U.S. patent application number 11/783163 was filed with the patent office on 2007-08-09 for biochemical analysis unit and method of producing thereof.
This patent application is currently assigned to FUJI PHOTO FILM CO., LTD.. Invention is credited to Masahiro Eto, Yuichi Hosoi, Akifumi Kato, Katsuhiro Kohda, Kenji Nakajima, Keiko Neriishi.
Application Number | 20070184483 11/783163 |
Document ID | / |
Family ID | 27531901 |
Filed Date | 2007-08-09 |
United States Patent
Application |
20070184483 |
Kind Code |
A1 |
Neriishi; Keiko ; et
al. |
August 9, 2007 |
Biochemical analysis unit and method of producing thereof
Abstract
The biochemical analysis unit has a base plate and absorptive
regions. The absorptive regions are surrounded by the base plate
formed of materials which shield a radioactive ray and a light. In
the absorptive regions are applied and absorbed specific binding
substances to be bound with substances derived from a living
organism that are labeled with labeling substances for generating
the radioactive ray or the light. The base plate prevents the
specific binding substances from penetrating in the other
absorptive regions. When an analysis of data of the radioactive ray
and the light is carried out, an image of the radioactive ray and
the light is generated without noises.
Inventors: |
Neriishi; Keiko; (Kanagawa,
JP) ; Hosoi; Yuichi; (Kanagawa, JP) ; Kohda;
Katsuhiro; (Kanagawa, JP) ; Eto; Masahiro;
(Tokyo, JP) ; Kato; Akifumi; (Kanagawa, JP)
; Nakajima; Kenji; (Kanagawa, JP) |
Correspondence
Address: |
SUGHRUE MION, PLLC
2100 Pennsylvania Avenue N.W.
Washington
DC
20037
US
|
Assignee: |
FUJI PHOTO FILM CO., LTD.
|
Family ID: |
27531901 |
Appl. No.: |
11/783163 |
Filed: |
April 6, 2007 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10147826 |
May 20, 2002 |
7220389 |
|
|
11783163 |
Apr 6, 2007 |
|
|
|
Current U.S.
Class: |
435/6.11 ;
435/287.2; 435/6.1; 435/7.1 |
Current CPC
Class: |
B01J 2219/00659
20130101; G01N 21/6452 20130101; G01N 21/76 20130101; G01N
2201/0642 20130101; B01J 2219/00621 20130101; B01L 3/5085 20130101;
B01J 2219/00317 20130101; B01J 2219/00626 20130101; G01N 21/6428
20130101; B01J 2219/00364 20130101; B01J 2219/00596 20130101; B01J
2219/00637 20130101; C40B 60/14 20130101; G01N 21/0303 20130101;
B01L 2300/168 20130101; B01J 2219/00527 20130101; G01N 23/04
20130101; B01J 2219/0061 20130101; B01J 2219/00644 20130101; B01J
2219/00702 20130101; B01L 3/02 20130101; B01J 2219/00585 20130101;
B01L 2300/0829 20130101; B01J 2219/00689 20130101; B01J 2219/00605
20130101; B01L 2300/069 20130101; B01J 2219/00612 20130101 |
Class at
Publication: |
435/006 ;
435/007.1; 435/287.2 |
International
Class: |
C12Q 1/68 20060101
C12Q001/68; G01N 33/53 20060101 G01N033/53; C12M 3/00 20060101
C12M003/00 |
Foreign Application Data
Date |
Code |
Application Number |
May 21, 2001 |
JP |
2001-150414 |
Sep 27, 2001 |
JP |
2001-298368 |
Jun 26, 2001 |
JP |
2001-192895 |
Jun 26, 2001 |
JP |
2001-192896 |
Jun 20, 2001 |
JP |
2001-186287 |
Claims
1. A biochemical analysis unit used for analyzing a data of a
radioactive ray and a light, comprising: an absorptive membrane
formed of an absorptive material; a shielding area formed in a
surface of said absorptive membrane, containing metal colloid
particles so as to shield a radioactive ray and a light; and plural
absorptive regions formed in said surface of said absorptive
membrane, to said absorptive regions substances emitting at least
one of said radioactive ray and said light being applied.
2. A biochemical analysis unit as described in claim 1, wherein in
said absorptive regions are absorbed specific binding substances
which can specifically bind with substances derived from living
organism that are labeled by at least one of labeling substances
including radioactive labeling substances, fluorescent substances
and chemiluminescent labeling substances.
3. A biochemical analysis unit as described in claim 2, wherein
said specific binding substances and said substances derived from
living organism are bound through one of hybridization,
antigen-antibody reaction and receptor-ligand.
4. A biochemical analysis unit as described in claim 2, wherein the
number of said absorptive regions is more than 10.
5. A biochemical analysis unit as described in claim 2, wherein the
averaged density of the number of said absorptive regions is more
than 10/cm.sup.2.
6. A biochemical analysis unit as described in claim 2, wherein
said plural absorptive regions are formed in a regular pattern.
7. A biochemical analysis unit as described in claim 2, wherein
said absorptive material is a porous material.
8. A biochemical analysis unit as described in claim 2, wherein
said absorptive material contains a fiber material.
9. A biochemical analysis unit for analyzing a data of a
radioactive ray and a light, comprising: a pair of plates members
formed of a material which shields at least one of said radioactive
ray and said light, said plate members having inner surfaces and
outer surfaces respectively and superposing on each other with
contact of said inner surfaces; plural through-holes which are
formed in said pair of said plate members; absorptive material
supplied in said plural through-holes; and absorptive regions
formed of said absorptive material in outer surfaces of said plate
members, to said absorptive regions substances emitting at least
one of said radioactive ray and said light being applied.
10. A biochemical analysis unit as described in claim 9, wherein in
said absorptive regions are absorbed specific binding substances
which can specifically bind with substances derived from a living
organism that are labeled by at least one of labeling substances
including radioactive labeling substances, fluorescent substances
and chemiluminescent labeling substances.
11. A method of producing a biochemical analysis unit including a
plate member and an absorptive membrane, said plate member having
plural through-holes and being formed of a material decreasing at
least one of a radioactive ray and a light, and said absorptive
membrane being formed of an absorptive material, said method
comprising steps of: pressing said plate member onto said
absorptive membrane such that a first surface of said plate member
contacts to said absorptive membrane; and supplying a part of said
absorptive membrane in said through-holes by pressing said plate
member to form absorptive regions in said through-holes in a second
surface of said plate member for applying substances emitting at
least one of said radioactive ray and said light.
12. A method as described in claim 11, wherein said plural
absorptive regions absorbs specific binding substances whose
structures and characteristics are known, and said binding
substances bind with substances derived from living organism that
are labeled by at least labeling substances of radioactive labeling
substances, fluorescent substances and chemiluminescent labeling
substances.
13. A method as described in claim 12, wherein said specific
binding substances and said substances derived from living organism
are bound through one of hybridization, antigen-antibody reaction
and receptor-ligand.
14. A method as described in claim 13, wherein said plate member is
heated in the thermal press processing when pressed onto said
absorptive membrane.
15. A method as described in claim 14, wherein a calender-roller
pair is used when said plate member is pressed onto said absorptive
membrane.
16. A method as described in claim 15, wherein said plate member is
fixed to said absorptive membrane through an adhesive agent.
17. A method as described in claim 13, wherein said plate member
decreases a density of said radioactive ray and the light less than
1/5 when said radioactive ray and the light passes in said plate
member for a length corresponding to a distance between the nearest
two of said absorptive regions.
18. A method as described in claim 17, wherein said plate member is
formed of at least one of metallic materials, ceramic materials and
plastic materials.
19. A method as described in claim 18, wherein said plate member is
formed of said plastic materials containing particles of oxides of
metals.
20. A method of producing a biochemical analysis unit having an
absorptive membrane formed of absorptive material, comprising steps
of: covering parts of a surface of said absorptive membrane with a
cover member; supplying a solution containing metal colloid
particles on other area than said parts so as to form a shielding
area for shielding at least one of a radioactive ray and a light;
and removing said cover member from said parts of said surface to
expose absorptive regions to which substances emitting at least one
of said radioactive ray and said light are to be applied.
21. A method as described in claim 20, wherein said plural
absorptive regions absorbs specific binding substances whose
structures and characteristics are known, and said binding
substances bind with substances derived from living organism that
are labeled by at least labeling substances of radioactive labeling
substances, fluorescent substances and chemiluminescent labeling
substances.
22. A method as described in claim 21, wherein said specific
binding substances and said substances derived from the living
organism are bound through one of hybridization, antigen-antibody
reaction and receptor-ligand.
23. A method as described in claim 21, wherein the number of said
absorptive regions is more than 10.
24. A method as described in claim 21, wherein the size of an area
in which said absorptive regions are formed is less than 5
mm.sup.2.
25. A method as described in claim 21, wherein the density of the
number of said absorptive regions is more than 10/cm.sup.2.
26. A method as described in claim 21, wherein said absorptive
regions are arranged in a regular pattern.
27. A method as described in claim 21, wherein said absorptive
material is a porous material.
28. A method as described in claim 27, wherein said porous material
is a carbon porous material or may be used for membrane filter.
29. A method as described in claim 21, wherein said absorptive
material contains a fiber material.
30. A method as described in claim 21, wherein said biochemical
analysis unit is superposed on a stimulable phosphor sheet on which
a stimulable phosphor regions are formed, such that each of said
stimulate phosphor region may be contact to said absorptive region
so as to expose said stimulate phosphor region, and stimulate
phosphors contained in said stimulate phosphor regions are excited
to generate an emission light when an exciting light beam is
applied on said stimulable phosphor region.
31. A method of producing a biochemical analysis unit including a
plate member and absorptive regions, said plate member being formed
of a material which shields at least one of a radioactive ray and a
light, said absorptive regions being formed of absorptive materials
in two surfaces of said plate member, said method comprising steps
of: forming plural through-holes in said plate member; and
supplying said absorptive material in said plural through-holes so
as to form in said through-holes said absorptive region to which
substances emitting at least one of said radioactive ray and said
light are to be applied.
32. A method as described in claim 31, wherein said plural
absorptive regions absorbs specific binding substances whose
structures and characteristics are known, and said binding
substances bind with substances derived from living organism that
are labeled by at least labeling substances of radioactive labeling
substances, fluorescent substances and chemiluminescent labeling
substances.
33. A method as described in claim 32, wherein said biochemical
analysis unit is laid on a stimulable phosphor sheet on which a
stimulable phosphor regions are formed, such that each of said
stimulate phosphor region may be contact to said absorptive region
so as to expose said stimulate phosphor region, and stimulate
phosphors contained in said stimulate phosphor regions are excited
to generate an emission light when an exciting light beam is
applied on said stimulable phosphor region.
34. A method as described in claim 32, wherein said absorptive
material contains a little of bad solvent and a main component of
good solvent, further comprising steps of: setting said plate
member in a solidifying solution after providing said absorptive
material in said through-holes; and cleaning out said solidifying
solution in water.
35. A method as described in claim 32, wherein said absorptive
material is provided on a surface of said plate member so as to
cover said surface, further comprising steps of: pressing said
absorptive material and said plate member so as to supply a part of
said absorptive material in said through-hole; and removing another
part of said absorptive material from said surface of said plate
member.
36. A method as described in claim 32, wherein said absorptive
material is a porous material.
