Note: Descriptions are shown in the official language in which they were submitted.
CA 02479872 2008-06-10
52675-5
IONIZATION APPARATUS AND METHOD FOR
MASS SPECTROMETER SYSTEM
Field of the Invention
This invention relates generally to the field of mass spectrometry, and more
particularly to sample ionization for mass spectrometer system. More
particularly,
this invention relates to an ionization apparatus and method for connection to
a mass
analyzer to improve mass analysis by seamlessly combining sample ionization
and
sample analysis.
Background of the Invention
Mass analysis of any, sample in a mass spectrometer requires sample ionization
as a first step. Sample ionization can be performed under either vacuum or
atmospheric pressure. Vacuum ionization techniques include electron impact
ionization, fast ion bombardment, secondary ion ionization, and matrix-
assisted laser
deposition/ionization. Vacuum ionization occurs inside a mass spectrometer
instrument under vacuum conditions. A disadvantage of vacuum ionizations is
that a
sample support must be inconveniently introduced into the vacuum via vacuum
locks,
making the linking of mass spectrometry with chromatographic and
electrophoretic
separation methods difficult.
Atmospheric pressure ionization takes place outside of the low pressure
components of a mass spectrometer instrument. To sample atmospheric pressure
ions,
a mass spectrometer must be equipped with an atmospheric pressure interface-
(API) to
transfer ions from an atmospheric pressure region to the mass analyzer under
high
vacuum. Atmosphericpressure ionization techniques include atmospheric pressure
chemical ionization and electrospray ionization (ESn among others. One problem
of
many prior art atmospheric pressure ionization techniques is the low
transmission
efficiency of sample ions to a mass analyzer due to ion losses and low
throughput of
ions for mass analysis due to non-seamless connection of atmospheric sample
ionization and sample analysis under high vacuum.
U.S. Patent No. 5,663,561 describes a device and method for ionizing analyte
molecules at atmospheric pressure by chemical ionization. According to this
method,
the analyte molecules deposited together with a decomposable matrix material
are first
decomposed in the surrounding gas under atmospheric pressure to produce
neutral
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gas-phase analyte molecules. Then these neutral gas-phase analyte molecules
are
ionized by atmospheric pressure chemical ionization. This method requires that
the
desorption of the analyte be carried out as a separate step from the
ionization of the
analyte.
U.S. Patent No. 5,965,884 describes an atmospheric pressure matrix assisted
laser desorption ionization (AP-MALDI) ion source. The AP-MALDI apparatus
contains an atmospheric pressure ionization chamber hosting a sample to be
analyzed,
a laser system outside the ionization chamber, and an interface that connects
the
ionization chamber to the spectrometer. While this AP-MALDI apparatus combines
analyte desorption and ionization in a single step, it cannot be operated at
an optimum
pressure regime, and ion transmission from the ionization chamber to the
spectrometer
is low. Moreover, analyte adducting is high and undesired molecular clusters
are
formed during the ionization process.
EP 0964427 A2 describes a MALDI ion source operating at pressures greater
than 0.1 torr. While the claimed ion source may be operated at a greater
pressure
range, it has the same problems as U.S. Patent No. 5,965,884: low ion
transmission,
high adducting among analytes and other molecules and undesired cluster
formation.
WO 99/38185 and U.S. Patent No. 6,331,702 BI describe a spectrometer
provided with a pulsed ion source and transmission device to damp ion motion
and
method of use. This design requires a sample loading chamber or lock chamber
and a
low pressure MALDI ion source, and has limited throughput.
WO 00/77822 A2 describes a MALDI ion source that is enclosed in a chamber
and operated under a low pressure and has a limited throughput.
U.S. Patent No. 6,331,702 B1 describes a MALDI ion source that is disposed
in a vacuum chamber and has a limited throughput.
Objects and Summary of the Invention
Accordingly it is an object of the present invention to provide an ionization
apparatus for connecting to a mass analyzer to seamlessly combine sample
ionization
and sample analysis.
It is another object of the present invention to provide an ionization
apparatus
for fast sample scanning to increase throughput of mass analysis.
It is a further object of the present invention to provide an ionization
apparatus
which allows sample preparation at atmospheric pressure to increase
reliability and
reduce construction cost of mass analysis systems.
