U.S. patent application number 15/905954 was filed with the patent office on 2018-09-06 for preprocessing apparatus and analysis system comprising the preprocessing apparatus.
This patent application is currently assigned to SHIMADZU CORPORATION. The applicant listed for this patent is SHIMADZU CORPORATION. Invention is credited to Nobuhiro HANAFUSA.
Application Number | 20180252682 15/905954 |
Document ID | / |
Family ID | 61526512 |
Filed Date | 2018-09-06 |
United States Patent
Application |
20180252682 |
Kind Code |
A1 |
HANAFUSA; Nobuhiro |
September 6, 2018 |
PREPROCESSING APPARATUS AND ANALYSIS SYSTEM COMPRISING THE
PREPROCESSING APPARATUS
Abstract
Disclosed herein is a preprocessing apparatus that makes it
possible to highly efficiently analyze specimens held by solid
media, such as dried blood spots to be used for newborn mass
screening or the like. The preprocessing apparatus includes: a
preprocessing container setting part in which a preprocessing
container containing a solid sample including a specimen to be
analyzed and a solid medium holding the specimen is to be set; a
carrying mechanism that carries the preprocessing container set in
the preprocessing container setting part; and a preprocessing part
that has a port for setting the preprocessing container carried by
the carrying mechanism and that is configured to perform
preprocessing including extraction processing for extracting the
specimen from the solid sample contained in the preprocessing
container set in the port.
Inventors: |
HANAFUSA; Nobuhiro;
(Kyoto-shi, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SHIMADZU CORPORATION |
Kyoto-shi |
|
JP |
|
|
Assignee: |
SHIMADZU CORPORATION
Kyoto-shi
JP
|
Family ID: |
61526512 |
Appl. No.: |
15/905954 |
Filed: |
February 27, 2018 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G01N 33/49 20130101;
G01N 30/06 20130101; G01N 1/405 20130101; G01N 2001/4011 20130101;
G01N 35/00584 20130101; B01L 2200/0631 20130101; G01N 1/4005
20130101; G01N 1/40 20130101; G01N 2001/288 20130101; G01N
2035/00524 20130101; G01N 35/10 20130101; G01N 2035/0441 20130101;
B01L 2300/0681 20130101; G01N 35/04 20130101; G01N 1/28 20130101;
G01N 2035/00485 20130101; G01N 2030/027 20130101; B01L 3/502
20130101; G01N 2030/009 20130101; G01N 2035/0443 20130101; B01L
2400/049 20130101; G01N 2030/062 20130101 |
International
Class: |
G01N 30/06 20060101
G01N030/06; G01N 1/28 20060101 G01N001/28; G01N 33/49 20060101
G01N033/49 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 3, 2017 |
JP |
2017-040356 |
Claims
1. A preprocessing apparatus comprising: a preprocessing container
setting part in which a preprocessing container containing a solid
sample comprising a specimen to be analyzed and a solid medium
holding the specimen is to be set; a carrying mechanism that
carries the preprocessing container set in the preprocessing
container setting part; and a preprocessing part that has a port
for setting the preprocessing container carried by the carrying
mechanism and that is configured to perform preprocessing including
extraction processing for extracting the specimen from the solid
sample contained in the preprocessing container set in the
port.
2. The preprocessing apparatus according to claim 1, wherein the
preprocessing container setting part is configured to allow an
empty preprocessing container containing no specimen to be also set
therein, the preprocessing apparatus further comprising: a specimen
setting part in which a specimen container containing a liquid
specimen is to be set; a specimen dispensing part that takes the
specimen from the specimen container set in the specimen setting
part and dispenses the specimen into the empty preprocessing
container placed in a predetermined dispensing position; and a
specimen recognition part that checks whether a specimen to be
analyzed is a liquid specimen or a specimen contained in the solid
sample.
3. The preprocessing apparatus according to claim 2, further
comprising a preprocessing operation part that is configured to,
when the specimen recognition part recognizes that a specimen to be
analyzed is a liquid specimen, allow the carrying mechanism to
carry the empty preprocessing container set in the preprocessing
container setting part to the dispensing position, allow the
specimen dispensing part to dispense the specimen to be analyzed
into the preprocessing container, and then allow the carrying
mechanism to carry the preprocessing container to the preprocessing
part to perform predetermined preprocessing, and that is configured
to, when the specimen recognition part recognizes that a specimen
to be analyzed is a specimen contained in the solid sample, allow
the carrying mechanism to carry the preprocessing container
containing the solid sample and set in the preprocessing container
setting part to the preprocessing part to perform predetermined
preprocessing including the extraction processing.
4. The preprocessing apparatus according to claim 3, wherein the
preprocessing part has a plurality of extraction ports for
performing the extraction processing, and the preprocessing
operation part is configured to, when the specimen recognition part
recognizes that a specimen to be analyzed is a specimen contained
in the solid sample, search the available extraction port and allow
the carrying mechanism to carry the target preprocessing container
to the available extraction port to perform the extraction
processing.
5. The preprocessing apparatus according to claim 2, wherein the
preprocessing container setting part is configured to allow a
plurality of preprocessing containers to be set therein, the
preprocessing apparatus further comprising: a solid sample setting
information holding part that holds information about a position
where the preprocessing container containing the solid sample is
set in the preprocessing container setting part; and a
preprocessing container identification part configured to, when a
specimen to be analyzed is a specimen contained in the solid
sample, identify the preprocessing container containing the solid
sample containing the specimen on a basis of the information held
in the solid specimen setting information holding part.
6. An analysis system comprising: the preprocessing apparatus
according to claim 1 comprising a transfer device that has a
transfer port where the preprocessing container containing a
specimen that has been subjected to preprocessing in the
preprocessing part is to be set by the carrying mechanism and that
is configured to move the transfer port to transfer the container
set in the transfer port to an outside of the preprocessing
apparatus; and a liquid chromatographic system that is provided
adjacent to the preprocessing apparatus and that has an analytical
flow path that allows a mobile phase to flow therethrough, a sample
injector that takes, as a sample, the specimen contained in the
container moved to the outside of the preprocessing apparatus by
the transfer device and injects the sample into the analytical flow
path, an analytical column provided on the analytical flow path to
separate the sample injected by the sample injector into individual
components, and a detector that detects the sample components
separated by the analytical column.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
[0001] The present invention relates to a preprocessing container
for performing preprocessing such as extraction processing for
extracting, as a sample, necessary components contained in a living
body-derived sample such as whole blood, blood serum, blood plasma,
dried blood spot, or urine by removing a specific component
unnecessary for analysis from the living body-derived sample, a
preprocessing apparatus that automatically performs preprocessing
using the preprocessing container, and an analysis system that
comprises the preprocessing apparatus and automatically performs a
series of processes from preprocessing of a sample to analysis.
2. Description of the Related Art
[0002] When the quantitative analysis of a sample such as a
biological sample is performed, there is a case where it is
necessary to perform processing for extracting necessary components
as a sample by removing a specific component unnecessary for
analysis from the biological sample or drying/solidifying
processing for concentrating or drying/solidifying an extracted
sample. Various preprocessing apparatuses that automatically
perform such preprocessing have heretofore been proposed and
practically used (see, for example, JP 2010-60474 A).
[0003] For example, JP 2010-60474 A discloses that a plurality of
cartridges holding a separating agent that separates a specific
component by allowing a sample to pass therethrough are held by a
common carrying mechanism, these cartridges are sequentially placed
in a pressure applying mechanism provided in a predetermined
position by the carrying mechanism, and pressure is applied to each
of the cartridges in the pressure applying mechanism to perform
sample extraction. In this case, a plurality of extract receivers
that receive extracts from the cartridges are moved relative to the
cartridges below the cartridges by a carrying mechanism different
from the carrying mechanism for cartridges so that the receivers
are sequentially placed in the pressure applying mechanism to
continuously perform sample extraction.
[0004] However, in the case of the above-described system, the
carrying mechanism for cartridges and the carrying mechanism for
extract receivers cannot be moved while sample extraction
processing is performed in the pressure applying mechanism, and
therefore there is a limit to improving preprocessing efficiency.
Therefore, the present inventor has proposed that a set of a
separation device having a filter for filtering a sample and a
collection container for collecting an extracted sample discharged
from the separation device is carried in a random access manner to
a port where processing such as filtration processing or stirring
processing is performed to improve preprocessing efficiency (see WO
2016/017042 A1 and JP 2016-170079 A).
