid bridge 4 formed by the
probe 1 scans a desired plane of the solid specimen 3 to be
measured.
[0079] The image forming unit 22 identifies a portion of the
surface of the solid specimen 3 to be ionized. That is, the image
forming unit 22 identifies a portion of the surface of the solid
specimen 3 to be analyzed by the mass spectrometry apparatus.
Thereafter, the image forming unit 22 can move the solid specimen 3
using the XY stage 8 and the Z stage 9 so that the substance
contained in the portion is included in the Taylor cone 5 via the
liquid bridge 4.
[0080] Each of the image forming unit 22 and the displacement
calculation device 23 is formed from, for example, a computer.
[0081] The image forming unit 22 receives at least a signal output
from the ion counter 21 and outputs signals to the specimen stage
control apparatus 10.
[0082] The displacement calculation device 23 receives at least a
signal output from the displacement sensor 16 and outputs signals
to the voltage applying apparatus 12 and the specimen stage control
apparatus 11.
[0083] When the probe 1 scans the surface of the solid specimen 3,
a movement process of the probe 1 and a process of ionization and
measurement of the number of ions are alternately performed. At
that time, by setting up the image forming unit 22 and the
displacement calculation device 23, scanning of the probe 1 can be
performed after a predetermined number of ionization processes and
measurements of the number of ions are performed. In this manner,
the quantitative capability of the three-dimensional data can be
increased and, thus, the amounts of ions in the mass images at all
the coordinates can be quantitatively compared with one another.
Any scanning unit that allows the probe 1 to relatively scan the
surface of the specimen can be used as the scanning unit of the
probe 1. That is, either the above-described scanning unit that
moves the specimen stage with the position of the probe 1 fixed or
a scanning unit that moves the probe 1 with the position of the
specimen stage fixed can be employed.
[0084] According to the present exemplary embodiment, the image
forming unit 22 of the mass spectrometry apparatus generates image
information used for displaying, as an image, the distribution of a
substance contained in the solid specimen 3 from information
regarding the position of the solid specimen 3 to be analyzed (a
portion of the solid specimen 3 to be analyzed) in the image
forming unit 22 and the mass information (the mass spectrum)
obtained from the ion counter 21 according to the above-described
present exemplary embodiment.
[0085] According to the present exemplary embodiment, the imaging
system includes the mass spectrometry apparatus according to the
above-described present exemplary embodiment and an image display
unit.
[0086] The image information output from an output sub-unit of the
image forming unit 22 is output to an output unit (the display unit
24, such as a flat panel display) connected to the image forming
unit 22. Thus, the image is displayed. The image information may be
two-dimensional image information or three-dimensional image
information. The output unit may be a unit that prints an image
(e.g., a printer).
[0087] As described above, a substance that is dissolved from a
particular position of the solid specimen 3 into the liquid bridge
4 can be detected on the basis of the result of mass spectrometry
at the particular position of the solid specimen 3. By changing the
particular position in the surface of the solid specimen 3 and
performing mass spectrometry at the position, mass spectrum data
can be obtained. By combining the mass spectrum data with the
information regarding the particular position, the distribution of
the substance in the solid specimen 3 (in most cases, the
distribution of the substance across the surface of the solid
specimen 3) is obtained and is displayed (superimposed) as an
image.
[0088] In addition to the position of the substance, the amount of
the substance is displayed. The amount of the substance is
represented by a color or the brightness of the image. In addition,
if multiple substances contained in the solid specimen 3 are
analyzed, the substances can be identified by using different
colors, and the amount thereof can be represented by the brightness
thereof. Furthermore, a pre-captured microscope image of the solid
specimen 3 may be superimposed on the image regarding the mass of
the solid specimen 3 and may be displayed.
Second Exemplary Embodiment
[0089] A second exemplary embodiment using a synchronization
circuit is described below.
[0090] To synchronize the timing of vibration of the probe 1 and
the timing of vibration of the stage with the gate signal, it is
desirable to use a circuit for generating a synchronous signal that
synchronizes the vibration control signal of the probe 1 with the
vibration control signal of the stage or that synchronizes the
output signal of the displacement sensor 16 with the output signal
of the displacement sensor 20.
[0091] FIG. 5 illustrates an example of a synchronization circuit
capable of performing such control, a device controlled by the
output signal output from the synchronization circuit, and a device
that generates an input signal input to the synchronization
circuit.