In accordance with the invention, there is provided an ionization apparatus
for
connection to a mass analyzer. The ionization apparatus comprises a sample
slide
having at least two sample spots containing analytes to be analyzed by a mass
analyzer, means for delivering energy to one of the sample spots to release
and ionize
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the sample analytes to form sample ions, and an interface for supplying the
sample
ions to the mass analyzer. The interface comprises a chamber having an orifice
in
close proximity to the irradiated sample spot and defining a first region
encompassing
the irradiated sample spot. An ion guide is disposed in the chamber and leads
to the
mass analyzer in a second region. Means for sustaining a pressure
substantially lower
than atmospheric within the first region is provided for capturing the ions
while other
sample spots are maintained at atmospheric pressure. Means for sustaining a
pressure
within the second region substantially lower than the pressure within the
first region is
provided.
The means for delivering energy is disposed such that the energy irradiates
one
of the sample spot through the orifice in front of the irradiated sample spot.
Alternatively, the means for delivering energy is disposed such that the
energy
irradiates one of the sample spots from the back of a transparent sample
slide.
The ionization apparatus may comprise a motorized stage for moving the
sample slide to sequentially present sample spots to the first region. The
motorized
stage can be computer controlled and moveable in three dimensions. The sample
slide
is preferably disposed in proximity of about from 50 to 100 microns to the
interface.
The ionization apparatus may comprise a cover slide that seamlessly takes
place of the sample slide with the same proximity to the orifice when the
sample slide
moves away during sample change.
The means for sustaining a pressure substantially lower than atmospheric
within the first region can maintain a pressure from few torr to few tens
torr. The
means for sustaining a pressure within the second region can maintain a
pressure from
about 0.001 to about 0.1 torr.
In another embodiment of the present invention, there is provided an
ionization
apparatus further comprising an external groove surrounding the orifice to
stabilize
the pressure within the first region. This ionization apparatus may further
comprise
spacing balls for engaging the sample slide and the interface to accurately
space the
slide from the orifice.
In another aspect of the present invention, there is provided a method for
ionizing analytes in a sample for mass spectrometer analysis. The method
comprises
providing a sample slide having at least two sample spots containing analytes
to be
analyzed by a mass analyzer and providing an interface connecting one of the
sample
spots to the analyzer. The interface is provided with a chamber having an
orifice in
close proximity to one of the sample spots and defining a first region
encompassing
the sample spot. An ion guide is disposed in the chamber leading to the mass
analyzer
in a second region. Energy is delivered to one of the sample spots to release
and
ionize the analytes to form ions. A pressure substantially lower than
atmospheric is
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sustained within the first region while maintaining atmospheric pressure at
other
sample spots. A pressure within the second region substantially lower than the
pressure within the first region is provided.
In another embodiment of the present invention, the ionization apparatus
comprises a sample slide that is provided with at least two channels
therethrough.
Samples are deposited on the inner surfaces of the channels. Means for
delivering
energy such as a laser irradiates the sample in one of the channels and
ionizes the
sample to form ions. An interfacial orifice is aligned with and in close
proximity to
the channel and collects ions formed in the channel. Preferably the sample
slide is
provided with a plurality of channels, and each channel is sequentially
brought in
registration with the interfacial orifice by moving the sample slide in three
directions.
The ionization apparatus may further comprise means for applying a voltage
between
the sample slide and the orifice for accelerating ion flow. The energy
delivery means
is disposed such that energy is directed to the samples. The energy delivery
means
may include a focusing lens aligned with and movable along the axis of the
channel to
deliver energy to the entire inner surface of the channel. Alternatively, the
energy
delivery means may include an optical fiber having an end movable along the
axis of
the channel to deliver energy to the entire inner surface of the channel.
In still another embodiment, the ionization apparatus includes a spacer
attached onto the sample slide on the side facing the orifice. The spacer is
provided
with holes that have the same pattern and dimension as and in registration
with the
channels in the sample slide. The spacer can be made of electrically non-
conductive
materials. In operation, the sample slide-spacer assembly can be brought in
tight
contact with the orifice to increase suction force of gas flow and provide
electrical
insulation between the sample slide and the orifice.
Brief Description of the Drawings
The foregoing and other objects of the invention will be more clearly
understood from the following description when read in conjunction with the
accompanying drawings in which:
Figure 1 is a schematic view of an ionization apparatus including a laser
source delivering energy to a sample spot through an orifice in front of a
sample slide.