SUMMARY OF THE INVENTION
[0005] The analysis of dried blood spots, such as newborn mass
screening, is generally performed in batch mode by placing dried
blood spots in wells of a plate having a plurality of wells, such
as a 96-well plate. However, such a batch mode analysis is poor in
operation efficiency and has high running costs unless a fairly
large number of specimens are analyzed. Further, it is necessary to
perform preprocessing sequentially from the first specimen, and
therefore, there is a time lag between the preprocessing of the
first specimen and the preprocessing of the last specimen, which
impairs the accuracy of analysis.
[0006] Further, in such a batch mode analysis method as described
above, specimen management and preprocessing such as reagent
dispensing are manually performed, and therefore, problems such as
mix-up of specimens and variation in the amount of a reagent
dispensed, are likely to occur. In order to overcome such problems,
it is desired that dried blood spots be automatically and more
efficiently analyzed.
[0007] It is therefore an object of the present invention to make
it possible to highly efficiently analyze specimens held by solid
media, such as dried blood spots to be used for newborn mass
screening or the like.
[0008] The present invention is directed to a preprocessing
apparatus comprising: a preprocessing container setting part where
a preprocessing container containing a solid sample comprising a
specimen to be analyzed and a solid medium holding the specimen is
to be set; a carrying mechanism that carries the preprocessing
container set in the preprocessing container setting part; and a
preprocessing part that has a port for setting the preprocessing
container carried by the carrying mechanism and that is configured
to perform preprocessing including extraction processing for
extracting the specimen from the solid sample contained in the
preprocessing container set in the port.
[0009] Here, the solid sample refers to a sample in which a
specimen is held by a solid medium. In the present invention, the
term "solid medium" refers to a medium having the function of
holding a liquid material or a dried and solidified liquid material
in or on its membrane, such as filter paper, cotton, gauze, a PTFE
(polytetrafluoroethylene) membrane, a nylon membrane, a
polypropylene membrane, a PVDF (polyvinylidene fluoride) membrane,
an acrylic copolymer membrane, a mixed cellulose membrane, a
nitrocellulose membrane, a polyethersulfone membrane, an
ion-exchange membrane, or a glass fiber membrane. Examples of the
specimen to be held by such a solid medium include living
body-derived specimens such as whole blood, blood serum, urine, and
saliva.
[0010] It is preferred that the preprocessing container setting
part is configured to allow an empty preprocessing container
containing no specimen to be also set therein, and the
preprocessing apparatus further comprises a specimen setting part
where a specimen container containing a liquid specimen is to be
set, a specimen dispensing part that takes the specimen from the
specimen container set in the specimen setting part and dispenses
the specimen into the empty preprocessing container placed in a
predetermined dispensing position, and a specimen recognition part
that checks whether a specimen to be analyzed is a liquid specimen
or a specimen contained in the solid sample. This makes it possible
to perform not only preprocessing of a specimen contained in the
solid sample but also preprocessing of a liquid specimen.
[0011] In this case, it is preferred that the preprocessing
apparatus further comprises a preprocessing operation part that is
configured to, when the specimen recognition part recognizes that a
specimen to be analyzed is a liquid specimen, allow the carrying
mechanism to carry the empty preprocessing container set in the
preprocessing container setting part to the dispensing position,
allow the specimen dispensing part to dispense the specimen to be
analyzed into the preprocessing container, and then allow the
carrying mechanism to carry the preprocessing container to the
preprocessing part to perform predetermined preprocessing, and that
is configured to, when the specimen recognition part recognizes
that a specimen to be analyzed is a specimen contained in the solid
sample, allow the carrying mechanism to carry the preprocessing
container containing the solid sample and set in the preprocessing
container setting part to the preprocessing part to perform
predetermined preprocessing including the extraction
processing.
[0012] It is preferred that the preprocessing part has a plurality
of extraction ports for performing the extraction processing, and
the preprocessing operation part is configured to, when the
specimen recognition part recognizes that a specimen to be analyzed
is a specimen contained in the solid sample, search the available
extraction port and allow the carrying mechanism to carry the
target preprocessing container to the available extraction port to
perform the extraction processing. This makes it possible to, when
there is an available extraction port, carry the preprocessing
container to the available extraction port to perform specimen
extraction processing in a random access manner, which improves
preprocessing efficiency.
[0013] It is preferred that the preprocessing container setting
part is configured to allow a plurality of preprocessing containers
to be set therein, and the preprocessing apparatus further
comprises a solid sample setting information holding part that
holds information about a position where the preprocessing
container containing the solid sample is set in the preprocessing
container setting part and a preprocessing container identification
part configured to, when a specimen to be analyzed is a specimen
contained in the solid sample, identify the preprocessing container
containing the solid sample containing the specimen on a basis of
the information held in the solid sample setting information
holding part. This makes it possible to previously register the
position of the preprocessing container containing the solid sample
on the solid sample setting information holding part so that the
position of the preprocessing container containing the solid sample
can be automatically identified, the target preprocessing container
can be carried to the preprocessing part by the carrying mechanism,
and preprocessing of a specimen contained in the solid sample can
be automatically performed.
[0014] The present invention is also directed to an analysis system
comprising: the above-described preprocessing apparatus including a
transfer device that has a transfer port where the preprocessing
container containing a specimen that has been subjected to
preprocessing in the preprocessing part is to be set by the
carrying mechanism and that is configured to move the transfer port
to transfer the container set in the transfer port to an outside of
the preprocessing apparatus; and a liquid chromatographic system
that is provided adjacent to the preprocessing apparatus and that
has an analytical flow path that allows a mobile phase to flow
therethrough, a sample injector that takes, as a sample, the
specimen contained in the container moved to the outside of the
preprocessing apparatus by the transfer device and injects the
sample into the analytical flow path, an analytical column provided
on the analytical flow path to separate the sample injected by the
sample injector into individual components, and a detector that
detects the sample components separated by the analytical
column.
[0015] The preprocessing apparatus according to the present
invention comprises: a preprocessing container setting part where a
preprocessing container containing a solid sample comprising a
specimen to be analyzed and a solid medium holding the specimen is
to be set; a carrying mechanism that carries the preprocessing
container set in the preprocessing container setting part; and a
preprocessing part that has a port for setting the preprocessing
container carried by the carrying mechanism and that is configured
to perform preprocessing including extraction processing for
extracting the specimen from the solid sample contained in the
preprocessing container set in the port. This makes it possible to
individually and efficiently perform preprocessing of a specimen
held by a solid medium such as filter paper regardless of the
number of specimens. Since the preprocessing of a specimen is
automatically performed in the preprocessing part, errors and
variations caused by manual work performed by an analyst are
eliminated, and therefore the accuracy of analysis results can be
improved.
[0016] In the analysis system according to the present invention, a
specimen can be subjected to preprocessing in the preprocessing
apparatus described above, and then the specimen that has been
subjected to preprocessing can be automatically introduced into a
liquid chromatographic system to be subjected to a separating
analysis. This makes it possible to fully automatically perform a
series of processes from the preprocessing of a specimen contained
in a solid sample such as dried blood spot to analysis without
human intervention. Since the analysis system is operated without
human intervention, errors and variations caused by manual work are
eliminated, and therefore the accuracy of analysis results is
improved.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1 is a plan view showing an embodiment of a
preprocessing apparatus;
[0018] FIG. 2A is a cross-sectional view showing an example of a
separation device of a preprocessing container;
[0019] FIG. 2B is a cross-sectional view showing an example of a
collection container of the preprocessing container;
[0020] FIG. 2C is a cross-sectional view showing the preprocessing
container in which the collection container is attached to the
separation device;
[0021] FIG. 2D is a cross-sectional view showing another example of
the separation device;
[0022] FIG. 3A is a schematic perspective view of an example of a
solid sample;
[0023] FIG. 3B is a diagram showing the separation device
containing a solid sample;
[0024] FIG. 4A is a plan view showing a filtration port;
[0025] FIG. 4B is a cross-sectional view taken along a line X-X in
FIG. 4A;
[0026] FIG. 4C is a cross-sectional view taken along a line Y-Y in
FIG. 4A;
[0027] FIG. 4D is a sectional configuration diagram showing a state
in which the preprocessing container is set in the filtration
port;
[0028] FIG. 5 is a schematic flow path configuration diagram
showing the configuration of a negative-pressure applying
mechanism;
[0029] FIG. 6A is a sectional configuration diagram showing the
structure of a stirring part;
[0030] FIG. 6B is a sectional configuration diagram showing a state
in which the stirring part is operated;
[0031] FIG. 7 is a block diagram showing a control system according
to this embodiment;
[0032] FIG. 8 is a flowchart showing an example of the operation of
checking the state of a specimen before the start of preprocessing
operations according to this embodiment;
[0033] FIG. 9 is a flowchart showing an example of preprocessing
operations for solid sample according to this embodiment;
[0034] FIG. 10 is a flowchart showing an example of preprocessing
operations for liquid specimen according to this embodiment;
[0035] FIG. 11 is a block diagram schematically showing an
embodiment of an analysis system;
[0036] FIG. 12 is a flow path configuration diagram showing the
configuration of a liquid chromatographic system according to this
embodiment;
[0037] FIG. 13A is a front view showing another example of the
separation device of the preprocessing container;
[0038] FIG. 13B is a cross-sectional view of the separation device
shown in FIG. 13A;
[0039] FIG. 14A is a front view showing another example of the
collection container of the preprocessing container; and
[0040] FIG. 14B is a cross-sectional view of the collection
container shown in FIG. 14A.