[0092] As illustrated in FIG. 5, the synchronization circuit
includes a reference clock generating circuit 101, the displacement
calculation device 23, a signal selection switch 102, and a gate
signal generating circuit 103. The displacement calculation device
23 includes a circuit for generating a vibration control signal for
a probe and a circuit for generating a vibration control signal for
the solid specimen.
[0093] In addition, the apparatuses that are controlled by the
output signal output from the synchronization circuit include the
voltage applying apparatus 12, the vibration providing unit 2, the
probe 1, the specimen stage control device 11, the Z stage 9, and a
data acquiring device 108. The data acquiring device 108 is formed
from an ion counter 104, a primary memory 105, a data filter 106,
and a storage 107.
[0094] Furthermore, the apparatuses that generate an input signal
input to the synchronization circuit include the displacement
sensor 16 and the displacement sensor 20.
[0095] To achieve the synchronization circuit according to the
present exemplary embodiment, a field programmable gate array
(FPGA) or an application specific integrated circuit (ASIC) can be
used. By using a FPGA or an ASIC, a plurality of control circuits
(23, 101, 102, and 103) can be implemented in an integrated
circuit. Thus, the control timing of the control circuits can be
accurately adjusted at high speed.
[0096] The displacement calculation devices 23 measure the
frequencies, the amplitudes, and the phases of vibration of the
probe 1 and the stage using the electric signal output from the
displacement sensor 16 and the displacement sensor 20. In addition,
the displacement calculation devices 23 output signals for
controlling the vibration of the probe 1 and the Z stage 9 to the
voltage applying apparatus 12 and the specimen stage control device
11. The voltage signal is one of a triangle wave signal, a square
wave signal, a sine wave signal, and a cosine wave signal. The
displacement calculation device 23 for vibration of the probe 1
includes a circuit that generates a signal for controlling
vibration of the probe 1, and the displacement calculation device
23 for vibration of the Z stage 9 includes a circuit that generates
a signal for controlling vibration of the Z stage 9. The
displacement calculation devices 23 may be provided as independent
circuits for the probe 1 and the Z stage 9. Alternatively, the
displacement calculation devices 23 may be provided in the same
circuit board.
[0097] Each of the displacement calculation devices 23 includes a
feedback circuit that makes the phase difference between each of a
signal output from the displacement sensor 16 and the displacement
sensor 20, which correspond to the actual vibration of the probe 1
and the Z stage 9, and a voltage signal generated on the basis of a
reference clock generated by the reference clock generating circuit
101 zero. When the feedback circuit operates, the probe 1 and the Z
stage 9 vibrate at a constant frequency and with a constant phase
difference. Such a drive mechanism is generally referred to as a
phase locked loop (PLL). In addition, by providing a delay
compensation circuit in the PLL circuit, a voltage signal having a
desired delay time with respect to the reference signal can be
generated.
[0098] The output signals output from the displacement sensor 16,
the displacement sensor 20, and the displacement calculation device
23 are also input to the signal selection switch 102. The signal
selection switch 102 selects one of the output signals output from
the displacement sensor 16 and the displacement calculation device
23 and inputs the selected signal to the gate signal generating
circuit 103.
[0099] The gate signal generating circuit 103 can use the input
signal as a reference signal. Thus, the gate signal generating
circuit 103 can be set up so as to output a particular voltage
signal for a period of time for which the voltage value of the
reference signal exceeds a predetermined threshold value. In
addition, a desired delay time can be set so that the output time
of the voltage is extended from the period of time for which the
voltage value of the reference signal exceeds a predetermined
threshold value forward and backward in the time direction.
According to the present exemplary embodiment, ionization occurs
during a period of time for which the reference signal exceeds the
threshold value. However, if the polarity of each of the output
signals of the displacement sensors and the displacement
calculation device 23 is reversed, the voltage signal may be output
for a period of time for which the voltage value of the reference
signal is less than the threshold value. The voltage signal is one
of a positive voltage, a negative voltage, and 0 volt.
[0100] The output signal generated by the gate signal generating
circuit 103 is input as the gate voltage signal of the ion counter
104. Setup is performed so that the ion counter 104 operates for a
period of time for which the gate signal is being output.