37. A method as described in claim 36, wherein said porous material
is used for forming a membrane filter.
38. A method as described in claim 32, wherein a fiber material
which does not solve in a solvent of said porous material is mixed
in said porous material.
39. A method as described in claim 32, wherein said plate member
decreases a density of said radioactive ray and the light less than
1/5 when said radioactive ray and the light passes in said plate
member at a length corresponding to a distance between the nearest
two of said through-holes.
40. A method as claimed in claim 32, wherein said plate member is
formed of metallic materials, ceramic materials and plastic
materials.
41. A method as claimed in claim 32, wherein said through-holes are
formed with a punch.
42. A method as claimed in claim 32, wherein said through-holes are
formed with an electric discharging machine.
43. A method as claimed in claim 32, wherein said through-holes are
formed through photo lithograph and etching.
44. A method as claimed in claim 32, wherein said through-holes are
formed through razor ablation.
45. A method as claimed in claim 32, wherein the size of each of
said through-holes is less than 5 mm.sup.2.
46. A method as claimed in claim 32, wherein the density of the
number of said through-holes is more than 10/mm.sup.2.
47. A method of producing a biochemical analysis unit including a
plate member and absorptive regions, said plate member being formed
of a material which shields at least one of a radioactive ray and a
light, said absorptive regions being formed of absorptive
materials, said method comprising steps of: forming plural
through-holes in said plate member; supplying for said
through-holes a solution or a diffusing solution of said porous
material; drying a solvent of said solution or said diffusing
solution to form said absorptive regions in said through-holes in
two surfaces of said plate member for applying substances emitting
at least one of said radioactive ray and said light.
48. A method as claimed in claim 47, wherein said solution or said
diffusing solution is provided in an anti-solvent of said porous
material.
49. A method as claimed in claim 48, wherein said porous material
is composed of organic high molecular substances and covers as a
membrane a wall surrounding each of said through-holes, and
extremely small holes are formed in said membrane.
50. A method as claimed in claim 49, wherein said plate member is
formed of at least one of metal material, plastic material and
ceramics.
51. A method as claimed in claim 50, wherein the averaged density
of said plate member is more than 0.6 g/cm.sup.3, and the averaged
density of said porous material is less than 1.0 g/cm.sup.3.
52. A method as claimed in claim 51, wherein said through-holes are
arranged in a pitch of 0.1-3 mm.
53. A method as claimed in claim 51, wherein said through-holes are
arranged with a distance between 0.05 and 1.5 mm.
54. A method as claimed in claim 51, wherein said absorptive
regions are retracted from one or both of surfaces of said plate
member.
55. A method of producing a biochemical analysis unit including two
plate members and absorptive regions, said two plate members being
formed of a material which shields at least one of a radioactive
ray and a light, said absorptive regions being formed of absorptive
materials, said method comprising steps of: forming through-holes
in each of said two plate members; disposing a porous material
sheet made of porous materials between said two plate members;
pressing said two plate members to each other to sandwich said
porous material sheet; and providing a part of said porous material
sheet into said through-holes by pressing said two plate members so
as to form said absorptive regions in said through-holes in an
outer surface of each of said plate members for applying substances
emitting at least one of said radioactive ray and said light.
56. A method as claimed in claim 55, wherein said two plate members
are heated when pressed to each other.
57. A method as claimed in claim 55, wherein said two plate members
are formed of metal materials or ceramic materials.
58. A method as claimed in claim 55, wherein a solvent is used for
solving said two plate members without solving said porous material
sheet when the two plate members are pressed to each other.
59. A method as claimed in claim 58, wherein said two plate members
are formed of plastic materials.
60. A method as claimed in claim 55, wherein said porous material
is organic high molecular material.
61. A method as claimed in claim 55, wherein the averaged density
of said plate member is more than 0.6 g/cm.sup.3, and the averaged
density of said porous material is less than 1.0 g/cm.sup.3.
62. A method as claimed in claim 61, wherein said through-holes are
arranged in a pitch of 0.1-3 mm.
63. A method as claimed in claim 61, wherein said through-holes are
arranged with a distance between 0.05 and 1.5 mm.
64. A method as claimed in claim 61, wherein said absorptive
regions are retracted from one or both of surfaces of said plate
member.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a divisional of application Ser. No. 10/147,826
filed May 20, 2002. The entire disclosure of the prior application,
application Ser. No. 10/147,826 is hereby incorporated by
reference.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to a biochemical analysis unit
and a method of producing it, and more particularly to a
biochemical analysis unit used for analyzing substances derived
from a living organism bound with the spot like specific-binding
substances and a method of the producing thereof.
[0003] Recently, in biology and a medical science studies of genes
are progressed. In order to analyze the genes, a radioactive
labeling substance is applied as a labeling substance to a
substance derived from a living organism. Thereafter the substance
derived from the living organism emits a radioactive ray.
[0004] A stimulable phosphor sheet is to the substance derived from
the living organism so as to absorb, store and record energies of
the radioactive ray. Thus the stimulable phosphor sheet is
stimulated by an electromagnetic wave having a specified
wavelength. Thereafter, the stimulable phosphor can release
stimulated emission into an emitted light.
[0005] In order to analyze the genes, an autoradiographic analyzing
system, as known in Japanese Patent Publications No. 1-70884,
1-70882, 4-3962, is used for detecting the radioactive ray emitted
from a stimulable phosphor sheet.
[0006] The autoradiographic analyzing system has merits. Unlike a
system in which a photographic film is used, in the
autoradiographic analyzing system, development of a chemical
processing is not necessary. Further, it is possible to reproduce a
desired image by effecting image processing on the obtained image
data and carry out quantitative analysis by using a computer.
[0007] On the other hand, a fluorescent analyzing system is known.
In the fluorescent analyzing system, a fluorescent substance is
applied as the labeling substance to the substance derived from the
living organism. With the fluorescent analyzing system, it is
possible to study genetic sequence, the expression level of a gene,
routs of metabolism, absorbance, and discharge, and to separate or
identify proteins, or estimates the molecular weight or properties
of the proteins or the like. As the fluorescent analyzing system,
there are, for example, a western blotting method, southern
blotting method and the like. In the fluorescent analyzing system,
a DNA probe, which is complement to DNA containing a target gene
labeled by the labeling substance, is hybridized with DNA on a
transfer support. The DNA labeled by the labeling substance is
combined with enzyme such that the enzyme may contact a fluorescent
substance. The fluorescent substance is excited by a stimulating
light to emit fluorescence, and the fluorescence is detected to
produce an image and the distribution of a target DNA on the
transfer support. There is a merit of the fluorescent analyzing
system in which a genetic sequence or the like can be easily
detected without using radioactive labeling substances.
[0008] Similarly, there is known a chemiluminescence detecting
system. In the chemiluminescence detecting system is used the
substance derived from a living organism that is labeled with a
chemiluminescent labeling substance. The chemiluminescent labeling
substance generates chemiluminescence when it contacts a
chemiluminescent substrate. The chemiluminescence is detected in
the wavelength of visible light to reproduce an image of the
chemiluminescence on a displaying means such as a CRT or a
recording material such as a photographic film. Thereby,
information relating to the high molecular substance is obtained
such as genetic information.
[0009] Further, a micro-array analyzing system has been recently
developed for analyzing a protein such as a nucleic acid, or
fragments thereof. The micro-array analyzing system comprises
following steps:
[0010] (1) using a spotting device to drop specific binding
substances at different positions on a surface of a carrier such as
a slide glass plate, a membrane filter or the like. The specific
binding substances can bind with the substance derived from a
living organism such as a hormone, tumor marker, enzyme, antibody,
antigen, abzyme, other protein, a nucleic acid, cDNA, DNA, RNA, or
the like, whose sequence, base length, composition and the like are
known;
[0011] (2) forming thereby independent spots of the specific
binding substance;
[0012] (3) binding or hybridizing, in using a hybridization method,
the specific binding substances with the substances which are
derived from a living organism and labeled with the labeling
substance such as the fluorescent substance, a dye or the like, so
as to produce a micro-array;
[0013] (4) irradiating the micro-array with a stimulating ray;
[0014] (5) photoelectrically detecting light such as the
fluorescence emitted from the labeling substances to generate
biochemical analysis data; and
[0015] (6) analyzing the biochemical analysis data.
[0016] The micro-array analyzing system has a merit in that
substances derived from a living organism can be analyzed in a
short time as many sorts of specific binding substances are spotted
at different positions on a carrier such as a slide glass plate at
high density, and further hybridized with the substance from a
living organism and labeled with the labeling substances.
[0017] Note that, in the micro-array analyzing system, a micro
filtration membrane is used as the biochemical analysis unit for
removing particles and bacteria. A method of producing the micro
filtration membrane is disclosed in Japanese Patent Laid-open
Publications No. 48-40050 and 58-37842.
[0018] Further, a macro-array analyzing system has been recently
developed for analyzing a protein such as a nucleic acid, or
fragments thereof. The macro-array analyzing system comprises
following steps:
[0019] (1) using a spotting device to drop specific binding
substances at different positions on a surface of a carrier such as
a slide glass plate, a membrane filter or the like. The specific
binding substances can bind with the substance derived from the
living organism such as a hormone, tumor marker, enzyme, antibody,
antigen, abzyme, other protein, a nucleic acid, cDNA, DNA, RNA, or
the like, whose sequence, base length, composition and the like are
known;
[0020] (2) forming thereby independent spots of the specific living
substances;
[0021] (3) binding or hybridizing, in using a hybridization method,
the specific binding substances with the substances which are
derived from a living organism and labeled with the radioactive
labeling substances, so as to produce a macro-array;
[0022] (4) superposing the macro-array and a stimulable phosphor
sheet formed with a stimulable phosphor layer;
[0023] (5) exposing the stimulable phosphor layer to radioactive
labeling substance;
[0024] (6) irradiating the stimulable phosphor layer with a
stimulating ray to excite the stimulable phosphor;
[0025] (7) photoelectrically detecting the stimulated emission
released from the stimulable phosphor to generate the biochemical
analysis data; and
[0026] (8) analyzing the biochemical analysis data.
[0027] In the macro-array analyzing system, when the stimulable
labeling substances are exposed to the radioactive labeling
substances, an electron beam (.beta.-ray) released from the
radioactive labeling substance are scattered in the carrier to
impinge on a region in the stimulable phosphor layer. However, the
radiation energy of the radioactive labeling substances is very
large. Accordingly, the electron beams are scattered and mixed with
the other electron beams emitted from the neighboring spots and
then impinge on the region of the stimulable phosphor layer. Thus a
noise is generated in a biochemical analysis data to make the
accuracy of the biochemical analysis lower when the substances from
the living organism is analyzed by quantifying the radiation amount
of each spot. The accuracy of biochemical analysis is markedly
degraded when spots are disposed closely to each other at high
density.
[0028] Further, in the fluorescent analyzing system and the
chemiluminescence detecting system, there is a similar problem. The
fluorescence and the chemiluminescence are scattered in the carrier
such as the membrane filter. Furthermore, the fluorescence and the
chemiluminescence emitted from any particular spots is scattered
and mixed with chemiluminescence or the fluorescence emitted from
the neighboring spots. Accordingly, a noise is generated in the
biochemical analysis data.