DETAILED DESCRIPTION OF THE INVENTION
[0041] An embodiment of a preprocessing apparatus will be described
with reference to FIG. 1.
[0042] A preprocessing apparatus 1 according to this embodiment
performs a necessary preprocessing item with the use of a prepared
preprocessing container comprising a set of a separation device 50
and a collection container 54 for each specimen. The preprocessing
apparatus 1 has a plurality of processing ports for performing
different preprocessing items, and is configured to allow the
preprocessing container containing a specimen to be set in any one
of the processing ports to perform a preprocessing item
corresponding to the processing port on the specimen contained in
the preprocessing container. Each of the processing ports will be
described later. The preprocessing item refers to the item of
preprocessing necessary for performing an analysis item designated
by an analyst.
[0043] The separation device 50 and the collection container 54
constituting the preprocessing container are carried by a carrying
arm 24 constituting a carrying mechanism. The carrying arm 24 has,
on its tip side, a holding part 25 for holding the separation
device 50 and the collection container 54. The base end of the
carrying arm 24 is held by a vertical shaft 29, and therefore the
carrying arm 24 rotates about the vertical shaft 29 in a horizontal
plane so that the holding part 25 draws an arc-shaped track. All
the processing ports and other ports, to which the separation
device 50 and the collection container 54 are to be carried, are
provided along the arc-shaped track drawn by the holding part
25.
[0044] A specimen setting part 2 for setting a specimen container 6
containing a liquid specimen is provided, and a sampling arm 20 is
provided adjacent to the specimen setting part 2 as a specimen
dispensing part for taking the specimen from the specimen container
set in the specimen setting part 2. In the specimen setting part 2,
a sample rack 4 for holding the specimen containers 6 is annularly
provided. The specimen setting part 2 rotates in a horizontal plane
so as to circumferentially move the sample rack 4, and therefore, a
desired one of the specimen containers 6 is placed in a
predetermined sampling position by the rotation of the specimen
setting part 2. The sampling position refers to a position which is
along the track of a sampling nozzle 20a provided at the tip of the
sampling arm 20 and in which a specimen is taken by the sampling
nozzle 20a.
[0045] The sampling arm 20 has a base end through which a vertical
shaft 22 passes, and therefore rotates about the shaft 22 in a
horizontal plane and moves up and down in a vertical direction
along the shaft 22. The sampling nozzle 20a is held on the tip side
of the sampling arm 20 in such a manner that the tip of the
sampling nozzle 20a faces vertically downward, and the sampling
nozzle 20a is moved in a horizontal plane so as to draw an
arc-shaped track and is moved up and down in a vertical direction
by the sampling arm 20.
[0046] A dispensing port 32 is provided in a position on the track
of the sampling nozzle 20a and on the track of the holding part 25
of the carrying arm 24. The dispensing port 32 is a port where the
sampling nozzle 20a dispenses a specimen into the unused separation
device 50. The unused separation device 50 is set in the dispensing
port 32 by the carrying arm 24. Further, the dispensing port 32 is
also used to add a reagent to the separation device 50 containing a
specimen or to add a reagent to the separation device 50 containing
a solid sample that will be described later.
[0047] A reagent setting part 8 for setting a reagent container 10
is provided on the inner side of the specimen setting part 2, and a
reagent arm 26 (reagent adding part) for taking a reagent from the
reagent container set in the reagent setting part 8 is provided.
The base end of the reagent arm 26 is supported by the vertical
shaft 29 shared with the carrying arm 24, and therefore, the
reagent arm 26 rotates in a horizontal plane and moves up and down.
A probe 27 is provided at the tip of the reagent arm 26. The probe
27 is provided in such a manner that its tip faces vertically
downward. The probe 27 is moved in a horizontal plane so as to draw
the same arc-shaped track as the holding part 25 of the carrying
arm 24 and is moved up and down. The proximal end of the probe 27
is connected to a syringe pump that sucks and discharges a liquid
so that a reagent is sucked and discharged through the distal end
of the probe 27.
[0048] The reagent setting part 8 rotates in a horizontal plane
independently of the specimen setting part 2. In the reagent
setting part 8, the reagent containers 10 are annularly placed.
When the reagent setting part 8 rotates, the reagent containers 10
are carried in the direction of rotation of the reagent setting
part 8 so that a desired one of the reagent containers 10 is placed
in a predetermined reagent taking position. The reagent taking
position is a position which is along the track of the probe 27 of
the reagent arm 26 and in which a reagent is taken by the probe 27.
After sucking a predetermined reagent, the probe 27 dispenses the
sucked reagent into the separation device 50 set in the dispensing
port 32 to add the reagent to a specimen.
[0049] A preprocessing container setting part 12 is provided in a
position different from a position where the specimen setting part
2 is provided and from a position where the reagent setting part 8
is provided. The preprocessing container setting part 12 is
configured to allow a plurality of preprocessing containers, each
of which comprises an unused set of the separation device 50 and
the collection container 54 that are stacked, to be annularly set
therein. The preprocessing container setting part 12 rotates in a
horizontal plane to circumferentially move the preprocessing
containers so that any one of the preprocessing containers is
placed in a position along the track of the holding part 25 of the
carrying arm 24. The carrying arm 24 can hold the unused separation
device 50 or collection container 54 placed in a position along the
track of the holding part 25.
[0050] An analyst may previously set two or more kinds (e.g., two
kinds) of the separation devices 50 having separating agents
different in separation performance in the preprocessing container
setting part 12. These separation devices 50 are selectively used
depending on the analysis item of a sample, and an appropriate one
of the separation devices 50 is selected by the preprocessing
container setting part 12 depending on an analysis item designated
by the analyst. The selection of an appropriate one of the
separation devices 50 is performed by a controller that controls
the operations of the preprocessing apparatus 1. The controller
will be described later. The term "analysis item" used herein
refers to the kind of analysis to be performed successively using a
sample that has been subjected to preprocessing in the
preprocessing apparatus 1. Examples of an analyzer that performs
such an analysis include a liquid chromatograph (LC) and a liquid
chromatograph-mass spectrometer (LC/MS).
[0051] Further, this embodiment is configured to allow the
preprocessing container comprising the separation device 50
containing a solid sample and the collection container 54 to be set
in the preprocessing container setting part 12. The solid sample
refers to a sample in which a liquid (or a solidified liquid) as a
specimen is held by a solid medium, such as a piece of filter paper
shown in FIG. 3A which is obtained by cutting a specimen portion
(or a portion containing at least a specimen) of filter paper
impregnated with blood (specimen) to a predetermined size (e.g., 3
mm in diameter). As shown in FIG. 3B, such a solid sample is placed
in the separation device 50, and the separation device 50 is set in
the preprocessing container setting part 12 so that preprocessing
such as extraction processing for extracting a specimen from the
solid sample is automatically performed.
[0052] When setting the separation device 50 containing a solid
sample in the preprocessing container setting part 12, an analyst
inputs information about a specimen contained in the solid sample
and the position of this separation device 50 set in the
preprocessing container setting part 12 to the apparatus. When
preprocessing is performed on the specimen, the apparatus
identifies the position of the separation device 50 containing the
specimen on the basis of the information input thereto and performs
a preprocessing item designated by the analyst on the separation
device 50. The details of preprocessing operations will be
described later.