[0101] A method for storing the voltage signal output from the ion
counter 104 as digital data is described below. The signal output
from the ion counter 104 is analog-to-digital (A/D) converted and
is stored in the primary memory 105 for a predetermined period of
time. The measurement data corresponding to the type of ion to be
measure are selected and are stored in the storage 107 formed from
a hard disk drive (HDD) or a solid state drive (SSD). The process
for selecting the data is performed in the data filter 106 by a
computer program. Thereafter, the primary memory 105 is overwritten
with new data. Alternatively, the new data is written in another
area. By selecting data and storing the data in the storage 107,
the total amount of data can be reduced. If ions to be measured are
predetermined, the method can be applied. In contrast, if ions that
are not predetermined are detected, all the data obtained by the
data filter 106 can be stored in the storage 107.
[0102] Note that the above-described synchronization method is
employed when both the probe 1 and Z stage 9 vibrate. However, when
one of the probe 1 and the Z stage 9 vibrates, a gate signal is
generated by stopping the displacement calculation device 23 for
vibration of the probe 1 or the Z stage 9 and the downstream
control device and inputting the output signals output from the
driven displacement calculation device 23 and displacement sensor
to the signal selection switch 102.
Third Exemplary Embodiment
[0103] According to a third exemplary embodiment, the ionization
device includes a holding table for holding a specimen, a probe for
identifying a portion of the specimen to be ionized, an ion
extraction electrode for extracting ions generated by ionizing the
specimen, a liquid supplying unit for supplying liquid to form a
liquid bridge between the specimen and the probe, and a voltage
applying unit for applying a voltage to a portion of the probe
between a portion in contact with the liquid bridge and the ion
extraction electrode.
[0104] In addition, the ionization device includes a vibrating unit
that causes at least the probe to repeatedly move close to and away
from the holding table. The vibrating unit causes the probe to
vibrate at one of at least two frequencies, one of which is the
frequency for forming a liquid bridge and the other is a frequency
higher than that frequency.
[0105] FIG. 6 is a schematic illustration of an imaging system
including the ionization device according to the third exemplary
embodiment. The imaging system includes a probe 201 having a flow
passage therein, where the flow passage allows liquid to flow
through, a probe vibrating unit 202 that vibrates the probe 201, a
solid specimen 203, a liquid bridge 204 formed between the probe
201 and the solid specimen 203, a Taylor cone 205, charged fine
liquid droplets 206, an ion entrapment unit 207 having an ion
extraction electrode for entrapping ions into a mass spectrometry
apparatus, an XY stage 208 serving as a holding table that holds
the solid specimen 203, a Z stage 209 for moving the solid specimen
203 serving as a holding table vibrating unit in the vertical
direction (a Z direction) in FIG. 6, specimen stage control units
210 and 211 serving as signal transmitters for transmitting
vibration signals to the stages, a voltage applying unit 212, a
liquid supply unit 213 that supplies liquid to the probe 201, a
voltage applying unit 214, light sources 215 and 219, displacement
sensors 216 and 220, a mass spectrometry unit 217, a voltage
applying unit 218, an image information generating unit 221, a
displacement calculation unit 222, and a display unit 223.
[0106] According to the present exemplary embodiment, liquid
supplied from the liquid supply unit 213 forms the liquid bridge
204 between the solid specimen 203 and the probe 201. The solid
specimen 203 is an object formed from an object to be measured that
is placed on one of a metal substrate, an insulating material
substrate, and a semiconductor substrate. The object to be measured
requires that the component distribution in the microregion of, for
example, a biological tissue or bodily fluid is measured. In
addition, part of the liquid that forms the liquid bridge 204 is
turned into charged fine liquid droplets 206 by the vibration of
the probe 201 and an electric field generated by the voltage
applying unit 214 and the voltage applying unit 218, where the
voltage applying unit 214 applies a voltage between a portion of
the probe 201 in contact with the liquid bridge 4 and the ion
extraction electrode. Thus, the charged fine liquid droplets 206
move away from the probe 201. The solvent components of the charged
fine liquid droplets 206 that move away from the probe 201 are
evaporated and, thus, the component to be measured can be entrapped
in the ion entrapment unit 207 in the form of ions. That is,
according to the present exemplary embodiment, the probe 201
functions as a supply unit for supplying liquid onto the substrate
and an acquiring unit of the substance, a transport unit for
transporting the liquid to a position that is suitable for
ionization, and a forming unit for forming a Taylor cone 205 for
ionization.