SUMMARY OF THE INVENTION
[0029] An object of the present invention is to provide a
biochemical analysis unit and a method of producing it which
prevents a generation of a noise in a biochemical analysis
data.
[0030] In order to achieve the object, a biochemical analysis unit
has an absorptive membrane formed of absorptive materials and a
plate member formed of a shielding material which can shield at
least one of a radioactive ray and a light. In the plate member,
plural through-holes are formed. The absorptive membrane covers a
first surface of the plate member and a part of the absorptive
membrane is supplied in the through-holes. Thus the part appears
from the through-holes in a second surface of the plate member to
form absorptive regions in the second surface that are surrounded
by a plate member.
[0031] A method of producing the biochemical analysis unit
comprises steps of pressing the plate member on to the absorptive
membrane and supplying thereby a part of the absorptive membrane in
the through-holes to form the absorptive regions.
[0032] In the absorptive regions, specific binding materials are
absorbed. The specific binding materials can specifically bind with
substances derived from a living organism that are labeled by at
least one of labeling substances. As the labeling substances there
are radioactive labeling substances, fluorescent substances and
chemiluminescent labeling substances. The radioactive labeling
substances emit a radioactive ray, and the fluorescent substances
and the chemiluminescent labeling substance can emit a fluorescence
and a chemiluminescence as the light.
[0033] Another biochemical analysis unit has an absorptive membrane
formed of the absorptive material and a shielding area formed on
the absorptive membrane. The shielding area contains metal colloids
particles for shielding the radioactive ray and the light. On a
surface of the absorptive membrane, plural absorptive regions are
also formed.
[0034] Such a biochemical analysis unit is produced through
covering parts of a surface of the absorptive membrane with a cover
member. In this situation, a solution containing metal colloids
particles is provided on other parts of the absorptive membrane.
The solution penetrates in the other parts. Thereby the other parts
become to the absorptive regions.
[0035] Further, a biochemical analysis unit may include the base
plate and absorptive regions which are formed on both surfaces of
the base plate. In the plate member, plural through-holes are
formed. In the through-holes, there are absorptive materials to
form the absorptive regions. In order to provide the absorptive
materials in the through-holes, a solution of the absorptive
materials may be doped on a surface of the plate member. Further, a
dispenser may be also used.
[0036] Furthermore, a biochemical analysis unit may have a pair of
the plate members which are superposed on each other. In this case
the absorptive regions are formed on outer surfaces of the plate
members.
[0037] According to the invention, the specific binding substances
are selectively absorbed in each of the absorptive regions, and
therefore do not penetrate in the other absorptive regions. In this
situation the specific binding substances are bound with the
substances derived from the living organism that are labeled with
the labeling substances for generating a radioactive ray and a
light to be measured. Therefore, the radioactive ray and the light
do not diffuse, and in their data there is no noise. Accordingly
the analysis of the data can be more accurately carried out.
Further, the number of the absorptive regions in a unit size is
large. The specific binding substances can be applied closer in the
biochemical analysis unit.
[0038] Especially, when the data of the radioactive ray is
obtained, the radioactive ray emitted from the respective absorbing
regions does not diffuse. When an image of the radioactive ray is
formed by using an autoradiography, noises in the image become
smaller.
BRIEF DESCRIPTION OF THE DRAWINGS
[0039] The above objects and advantages of the present invention
will become easily understood by one of ordinary skill in the art
when the following detailed description would be read in connection
with the accompanying drawings:
[0040] FIG. 1A is a perspective view of a biochemical analysis unit
of the first embodiment of the present invention;
[0041] FIG. 1B is a cross-sectional view taken along a line 1B-1B
in FIG. 1A;
[0042] FIG. 2 is a perspective view of a base plate of the
biochemical analysis unit in FIG. 1A;
[0043] FIG. 3 is a cross-sectional view illustrating a situation in
which the biochemical analysis unit is formed by using a pair of
press rollers;
[0044] FIG. 4 is a cross-sectional view illustrating a positional
relation between a spotting device and the biochemical analysis
unit;
[0045] FIG. 5 is a cross-sectional view of a hybridization
vessel;
[0046] FIG. 6 is a perspective view of a stimulable phosphor
sheet;
[0047] FIG. 7 is a cross-sectional view illustrating a situation
when the stimulable phosphor sheet is superposed on the biochemical
analysis unit;
[0048] FIG. 8 is a diagrammatic plan view of a scanner;
[0049] FIG. 9 is a partially enlarged view of the scanner,
illustrating a structure of a filter unit;
[0050] FIG. 10 is a sectional view taken along a line A-A in FIG.
9;
[0051] FIG. 11 is a sectional view taken along a line B-B in FIG.
9;
[0052] FIG. 12 is a sectional view taken along a line C-C in FIG.
9;
[0053] FIG. 13 is a sectional view taken along a line D-D in FIG.
9;
[0054] FIG. 14 is a plan view of a optical head of the scanner;
[0055] FIG. 15 is a block diagram of a scanner control system;
[0056] FIG. 16 is a front view of a data producing system;
[0057] FIG. 17 is a sectional view of a cooled CCD camera of the
data producing system;
[0058] FIG. 18 is a sectional view of a dark box of the data
producing system;
[0059] FIG. 19 is a block diagram of the data producing system;
[0060] FIG. 20 is a perspective view of a biochemical analysis unit
of the second embodiment of the present invention;
[0061] FIG. 21 is a cross-sectional view taken along a line 21-21
in FIG. 20;
[0062] FIG. 22 is a front view illustrating a positional relation
of the press plate to the biochemical analysis unit;
[0063] FIG. 23 is a perspective view of a stimulable phosphor
sheet;
[0064] FIG. 24 is a cross-sectional view illustrating a situation
when the stimulable phosphor sheet in FIG. 23 is superposed on the
biochemical analysis unit in FIG. 22;
[0065] FIG. 25 is a perspective view of a biochemical analysis unit
of the third embodiment of the present invention;
[0066] FIG. 26 is a cross-sectional view taken along a line 26-26
in FIG. 25;
[0067] FIG. 27 is a perspective view of a biochemical analysis unit
of the forth embodiment of the present invention;
[0068] FIG. 28 is a cross-sectional view taken along a line IX-IX
in FIG. 27;
[0069] FIG. 29 is perspective view illustrating a situation when
through-holes are formed by a punch;
[0070] FIG. 30 is perspective view illustrating a situation when
the through-holes are formed by photo lithography and etching;
[0071] FIG. 31 is a perspective view of a base plate used for the
biochemical analysis unit of the forth embodiment;
[0072] FIG. 32 is a diagrammatic view illustrating a situation when
absorptive regions are formed in the through-holes by using a
dye;
[0073] FIG. 33 is an exploded schematic view illustrating a
situation when the absorptive regions are formed in the
through-holes by using dispensers;
[0074] FIG. 34A is a sectional view of the base plate illustrating
a situation when a layer of oxide of metal is formed;
[0075] FIG. 34B is an exploded view of FIG. 33A, illustrating a
situation of a coupling agent in the through-hole;
[0076] FIG. 34C is a same view of FIG. 33B, illustrating a
situation when coupling agent is bound to the layer of oxide of
metal;
[0077] FIG. 35A is a sectional view of the base plate formed of
plastic;
[0078] FIG. 35B is an exploded view of FIG. 33A, illustrating a
situation of a coupling agent in the through-hole;
[0079] FIG. 35C is a same view of FIG. 34B, illustrating a
situation when coupling agent is bound to the layer of oxide of
metal;
[0080] FIG. 36 is a sectional view illustrating a situation in
which the biochemical analysis unit of the forth embodiment is
formed by using a press roller and a back-up roller;
[0081] FIG. 37 is a plan view of the biochemical analysis unit of
the forth embodiment, in which the absorptive regions are formed in
another pattern;
[0082] FIG. 38 is a plan view of the biochemical analysis unit of
the forth embodiment, in which the absorptive regions are
tetragonaly-shaped;
[0083] FIG. 39 is a plan view of the biochemical analysis unit of
the forth embodiment, in which the absorptive regions are
triangularly shaped;
[0084] FIG. 40 is a perspective view of a biochemical analysis unit
of the fifth embodiment;
[0085] FIG. 41 is a cross-sectional view taken along a line 41-41
in FIG. 40;
[0086] FIG. 42 is a perspective view of a base plate used for the
biochemical analysis unit of the fifth embodiment;
[0087] FIG. 43 is a diagrammatic view illustrating a situation of
forming absorptive regions in the base plate in FIG. 42;
[0088] FIG. 44A is a plan view of the biochemical analysis unit of
the fifth embodiment, in which the absorptive regions are arranged
in another pattern;
[0089] FIG. 44B is a plan view of the biochemical analysis unit of
the fifth embodiment, in which the absorptive regions are
tetragonaly formed;
[0090] FIG. 44C is a plan view of the biochemical analysis unit of
the fifth embodiment, in which the absorptive regions are
triangularly formed;
[0091] FIG. 45 is a perspective view of a biochemical analysis unit
of the sixth embodiment of the present invention;
[0092] FIG. 46 is a cross-sectional view taken along a line I-I in
FIG. 45;
[0093] FIG. 47 is a diagrammatic view illustrating a situation of
forming the biochemical analysis unit in FIG. 45;
[0094] FIG. 48 is a sectional view illustrating a situation of the
two base plates and a porous material when the biochemical analysis
unit is formed;
[0095] FIG. 49 is a diagrammatic view illustrating another
situation for forming the biochemical analysis unit of the sixth
embodiment;
[0096] FIG. 50A is a same view of the biochemical analysis unit of
the sixth embodiment, in which the absorptive regions are arranged
in another pattern;
[0097] FIG. 50B is a same view of the biochemical analysis unit of
the sixth embodiment, in which the absorptive regions are
tetragonaly formed;
[0098] FIG. 50C is a same view of the biochemical analysis unit of
the sixth embodiment, in which the absorptive regions are
triangularly formed.
DETAILED DESCRIPTION OF THE INVENTION
[0099] In FIG. 1A, a biochemical analysis unit 1 includes a base
plate 5 formed of aluminum and an absorptive material 2 formed of
nylon-6 which can be used for forming a membrane filter. On the
absorptive material 2, absorptive regions 4 having a nearly
circular-shape are formed in a regular pattern. As shown in FIG.
1B, in the base plate 5 through-holes 6 are formed, and the
absorptive regions 4 are fitted in the through-holes 6 when the
base plate 5 is pressed onto the absorptive material 2. Note that
in the embodiment the number of the absorptive regions 4 is about
10000 and each of them has a size of about 0.01 mm.sup.2. A density
thereof is 5000/cm.sup.2.
[0100] In FIG. 2, an adhesive agent 3 is applied on a rear face of
the base plate 5. Therefore the base plate 5 is adhered with the
absorptive material 2 so as to increase an endurance of the
biochemical analysis unit 1. Further, the absorptive region 4 and
the aluminum sheet 5 form a plat surface after adhering the base
plate 5 to the absorptive material 2.
[0101] In FIG. 3, the biochemical analysis unit 1 is produced with
a calendar roller 15 included in a device for producing the
biochemical analysis unit 1. Before pressed by the calendar roller
15, the base plate 5 is laid on the absorptive material 2. Then the
base plate 5 and the absorptive material 2 are pressed by the
calendar roller 15 while the absorptive regions 4 on the absorptive
material 2 are fitted into the through-hole 6 of the base plate 5.