[0053] The separation device 50 and the collection container 54
constituting the preprocessing container will be described with
reference to FIG. 2A, FIG. 2B, FIG. 2C, and FIG. 2D.
[0054] As shown in FIG. 2A, the separation device 50 is a
cylindrical container having an internal space 50a in which a
specimen and a reagent are to be contained. A separating layer 52
is provided at the bottom of the internal space 50a. The separating
layer 52 is a separating agent or a separating membrane having the
function of selectively separating a specific component in a
specimen by allowing the specimen to pass therethrough to allow the
specific component to physically or chemically react therewith.
Examples of the separating agent used to form the separating layer
52 include an ion-exchange resin, silica gel, cellulose, and
activated carbon. Examples of the separating membrane to be used
include a PTFE (polytetrafluoroethylene) membrane, a nylon
membrane, a polypropylene membrane, a PVDF (polyvinylidene
fluoride) membrane, an acrylic copolymer membrane, a mixed
cellulose membrane, a nitrocellulose membrane, a polyethersulfone
membrane, an ion-exchange membrane, and a glass fiber membrane.
[0055] Further, as a deproteinizing filter (separating membrane)
for removing protein in a specimen by filtration, a PTFE membrane,
an acrylic copolymer membrane, or the like can be used. In this
case, in order to prevent clogging of the deproteinizing filter, as
shown in FIG. 2D, a prefilter 52b may be provided above the
deproteinizing filter 52a. As such a prefilter 52b, a nylon
membrane, a polypropylene membrane, a glass fiber membrane, or the
like can be used. The prefilter 52b is provided to remove insoluble
matter and foreign matter having a relatively large particle
diameter from a specimen, which makes it possible to prevent the
deproteinizing filter 52a from being clogged with insoluble matter
and foreign matter having a relatively large particle diameter.
[0056] The separation device 50 has an opening 50b provided in its
upper surface to inject a specimen or a reagent and an extract
outlet 50d provided in its lower surface to discharge a liquid that
has passed through the separating agent 52. Further, the separation
device 50 has a flange 50c provided on its upper outer
circumferential surface, and the flange 50c circumferentially
protrudes so as to be engaged with the holding part 25 of the
carrying arm 24 that will be described later.
[0057] Below the flange 50c, a skirt 51 is provided so as to
circumferentially protrude and then extend downward some distance
to surround the outer circumferential surface of the separation
device 50. As will be described later, the skirt 51 comes into
close contact with the edge of a filtration port 30 of a processing
part 28 when the separation device 50 is held in the filtration
port 30 together with the collection container 54 so that an
enclosed space is formed inside the skirt 51.
[0058] As shown in FIG. 2B and FIG. 2C, the collection container 54
is a cylindrical container that holds the lower portion of the
separation device 50 and collects an extract discharged through the
extract outlet 50d of the separation device 50. The collection
container 54 has, in its upper surface, an opening 50b through
which the lower portion of the separation device 50 is to be
inserted, and has an internal space 54a in which a portion of the
separation device 50 located below the skirt 51 is to be held.
Similarly to the separation device 50, the collection container 54
has a flange 54c provided on its upper outer circumferential
surface, and the flange 54c circumferentially protrudes so as to be
engaged with the holding part 25 of the carrying arm 24. The flange
54c has the same shape and outer diameter as the flange 50c of the
separation device 50. The holding part 25 of the carrying arm 24
can hold the flange 50c of the separation device 50 and the flange
54c of the collection container 54 in the same manner.
[0059] When the collection container 54 is attached to the
separation device 50, the upper portion of the collection container
54 enters inside the skirt 51. The outer diameter of the separation
device 50 and the inner diameter of the collection container 54 are
designed so that when the separation device 50 is held in the
internal space 54a of the collection container 54, a slight
clearance is created between the outer circumferential surface of
the separation device 50 and the inner circumferential surface of
the collection container 54. In the preprocessing container setting
part 12, the preprocessing container 50 and the collection
container 54 are set in a state where the lower portion of the
separation device 50 is held in the collection container 54 (i.e.,
in a state shown in FIG. 2C).
[0060] The preprocessing apparatus 1 will be further described with
reference to FIG. 1. As ports for holding the preprocessing
containers and performing specific preprocessing items, filtration
ports 30, stirring ports 36a, temperature-control ports 38 for
separation device 50, and temperature-control ports 40 for
collection container 54 are provided in a preprocessing part. The
filtration ports 30 are provided in two positions on the inner side
of the preprocessing container setting part 12. The three stirring
ports 36a are provided in a stirring part 36 provided adjacent to
the preprocessing container setting part 12. The
temperature-control ports 38 and 40 are provided along an arc. A
dilution port 41 is provided adjacent to the temperature-control
ports 40.
[0061] The filtration ports 30 are connected to a negative-pressure
applying mechanism 55 (see FIG. 4C and FIG. 5), and the
negative-pressure applying mechanism 55 is configured to apply a
negative pressure to the preprocessing container set in the
filtration port 30. The filtration ports 30 and the
negative-pressure applying mechanism 55 constitute the
preprocessing part that performs the filtration of a specimen as
preprocessing. The stirring part 36 also constitutes the
preprocessing part. The stirring part 36 has a mechanism that
periodically operates each of the stirring ports 36a in a
horizontal plane individually to stir a specimen solution contained
in the separation device 50 placed in each of the stirring ports
36a. The temperature-control ports 38 and 40 also constitute the
preprocessing part. Each of the temperature-control ports 38 and 40
is provided in, for example, a heat-conductive block whose
temperature is controlled by a heater and a Peltier element so that
the separation device 50 or the collection container 54 held in the
temperature-control port 38 or 40 is adjusted to a certain
temperature.
[0062] The filtration port 30 will be described with reference to
FIG. 4A, FIG. 4B, FIG. 4C, and FIG. 4D.
[0063] The filtration port 30 includes a recess in which the
preprocessing container is to be held. As shown in FIG. 4D, the
collection container 54 is first held in the filtration port 30,
and then the lower portion of the separation device 50 is held in
the internal space 54a of the collection container 54.
[0064] In the filtration port 30, a collection container holding
member 31 is provided. The collection container holding member 31
evenly presses the collection container 54 from two opposite
directions so as to sandwich the collection container 54 to center
the collection container 54 (see FIG. 4B and FIG. 4D). The
collection container holding member 31 is a U-shaped metal member
that is upwardly open, and its two arms extending upwardly
constitute two plate springs configured to be elastically displaced
in the inner diameter direction of the filtration port 30. Each of
the two plate springs of the collection container holding member 31
has a curved or bent shape that is inwardly curved or bent so that
the distance between the two plate springs in a portion between the
upper end and the lower end of the collection container holding
member 31 is the smallest. The distance between the two plate
springs at the upper end and lower end of the collection container
holding member 31 is larger than the outer diameter of the
collection container 54, and the smallest distance between the two
plate springs is smaller than the outer diameter of the collection
container 54. Since the collection container holding member 31 has
such a shape, when the collection container 54 is inserted into the
filtration port 30, the two plate springs of the collection
container holding member 31 are opened as the collection container
54 comes down, and the collection container 54 is kept in the
center of the filtration port 30 because of the elastic force of
the plate springs. The collection container holding member 31 is
fixed in the filtration port 30 so as not to be lifted up together
with the collection container 54 when the collection container 54
is taken out of the filtration port 30.
[0065] A ring-shaped sealing member 60 having elasticity is
provided at the edge of the upper opening of the filtration port
30. The sealing member 60 is fitted into a recess provided around
the edge of the upper opening of the filtration port 30. The
sealing member 60 is made of an elastic material such as silicone
rubber or EPDM (ethylene-propylene-diene rubber). When the
collection container 54 and the separation device 50 are set in the
filtration port 30, the lower end of the skirt 51 of the separation
device 50 abuts against the sealing member 60 so that a space
surrounded by the inner side surface of the skirt 50 and the inner
side surface of the filtration port 30 is hermetically sealed.
[0066] The bottom surface of the filtration port 30 communicates
with a flow path 56 for decompression (see FIG. 4A and FIG. 4C).