Figure 2 is a schematic view of an ionization apparatus including a laser
source delivering energy to a sample spot from the back of a transparent
sample slide.
Figure 3 is a schematic view of an ionization apparatus having an interface
including a groove and spacing balls at an orifice in front of the sample
slide.
Figure 4 is a schematic view of an ionization apparatus including a sample
slide provided with a plurality of sample channels.
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Figure 5 is a schematic view of an ionization apparatus including a spacer
attached to the sample slide illustrated in Figure 4.
Figure 6 is an exploded view illustrating depositing samples into channels in
a
sample slide and attaching a spacer to the sample slide.
Figure 7 is a partial sectional view of an ionization apparatus illustrating
an
orifice in form of a truncated cone in contact with a spacer attached to a
sample slide
provided with channels.
Figure 8 is a partial sectional view of an ionization apparatus illustrating
an
orifice in form of a tube in contact with a spacer attached to a sample slide
provided
with channels.
Figures 9 and 10 are partial sectional views of ionization apparatus
illustrating
that energy beam irradiates samples in a channel at an angle with respect to
the axis of
the channel.
Figures 11 and 12 are partial sectional views of ionization apparatus
comprising a focus lens movable along the axis of the channel.
Figures 13 and 14 are partial sectional views of ionization apparatus
comprising an optical fiber having an end movable along the axis of the
channel.
Description of Preferred Embodiments
Figure 1 shows an embodiment 10 of an ionization apparatus of the present
invention. This ionization apparatus 10 comprises a sample slide 101 having at
least
two sample spots 100 containing sample analytes to be ionized, a laser source
104 for
delivering energy 112 to one of the sample spots 100 through a focus lens 105.
The
energy 112 ionizes the sample at the irradiated sample spot 100. An interface
15
collects ions generated at the irradiated sample spot 100 and delivers them to
a mass
analyzer (not shown) as indicated by arrow 103. The mass analyzer 103 can
comprise
a time of flight (TOF) mass analyzer, an ion trap mass analyzer, an orbitrap
mass
analyzer, a magnetic sector mass analyzer, or a Fourier transform mass
analyzer.
The sample slide 101 is maintained at atmospheric pressure and brought in
close proximity to the interface 15 by a motorized stage 111. The motorized
stage 111
is computer controlled and movable in three dimensions (x, y, z). A plurality
of
sample spots 100 are provided on the sample slide 101 so that they are brought
sequentially into position for ionization and analysis. Each individual sample
spot
100 is brought sequentially in registration with the interface 15 by driving
the
motorized stage 111 controlled by a computer (not shown). Materials that can
be used
for the sample slide 101 include electrically conductive metals such as
stainless steel,
insulating polymers such as teflon, and porous silica. It is apparent that the
sample
can be deposited together with a decomposable matrix material at the sample
spot 100
and the sample slide can be moved in the x-y-z directions to bring the spot in
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registration with the orifice 102 of the interface 15. A cover slide (not
shown)
seamlessly takes place of the sample slide with the same proximity to the
orifice
during sample change.
The walls of interface 15 form a chamber 118 having an orifice 102 which
captures ions generated at the irradiated sample spot 100. An ion guide 106 is
disposed in the chamber 118 to transport ions to the mass analyzer as
indicated by
arrow 103. Preferably, the orifice 102 is in the shape of a truncated cone and
is
brought into a close proximity to the sample slide 101 so that the irradiated
sample
spot 100 is located opposite the opening of the cone. The distance between the
irradiated sample spot 100 and the front surface of the orifice 102 can be
precisely
controlled by moving the motorized stage 111 in the x direction. Preferably,
the
distance is within from about 50 to 100 microns. A wall 17 is spaced from the
end of
the interface walls to define a subchamber 16 adjacent to the orifice 102. A
pump (not
shown) is connected to port 108 which communicates with the subchamber to
sustain
a pressure within the region 107 of the orifice 102 which is higher than the
pressure in
chamber 118. The pump can be a rotary vacuum pump and sustain a pressure from
few torr to few tens torr at the sample spot 100 being ionized. Accordingly,
the region
surrounding the sample spot 100 being ionized can be sustained a pressure
substantially lower than atmospheric while other sample spots 100 outside the
region
107 encompassed by the orifice 102 are maintained at atmospheric pressure.