Note that the absorptive material 2, as formed of nylon-6 for
forming membrane filter, has a lot of extremely small holes. The
holes are however disappeared by pressing the absorptive material 2
onto the base plate 5.
[0102] As shown in FIG. 4, when a biochemical analysis is carried
out, a plurality of cDNA whose sequences are known but different
from each other are spotted as specific binding substances by using
a spotting device on the absorptive region 4. The spotting device
includes an injector 6 and a CCD camera 7. The CCD camera 7 is used
for inspecting the absorptive region 4 on which the cDNA is
spotted. When a tip end portion of the injector 6 confronts to a
center of the absorptive region 4, the cDNA is spotted at an
accurate position on the absorptive region 4.
[0103] Further, U.S. Pat. No. 5,807,522 describes a method for
spotting the specific binding substances to the absorptive regions,
in which the specific binding substances are applied to a pin.
Furthermore the specific binding substances may be jetted onto the
absorptive regions 4.
[0104] As the specific binding substances, poly-nucleotides and
oligonucleotide are used; for example, cDNA, parts of cDNA,
poly-nucleotide of PCR sub-production produced in PCR method such
as EST, and the synthetic oligonucleotide. Further there may be
artificial nucleus acid, peptide nucleus acid (PNA), and their
derivatives. The artificial nucleus acid is produced by transform
the phosphodiester bound of the DNA into the peptide bound. Further
there are substances which specifically bounds with hormones, tumor
markers, enzymes, antibodies, antigens, abzyme, other proteins,
nucleic acids, DNA, RNA and the like.
[0105] The DNA of the specific binding substances is bound with DNA
and RNA. The PNA, the antigene and avidine of the specific binding
substances are bound with the PNA, the antibody, and biotine
respectively.
[0106] Note that instead of the inspecting of the absorptive region
4 a positional relation between the injector 6 and the absorptive
region 4 may be previously detected for spotting the cDNA. In this
case, the injector 6 and the biochemical analysis unit 1 are
relatively moved in a predetermined speed.
[0107] In the biochemical analysis unit 1, an area between the
absorptive regions 4 on the absorptive material 2 is entirely
covered with the base plate 5. Accordingly, the specific binding
material on the absorptive region 4 does not flow onto the area
between the absorptive regions 4. Further, as the extremely small
holes of the absorptive material 2 are disappeared by pressing onto
the base plate 5, the specific binding material is absorbed only in
the absorptive regions 4.
[0108] As shown in FIG. 5, a hybridization vessel 8 is formed
cylindrically and contains a hybridization solution 9. In the
hybridization solution 9 there is one or more of substances derived
from a living organism which are labeled with a labeling
substance.
[0109] When the specific binding substance such as cDNA is
selectively labeled with one of radioactive labeling substances,
the substance derived from a living organism is labeled with the
radioactive labeling substance in the hybridization solution 9.
[0110] When the specific binding substance such as cDNA is
selectively labeled with one of chemiluminescent labeling
substances, the substance derived from the living organism is
labeled with the chemiluminescent labeling substance in the
hybridization solution 9.
[0111] Further, when the specific binding substance such as cDNA is
selectively labeled with one of fluorescent substances, the
substance derived from the living organism is labeled with the
fluorescent substance in the hybridization solution 9.
[0112] When the hybridization is performed, the biochemical
analysis unit 1 is inserted in the hybridization vessel 8.
[0113] Thus, the specific binding substances in the absorptive
region 4 are selectively hybridized with the substances from the
living organism that are labeled with the radioactive labeling
substances, the chemiluminescent labeling substances or the
fluorescent substances.
[0114] Accordingly, the following data are recorded on the
absorptive region 4: a radioactive data of the radioactive labeling
substances; a chemiluminescent data of the chemiluminescent
labeling substance; and a fluorescent data of the fluorescent
substance.
[0115] The radioactive data is transmitted on a stimulable phosphor
sheet 10 (see FIG. 6), and read from the stimulable phosphor sheet
10 by a scanner (see FIG. 8) so as to generate a biochemical
analysis data.
[0116] Further, the fluorescent data recorded on the absorptive
region 4 are read by the scanner to generate the biochemical
analysis data. Furthermore, the chemiluminescent data recorded in
the absorptive region 4 are read by a data producing system (see
FIG. 16) to generate the biochemical analysis data.
[0117] As shown in FIG. 6, the stimulable phosphor sheet 10
includes a supporter 11. On a surface of the supporter 11 is formed
plural recesses 13 in the same regular pattern as that of the
through-holes 6 formed on the biochemical analysis unit 1. The
recesses 13 are dot-like and substantially circular shaped. In the
recesses 13, stimulable phosphor substances are provided to form a
stimulable phosphor layer region 12. Thereby the stimulable
phosphor layer region 12 has such a thickness that a surface of the
supporter 11 becomes flat.
[0118] In this embodiment, the supporter 11 is formed of stainless
capable of reducing radiation energy, and the stimulable phosphor
layer region 12 is formed on the supporter 11 so as to have the
same diameter as the absorptive region 4.
[0119] As shown in FIG. 7, the stimulable phosphor sheet 10 is
superposed on the biochemical analysis unit 1 by exposure such that
the absorptive regions 4 may confront to the stimulable phosphor
layer region 12.
[0120] In this embodiment, since the absorptive material 2 is
pressed onto the base plate 5, the biochemical analysis unit 1 is
hardly stretched and shrunk even if it is subjected to liquid
processing such as hybridization. Therefore, the absorptive regions
4 can correctly confront to the stimulable phosphor layer regions
12.
[0121] Thereby the radioactive labeling substance on the absorptive
region 4 emits electron beam only onto the confronting stimulable
phosphor layer regions 12 so as to carry out the exposure. The
electron beams are not scattered on the absorptive material 2 as
the base plate 5 attached thereto has an effect of reduction of the
density of the radioactive ray. Namely, the base plate 5 prevents
the electron beam from tending to the neighboring stimulable
phosphor layer regions 12.
[0122] Thus, the radioactive data are recorded in the stimulable
phosphor layer regions 12.
[0123] Note that the substances derived from the living organism
may be labeled with the radioactive labeling substances and only
one of the fluorescent substances and the chemiluminescent labeling
substances. Further, the substances derived from the living
organism may be bound to the specific labeling material through the
antigen-antibody reaction, the receptor-ligand reaction or the like
instead of hybridization.
[0124] In FIG. 8, the scanner can read the radiation data from the
stimulable phosphor layer regions 12 and the fluorescent data from
the absorptive regions 4 so as to generate the biochemical analysis
data. The scanner includes first, second and third laser sources
21, 22, 23. The first laser source 21 is constructed of a
semiconductor laser, and projects a laser beam 24a having
wavelength of 640 nm. The second and third laser sources 22, 23 are
constructed of second harmonic generation elements and projects a
laser beam 24b having wavelength of 532 nm and a laser beam 24c
having wavelength of 473 nm, respectively.
[0125] The scanner includes further first and second diachronic
mirrors 27, 28 which selectively reflect the laser beams 24a, 24b,
and 24c.
[0126] A laser beam 24a emitted from the first laser 21 is formed
through a collimator lens 25 into a parallel beam, and is reflected
by a mirror 26. A first diachronic mirror 27 and the second
diachronic mirror 28 transmit the laser beam 24a. A laser beam 24b
emitted from the second laser 22 is formed through a collimator
lens 30 to be a parallel beam, and reflected by the first
diachronic mirror 27. Then, the second diachronic mirror 28
transmits also the laser beam 24b. A laser beam 24c emitted from
the third laser 23 passes through a collimator lens 31 to be a
parallel beam, and reflected by the second diachronic mirror
28.
[0127] Thereafter, each of the laser beams 24a, 24b, 24c passes as
an exiting beam 24 on an optical axis L in a light path and is
reflected by mirror 29 and 32.
[0128] Downstream of the mirror 32, a perforated mirror 34 is
disposed in the optical path. In a center of the perforated mirror
34 is formed a hole 33 through which the exiting beam 24 passes.
Then the exiting beam 24 is reflected by a concave mirror 38 and
enters into an optical head 35.
[0129] The optical head 35 includes a mirror 36 and an aspherical
lens 37. After entering into the optical head 35, the exiting beam
24 is reflected by the mirror 36, and condensed by the aspherical
lens 37 onto the stimulable phosphor sheet 10 or the biochemical
analysis unit 1, which is placed on a glass plate 41 of the stage
40. Thereby, the biochemical analysis unit 1 is placed such that
each of the absorptive region 4 and the stimulable phosphor layer
regions 12 may be scanned.
[0130] The optical head 35 is movable in a main-scanning direction
X and a sub-scanning direction Y by a scanning mechanism 59 (see
FIG. 14). Accordingly, all of stimulable phosphor layer regions 12
and the absorptive regions 4 are scanned.
[0131] When the exiting beam 24 impinges on the stimulable phosphor
layer region 12, the stimulable phosphor in the stimulable phosphor
layer region 12 is excited to release stimulated emission as an
emission light 45. On the other hand, when the exiting beam 24
impinges on the biochemical analysis unit 1, a fluorescent dye or
the like contained in the absorptive region 4 is excited to release
a fluorescence as the emission light 45.
[0132] Then the emission light 45 is formed to a parallel light
beam by the aspherical lens 37 and reflected by the mirror 36.
Thereafter, the emission light 45 is reflected to the perforated
mirror 34 by the concave mirror 38. When reflecting on the
perforated mirror 34, the emission light 45 is focused onto the
photomultiplier 50. Thereby the emission light 45 passes through a
filter unit 48 in which a part of the emission light 45 having a
predetermined wavelength is cut off.
[0133] In FIG. 9, the filter unit 48 includes four filter members
51a, 51b, 51c, 51d and is slidable in left and right direction. The
photomultiplier 50 is connected through a A/D converter 53 to a
data processing device 54.
[0134] As shown in FIG. 10, the filter member 51a includes a filter
52a. The filter 52a is used for reading the fluorescent data when
the laser beam 24a from the first laser 21 excites the fluorescent
substances on the absorptive region 4. The filter 52a cuts a light
having the wavelength of 640 nm and transmits a light having the
wavelength more than 640 nm.
[0135] As shown in FIG. 11, the filter member 51b includes a filter
52b. The filter 52b is used for reading the fluorescent data when
the laser beam 24b from the first laser 22 excites the fluorescent
substances on the absorptive region 4. The filter 52b cuts a light
having the wavelength of 532 nm and transmits a light having the
wavelength more than 532 nm.
[0136] As shown in FIG. 12, the filter member 51c includes a filter
52c. The filter 52c is used for reading the fluorescent data when
the laser beam 24c from the first laser 22 excites the fluorescent
substances on the absorptive region 4. The filter 52c cuts a light
having the wavelength of 473 nm and transmits a light having the
wavelength more than 473 nm.
[0137] As shown in FIG. 13, the filter member 51d includes a filter
52d. The filter 52d is used for reading the radioactive data when
the laser beam 24a from the first laser 21 excites the stimulable
phosphor on the stimulable phosphor layer region 12. The filter 52d
cuts a light having the wavelength of 640 nm and transmits a light
having the wavelength in a region of the stimulated emission.