The flow path 56 is connected to a flow path 57 of the
negative-pressure applying mechanism 55. Although the specific
configuration of the negative-pressure applying mechanism 55 will
be described later, the negative-pressure applying mechanism 55 is
designed to apply a negative pressure to the filtration port 30
with the use of a vacuum pump.
[0067] When the filtration port 30 is decompressed by the
negative-pressure applying mechanism 55 with the separation device
50 and the collection container 54 being held in the filtration
port 30, a negative pressure is caused in a space surrounded by the
inner side surface of the skirt 50 and the inner side surface of
the filtration port 30. The space in which a negative pressure is
created communicates with the internal space 54a of the collection
container 54. Since the upper surface of the separation device 50
is open to the atmosphere, a pressure difference is caused between
the internal space 50a of the separation device 50 and the internal
space 54a of the collection container 54 with the separating agent
52 being interposed therebetween so that only components, which can
pass through the separating agent 52, of a sample solution
contained in the internal space 50a of the separation device 50 are
extracted and collected in the internal space 54a of the collection
container 54 due to the pressure difference.
[0068] An example of the negative-pressure applying mechanism 55 is
shown in FIG. 5.
[0069] The two filtration ports 30 are connected to a common vacuum
tank 66. Each of the flow paths 57 that connects each of the
filtration ports 30 to the vacuum tank 66 includes a pressure
sensor 62 and a three-way valve 64. The pressure sensor 62 senses
the pressure of the filtration port 30. The three-way valve 64 can
select any one of a state where the filtration port 30 is connected
to the vacuum tank 62, a state where the filtration port 30-side
end of the flow path 57 is open to the atmosphere (i.e., a state
shown in FIG. 5), and a state where the filtration port 30-side end
of the flow path 57 is sealed.
[0070] The vacuum tank 66 is connected to a pressure sensor 68, and
is connected also to a vacuum pump 58 through a three-way valve 70.
Therefore, the vacuum tank 66 can be connected to the vacuum pump
58, if necessary, to adjust the pressure in the vacuum tank 66.
[0071] When extraction processing is performed on a specimen in any
one of the filtration ports 30, the filtration port 30 is connected
to the vacuum tank 66 to adjust a value sensed by the pressure
sensor 62 that senses the pressure in the filtration port 30 to a
predetermined value, and then the filtration port 30-side end of
the flow path 57 is sealed. As a result, a sealed system is created
in the filtration port 30 so that the inside of the filtration port
30 is kept decompressed to perform extraction processing on a
specimen.
[0072] Hereinbelow, the structure of the stirring part 36 will be
described with reference to FIG. 6A and FIG. 6B. FIG. 6A and FIG.
6B show one of the stirring ports 36a of the stirring part 36.
[0073] The stirring port 36a of the stirring part 36 is a container
that holds the separation device 50. The stirring port 36a is
driven by a stirring mechanism provided below the stirring port
36a.
[0074] The stirring mechanism that drives the stirring port 36a
will be described. A rotor 76 is provided below the stirring port
36a, and a driving shaft 74 is vertically attached to the upper
surface of the rotor 76 in a position displaced from the center of
the rotor 76. The upper end of the driving shaft 74 is inserted
into a supporting hole 72 provided in the lower surface of the
stirring port 36a. The rotor 76 is supported by a rotating shaft 78
that is rotated by a motor 80. Therefore, the rotor 76 is rotated
by driving the motor 80 so that the driving shaft 74 is turned in a
horizontal plane.
[0075] A supporting frame 82 is attached to the motor 80. The
supporting frame 82 has a side wall that extends vertically upward
from the motor 80 side, and one end of an elastic member 83, such
as a coil spring, is attached to the upper end of the side wall.
The other end of the elastic member 83 is attached to the outer
surface of the upper portion of the stirring port 36a to
elastically hold the upper portion of the stirring port 36a. The
elastic member 83 is provided in each of two or more positions
(e.g., four positions) so that the elastic members 83 are evenly
spaced around the stirring port 36a.
[0076] When the motor 80 is driven in a state where the separation
device 50 containing a sample and a reagent is held in the stirring
port 36a, as shown in FIG. 6B, the driving shaft 74 is turned in a
horizontal plane so that the lower portion of the collection
container 72 is turned. As a result, the specimen and the reagent
contained in the separation device 50 held in the stirring port 36a
are stirred and mixed.
[0077] Again referring to FIG. 1, the preprocessing apparatus 1
includes a sample transfer device 42 at the side edge of its
housing. The sample transfer device 42 is provided to transfer an
extracted sample collected in the collection container 54 to a
sample injector (e.g., an automatic sampler) provided adjacent to
the preprocessing apparatus 1. The sample transfer device 42
includes a moving part 44 that is moved by a driving mechanism
having a rack and pinion mechanism in one direction (i.e., in a
direction indicated by arrows in FIG. 1) in a horizontal plane. In
the upper surface of the moving part 44, a transfer port 43 for
setting the collection container 54 containing an extracted sample
is provided.
[0078] While sample transfer to the sample injector is not
performed, the transfer port 43 is placed in a position along the
track of the holding part 25 of the carrying arm 24 (i.e., in a
position indicated by a solid line in FIG. 1). In a state where the
transfer port 43 is placed in such a position, setting of the
collection container 54 in the transfer port 43 or collection of
the collection container 54 from the transfer port 43 is performed
by the carrying arm 24.
[0079] When specimen transfer to the sample injector is performed,
the collection container 54 containing an extracted specimen is set
in the transfer port 43, and then the moving part 44 is moved
toward the outside of the preprocessing apparatus 1, and the
transfer port 43 is placed in a position closer to the sample
injector adjacent to the preprocessing apparatus 1 (i.e., in a
position indicated by a dashed line in FIG. 1). In a state where
the transfer port 43 is placed in such a position, a sampling
nozzle provided in the sample injector sucks the specimen contained
in the collection container 54. When the suction of the specimen by
the sample injector is finished, the moving part 44 is returned to
its original position (i.e., a position indicated by a solid line
in FIG. 1), and the collection container 54 is collected by the
carrying arm 24. The used collection container 54 is carried to a
disposal port 34 and disposed of by the carrying arm 24.
[0080] The preprocessing apparatus 1 includes the disposal port 34
for disposing of the used separation device 50 and the used
collection container 54. The disposal port 34 is provided in a
position that is close to the dispensing port 32 and along the
track of the holding part 25 of the carrying arm 24. Further, the
preprocessing apparatus 1 includes a washing port 45 for washing
the sampling nozzle 20a. The washing port 45 is provided in a
position along the track of the sampling nozzle 20a. Although not
shown in the drawing, a washing port for washing the probe 27 is
provided in a position along the track of the probe 27.
[0081] Hereinbelow, the control system of the preprocessing
apparatus 1 will be described with reference to FIG. 7. In the
following description, the term "port" refers to any one of the
filtration port 30, the dispensing port 32, the stirring port 36a,
the temperature-control ports 38 and 40, and the transfer port 43
in which the separation device 50 or the collection container 54 is
to be set.
[0082] The operations of the specimen setting part 2, the reagent
setting part 8, the preprocessing container setting part 12, the
sampling arm 20, the carrying arm 24, the reagent arm 26, the
stirring part 36, the sample transfer device 42, and the
negative-pressure applying mechanism 55 provided in the
preprocessing apparatus 1 are controlled by a controller 84. The
controller 84 is implemented by a computer provided in the
preprocessing apparatus 1 and software executed by the computer.
The controller 84 is connected to an arithmetic processing unit 86
implemented by, for example, a personal computer (PC) or a
dedicated computer, and an analyst controls the preprocessing
apparatus 1 through the arithmetic processing unit 86. The
arithmetic processing unit 86 is electrically connected to a liquid
chromatographic system (hereinafter referred to as "LC system") 200
(see FIG. 11 and FIG. 12) that is provided adjacent to the
preprocessing apparatus 1 to analyze a sample that has been
subjected to preprocessing in the preprocessing apparatus 1. A
sample injector 202 provided in the LC system 200 is configured to
operate in conjunction with the preprocessing apparatus 1. FIG. 7
shows only the sample injector 202 in the LC system 200.