An ion guide 106 is disposed inside the chamber 118 and extends from the
orifice 102 to a mass analyzer 103, forming a multipole region 109 through
which
sample ions are transported by combination of gas flows and electric fields.
The ion
guide 106 can be any transmission or trapping device. Preferably the ion guide
106 is
a RF-only multipole and can be heated. A turbo pump (not shown) is connected
to a
port 110 for sustaining a vacuum within the chamber 118. A valve (not shown)
is also
equipped at port 110 so that the pressure within the multipole region 109 can
be
adjusted from 0.001 to 0.1 torr for optimal performance.
A laser source 104 delivers energy such as a UV light, visible light, or IR
light
112 through a lens 105, which focuses the energy on one of the sample spots to
release and ionize the sample. The laser source 104 can irradiate pulsed or
continuous
energy to at least one sample at a time. In this embodiment 10 of the
ionization
apparatus, the laser source 104 and the lens 105 are disposed such that laser
energy
112 is delivered to one of the sample spots 100 through the orifice 102 in
front of the
sample spot 100.
Figure 2 shows another embodiment 20 of the ionization apparatus of the
present invention. The laser source 104 and the lens 105 are disposed such
that the
laser energy 112 is delivered to one of the sample spots 100 from the back of
the
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sample slide 101, either through a transparent slide, or the sample can be on
the end of
a transparent optical fiber. Preferably the sample slide or optical fiber is
made of
quartz.
Figure 3 shows another embodiment 30 of the ionization apparatus of the
present invention. In comparison with embodiments 10 and 20, embodiment 30 has
an external groove 113 surrounding the orifice at the end of the chamber 118.
The
groove 113 is evacuated through the chamber passage 116 connected to port 108,
preferably by a rotary pump connected to the port 108. This increases
robustness of
the differential pumping and stability of the pressure in the orifice region
107. To
further increase stability of the pressure in the orifice region 107, the gap
between the
sample slide 101 and the orifice 102 is fixed by introducing spaced ball
bearings 114.
This design provides a greater precision and accuracy for the gap between the
sample
slide 101 and orifice 102. The ball size can be chosen large enough, so that
the balls
roll over the sample spots 100 without reaching the bottoms of the wells 100
in which
the samples are located. This embodiment 30 can use either front or back laser
irradiation as illustrated in embodiments 10 and 20.
One advantage of the present invention is that sample analysis may be
seamlessly combined with sample ionization that makes the system ideal for
high-
throughput proteomics. Ion losses on the orifice are low. Another advantage is
that
vacuum seals are not needed between the sample spot being ionized and other
spots.
The motorized stage moving the sample slide can be operated at atmospheric
pressure.
This results in higher reliability and lower construction cost of ionization
system.
Moreover, the present ionization apparatus can increase throughput up to 1
second per
sample due to fast sample scanning and no time losses on sample introduction.
The
ionization system of the present invention is also advantageous in that it is
easy to
automate and interchangeable with ESI ion source, thus both proteomic tools
can be
used in parallel for the same sample.
Figure 4 shows another embodiment 40 of the ionization apparatus of the
present invention. In this embodiment 40, the sample slide 101 is provided
with at
least two channels 119. Samples 100 to be analyzed are deposited on the inner
surfaces of the channels 119. Preferably a plurality of channels 119 are
provided in
the sample slide 101 to increase throughput of mass analysis. The sample slide
101
can be moved in three directions (x-y-z) by the motorized stage 111 controlled
by a
computer to sequentially bring each channel 119 in registration with the
orifice 102.
The gap between the sample slide 101 and the orifice 102 is controlled by
moving the
sample slide 101 in x direction until it is closely adjacent the orifice 102.
In operation,
one channel is aligned with the orifice 102 and laser energy 112 irradiates
sample 100
to form ions which are captured at region 107 and guided to the mass analyzer
103 by
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combination of electrical field and gas flow. This embodiment 40 is
advantageous in
that the channels 119 in the sample slide 101 enhance the air-dynamic
properties of
gas flow and improve ion entrainment at the entrance to the orifice 102.