[0138] As described above, in accordance with the biochemical
analysis data, one of the filter members 51a, 51b, 51c, 51d is
selected and disposed in front of the photomultiplier 50.
[0139] The photomultiplier 50 photoelectrically detects the
emission light 45 to generate analog data. The analog data are
converted with an A/D converter 53 into digital data, and the
digital data are fed to the data processing device 54.
[0140] As shown in FIG. 14, the optical head 35 is attached to the
scanning mechanism 59. The scanning mechanism 59 includes a board
60 on which a sub-scanning stepping motor 61 and a pair of rails 62
are fixed. The board 60 is provided with a movable plate which can
move in the sub-scanning direction Y.
[0141] The movable plate 63 is formed with a threaded hole (not
shown). In the threaded hole is fitted a threaded rod 64 rotated by
the sub-scanning stepping motor 61. On the movable plate 63, a
main-scanning stepping motor 65 is provided. The main-scanning
pulse motor drives an endless belt 66 at a certain interval. To the
endless belt 66 the optical head 35 is attached. Accordingly, when
the endless belt 66 is driven, the optical head 35 is moved.
Thereby the main-scanning pulse motor 65 drives the endless belt 66
so as to intermittently move the optical head 35 in the
main-scanning direction X for a distance between the neighboring
absorptive regions 4.
[0142] Further, an indication 67 is a linear encoder for detecting
a position of the optical head in the main-scanning direction X,
and an indication 68 is a slit of the linear encoder 67.
[0143] When a line of the scanning is complete, the sub-scanning
stepping motor 61 causes to move the movable plate 63 in the
sub-scanning direction Y. Thus, the stimulable phosphor layer
regions or the absorptive regions are entirely scanned.
[0144] As shown in FIG. 15, a scanner control system includes a
control unit 70 for a whole operation of the scanner, and a scanner
input system includes a keyboard 71 which can be operated by an
operator and through which various instruction signals can be
input. A drive system of the scanner includes the main-scanning
stepping motor 65, the sub-scanning stepping motor 61, and the
filter unit motor 72 for moving the filter unit 48.
[0145] The control unit 70 selectively outputs drive signals to the
first laser 21, the second laser 22, the third laser 23, and
further send drive signals to a filter unit motor 72. A scanner
detecting system includes the photomultiplier 50 and the linear
encoder 67.
[0146] In the embodiment, the control unit 70 receives a detection
signal of positions of the optical head 35. In accordance with the
detection signal the control unit 70 controls to set the first,
second third lasers 21, 22, 23 in ON/OFF situations.
[0147] The scanner described above reads the radioactive data of
the radioactive labeling substances from the stimulable phosphor
sheet 10 to generate the biochemical analysis data while the
stimulable phosphor layer regions 12 of the stimulable phosphor
sheet 10 are exposed by the radioactive labeling substances on the
absorptive regions 4.
[0148] Now an operation for exposure of the stimulable phosphor
layer regions is described. The stimulable phosphor sheet 10 is set
on the glass plate 41 of the stage 40 such that the stimulable
phosphor layer regions 12 may contact to a surface of the glass
plate 41. Then, the user inputs an instruction signal through the
keyboard 71 to instruct to the control unit 70 that the stimulable
phosphor sheet 10 is scanned in the laser beam 24a.
[0149] After inputting the instruction signal, the control unit 70
outputs the drive signal to the filter unit motor 72 to move the
filter unit 48. Thereby the filter member 51d including the filter
52d is set in the passage of the emission light 45. Thus only the
emission light 45 can pass through the filter 52d when it is
emitted from the stimulable phosphor substances.
[0150] Further, the control unit 70 outputs the drive signal to the
main-scanning stepping motor 65 to move the optical head 35 in the
scanning direction from an initial position. Then, based on the
detection signal of the position of the optical head 35, the
control unit 70 determines whether the optical head is correctly
positioned so as to illuminate the first stimulable phosphor layer
region 12 in the laser beam 24. Thereafter, the control unit 70
outputs to the main-scanning stepping motor 65 a signal for
stopping the drive of the main-scanning stepping motor 65, and
thereby also send the drive signal to the first laser 21 to drive
it for emitting the laser beam 24a having the wavelength of 640
nm.
[0151] When the laser beam 24a is emitted from the first laser 21,
the first stimulable phosphor layer region 12 is illuminated in the
laser beam 24a and excited to emit the stimulous emission as the
emission light beam. Thereby, the laser beam 24a may be reflected
on the stimulabel phosphor layer region 12 and mixed with the
emission light beam. However, the reflected laser beam 24a is cut
by the filter 52d of the filter member 51d. Accordingly, the
photomultiplier 50 photoelectrically detects only the stimulous
emission which can pass through the filter 52d to generate the
analog data of the first stimulable phosphor layer region 12.
[0152] After the analog data is transformed in the digital data by
the A/D converter 53, the digital data is sent to the data
processing device 54. Corresponding to receiving the digital data
of the data processing device 54, the control unit 70 outputs the
drive signal for stopping the drive of the first laser 21, and
controls the optical head 35 to move for a distance to the second
stimulable phosphor layer regions 12.
[0153] Thereafter, when it is ascertained that the second
stimulable phosphor layer region 12 may be illuminated in the laser
beam, the first laser 21 is driven to project the laser beam 24a,
and the second stimulable phosphor layer regions 12 are excited to
emit the stimulous emission as the emission light 45. Then, the
photomultiplier 50 photoelectrically detects only the stimulous
emission which can pass through the filter 52d to generate the
analog data of the first stimulable phosphor layer region 12. When
the photomultiplier 50 generates the analog data, the first laser
21 is turned OFF and the optical head 35 is moved again.
[0154] Thus the scanning of one line on the stimulable phosphor
sheet 10 is completely performed by intermittently moving the
optical head 35. When ascertaining it the control unit 70 outputs
the drive signal to the main-scanning stepping motor 65 to shift in
the initial position, and outputs the drive signal to the
sub-scanning stepping motor 61 to slide the movable plate 63 for a
line in the sub-scanning direction. Then the scanning of the second
line is performed.
[0155] In repeating the operations above described, the stimulable
phosphor sheet 10 is entirely scanned.
[0156] The biochemical analysis unit 1 is set on the glass plate 41
of the stage 40. The user inputs an instruction signal through the
keyboard 71 to instruct to the control unit 70 that the biochemical
analysis unit 1 is scanned in one of the laser beams 24a, 24b,
24c.
[0157] After inputting the instruction signal, the control unit 70
determines, based on a table memorized in a memory (not shown),
what may be used among the first, second, third lasers 21, 22, 23,
and what may be set in the light path among the filters 52a, 52b,
52c, 52d.
[0158] For example, Rohdamine is used as the fluorescent substance
that can be most effectively excited by the laser beam 24b. The
user inputs information thereof through the keyboard 71. Based on
the information, the control unit 70 selects the second laser 22
and the filter 52b. Thereby, the drive signal is output to the
filter unit motor 72 to move the filter unit 48 such that the
filter member 51b including the filter 52b is set in the light path
of the emission light 45. Thus only the emission light 45 can pass
through the filter.
[0159] Further, the control unit 70 outputs the drive signal to the
main-scanning stepping motor 65 to move the optical head 35 in the
scanning direction from an initial position. Then, based on the
detection signal of the position of the optical head 35, the
control unit 70 determines whether the optical head 35 is correctly
positioned so as to illuminate the first absorptive region 4 in the
laser beam 24b. Thereafter, the control unit 70 outputs to the
main-scanning stepping motor 65 a signal for stopping the drive of
the main-scanning stepping motor 65, and thereby also send the
drive signal to the second laser 22 to drive it for emitting the
laser beam 24b having the wavelength of 532 nm.
[0160] When the laser beam 24b is emitted from the second laser 21,
the first absorptive region 4 is illuminated in the laser beam 24b,
and the fluorescent substance, Rohdamine, is excited to emit the
fluorescence as the emission light beam.
[0161] In the biochemical analysis unit 1 of this embodiment, as
the base plate 5 is applied to the absorptive material 2, the
fluorescent substances on the neighboring absorptive regions 4 is
not excited.
[0162] Further, the laser beam 24b may be reflected on first
absorptive region 4 and mixed with the emission light 45. However,
the reflected laser beam 24b is cut by the filter 52b of the filter
member 51b. Accordingly, the photomultiplier 50 photoelectrically
detects only the stimulous emission emitted by Rohdamine on the
first absorptive region 4, which can pass through the filter 52b to
generate the analog data of the first absorptive region 4.
[0163] After the analog data is transformed in the digital data by
the A/D converter 53, the digital data is sent to the data
processing device 54. Corresponding to receiving the digital data
of the data processing device 54, the control unit 70 outputs the
drive signal for stopping the drive of the second laser 22, and
controls the optical head 35 to move for a distance to the second
absorptive region 4.
[0164] Thereafter, when it is ascertained that the second
absorptive region 4 may be illuminated in the laser beam 24b, the
second laser 22 is driven to project the laser beam 24b, and the
second absorptive region 4 is excited to emit the fluorescence as
the emission light 45. Then, the photomultiplier 50
photoelectrically detects only the fluorescence which can pass
through the filter 52b to generate the analog data of the first
absorptive region 4. When the photomultiplier 50 generates the
analog data 4, the second laser 22 is turned OFF and the optical
head 35 is moved again.
[0165] Thus the scanning of one line on the biochemical analysis
unit 1 is completely performed by intermittently moving the optical
head 35. When ascertaining it, the control unit 70 outputs the
drive signal to the main-scanning stepping motor 65 to shift in the
initial position, and outputs the drive signal to the sub-scanning
stepping motor 61 to slide the movable plate 63 for a line in the
sub-scanning direction. Then the scanning of the second line is
performed.
[0166] In repeating the operations above described, the biochemical
analysis unit 1 is entirely scanned.
[0167] Note that the scanner is not restricted in the above
embodiments. For example, the scanner cannot selectively read the
radioactive data, the chemiluminescent data and the fluorescent
data, but only one of them. In this case, three scanners are used
for reading all of the three data, and in each scanner, the light
emitting diode, the filters, the diffusing plate or the like may be
omitted.
[0168] Further, the optical head 35 may be fixed. In this case, the
stage 40 is moved in the main-scanning direction x and the
sub-scanning direction y. Furthermore, instead of the
photomultiplier 50, CCDs may be arranged in a line or plane.
[0169] In FIG. 16, the data producing system includes a cooled CCD
camera 81, a dark box 82 and a personal computer 83. The personal
computer 83 has a CRT 84 and a keyboard 85.
[0170] The data producing system reads the chemiluminescent data of
the chemiluminescent labeling substance recorded in the absorptive
regions 4 on the biochemical analysis unit 1 to generate the
biochemical analysis data. The chemiluminescent labeling substance
emits the chemiluminescence when it contact to the chemiluminescent
substrate. Note that the data producing system can also read the
fluorescence data of the fluorescent substance on the absorptive
region 4, such as the fluorescent dye.
[0171] As shown in FIG. 17, the cooled CCD camera 81 includes a CCD
86, a heat transfer plate 87 made of metal, such as aluminum, a
Pelitier element 88 for cooling the CCD 86, a shutter 89 disposed
in front of the CCD 86, and A/D converter 90 for converting an
analog data into a digital data, a data buffer 91 for temporarily
storing the digital data, and a camera control circuit 92 for
controlling the operation of the cooled CCD camera 81.