[0083] The controller 84 includes a preprocessing operation part
84a, a specimen recognition part 84b, a preprocessing container
identification part 84c, and a solid sample setting information
holding part 84d. Each of the preprocessing operation unit 84a, the
specimen recognition part 84b, and the preprocessing container
identification part 84c is a function achieved by execution of
software by an arithmetic element such as a CPU constituting the
controller 84. Further, the solid sample setting information
holding part 84d is a function achieved by the storage area of a
storage device provided in a computer constituting the controller
84.
[0084] As described above, the preprocessing apparatus 1 according
to this embodiment processes two kinds of specimens, one of which
is a liquid specimen contained in the specimen container set in the
specimen setting part 2 and the other of which is a specimen
contained in a solid sample contained the separation device 50 set
in the preprocessing container setting part 12. Information about a
specimen to be analyzed is previously registered on the apparatus
by an analyst. The controller 84 identifies a position where a
specimen to be subjected to preprocessing next is set and a
preprocessing item to be performed on the specimen on the basis of
the registered information, and performs operations necessary for
performing the preprocessing item.
[0085] The preprocessing operation part 84a is configured to
confirm a processing item to be performed next on each specimen,
check the availability of a port for performing the processing
item, carry the separation device 50 containing the specimen or the
collection container 54 to the port when the port is available, and
perform the processing item. On the other hand, when there is no
available port for performing the processing item, the target
separation device 50 or collection container 54 is carried to the
port as soon as the port becomes available.
[0086] The specimen recognition part 84b is configured to check
whether a specimen to be analyzed is a liquid specimen or a
specimen contained in a solid sample on the basis of
previously-registered information. When the specimen recognition
part 84b recognizes that a specimen to be analyzed is a liquid
specimen, preprocessing operations for liquid specimen are
performed. On the other hand, when the specimen recognition part
84b recognizes that a specimen to be analyzed is a specimen
contained in a solid sample, preprocessing operations for solid
sample are performed. Each of the preprocessing operations will be
described later.
[0087] The preprocessing container identification part 84c is
configured to, when the specimen recognition part 84b recognizes
that a specimen to be analyzed is a specimen contained in a solid
sample, identify the position of the preprocessing container
(separation device 50) containing the solid sample on the basis of
information about the specimen previously registered by an analyst.
Information about a position where a solid sample is set is
registered by an analyst and stored in the solid sample setting
information holding part 84d when the separation device 50
containing the solid sample is set in the preprocessing container
setting part 12.
[0088] An example of preprocessing operations performed on one
sample according to this embodiment will be described with
reference to FIG. 1 and flow charts shown in FIG. 8, FIG. 9, and
FIG. 10. The flow charts shown in FIGS. 8 to 10 show only the flow
of preprocessing performed on one specimen, and the operations of
the preprocessing are performed in parallel with but independently
of the operations of preprocessing performed on another specimen.
"To perform preprocessing in parallel with but independently of"
means that while filtration processing or stirring processing is
performed on a certain specimen in the filtration port 30 or the
stirring port 36a, the separation device 50 or collection container
54 containing another specimen is carried to another port by the
carrying arm 24 to independently perform processing on the another
specimen.
[0089] First, as shown in FIG. 8, the state of a specimen to be
analyzed is checked, that is, it is checked whether a specimen to
be analyzed is a liquid specimen or a specimen contained in a solid
sample on the basis of information previously registered by an
analyst (Step S1). When the specimen to be analyzed is a specimen
contained in a solid sample (Step S2), preprocessing operations for
solid sample are performed (Step S3). On the other hand, when the
specimen to be analyzed is not a specimen contained in a solid
sample, that is, when the specimen to be analyzed is a liquid
specimen contained in the specimen container (Step S2),
preprocessing operations for liquid specimen are performed (Step
S4).
[0090] When the sample to be analyzed is a specimen contained in a
solid sample, an example of preprocessing operations performed on
the specimen is preprocessing operations for newborn mass
screening. An example of such preprocessing operations will be
described with reference to FIG. 9.
[0091] First, a position where the separation device 50 containing
a solid sample containing a specimen to be analyzed is set is
identified (Step S101), and an analysis item designated for the
specimen is confirmed (Step S102).
[0092] Then, the availability of the dispensing port 32 is checked.
When the dispensing port 32 is available, the separation device 50
containing a solid sample is taken out of the preprocessing
container setting part 12 and set in the dispensing port 32 by the
carrying arm 24 (Step S103 and Step S104). The separation device 50
and the collection container 54 are set in the preprocessing
container setting part 12 in a state where they are stacked (i.e.,
in a state shown in FIG. 2). However, the carrying arm 24 holds
only the separation device 50 stacked on the collection container
54 with the use of the holding part 25 and carries the separation
device 50 to the dispensing part 32.
[0093] The reagent dispensing nozzle 26a takes a reagent for
extracting the specimen from the solid sample from the reagent
container 10 and dispenses the reagent into the separation device
50 set in the dispensing port 32 (Step S105). It is to be noted
that a reagent dispensing port for dispensing a reagent may be
provided in a position different from the position of the
dispensing port 32 so that the separation device 50 is set in the
reagent dispensing port by the carrying arm 24 to perform
dispensing of a reagent in the position of the reagent dispensing
port. An example of the reagent for specimen extraction is one
obtained by dissolving stable isotopes (IS) of amino acids and
acylcarnitines-32.
[0094] After the reagent for specimen extraction is dispensed into
the separation device 50, the availability of the stirring port 36a
is checked (Step S106). When the stirring port 36a is available,
the separation device 50 set in the dispensing port 32 is carried
and set in the available stirring port 36a by the carrying arm 24,
and stirring is performed to extract the specimen from the solid
sample (Step S107).
[0095] The stirring processing is preferably performed under a
temperature condition of about 45.degree. C. for about several tens
of minutes. Therefore, the separation device 50, to which the
reagent for specimen extraction has been added, is preferably
carried to the temperature-control port 38 before the separation
device 50 is carried to the stirring port 36a, that is, the
separation device 50 is preferably carried to the stirring port 36a
to perform stirring after the temperature of the separation device
50 is adjusted to about 45.degree. C. Further, in order to
stabilize the temperature of the separation device 50, the
separation device 50, to which the reagent for specimen extraction
has been added, may be alternately set in the temperature-control
port 38 and the stirring port 36a to alternate temperature control
and stirring.
[0096] The processing from addition of a reagent to stirring is
extraction processing for extracting the specimen from the solid
sample. During the extraction processing, the availability of the
filtration port 30 is checked (Step S108). When the filtration port
30 is available, the collection container 54 is set in the
filtration port 30 by the carrying arm 24 (Step S109). The
collection container 54 set in the filtration port 30 is one paired
with the separation device 50 that is being stirred in the stirring
port 36a, that is, one that has been set in the preprocessing
container setting part 12 with the separation device 50, which is
being stirred, being stacked thereon. It is to be noted that during
the stirring processing, the carrying arm 24 may carry the
separation device 50 or the collection container 54 for another
sample.
[0097] When the stirring processing (extraction processing) in the
stirring part 36 is finished, the carrying arm 24 carries the
separation device 50 to the filtration port 30 and sets the
separation device 50 on the collection container 54 so that the
lower portion of the separation device 50 is held in the collection
container 54 set in the filtration port 30 (a state shown in FIG.
4, Step S110). At this time, the separation device 50 is pressed
downward (i.e., toward the filtration port 30) so that the lower
end of the skirt 51 of the separation device 50 comes down to a
level slightly lower (e.g., about 0.1 mm) than the level of the
upper surface of the sealing member 60 provided around the
filtration port 30. As a result, the lower end of the skirt 51 of
the separation device 50 compresses the sealing member 60, which
improves air tightness between the lower end of the skirt 51 and
the sealing member 60. The carrying arm 24 keeps pressing the
separation device 50 downward until a negative pressure is caused
in the filtration port 30 after the start of filtration processing
that will be described below.
[0098] Filtration processing is started in a state where the
separation device 50 is set on the collection container 54 set in
the filtration port 30 and the filtration port 30 is hermetically
sealed. In the filtration processing, the filtration port 30 is
decompressed by the negative-pressure applying mechanism 55 so that
a negative pressure is caused in the filtration port 30 holding the
separation device 50 and the collection container 54. The
filtration port 30 is kept at negative pressure for a certain
period of time so that the solution contained in the separation
device 50 is filtered and an extracted specimen is collected in the
collection container 54 (Step S111).