[0107] The liquid supply unit 213 supplies the solvent for
dissolving a component to be analyzed contained in the solid
specimen 203 or mixed solution of a component to be analyzed and
the solvent (hereinafter, the solvent and the mixed solution are
collectively and simply referred to as "liquid"). The liquid
supplied from the liquid supply unit 213 is led to the flow passage
in the probe 201. At that time, a voltage is applied to the liquid
by the voltage applying unit 214. The voltage applied to the liquid
is one of a DC voltage, an AC voltage, a pulse voltage, and zero
volt.
[0108] The configurations of the probe 201 and a connection pipe
that connects the probe 201 to the liquid supply unit 213 are
similar to those of the above-described exemplary embodiments.
[0109] The liquid supplied from the liquid supply unit 213 is
supplied from the top end of the probe 201 onto the solid specimen
203. In this manner, a minutely small amount of the substance
contained in the solid specimen 203 can be ionized in an
atmospheric pressure environment.
[0110] In the above-described configuration according to the
present exemplary embodiment, the probe 201 is also vibrated. Note
that according to the present exemplary embodiment, the vibration
of the probe 201 is the periodic motion of the probe 201 such that
the position of the top end of the probe 201 adjacent to the solid
specimen 203 is spatially displaced. In particular, it is desirable
that the probe 201 is bending-vibrated in a direction crossing the
axis direction of the probe 201. In addition, it is desirable that
the probe 201 be vibrated due to mechanical vibration provided from
the probe vibrating unit 202.
[0111] The frequency and amplitude of the vibration of the probe
201 may be set to desired values. The values may be constant values
or modulated values. For example, by varying a voltage value or a
frequency value output from the voltage applying unit 212 that is
electrically connected to the probe vibrating unit 202, the
amplitude and frequency of the vibration of the probe 201 can be
adjusted to the desired values.
[0112] The Z stage 209 is used to bear the solid specimen 203 and
vibrate the solid specimen 203 in a direction perpendicular to the
surface of the solid specimen 203. The Z stage 209 can vibrate on
the basis of a control signal output from the specimen stage
control unit 211 connected to the Z stage 209. The frequency and
amplitude of the vibration may be set to desired values. The values
may be constant values or modulated values. In such a case, by
varying a voltage value or a frequency value output from the
specimen stage control unit 211, the amplitude and frequency of the
vibration can be adjusted to the desired values.
[0113] Like the first exemplary embodiment, the light source 215
and the displacement sensor 216 serve as a displacement measuring
unit used to measure the vibration of the probe 201.
[0114] Similarly, the light source 219 and the displacement sensor
220 serve as a displacement measuring unit used to measure the
vibration of the XY stage 208 and the Z stage 209.
[0115] The electric signals output from the displacement sensor 216
and the displacement sensor 220 are input to the displacement
calculation unit 222. The frequency, the amplitude, and the phase
of the vibration of the probe and the stage can be measured using
the electric signals.
[0116] According to the present exemplary embodiment, a vibration
unit that vibrates the probe is independent from a vibration unit
that vibrates the specimen. Accordingly, the following three
vibratory modes can be provided as a drive mode.
[0117] That is, the three vibratory modes are (D) a mode for
vibrating the probe, (E) a mode for vibrating the solid specimen,
and (F) a mode for independently vibrating the probe and the solid
specimen at the same time.
[0118] FIG. 6 illustrates the drive modes (D) and (F). In the drive
mode (E), provision of a signal from the voltage applying unit 212
to the probe vibrating unit 202 is stopped, and the probe 201 is
located in close proximity to the solid specimen 203 or is in
contact with the solid specimen 203.
[0119] In the drive mode (D) in which only the probe 201 is
vibrated, a signal is input to the probe vibrating unit 202, and
provision of a signal to the specimen stage control unit 211 is
stopped. As a result, the probe 201 vibrates, and the vibration of
the Z stage 209 is stopped.
[0120] In the drive mode (E) in which the solid specimen 203 is
vibrated, provision of a signal to the probe vibrating unit 202 is
stopped, and a signal is input to the specimen stage control unit
211. As a result, the probe 201 is stopped, and the Z stage 209
vibrates. If the probe 201 is in contact with a surface of the
solid specimen 203, vibration of the Z stage 209 propagates to the
probe 201. Accordingly, the probe 201 can be vibrated. Even in such
a case, the drive mode (E) is applied.