[0172] An opening between the dark box 82 and the cooled CCD camera
81 is closed with a glass plate 95. A periphery of the cooled CCD
camera 81 is formed with heat dispersion fins 96 over substantially
half its length for dispersing heat. In the cark box 82, a camera
lens 97 is disposed on the glass plate 95.
[0173] As shown in FIG. 18, the dark box 82 is equipped with a
light emitting diode 100 for emitting a stimulating ray. The light
emitting diode 100 is provided with a filter 101. On an upper
surface of the filter 101 is disposed a diffusion plate 103 for
superposing the biochemical analysis unit 1 thereon. Through the
diffusion plate 103, the biochemical analysis unit 1 can be
uniformly irradiated with the stimulating ray. The filter 101 cuts
a light having the wavelength not close to that of the stimulating
ray. On a front face of the camera lens 97, a filter 102 is
provided for cutting a light having the wavelength close to that of
the stimulating ray.
[0174] As shown in FIG. 19, the personal computer 83 includes a CPU
110 for controlling the exposure of the cooled CCD camera 81, a
data transferring means 111, a storing means 112, a data processing
device 113, and a data display means 114. The data transferring
means 111 reads the digital data from the data buffer 91, and the
digital data is stored in the data storing means 112. Then the
digital data is processed by the data processing device 113, and
the data display means 114 displays a visual data on a screen of
the CRT based on the processed digital data.
[0175] The light emitting diode 100 is controlled by a control
means 115, in which an instruction is input from the keyboard 85
through the CPU 110. The CPU 110 outputs several signals to the
camera controlling circuit 92 of the cooled CCD camera 81.
[0176] When the chemiluminescent data are read out, the filter 102
is removed. Then, while the light emitting diode 100 is kept off,
the biochemical analysis unit 1 is placed on the diffusion plate
103 in the situation that the labeling substances in the absorptive
regions 4 contacts the chemiluminescent substances.
[0177] Then, the focusing of the camera lens 97 is carried out by
an operator, and the black box 82 is closed. Thereafter, the
operator inputs an exposure starting signal from the keyboard 85
through the CPU 110 into the camera controlling circuit 92 of the
cooled CCD camera 81. The camera control circuit 92 drives to open
the shutter 89 and the CCD 86 to carry out the exposure.
[0178] The chemiluminescent emission emitted from the biochemical
analysis unit 1 reaches a surface of the cooled CCD 81 in the
cooled CCD camera 81 to form an image on the surface. The cooled
CCD camera 81 receives thus the chemiluminescent emission and
accumulates an analog data thereof in form of electric charges
therein.
[0179] Note that in order to receive chemifluorescent emission, the
chemiluminescent substrates may be recorded on the absorptive
regions 4. After contacting to the chemiluminescent substrates, the
labeling substances emit the chemiluminescence, and the
chemiluminescence is received. In this case, the data generating
system may have none of the light emitting diode 100, the filters
101, 102, and the diffusion plate 103.
[0180] As the base plate 5 is pressed to the absorptive material 2
in the biochemical analysis unit 1, the chemiluminescent emission
emitted from the absorptive region 4 does not mixed with that from
the neighboring absorptive region 4.
[0181] When a predetermined time has passed for the exposure, the
CPU 110 outputs an exposure completion signal to the camera control
circuit 92 of the cooled CCD camera 81. When the camera control
circuit 92 receives the exposure completion signal from the CPU
110, the analog data is transmitted to the A/D converter 90 and
transformed into a digital data. The digital data is stored in the
data storing means 112.
[0182] When the operator inputs an instruction signal through the
keyboard 85 in the CPU 110, the CPU 110 controls the data storing
means 112 to send the digital data in the data processing device
113. The data processing device 113 processes the digital data.
Thereafter, the CPU 110 sends the instruction signal to the data
display means 114, and the chemiluminescent data is indicated on
the CRT 84 based on the digital data.
[0183] When the fluorescent data are read out, the biochemical
analysis unit 1 is placed on the diffusion plate. Then, the
focusing of the camera lens 97 is carried out by an operator, and
the black box 82 is closed. Thereafter, the operator inputs an
exposure starting signal from the keyboard 85 through the CPU 110
into the camera controlling circuit 92 of the cooled CCD camera 81.
The camera control circuit 92 drives the shutter 89 to open and the
CCD 86 to perform the exposure.
[0184] The fluorescence emitted from the biochemical analysis unit
1 reaches a surface of the CCD 86 in the cooled CCD camera 81 to
form an image on the surface. The CCD 86 receives thus the
fluorescence and accumulates an analog data thereof in form of
electric charges therein.
[0185] As the base plate 5 is pressed to the absorptive material 2
in the biochemical analysis unit 1, the fluorescence emitted from
the absorptive region 4 does not mixed with that from the
neighboring absorptive regions 4.
[0186] When a predetermined time has passed for the exposure, the
CPU 110 outputs an exposure completion signal to the camera control
circuit 92 of the cooled CCD camera 81. When the camera control
circuit 92 receives the exposure completion signal from the CPU
110, the analog data is transmitted to the A/D converter 90 and
transformed into a digital data. The digital data is stored in the
data storing means 112.
[0187] When the operator inputs an instruction signal through the
keyboard 85 in the CPU 110, the CPU 110 controls the data storing
means 112 to send the digital data in the data processing device
113. The data processing device 113 processes the digital data.
Thereafter, the CPU 110 sends the instruction signal to the data
display means 114, and the fluorescent data is indicated on the CRT
84 based on the digital data.
[0188] In the embodiment, the absorptive material 2 is covered with
the base plate 5, and the supporter 11 of the stimulable phosphor
sheet 10 is formed of stainless which hardly transmits the
radioactive ray. Accordingly, the electric beams emitted from the
radioactive labeling substances are not scattered, and even if the
absorptive regions 4 are formed in high density, the noise does not
generate.
[0189] Further, the base plate 5 prevents the mixture of the
fluorescence or the chemiluminescence emitted from the two or more
absorptive regions 4.
[0190] In the embodiments the extremely small holes of the
absorptive material 2 are disappeared by pressing onto the base
plate 5, the specific binding material is absorbed only in the
absorptive regions 4.
[0191] Further, by pressing of the absorptive material 2, it is
neither stretched nor shrunken even after processing of
hybridization. Accordingly, the stimulable phosphor sheet 10 is
laid on the biochemical analysis unit 1 such that each stimulable
phosphor layer region 12 may confront to each absorptive region
4.
[0192] Therefore, the biochemical analysis is more quantitatively
carried out.
[0193] Other preferred embodiments will be now described.
[0194] In FIG. 20, a biochemical analysis unit 121 includes a base
plate 125 formed of plastics. In FIG. 21, absorptive regions 124
are fitted in through-holes of the base plate 125, and a top of the
absorptive region 4 is lower than a top of the base plate 125. The
density of the absorptive regions 124 is as same as that of the
absorptive regions 4.
[0195] In FIG. 22, the biochemical analysis unit 121 is produced
with a thermal pressing device including in a stage 127 and a press
plate 128 whose temperature is adjusted.
[0196] The absorptive material 122 is set on the stage 127, and the
base plate 125 is laid on the absorptive material 122. Then the
plastic plate 5 is pressed by the press plate 128 while the
absorptive regions 124 on the absorptive material 122 are fitted
into the through-holes of the base plate 125. Note that the base
plate 125, as formed of plastics, decreases the radioactive
ray.
[0197] In the biochemical analysis unit 121, an area between the
neighboring absorptive regions 4 on the absorptive material 2 is
entirely covered with the base plate 125. Accordingly, the specific
binding material on the absorptive region 4 does not flow onto the
area of the absorptive material. Further, as the extremely small
holes of the absorptive material 2 are disappeared by pressing onto
the base plate 125, the specific binding material is absorbed only
in the absorptive regions 124.
[0198] In FIG. 23, a stimulable phosphor sheet 130 includes a
supporter 131 formed of stainless so as to shield the radioactive
ray. The stimulable phosphor sheet 130. On a surface of the
supporter 131 are formed a nearly circular stimulable phosphor
layer regions 132 in the same pattern as that of the absorptive
region 124 on the biochemical analysis unit 121 so as to protrude
from the supporter 131.
[0199] As shown in FIG. 24, when the exposure is carried out, the
stimulable phosphor layer sheet 130 is laid on the biochemical
analysis unit 121 such that the stimulable phosphor layer region
132 may confront to the absorptive region 124.
[0200] In the embodiment, as the base plate 125 is pressed on the
absorptive material 122, the biochemical analysis unit 121 is
neither stretched nor shrunken by processing in a solution such as
hybridization. Therefore, each absorptive regions 124 confronts to
the stimulable phosphor layer regions 132 when the stimulable
phosphor sheet 130 is superposed on the biochemical analysis unit
121.
[0201] In FIG. 25, a biochemical analysis unit 141 includes an
absorptive material 142 having absorptive regions 144 and a
shielding region 145 formed around the absorptive regions 144. The
shielding region 145 contains metallic colloids so as to shield the
radioactive ray, the fluorescence and the chemiluminescence.
[0202] As shown in FIG. 26, the absorptive regions 144 and the
shielding region 145 construct a plat surface of the biochemical
analysis unit 141. In order to form the absorptive regions 144, a
surface of the absorptive material 142 is partly masked in the same
pattern as that of the absorptive regions 144. Another part of the
absorptive material 142 is applied with a disperse solution
including the metallic colloids. Note that the number of the
absorptive regions 144 is about 10000 and each of them has a size
of about 0.01 mm.sup.2. A density thereof is 5000 per cm.sup.2.
[0203] In the embodiments the absorptive materials 2, 122, 142 of
the respective biochemical analysis units 1, 121, 141 may be formed
of not only the nylon-6, but also carbonated porous material, for
example activated carbon, and other porous materials each of which
has the extremely small holes and can be used for the membrane
filter. As the porous materials there are, for example, aliphatic
polyamide (nylon-6,6, nylon-4,10); cellulose derivatives
(nitrocellulose, acetyl cellulose, cellulose acetate butyrate);
collagen; alginic acid derivatives (alginic acid, calcium alginate,
alginic acid/polylisinepolyion complex); polyolefins (polyethylene,
polypropylene); polychlorovinyl; polychlorovinylidene;
polyfluorovinylidene; polytetrafluoride, and their copolymers or
complexes. Further, the absorptive materials 2, 122, 142 may be
formed of inorganic porous materials, such as metals (platinum,
gold, iron, silver, nickel, aluminum); oxides of metals (alumina,
silica gel, titania, zeolite); salts of metals and their complexes
(hydroxiapatite, calcium sulfate); and plural fibers.
[0204] The base plates 5 and 125 may be attached with other
appropriate method than the pressing and the thermal pressing.