[0099] When the pressure sensor 62 (see FIG. 5) senses that a
negative pressure is caused in the filtration port 30 after the
filtration processing is started, the carrying arm 24 stops
pressing the separation device 50 downward and holding the
separation device 50. After stopping of holding the separation
device 50, the carrying arm 24 can carry another separation device
50 or collection container 54. The stopping of downward pressing of
the separation device 50 and holding of the separation device 50,
which are performed by the carrying arm 24, is not necessarily
performed on the basis of the detection signal of the pressure
sensor 62, and may be performed after predetermined time elapses
from the start of the filtration processing.
[0100] After the filtration processing of the specimen is finished
(Step S112), the three-way valve 64 (see FIG. 5) is switched to
return the pressure in the filtration port 30 to atmospheric
pressure, and the used separation device 50 is taken out of the
filtration port 30 and disposed of in the disposal port 34 by the
holding part 25 of the carrying arm 24 (Step S113). Then, the
collection container 54 containing the filtered specimen is allowed
to stand to allow a derivatization reaction of succinylacetone with
hydrazine under acidic conditions to proceed. The time required for
this processing is about several tens of minutes to 2 hours. This
processing can be performed in the temperature-control port 40.
[0101] After the completion of the above processing, the
availability of the transfer port 43 is checked. When the transfer
port 43 is available, the collection container 54 is set in the
transfer port 43 by the carrying arm 24. When the collection
container 54 is set in the transfer port 43, the moving part 44 is
moved to a position (i.e., a position indicated by a dashed line in
FIG. 1) closer to the sample injector 202 provided in the LC system
200 (see FIG. 11 and FIG. 12) provided adjacent to the
preprocessing apparatus 1 so that the collection container 54 is
transferred to the sample suction device 90 (Step S114).
[0102] In the sample injector 202, the specimen contained in the
collection container 54 transferred by the transfer device 42 is
sucked by a sampling nozzle. The moving part 44 stops in the
position closer to the LC system 200 until the suction of the
specimen performed in the sample injector 202 is finished, and then
the moving part 44 returns to its original position (i.e., a
position indicated by a solid line in FIG. 1) when receiving a
signal indicating that the suction of the specimen has finished
from the LC system 200.
[0103] After the completion of sample transfer, the used collection
container 54 is collected from the transfer port 43 and disposed of
in the disposal port 34 by the carrying arm 24 (Step S115).
[0104] Hereinbelow, an example of preprocessing operations
performed when a specimen to be analyzed is a liquid specimen will
be described with reference to FIG. 10.
[0105] When a specimen to be analyzed is a liquid specimen, an
analysis item previously designated by an analyst for the specimen
is first confirmed (Step S201), and a preprocessing item necessary
for performing the analysis item is determined. The availability of
the dispensing port 32 is checked. When the dispensing port 32 is
available, the carrying arm 24 takes the unused separation device
50 for containing the specimen out of the preprocessing container
setting part 12 and sets the separation device 50 in the dispensing
port 32 (Steps S202 and S203). As has been described above, the
separation device 50 and the collection container 54 are set in the
preprocessing container setting part 12 in a state where they are
stacked (i.e., in a state shown in FIG. 2C), but also in this case,
the carrying arm 24 holds only the separation device 50 stacked on
the collection container 54 with the use of the holding part 25 and
carries the separation device 50 to the dispensing part 32.
[0106] The sampling nozzle 20a dispenses the specimen into the
separation device 50 (Step S204). After dispensing the specimen
into the separation device 50, the sampling nozzle 20a is washed in
the washing port 45 and prepared for dispensing of a next specimen.
The reagent dispensing nozzle 26a takes a reagent appropriate to
preprocessing to be performed on the specimen dispensed into the
separation device 50 from the reagent container 10 and dispenses
the reagent into the separation device 50 set in the dispensing
port 32 (Step S205). It is to be noted that the dispensing of the
reagent into the separation device 50 may be performed before the
dispensing of the sample.
[0107] After the specimen and the reagent are dispensed into the
separation device 50, the availability of the stirring port 36a is
checked (Step S206). When the stirring port 36a is available, the
separation device 50 set in the dispensing port 32 is carried and
set in the available stirring port 36a by the carrying arm 24 to
perform stirring (Step S207). This stirring processing is performed
for a predetermined certain period of time to mix the specimen and
the reagent contained in the separation device 50. During the
stirring processing, the availability of the filtration port 30 is
checked (Step S208). When the filtration port 30 is available, the
collection container 54 is set in the filtration port 30 by the
carrying arm 24 (Step S209).
[0108] When the stirring processing in the stirring part 36 is
finished, the carrying arm 24 carries the separation device 50 to
the filtration port 30 and sets the separation device 50 on the
collection container 54 (a state shown in FIG. 4D), and further
presses the separation device 50 downward (i.e., toward the
filtration port 30) to improve air tightness between the lower end
of the skirt 51 and the sealing member 60 (Step S210). The carrying
arm 24 keeps pressing the separation device 50 downward until a
negative pressure is caused in the filtration port 30 after the
start of filtration processing that will be described below.
[0109] In a state where the separation device 50 is set on the
collection container 54 set in the filtration port 30 and the
filtration port 30 is hermetically sealed, the filtration port 30
is decompressed by the negative-pressure applying mechanism 55 to
perform filtration processing. The filtration port 30 is kept at
negative pressure for a certain period of time so that the solution
contained in the separation device 50 is filtered and an extracted
specimen is collected in the collection container 54 (Step
S211).
[0110] When the pressure sensor 62 (see FIG. 5) senses that a
negative pressure is caused in the filtration port 30 after the
filtration processing is started, the carrying arm 24 stops
pressing the separation device 50 downward and holding the
separation device 50. After stopping of holding the separation
device 50, the carrying arm 24 can carry another separation device
50 or collection container 54. The stopping of downward pressing of
the separation device 50 and holding of the separation device 50,
which are performed by the carrying arm 24, is not necessarily
performed on the basis of the detection signal of the pressure
sensor 62, and may be performed after predetermined time elapses
from the start of the filtration processing.
[0111] Although not incorporated in the preprocessing operations,
temperature treatment is sometimes incorporated in which the sample
contained in the separation device 50 is kept at a given
temperature for a certain period of time after the sample contained
in the separation device 50 is stirred. In this case, after the
completion of the stirring processing, the availability of the
temperature control port 40 is checked. When the temperature
control port 38 is available, the separation device 50 is set in
the available temperature control port 38. After a lapse of a
certain period of time, the separation device 50 is taken out of
the temperature control port 38 and then set on the collection
container 54 set in the filtration port 30.
[0112] After the completion of the filtration processing of the
specimen (Step S212), the three-way valve 64 (see FIG. 5) is
switched to return the pressure in the filtration port 30 to
atmospheric pressure, and the used separation device 50 is taken
out of the filtration port 30 and disposed of in the disposal port
34 by the holding part 25 of the carrying arm 24 (Step S213).
[0113] Then, the availability of the transfer port 43 is checked.
When the transfer port 43 is available, the carrying arm 24 sets
the collection container 54 in the transfer port 43 to transfer the
specimen to the sample injector 202 (Step S214), and collects the
used collection container 54 from the transfer port 43 to dispose
of the used collection container 54 in the disposal port 34 (Step
S215).
[0114] It is to be noted that after the completion of the
filtration processing of the sample, temperature treatment is
sometimes performed in which the extracted sample collected in the
collection container 54 is kept at a certain temperature for a
certain period of time. In this case, the availability of the
temperature control port 40 is checked. When the temperature
control port 40 is available, the collection container 54 is set in
the available temperature control port 40. Then, after a lapse of a
certain period of time, the collection container 54 is carried from
the temperature control port 40 to the transfer port 43 to perform
sample transfer.
[0115] Hereinbelow, a separation device 550 and a collection
container 554 that can be used instead of the separation device 50
and the collection container 54 shown in FIG. 2A to FIG. 2D will be
described with reference to FIG. 13A, FIG. 13B, FIG. 14A, and FIG.
14B. In the following description, differences between the
separation device 50 and the separation device 550 and differences
between the collection container 54 and the collection container
554 will be described.