[0121] In the drive mode (F) in which the probe 201 and the solid
specimen 203 are independently vibrated, a signal is input to the
probe vibrating unit 202. At the same time, a signal is input to
the specimen stage control unit 211. As a result, the probe 201 and
the Z stage 209 independently vibrate.
[0122] If the drive modes (D) and (E) are selected, the amplitudes
of vibration of the probe 201 and the Z stage 209 are modulated,
respectively. FIGS. 7A and 7B illustrate examples of the amplitude
modulation in the drive modes (D) and (E).
[0123] When the drive mode (D) is selected, the amplitude of
vibration corresponds to a time variation of the input signal input
to the probe 201. When the drive mode (E) is performed, the
amplitude of vibration corresponds to a time variation of the input
signal input to the Z stage 209. There is a correspondence between
the input signal and the amplitude of each of the probe 201 and the
Z stage 209. Accordingly, by measuring the input signal, the
amplitude of each of the probe 201 and the Z stage 209 can be
estimated.
[0124] FIGS. 7A and 7B illustrate different input signal patterns.
In FIG. 7A, a waveform obtained by combining a sine wave and a
square wave is illustrated. In FIG. 7B, a waveform obtained by
combining a sine wave and a triangle wave is illustrated. In such a
case, a sine wave is used as a fundamental vibration signal, and a
square wave or a triangle wave is used as a vibration signal for
modulation. Thus, the combined signal is generated. To generate the
combined signal, the two types of signal are multiplied together,
and the product is used as the combined signal. However, addition,
subtraction, or division and any combination thereof can be
employed to generate the combined signal. The frequency of the
fundamental vibration signal is set so as to be the same as the
resonance frequency of the probe 201 or the Z stage 209. In
addition, the frequency of the vibration signal for modulation is
set so as to be the same as the frequency used for generating the
liquid bridge 204. It is desirable that two types of signal be
selected from among a triangle wave signal, a sine wave signal, a
square wave signal, and a saw-tooth wave signal as the fundamental
vibration signal and the vibration signal for modulation.
[0125] In addition, it is desirable that the frequency of one of
the two vibration signals be an integral multiple (2 or more) of
the frequency of the other vibration signal, and the phase
difference between the vibration indicated by one of the vibration
signals and the vibration indicated by the other vibration signal
be 0 or 180 degrees.
[0126] That is, according to the present exemplary embodiment, the
vibrating unit is a probe vibrating unit for vibrating the probe. A
configuration to reduce the frequency used for forming the liquid
bridge to an integer fraction of the frequency of vibration of the
probe by modulating the amplitude of vibration of the probe is
provided.
[0127] Setup is made so that at times 201 and 203 at which the
absolute value of the amplitude is maximized, the probe 201 is
located so as to be the closest to the solid specimen 203. In a
time window around each of the times 201 and 203, the liquid bridge
204 is formed between the probe 201 and the solid specimen 203, and
ionization is performed. In contrast, in the durations 202 and 204
for which the amplitude is small, the liquid bridge 204 is not
formed between the probe 201 and the solid specimen 203 and, thus,
the component of the solid specimen is not ionized. In this manner,
by adjusting the modulation frequency of the vibration amplitude,
the number of formation processes of the liquid bridge 204 can be
controlled. The liquid bridge 204 is formed at the time 201 and the
times 203, and the component contained in the surface of the solid
specimen 203 is dissolved in the liquid deposited to the top end of
the probe 201. The component is ionized in the durations 202 or the
durations 204. Since the solvent continuously flows into the probe
201 even in the duration 202 and the duration 204, the liquid
deposited onto the top end of the probe 201 is diluted by the
solvent. The component contained in the surface of the solid
specimen 203 is ionized over time and, thus, the component in the
liquid disappears. In addition, the top end of the probe 201 is
cleaned by the solvent that newly flows into the probe 201. As
described above, by modulating the vibration amplitude, each of the
duration in which the liquid bridge 204 is formed and the duration
in which the liquid bridge 204 is not formed can be set to a
desired value. As a result, unlike Tapping-mode SPESI described in
Non-patent literature above, carry-over can be prevented.