Figure 5 shows another embodiment 50 of the ionization apparatus of the
present invention. In this embodiment 50, a spacer 120 provided with channels
or
holes 121 is attached to the sample slide 101 on the side that faces the
orifice 102.
The holes 121 have substantially the same dimensions and patterns as the
channels
119 in the sample slide 101. When laser energy 112 irradiates the sample 100
in
operation, all three of the channel 119 in the sample slide 101, the hole 121
in the
spacer 120, and the orifice 102 are aligned on one axis. The sample slide 101
and
spacer 120 assembly can be moved in three directions (x-y-z) by the motorized
stage
111 to bring each channel 119 and hole 121 in registration with the orifice
102.
Preferably the sample slide and spacer assembly is brought in tight contact
with the
orifice 102 and slides across the orifice 102. This embodiment 50 is
advantageous in
that the spacer 120 increases suction force of gas flow through the channel
119 to the
orifice 102 and reproducibility of sample positioning with respect to the
orifice 102.
The spacer 120 also provides electrical insulation between the sample slide
120 and
the orifice 102 when a voltage is applied. In addition, the spacer protects
orifice 102
from sample carryover and prevents sample cross contamination.
In the embodiments 40 and 50 of the present ionization apparatus illustrated
in
Figures 4 and 5, the laser source 104 and lens 105 are disposed such that
laser energy
112 is delivered to one of the channels 119 from the back of the sample slide
101.
Alternatively, the laser source 104 can be disposed such that laser energy 112
is
delivered to one of the channels 119 through the orifice 102 in front of the
channel
119, as illustrated in Figures 2 and 3.
More detail structure of embodiments 40 and 50 of the ionization apparatus of
the present invention are now described with reference to Figures 6 to 14.
Figure 6 schematically shows channels 119 in sample slide 101 and deposition
of samples 100 in the channels 119. While Figure 6 shows the channels 119 in
shape
of a cylinder for illustration purpose, other shapes of channel can also be
used as long
as they increase gas flow in the channels and improve ion entrainment at the
orifice.
For example, the channels can also be shaped in a truncated cone. The channels
119
can be fabricated in an array on one plate 101 to enhance throughput of sample
deposition. The prior art methods of depositing samples on a flat surface can
be used
in depositing samples 100 in the channels 119. For instance, the samples 100
can be
mixed with an MALDI matrix and deposited in the channels 119 using known
deposition protocols and robots. The samples 100 are sucked inside the
channels 119
by capillary force. For example, a channel having a diameter of 0.65mm and a
length
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of 3mm can accommodate 1.O 1 of samples. After drying for a few minutes, only
solid residue remains in the channels 119. In the embodiment where a spacer
120 is
attached onto the sample slide 101 as illustrated in Figure 5, the sample
slide 101
provided with an array of channels 119 can be covered by an electrically
insulating
plate or spacer 120. The electrical insulating plate 120 is provided with a
plurality of
holes 121 that are of the same dimension and pattern as the channels 119 in
the sample
slide 101. The holes 121 in the insulating plate 120 are in registration with
the
channels 119 in the sample slide 101. The insulating plate 120 can be made
from
electrically nonconductive materials, such as glass, teflon, and plastic.
Preferably the
insulating plate 120 has smooth surfaces for tight attachment to the sample
slide and
better sliding across the orifice 102. The insulating plate or spacer 120
provides
electrical insulation between the sample slide 101 and orifice 102 and also
protects the
orifice 102 from cross contamination from different samples. The sample slide
and
spacer assembly so prepared can be stored in an autosampler waiting for
analysis.
After analysis, the sample slide 101 and spacer 120 can be washed and reused.
The channels 119 in the sample slide 101 preferably have a diameter that is
substantially same as or similar to the diameter of the orifice 102 at the
interface,
preferably ranging from about 0.2mm to 2mm. The length of the channels 119 can
be
several millimeter, preferably ranging from 0.5mm to 20mm. Preferably, a
plurality
of channels 119 are provided in the sample slide 101 to increase analysis
throughput.