[0116] In the separation device 550 shown in FIG. 13A and FIG. 13B,
the inner diameter and outer diameter of a portion located below
the base of a skirt 551 (i.e., a lower portion of the device) are
smaller than those of a portion located above the base of the skirt
551. The lower portion of the device is to be held in a space 554a
of the collection container 554. This allows a portion of the
separation device 550 where a flange 550c is provided to have the
same outer diameter as a portion of the collection container 554
where a flange 554c is provided. As a result, the flange 550c of
the separation device 550 and the flange 554c of the collection
container 554 can have completely the same shape and size, and
therefore the holding part 25 of the carrying arm 24 can hold the
separation device 550 and the collection container 554 in the same
manner
[0117] A protrusion 550e is provided between the flange 550c and
the base of the skirt 551 on the outer circumferential surface of
the separation device 550 so as to circumferentially protrude in
the form of a flange like the flange 550c. The protrusion 550e is
provided in a position such that the upper edge of the inner wall
surface of the stirring port 36a is located when the separation
device 550 is set in the stirring port 36a. The protrusion 550e has
the same outer diameter as the skirt 551, which allows, when the
stirring processing is performed, the protrusion 550e to abut
against the upper edge of the inner wall surface of the stirring
port 36a to prevent the vibration of the separation device 550 in
the stirring port 36a.
[0118] In the collection container 554 shown in FIG. 14A and FIG.
14B, notches 554d are provided in two or more (e.g., three)
positions at the edge of an upper opening 554b. The notches 554d
form openings for the ventilation of air between the inner wall
surface of the base of the skirt 551 and the upper edge of the
collection container 554 when the separation device 550 and the
collection container 554 are integrated with each other so that the
upper portion of the collection container 554 enters the inside of
the skirt 551 of the separation device 550. The filtration
processing in the filtration port 30 is performed by sucking air in
the filtration port 30 to cause a negative pressure in the
collection container 554 integrated with the separation device 550
and set in the filtration port 30. At this time, air in the
collection container 554 passes through the openings formed by the
notches 554d so that the collection container 554 is efficiently
decompressed.
[0119] Hereinbelow, an embodiment of an analysis system including
the preprocessing apparatus 1 will be described with reference to
FIG. 11.
[0120] An LC system 200 is provided adjacent to the preprocessing
apparatus 1 described with reference to the above embodiment, and a
mass spectrometer (MS) 300 is further provided adjacent to the LC
system 200. The operations of the preprocessing apparatus 1, the LC
system 200, and the MS 300 are managed by a common system
management unit 400. The system management unit 400 is a dedicated
computer or a general-purpose personal computer that includes
software for controlling or managing the preprocessing apparatus 1,
the LC system 200, and the MS 300, and also has the function of the
arithmetic processing unit 100 shown in FIG. 7.
[0121] The LC system 200 includes the sample injector 202 that
takes a specimen that has been subjected to preprocessing in the
preprocessing apparatus 1 and injects the specimen into the
analytical flow path of a liquid chromatograph. As has been
described above, the preprocessing apparatus 1 includes the
transfer device 42 that transfers the collection container 54 (or
554) containing a specimen that has been subjected to preprocessing
to the LC system 200, and the sample injector 202 is configured to
take the specimen from the collection container 54 (or 554)
transferred to the LC system 200 by the transfer device 42. When
the moving part 44 of the transfer device 42 is moved toward the LC
system 200, the collection container 54 (or 554) set in the
transfer port 43 of the moving part 44 is placed in a predetermined
position in the sample injector 202.
[0122] When the collection container 54 (or 554) containing a
specimen that has been subjected to preprocessing in the
preprocessing apparatus 1 is set in the transfer port 43 of the
transfer device 42, and the moving part 44 is moved toward the LC
system 200 so that the collection container 54 (or 554) is placed
in a predetermined position in the sample injector 202, a signal
indicating this is sent to the sample injector 202 through the
system management unit 400, and the sample injector 202 starts
taking the specimen from the collection container 54 (or 554). The
transfer device 42 keeps the collection container 54 (or 554) in a
predetermined position in the sample injector 202 until the sample
injector 202 finishes taking the specimen as a sample. When the
sample injector 202 finishes taking the specimen as a sample, a
signal indicating this is sent to the preprocessing apparatus 1
through the system management unit 400 so that the transfer device
42 moves the moving part 44 toward the preprocessing apparatus 1 to
return the collection container 54 (or 554) to a predetermined
position in the preprocessing apparatus 1. The collection container
54 (or 554) returned to the preprocessing apparatus 1 is carried to
the disposal port 34 and disposed of by the carrying arm 24.
[0123] The LC system 200 according to this embodiment will be
described with reference to FIG. 12.
[0124] The LC system 200 includes, in addition to the sample
injector 202, a liquid sending device 204, a column oven 206, and a
detector 208. The liquid sending device 204 is a device that sends,
for example, two kinds of solvents with the use of liquid sending
pumps to a mixer and sends a solution obtained by mixing them with
the mixer as a mobile phase. The column oven 206 has an analytical
column 207 that separates a sample (a specimen that has been
subjected to preprocessing) into individual components. The
detector 208 is a detector such as an ultraviolet absorption
detector that detects sample components separated by the analytical
column 207.
[0125] The liquid sending device 204 is located at the upstream end
of an upstream analytical flow path 218 to send a mobile phase
through the upstream analytical flow path 218. The analytical
column 207 and the detector 208 are provided on a downstream
analytical flow path 220. Both the upstream analytical flow path
218 and the downstream analytical flow path 220 are connected to
ports of a two-position valve 210 provided in the sample injector
202, and are therefore connected to each other through the
two-position valve 210.
[0126] The two-position valve 210 of the sample injector 202 have 6
ports. The ports of the two-position valve 210 are connected not
only to the upstream analytical flow path 218 and the downstream
analytical flow path 220 but also to a sample introduction flow
path 212, a drainage flow path 214, and one end and the other end
of a sample loop 216. They are configured so that one of the
following states (1) and (2) can be selected by switching the
two-position valve 210: (1) a state where the sample introduction
flow path 212, the sample loop 216, and the drainage flow path 214
are connected in series so that the downstream end of the upstream
analytical flow path 218 is directly connected to the downstream
analytical flow path 220 (i.e., a state shown in FIG. 12) and (2) a
state where the upstream analytical flow path 218, the sample loop
216, and the downstream analytical flow path 220 are connected in
series. The sample introduction flow path 212 communicates with an
injection port 213.
[0127] The sample injector 202 has a needle 222 that can inject and
discharge a liquid from its tip and a syringe pump 226 connected to
the needle 222 through a flow path. The needle 222 is configured to
be horizontally and vertically moved by a driving mechanism not
shown in the drawing, and therefore can take a sample from the
collection container 54 (or 554) transferred to the LC system 200
by the transfer device 42 and inject the sample through the
injection port 213. The syringe pump 226 is configured to be
connected also to a washing liquid container 228 that stores a
washing liquid by switching a flow path switching valve 230. The
inner surfaces of a sample loop 224, the needle 222, and the sample
introduction flow path 212 can be washed by sending the washing
liquid from the syringe pump 226 containing the washing liquid
sucked thereinto in a state where the syringe pump 228 is connected
to the needle 222 and the needle 222 is connected to the injection
port 213.
[0128] When a specimen contained in the collection container 54 (or
554) is taken as a sample, the tip of the needle 22 is inserted
into the collection container 54 (or 554), the syringe pump 226
sucks the sample, and the sample is held in the sample loop 224
provided between the needle 222 and the syringe pump 226. The
sample held in the sample loop 224 is injected through the
injection port 213. When the sample is injected through the
injection port 213, the two-position valve 210 is operated to
select the state (1) where the sample introduction flow path 212,
the sample loop 216, and the drainage flow path 214 are connected
in series so that the sample injected through the injection port
213 is held in the sample loop 216. Then, the two-position valve
210 is switched to select the state (2) where the upstream
analytical flow path 218, the sample loop 216, and the downstream
analytical flow path 220 are connected in series so that the sample
held in the sample loop 216 is introduced into the analytical
column 207 by a mobile phase sent by the liquid sending device 204
and separated into individual components by the analytical column
207. The individual components separated by the analytical column
207 are detected by the detector 208 and then further introduced
into the MS 300.
[0129] Signals obtained by the detector 208 and the MS 300 are
input into the system management unit 400 (see FIG. 11) and
arithmetic processing such as quantitative determination and
composition analysis of individual components separated by the
analytical column 207 is performed by software installed in the
system management unit 400 and hardware, such as a CPU, that
executes the software.
* * * * *