[0128] If the drive mode (F) is selected, two types of vibration
signal (i.e., a signal for vibration of a probe transmitted to the
probe vibrating unit 202 and a signal for vibration of a holding
table transmitted to the holding table vibrating unit are employed.
Thus, the probe 201 and the Z stage 209 vibrate at their own
frequencies. At that time, it is desirable that the frequency of
vibration of the probe 201 be an integral multiple (2 or more) of
the frequency of the Z stage 209, which is the vibrating unit of
the holding table, and the phase difference between the vibration
of the probe 201 and the vibration of the Z stage 209 be 0 or 180
degrees. FIG. 8 illustrate an example of the vibration signals
input to the probe 201 and the Z stage 209.
[0129] In this example, signals input to the specimen stage control
unit 211 and the voltage applying unit 212 are illustrated. Note
that in this example, the frequency of vibration of the probe 201
is 5 times the frequency of vibration of the Z stage 209.
Accordingly, the Z stage 209 moves closest to the probe 201 once
every five vibrations of the probe 201. A waveform chart (a) of
FIG. 8 illustrates the input signal input to the probe 201.
Waveform charts (b), (c), and (d) of FIG. 8 illustrate examples of
the input signals input to the Z stage 209. In the waveform chart
(a) of FIG. 8, the ordinate is correlated with the position of the
probe 201 in the Z direction. As can be seen from the waveform
chart (a) in FIG. 8, the probe 201 vibrates between a state 1 in
which the probe 201 is the closest to the solid specimen 3 and a
state 2 in which the probe 201 is the closest to the ion entrapment
unit 207. The ordinates in waveform charts (b), (c), and (d) of
FIG. 8 are correlated with the position of the surface of the solid
specimen 203 in the Z direction. As can be seen from the waveform
charts (b), (c), and (d) of FIG. 8, the probe 201 vibrates between
a state 4 in which the probe 201 is the closest to the solid
specimen 3 and, thus, a liquid bridge is formed and a state 3 in
which the solid specimen 203 moves away from the probe 201 and,
thus, the liquid bridge 204 disappears.
[0130] In a time window around the time 201 at which the probe 201
is located closest to the solid specimen 203, a liquid bridge is
formed between the probe 201 and the solid specimen 203, and
ionization occurs. In the other time window, a liquid bridge is not
formed and, thus, the component of the solid specimen is not
ionized. As described above, by independently adjusting the
frequencies of vibration of the probe 201 and the Z stage 209, each
of the duration in which a liquid bridge is formed and the duration
in which a liquid bridge is not formed can be set to a desired
value. Thus, carry-over can be prevented. According to the present
exemplary embodiment, in addition to advantages that are the same
as in the above-described drive modes (D) and (E), an advantage
that the absolute value of the distance between the probe 1 and the
Z stage 9 is increased due to vibration of both the probe 201 and Z
stage 209 can be provided. Note that it is desirable that the
present exemplary embodiment be applied when the irregularity of
the surface profile of the solid specimen 203 is significant and,
thus, the vibration amplitude of the probe 201 is increased so that
formation of the liquid bridge 204 and ionization are stably
performed. While the present exemplary embodiment has been
described with reference to the control signals of the specimen
stage control unit 211 and the voltage applying unit 212 being a
triangle wave, a sine wave, or a square wave, the waveform is not
limited thereto. For example, the waveform may be a sawtooth
waveform or a waveform obtained by combining a triangle wave, a
sine wave, a square wave, and a sawtooth wave illustrated in FIG.
7B.
[0131] In each of the drive modes (D), (E), and (F), the vibration
state is measured by using the displacement calculation unit 122.
Thereafter, control signals are output from the displacement
calculation unit 222 to the specimen stage control unit 211 and the
voltage applying unit 212 so that a desired vibration state is
obtained. At that time, by providing a feedback circuit in the
displacement calculation unit 222, a stable vibration condition can
be automatically maintained. In addition, a slight timing shift may
occur between vibration of the probe 201 and vibration of the Z
stage 209 due to, for example, electrical wiring between the parts
and the electric capacitances of the parts illustrated in FIG. 6.
In such a case, by providing a delay circuit that controls the
timing in the feedback circuit, the timing shift between actual
vibration of the probe 201 and a control signal and the timing
shift between actual vibration of the Z stage 209 and a control
signal can be compensated for.