[0205] The base plates 5 and 125 may be formed of a material which
decreases the radioactive ray and the light and has a plurality of
through-holes. Further, the supporter of the stimulable phosphor
sheet may be also formed of the material which decreases the
radioactive ray. As the material used for the base plate and the
supporter, there are metals (for example, gold, silver, copper,
zinc, aluminum, titanium, tantalum, chromium, iron, nickel, cobalt,
lead, tin, selenium and the like); alloys (for example, brass,
stainless, bronze and the like); silicone materials (silicone,
amorphous silicone, glass, quartz, silicone carbide, silicone
nitrate and the like); oxides of metals (aluminum oxide, magnesium
oxide, zirconium oxide and the like); inorganic salts (tungsten
carbide, calcium carbonate, calcium sulfate, hydroxiapatite,
gallium arsenide, and the like). These may have a structure of
single crystal, amorphous, or sintered polycrystal. As the organic
materials, high molecular compounds are preferably used, for
example, polyolefin (polyethylene, polypropyrene and the like);
acryl resins (polymethyl methacrylate,
butylacrylate/methylmethacrylate copolymer and the like);
polyacrylonitrile; polyvinylchrolide; polyvinylidenechrolide;
polyvinylidenefluoride; polytetrafluoroethylene;
polychlorotrifluoroethylene; polycarbonate; polyesters
(polyethylene naphthalate, polyethylene terephthalete and the
like); aliphatic polyamides (nylon-6, nylon-6,6, nylon-4,10 and the
like); polyimide; polysulfone; (polyphenylene sulfide); silicon
resins (polydiphenylsiloxane and the like); phenol resins (novolac
and the like); epoxy resins; polyurethane; polystyrene;
butadiene-styrene copolymer; polusaccharides (cellulose, acetyl
cellulose, nitrocellulose, starch, calcium alginate, hydroxypropyl
methyl cellulose and the like); chitin; chitosan; urushi (Japanese
lacquer); polyamide (gelatin, collagen, keratin and the like),
copolymers of these high molecular materials. These may be complex
materials. In the complex materials particles of oxides of metals
or glass fiber may be added, or the organic compound may be blended
if necessary.
[0206] Note that in the biochemical analysis units 1, 121 it is not
necessary to apply the adhesive agents 3, 123. Further, when only
the radioactive data is read, there may be formed around the
absorptive regions 4, 124, 144 a region through which the
radioactive ray transmits and the chemiluminescence and the
fluorescence do not. When only the chemiluminescent data and the
fluorescent data are read, there may be formed around the
absorptive regions 4, 124, 144 a region through which the
chemiluminescence and the fluorescence transmit and the radioactive
ray does not.
[0207] The absorptive regions 4, 124, 144 may have other shapes
such as rectangularly-formed shape. The size thereof may be
optionally decided, and preferably ten or more thereof is arranged
in 5 mm.sup.2. The density thereof may be 10/cm.sup.2 or more.
Further, the absorptive regions 4, 124, 144 may be not formed
regularly.
[0208] Each of the stimulable phosphor layer regions 12, 132 may
have a size more than the absorptive regions 4, 124. Further, the
stimulable phosphor layer regions 12, 132 may have other shapes
such as rectangularly-formed shape. They may be not formed
regularly when in same pattern as that of the absorptive regions 4,
124.
[0209] The stimulable phosphor is preferably exited by a visible
rays as follows: for example, Japanese Patent Laid-Open Publication
No. S55-12145 discloses alkaline earth material fluoride halide
phosphors (Ba.sub.1-xM.sub.2+x)FX:yA (herein M.sup.2+ is at least
one of alkaline earth material Mg, Ca, Sr, Zn and Cd, X is at least
one halogen of Cl, Br and I, and A is Eu, Tb, Ce, Tm, Dy, Pr, He,
Nd, Yb and Er; 0.ltoreq.x.ltoreq.0.6, 0.ltoreq.y.ltoreq.0.2.
Japanese Patent Laid-Open Publication No. H2-276997 discloses
alkaline earth material fluoride halide phosphors SrFX:Z (herein X
is halogen, at least one of Cl, Br and I, and Z is Eu or Ce).
Japanese Patent Laid-Open Publication No. S59-56479 discloses
europium activated complex halogen phosphors
BaFX.quadrature.xNaX':aEu.sup.2+ (herein each X and X' is halogen,
at least one of Cl, Br and I; 0<x.ltoreq.2, 0<a.ltoreq.0.2).
Japanese Patent Laid-Open Publication No. 58-69281 discloses cerium
activated metal Oxyhalide, MOX:xCe (herein M is at least one of
metals, Pr, Nd, Pm, Sm, Eu, Tb, Dy, Ho, Er, Tm, Yb and Bi, X is
halogen, one or both of Br and I; 0<x<0.1). Japanese
Laid-Open Publications No. 60-101179 and 60-90288 disclose cerium
activated rear earth material oxyhalide phosphors LnOX:xCe (herein
Ln is at least one of rear earth elements Y, La, Gd and Lu, X is at
least one of halogens Cl, Br and I; 0<x.ltoreq.0.1). Japanese
Patent Laid-Open Publication No. S59-75200 discloses europium
activated complex halide phosphor,
M.sup.(2)FX.quadrature.aM.sup.(1)X'.quadrature.bM'.sup.(2)X''.sub.2.quadr-
ature.cM.sup.(3))X'''.sub.3.quadrature.xA:yEu.sup.2+ (herein
M.sup.(2) is at least one of alkaline earth materials Li, Na, K, Rb
and Cs, M'.sup.(2) is at least one of Be and Mg, M.sup.(3) is at
least one of Al, Ga, In and Tl, A is at least one of oxides of
metal, X is at least one of halogens Cl, Br and I, each X', X'' and
X''' is one of halogens F, Cl, Br and I; 0.ltoreq.a.ltoreq.2,
0.ltoreq.b.ltoreq.10.sup.-2, 0.ltoreq.c.ltoreq.10.sup.-2,
a+b+c.gtoreq.10.sup.-2, 0<x.ltoreq.0.5,and
0<y.ltoreq.0.2).
[0210] There are further other embodiments of the present
invention, which will be described now.
[0211] As shown in FIG. 27, a biochemical analysis unit 201
includes a base plate 205 in which through-holes 206 are formed.
The through-hole 206 is provided with an absorptive region 204
which is formed of the porous materials used for producing the
absorptive region 4. On the absorptive region 204, specific binding
materials are dropped.
[0212] The base plate 205 has a thickness between 50-1000
.quadrature.m, preferably 100-500 .quadrature.m, and is formed of
the same materials for the base plates 5 and 125. Accordingly, the
intensity of the radioactive ray, the fluorescence and the
chemiluminescence each preferably becomes under 1/5, especially
under 1/10.
[0213] The density of the base plate 205 is more than 0.6
g/cm.sup.3, preferably 1-20 g/cm.sup.3, especially more than 2-10
g/cm.sup.3. If the radioactive labeling substances, such as
.sup.32P, .sup.33P, .sup.35S, .sup.14C and the like are applied on
the absorptive region 204, the base plate 205 of the above density
can effectively shield the radioactive ray such that the noise may
not generate in the biochemical analysis data.
[0214] Further, according to the number, the density and the
pattern, the absorptive region 204 are formed as same as the
absorptive region 4. Usually, a length or hole pitch P1 between
centers of the nearest absorptive regions 204 is 0.05-3 mm, and a
distance LI between the nearest absorptive regions 204 is 0.01-1.5
mm.
[0215] As shown in FIG. 28, the absorptive regions 204 are
preferably retracted from the surface of the base plate 205. In
this structure, the specific binding substances can be more easily
absorbed in each of the absorptive regions 204, and the specific
binding substances hardly flow out to the other absorptive regions
204.
[0216] Further, the through-holes 206 may be formed by a method of
an electrical discharging. In the method, a discharging member is
used and has electrodes arranged in the same pattern as the
through-holes 6. The discharging member is closed to the base
plate, and thereafter biases a high voltage between the electrodes
in a pulse-like manner. Thereby the base plate is heated such that
parts thereof are volatilized.
[0217] As shown in FIG. 29, the through-holes 206 may be formed by
using a punch 209. Further, as shown in FIG. 30, the though-holes
206 may be formed by photo lithography and etching. In this case, a
supporter 210 is coated with a coating layer 208 which is formed of
a photosensitive material. Then, a mask sheet 207 for
photolithograph is laid on the coating layer 208. The mask sheet
207 has light-shielding regions 207a arranged in a pattern of the
through-holes 206 to be formed in the base plate 205. An
ultraviolet ray 202 is applied through the mask-sheet 207 to the
coating layer 208. However, as the light shielding regions 207a
shield the light, the coating layer 208 is solidified without parts
corresponding to the light-shielding regions 207a. Thereafter,
etching is carried out. Namely, the coating layer 208 is dipped in
an organic solution to remove the parts thereof that are not
solidified, peeled from the supporter 210, and formed into the base
plate 205 in FIG. 31. Note that the supporter 210 may be formed of
polyethylene, polypropyrene, polyethylene terephthalate,
polytetrafluoroethylene and the like. However, the present
invention is not restricted in them.
[0218] As the photosensitive materials, ultraviolet curting
compounds are preferably used. The ultraviolet curting compounds
are composed of photo polymerization initiator and ultraviolet
curting resins. There are several types of the photo polymerization
initiator, such as hydrogen-pull initiator (for example,
benzophenone type stabilizer), and radical cleavage type stabilizer
(for example, acetophenone type stabilizer and triazine type
stabilizer). Further, as the ultraviolet curting resins, there are
acrylic acid ester (for example, acrylic acid ethyl, acrylic acid
butyl, acrylic acid-2-ethylhexyl), methacrylic acid ester
(methacrylic acid methyl, methacrylic acid ethyl, methacrylic acid
butyl, ethylenegrycol dimethacrylate), higher alcohol, (metha-)
acrylic acid ester (for example, ethylene grycole dimethacrylate,
1,4-dicycrohexane diacrylate, pentaerythritol tetra(metha)acrylate,
pentaerythritol tri(metha)acrylate, trimethylol
propanetri(metha)acrylate, trimethylol ethane tri(metha)acrylate,
dipentaerythritol tetra(metha)acrylate, dipentaerythritol
penta(metha)acrylate, penta erythritol hexa(metha)acrylate,
1,2,3-cycrohexane tetramethacrylate, polyurethane polyacrylate,
polyester polyacrylate). However, present invention is not
restricted in them. Further, they may be used separately or
mixed.
[0219] As the organic solvents for the etching, ketones such as
acetone and ethylmethylketone are used. The organic solvent may
solve the ultraviolet cursing materials and is not restrict in
them. Further, the etching is preferably carried in ultrasonic
wave.
[0220] In order to form the through-holes 206 in the base plate
205, high power laser beams emitted from exima laser, the YAG laser
and the like may be also applied to the base plate 205. Thereby
parts of the base plate 205 may be are evaporated. Furthermore,
electrodes arranged in the same pattern of the through-holes 206
may be also set to the base plate 205 in nonconductors such as oils
or air. The electrodes are electrically biased in high voltage.
Thus, there may occur s discharge between them to form
through-holes 206.
[0221] When the base plate 205 is formed of metal, the
through-holes 206 are etched on the base plate 205. A resist sheet
having the same pattern of the through-holes 206 is laid on a metal
plate. The metal plate is set to a light. Thereafter, the metal
plate is disposed in solutions of strong acid such as sulfuric
acid, fluoric acid, phosphoric acid. In the solutions an anode of
the platinum plate and a cathode of metallic plate are provided to
carry out etching. Thereby corresponding to the pattern of the
resist sheet, the through-holes 206 are formed in the metal plate.
Then, the resist sheet is removed to obtain the base plate 205.
[0222] In order to form the absorptive region 204 in the
through-hole 206, there are at least two methods.