In operation, each individual channel 119 is sequentially brought in
registration with
the orifice 102 for ionization and analysis. The distance between the sample
slide 101
and the orifice 102 is preferably within from about 50 to 100 microns for easy
access
of laser radiation to sample 100 and efficient collection of ions. In the
embodiment
where a spacer 120 is attached to the sample slide 101 as illustrated in
Figure 5, the
sample slide 101 and spacer 120 assembly is preferably brought in tight
contact with
the orifice 102. Any gap between the spacer 120 and the orifice 102 is defined
by the
surface roughness and tolerances of the spacer 120 and orifice 102, and is
much
smaller than the diameter of the channel 119, allowing the main gas stream
flows
through the channel 119.
Figures 7 and 8 schematically show the orifice 102 that is in alignment with
an
individual channel 119. In Figures 7 and 8, an insulating spacer 120 is
disposed
between the channel 119 and the orifice 102. Though the sample slide 101 and
spacer
assembly is shown as in contact with the orifice 102, this is not required. A
small gap
between the orifice 102 and sample slide 101 allows a faster sample changeover
and
therefore improve throughput of analysis. In the embodiment where spacer is
not used
as shown in Figure 4, the gap between the sample slide 101 and the orifice 102
is
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preferably controlled within 50 to 100 microns for better access for laser
irradiation of
samples and better gas flow and ion entrainment at the entrance to the orifice
102.
The orifice 102 can be in form of a skimmer as shown in Figure 7, or a tube as
shown in Figure 8. In both embodiments of skimmer and tube, the orifice 102
has a
diameter substantially same as the diameter of the channel 119 in the sample
slide
101, or the hole 121 in the spacer 120, at the interface between the orifice
102 and the
channel 119 or the hole 121. Preferably the diameter of the orifice 102 at the
interface
is from 0.2mm to 2mm.
To facilitate gas flow of ions formed in the channel 119 to the orifice 102,
and
eventually to the mass analyzer 103 through an ion guide, the pressure in the
channel
119 can be controlled. In the embodiment of a skimmer orifice 102 as shown in
Figure 7, the pressure in the channel 119 is preferably maintained from a few
Torr to a
few tenths of Torr. In the embodiment of a tube orifice 102 as shown in Figure
8, the
pressure in the channel 119 is preferably maintained from below atmosphere to
10
Torr. In one embodiment, a voltage 122 is applied between the channel 119 and
the
orifice 102 to facilitate gas flow of ions, as shown in Figures 7 and 8. Ions
of one
polarity are accelerated towards the orifice 102 by electrical field, while
ions of
opposite polarity are prevented from entering the orifice 102 by the voltage
122.
Figures 9 to 14 illustrate various means for delivering energy to the channel
119 to release and ionize samples 100. To better irradiate samples 100 on the
inner
surface of the channel 119, the laser beam 112 is preferably non-parallel to
the axis of
the channel 119. In one embodiment illustrated in Figures 9 and 10, the laser
beam
112 irradiates the sample 100 at a small angle with respect to the axis of the
channel
119. Preferably the angle ranges from 5 to 85 degrees with respect to the axis
of the
channel 119. In another embodiment illustrated in Figures 11 and 12, a focus
lens 105
is used where the laser beam 112, the focus lens 105, and the channel 119 are
aligned
on one axis. The laser beam 112 is focused in a focal point 124 in front of
the channel
119. Modern nitrogen lasers can be focused in a spot of 0.1 mm in diameter.
After
the focal point 124, divergent beam 126 irradiates entire channel 119. To
reach
deeper into the channel 119, the focusing lens 105 is preferably movable along
the
axis of the channel 119 in x direction. In another embodiment illustrated in
Figures 13
and 14, an optical fiber 130 is used to create a symmetrical, divergent laser
beam 132
with point source in front of the channel 119. To reach deeper into the
channel 119,
the end 131 of the optical fiber 130 is preferably movable along the axis of
the
channel 119 in x direction.
One advantage of the ionization apparatus comprising a sample slide provided
with channels is that during sample preparation steps, the channels can be
used for
fraction collection from HPCL, for automatic sample deposition by an
autosampler,
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for mixing sample and MALDI matrix solutions, and for sample purification and
affinity separation.
The foregoing description of specific embodiments and examples of the
invention have been presented for the purpose of illustration and description,
they are
not intended to be exhaustive or to limit the invention to the precise forms
disclosed.
Obviously many modifications, embodiments, and variations are possible in
light of
the above teaching. It is intended that the scope of the invention encompass
the
generic area as herein disclosed, and by the claims appended hereto and their
equivalents.
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