[0132] According to the present exemplary embodiment, by using one
of the drive modes (D), (E), and (F), the following processes are
alternately performed: (i) a process to supply liquid from a probe
onto a solid specimen and form a liquid bridge containing the
substance between the probe and the solid specimen, and (ii) a
process to generate an electric field for generating ions between
the conductive portion of the probe in contact with the liquid and
an ion extraction electrode. That is, by changing the position of
one end of the probe that vibrates, an optimum positional
relationship can be set in each of the processes (i) and (ii). In
terms of the timing of formation of the liquid bridge, in the drive
mode (D), the liquid bridge is formed at a frequency lower than the
resonance frequency of the probe. In the drive mode (E), the liquid
bridge is formed at a frequency lower than the resonance frequency
of the Z stage. In the drive mode (F), the liquid bridge is formed
at a frequency lower than each of the probe and the Z stage.
[0133] By intermittently or continuously providing the liquid from
the probe 201, the liquid bridge 204 is formed.
[0134] When the probe 201 moves away from the solid specimen 203
due to the vibration, liquid that forms the liquid bridge 204 moves
closer to the ion entrapment unit 207 including the ion extraction
electrode electrically connected to the voltage applying unit 218.
At that time, the liquid moves to the side surface of the probe 201
adjacent to the ion entrapment unit 207 to form the Taylor cone 205
due to the potential difference between the electric potential of
the liquid having the voltage applied thereto and the electric
potential of the ion extraction electrode having the voltage
applied by the voltage applying unit 218 (preferably 0.1 kV or
higher and 10 kV or lower and, more preferably, 3 kV or higher and
5 kV or lower).
[0135] The magnitude of the electric field increases in the top end
portion of the Taylor cone 205 and, thus, electrospray is generated
from the mixed solution. Accordingly, fine charged liquid droplets
206 are generated.
[0136] The ion entrapment unit 207 is heated at a particular
temperature between a room temperature and several hundred degrees.
In addition, a voltage is applied to the ion entrapment unit
207.
[0137] Subsequently, the ions are introduced into the mass
spectrometry unit 217 connected to the ion entrapment unit 207
through a differential exhaust system, and the mass-to-charge ratio
of the ions is measured in the mass spectrometry unit 217.
[0138] In addition, by measuring a correlation between the
mass-to-charge ratio (mass number/charge number) of the ions and
the amount of generated ions, the mass spectrum can be
obtained.
[0139] According to the present exemplary embodiment, unlike the
case in which one of a probe and a Z stage is vibrated with a
constant amplitude and at a constant frequency and, in addition,
the number of vibrations per unit time is the same as the number of
formation processes of the liquid bridge, carry-over can be
prevented.
[0140] In addition, to fix a specimen onto the substrate and ionize
the specimen, the coordinates of the position of a portion of the
specimen to be ionized can be controlled by changing the position
of the XY stage 208 using the specimen stage control unit 210.
Furthermore, by associating the coordinates of the ionized
positions (positional information) with the obtained mass spectra,
the two-dimensional distribution of the mass spectrum can be
obtained. Data obtained using this technique is three-dimensional
data containing the coordinates (an X coordinate and a Y
coordinate) of the ionized position and the mass spectrum. After
the ionization and the mass spectrum acquisition are performed at
different positions, the amount of ions having a desired
mass-to-charge ratio is selected, and the distribution thereof is
displayed. In this manner, a mass image can be obtained for each of
the components, and the distribution of a particular component
across the surface of the specimen can be captured. The specimen
can be moved so that the liquid bridge 204 formed by the probe 201
scans a desired plane to be measured.
[0141] Waveform charts (a) to (e) of FIG. 9 illustrate the timing
of driving the probe 201, the Z stage 209, and the XY stage 208 in
the drive modes (D), (E), and (F). The waveform chart (a) of FIG. 9
illustrates the pattern of an input signal input to the probe 201
or the Z stage 209 in the drive mode (D) or (E). The waveform chart
(b) of FIG. 9 illustrates the pattern of a signal input to the XY
stage 208 in the drive mode (D) or (E). As in FIGS. 7A and 7B, the
liquid bridge 204 is formed in the time window around the time 201.
Thereafter, the liquid bridge 204 disappears, and ionization
occurs. Subsequently, at the time 202, a signal is input to the XY
stage 208 and, thus, the position in the surface of the solid
specimen 203 to be analyzed is moved.
[0142] The waveform chart (c) of FIG. 9 illustrates the pattern of
an input signal input to the probe 201 in the drive mode (F). The
waveform chart (d) of FIG. 9 illustrates the pattern of an input
signal input to the Z stage 209 in the drive mode (F). The waveform
chart (e) of FIG. 9 illustrates the pattern of an input signal
input to the XY stage 208 in the drive mode (F). As in the waveform
charts (a) to (d) of FIG. 8, the liquid bridge 204 is formed in the
time window around the time 201. Thereafter, the liquid bridge 204
disappears, and ionization occurs. Subsequently, at the time 202, a
signal is input to the XY stage 208 and, thus, the position in the
surface of the solid specimen 203 to be analyzed is moved. By
adjusting the time 202 so that the component dissolved in the
liquid bridge 204 is ionized between the time 201 and the time 202
in this manner, carry-over in the liquid bridge 204 formed after
the time 202 can be prevented.
[0143] The displacement calculation unit 222 identifies a portion
of the surface of the solid specimen 203 to be ionized. That is,
the displacement calculation unit 222 identifies a portion of the
surface of the solid specimen 203 to be analyzed by the mass
spectrometry unit 217. Thereafter, the displacement calculation
unit 222 can move the solid specimen 203 using the XY stage 208 and
the Z stage 209 so that the substance contained in the portion is
included in the Taylor cone 205 via the liquid bridge 204. The
displacement calculation unit 222 is formed from, for example, a
computer. The displacement calculation unit 222 receives at least a
signal output from the displacement sensor 216 and outputs signals
to the voltage applying unit 212, the specimen stage control unit
210, and the specimen stage control unit 211.
[0144] According to the present exemplary embodiment, the image
information generating unit 221 connected to the mass spectrometry
unit 217 generates image information used for displaying, as an
image, the distribution of a substance contained in the solid
specimen 203 from information regarding the position of the solid
specimen 203 to be analyzed (a portion of the solid specimen 203 to
be analyzed) received from the displacement calculation unit 222
and the mass information (the information regarding the signal
intensity of the mass spectrum) obtained from the mass spectrometry
unit 217 according to the above-described present exemplary
embodiment.
[0145] According to the present exemplary embodiment, the imaging
system includes the mass spectrometry apparatus according to the
above-described present exemplary embodiment as a mass spectrometry
apparatus unit. The imaging system further includes the image
information generating unit and the image display unit.
[0146] The image information output from an output sub-unit of the
image information generating unit 221 is input to the display unit
223, such as a flat panel display, connected to the image
information generating unit 221. Thus, the image is displayed. The
image information may be two-dimensional image information or
three-dimensional image information.
[0147] As described above, a substance that is dissolved from a
particular position of the solid specimen 203 into the liquid
bridge 204 can be detected on the basis of the result of mass
spectrometry at the particular position of the solid specimen 203.
By changing the particular position in the surface of the solid
specimen 203 and performing mass spectrometry at the position, mass
spectrum data can be obtained. By combining the mass spectrum data
with the information regarding the particular position, the
distribution of the substance in the solid specimen 203 (in most
cases, the distribution of the substance across the surface of the
solid specimen 203) is obtained and is displayed (superimposed) as
an image.
[0148] In addition to the position of the substance, the amount of
the substance is displayed. The amount of the substance is
represented by a color or the brightness of the image. In addition,
if multiple substances contained in the solid specimen 203 are
analyzed, the substances can be identified by using different
colors, and the amount thereof can be represented by the brightness
thereof. Furthermore, a pre-captured microscope image of the solid
specimen 203 may be superimposed on the image regarding the mass of
the solid specimen 203 and may be displayed.
[0149] While the present invention has been described with
reference to exemplary embodiments, it is to be understood that the
invention is not limited to the disclosed exemplary embodiments.
The scope of the following claims is to be accorded the broadest
interpretation so as to encompass all such modifications and
equivalent structures and functions.
[0150] This application claims the benefit of Japanese Patent
Application No. 2013-161331 filed Aug. 2, 2013, and No. 2013-183962
filed Sep. 5, 2013, which are hereby incorporated by reference
herein in their entirety.
* * * * *