[0223] First, as shown in FIG. 32, the base plate 205 is fed in an
arrowed direction, and a dye 211 containing a dope 204a is disposed
upwards from the base plate 205. The dye 211 feeds out the dope
204a over the base plate 205. A part of the dope 204a enters in the
through-hole 206, and an excess of the dope 204a that remains on
the base plate 205 is removed by a blade 212. Thereafter, the base
plate 205 is set in a solidizing liquid 13 composed of at least one
of good solution and bad solution of the porous materials. Thus the
absorptive regions 204 are formed and the base plate 205 is cleaned
in a water 14 and dried.
[0224] A density of the dope 4 is usually 5-35 wt. %, preferably
10-30 wt. %. If the density is less than 5 wt. %, a structure of
the porous materials forming the absorptive regions 204 is not
enough strong. If the density is more than 35 wt. %, porous spaces
becomes smaller, which decreases the chemical affinity of the
porous material to the substances derived from the living
organism.
[0225] In FIG. 33, the base plate 205 is fed in an arrowed
direction. Above the base plate 205, dispensers 217 provide the
dope 204a in the through-holes 206. After providing the dope 204a,
an air of regulated temperature and humidity is blown to the base
plate 205 to volatile the solvents. Thus the dope 204a is separated
into several layers and gelated.
[0226] In order to remove the excess of the dope 204a, suctioning
devices (not shown) are provided up- and downward of the base plate
205.
[0227] In order that the specific binding substances are more
effectively absorbed, the porous material may contain
surface-active agent. As the surface-active agents, there are
cation, fluoride types: for example, dodecylbenzenesulfonic
potassium, saponin, p-tert-octylphenoxyethoxyethylsulfonic
potassium, nonylphenoxy-polyethoxy-ethanol; fluoride type
surface-active agents which are disclosed in Japanese Patent
Laid-Open Publications No. S62-170950, S63-188135 and U.S. Pat. No.
5,380,644; and polyalkyreneoxide and anion type surface-active
agents which are disclosed in Japanese Laid-Open publication No.
H6-301140.
[0228] According to the porous material in the absorptive regions
204, an angle of contact to water is preferably less than
60.degree., especially less than 50.degree..
[0229] The porous materials may be adhered to the base plate 205
with an adhesive agent such as epoxy. There is also another
preferable method, for example, oxides of metals had to be provided
on a surface of the base plate 205.
[0230] When the base plate 205 is formed of metal, the oxides of
the metals are produced on the surface of the base plate 205 by a
cathode oxidizing process. In the cathode oxidizing process, the
base plate 205 is disposed as a cathode in a solution of sulfuric
acid, phosphoric acid and chromic acid. Then the straight flow is
applied through the base plate 205. Thereafter, as shown in FIG.
34A, a layer 231 of the oxides of metals is formed on a wall
surrounding the through-hole 206. Then the base plate 205 is set in
a coupling agent 232 of silane type or titanate type having an
alcoxyde in an end and an amino group or a carboxylic group in
another end. Thus, as shown in FIG. 34B, the coupling agent 232 is
provided in the through-hole 206. While the base plate 205 and the
coupling agent 232 is heated in a temperature above 50.degree. C.,
as shown in FIG. 34C, a hydroxide group on the surface of the layer
231 combines with the coupling agent 232.
[0231] When the base plate 205 is made of plastics, as shown in
FIG. 35A, particles 233 of the oxides of metals are diffused in the
base plate 205. As shown in FIG. 35B, the particle 233 on the
surface of the base plate 205 has a hydroxide group. While the base
plate 205 and the coupling agent 232 are heated in a temperature
above 50.degree. C., as shown in FIG. 35C, the hydroxide group on
the particle 233 combines with the coupling agent 232.
[0232] After combining of the hydroxide group with the coupling
agent 232, the porous material is combined with another end of the
coupling agent 232. Thus the porous material is adhered to the base
plate 205. Note that the coupling agent 232 may be sprayed for
providing in the base plate 205.
[0233] In FIG. 36, a porous material layer 221 formed of the porous
material is provided on the base plate 205, and a pair of a press
roller 222 and a back-up roller 223 nips the base plate 205 to
pressing the porous material of the porous material layer 221 into
the through-hole 206. Thereby the press roller 222 and the back-up
roller 223 may be heated such that the porous material layer 221
may be softened. After pressing the porous material into the
through-hole 206, the absorptive regions 204 are formed.
[0234] In order to provide the porous material layer 221, a dope is
applied on a supporter (not shown). Then, the supporter is laid in
a bad solution, or in the mixture of the bad solution and good
solution. Thereafter, the dope is dried by cleaning in water or by
applying the dope on the supporter.
[0235] A density of the porous materials in the absorptive region
204 and the porous material layer 221 is usually less than 1.0
g/cm.sup.3, preferably less than 0.5 g/cm.sup.3, especially 0.1
g/cm.sup.3, in order to effectively absorb the specific binding
substances bound such as nucleic acid, fragments thereof, and
synthetized oligonucleotide (synthetic oligonucleotide). The
density of the porous material in the absorptive region 204 must be
smaller that of the base plate.
[0236] The porous material in the absorptive material 204 has
extremely small holes whose radius is 0.1-50 .quadrature.m. The
extremely small holes form free spaces of 10-90% therein.
[0237] In FIG. 37, the pattern of the absorptive regions 204 is
arranged. Further, the absorptive regions 204 may be formed in
other shapes such as hexangular, ellipse and the like. In FIG. 38,
absorptive regions 204 are tetragonaly-formed, and in FIG. 39,
absorptive regions 204 is triangularly-formed.
EMBODIMENT 1
[0238] Produce of a base plate having through-holes
[0239] A polyesther sheet has a size 80 mm.times.80 mm and a width
of 120 .quadrature.m. A density of the polyesther sheet is 1.0
g/cm.sup.3. Circular holes whose radius is 0.2 mm are formed in the
polyesther sheet (base material sheet) with a hole pitch 0.3 mm,
and a distance 0.1 mm. 10.times.10 holes construct a unit and 6400
holes are formed in the polyester sheet. TABLE-US-00001 (2) Supply
for porous material Polysulfone (P-3500, UCC Corporations) 15 part
by weight N-methyl-2-pyrrolidone 72 part by weight
Polyvinyl-pyrrolidone 13 part by weight Water 1.2 part by
weight
[0240] Above materials are solved to prepare a solution for
supplying for the porous material. The solution is flown out on the
polyesther sheet with a casting coaster, supplied in the
through-hole. Thereafter, the excess of the solution is removed
with a blade. The polyester sheet is set in an air blowing in 1.2
m/s at 25.degree. C., and humidity of 50%. Then, the polyester
sheet is set in a water of 25.degree. C. to form the extremely
small holes. Thereafter, the polyester sheet is set in diethylene
glycol for five minutes, washed in water and dried. Thus the
biochemical analysis unit 201 is obtained that is constructed of
polyester dissepiment and porous polymer filled area. Herein an
average of radius of the holes is 0.2 .quadrature.m, and a dried
layer is formed to be 120 .quadrature.m in width.
EMBODIMENT 2
[0241] Produce of Base Plate Having Through-Holes
[0242] A SUS 340 sheet has a size 80 mm.times.80 mm and a width of
100 .quadrature.m. A density of the SUS 340 sheet is 1.0
g/cm.sup.3. Circular holes whose radius is 0.2 mm are formed in the
polyesther sheet with a hole pitch 0.3 mm, and a distance 0.1 mm.
10.times.10 holes construct a unit and 6400 holes are formed in the
polyester sheet. TABLE-US-00002 (2) Supply for porous material
Nylon-6 (Polysciences Corporation) 14 part by weight Formic acid 66
part by weight Water 20 part by weight
[0243] Above materials are solved to prepare a solution for forming
porous structure. The solution is doped on the polyesther sheet
with a casting coaster, supplied in the through-hole. Thereafter,
the excess of the solution is removed with a blade. The SUS 340
sheet is set in 40% formic acid aqueous solution to form the
extremely small holes. Thereafter, the SUS 340 sheet is washed in
water and dried. Thus the biochemical analysis unit is obtained
that is constructed of polyester dissepiment and porous polymer
filled area. Herein an average of radius of the holes is 0.5
.quadrature.m, and a dried layer is formed to be 160 .quadrature.m
in width. TABLE-US-00003 (3) Prepare of porous structure Nylon-6
(Polysciences Corporation) 14 part by weight Formic acid 66 part by
weight Water 20 part by weight
[0244] Above materials are solved to prepare a solution for
supplying for the porous material. The solution is doped as the
dope on the polyesther sheet with a casting coaster, supplied in
the through-hole. Thereafter, the excess of the solution is removed
with a blade. The SUS 340 sheet is set in 40% formic acid aqueous
solution to form the extremely small holes. Thereafter, the SUS 340
sheet is washed in water and dried. Thus the biochemical analysis
unit is obtained that is constructed of polyester dissepiment and
porous polymer area. Herein an average of radius of the holes is
0.5 .quadrature.m, and a dried layer is formed to be 160
.quadrature.m in width.
[0245] (4) Forming of Biochemical Analysis Unit
[0246] The base plate obtained in the process (1) that the porous
material obtained in the process (3) is laid on is fed to a pair of
a press roller and a back-up roller, and pressed in a pressure 20
kgf/cm.sup.2 to obtain a biochemical analysis unit.
[0247] (5) Estimation of Biochemical Analysis Unit
[0248] A fragment of nucleic acid is supplied in porous material of
each of the biochemical analysis units obtained in the embodiments
1 and 2. Thereafter, the biochemical analysis unit is set in an
aqueous solution of radioactive labeling substances to carry out
the hybridization. After withdrawing the biochemical analysis unit
from the aqueous solution, it is washed in water and dried. A
stimulable phosphor sheet is laid on the biochemical analysis unit
and operation of radio autography is carried out in a room
temperature. Then, a radioactive data can be read out from the
stimulable phosphor sheet in high resolution and high
sensitivity.
[0249] In FIG. 40, a biochemical analysis unit 301 has a base plate
305 and an absorptive region 304. As shown in FIG. 41, the
absorptive region 304 is retracted from a surface of the base plate
305.
[0250] In FIG. 42, the base plate 305 has through-holes 306 formed
in a predetermined pitch. A distance L2 between the nearest
through-holes 306 is usually 0.1-3 mm, and a length or a hole pitch
P2 of centers of the nearest through-holes 306 is 0.05-1.5 mm. A
width of the base plate 305 is usually 50-1000 .quadrature.m,
preferably 100-500 .quadrature.m.
[0251] A size and the number of the through-hole 306 are as same as
those of the through-holes 206. Further, the base plate 305 is
formed of the same materials, for example porous materials, as the
base plates 5, 125.
[0252] In FIG. 43, a continuous base plate 311 is fed from a plate
roll 311a in an arrowed direction by a roller 323a, and contacts a
dram 324. The continuous base plate 311 is moved on the dram 324 to
confront to a casting coaster 326. The casting coaster 326 is
supplied with a solution 327 of the porous material (or diffusing
solution) from a tank 325. The solution 327 is doped (in casting)
on the continuous base plate 311 by the casting coaster 326. Thus
the solution 327 is provided in the through-holes 306 of the
continuous base plate 311. A surface of the dram 324 is previously
matted or meshed overall. Accordingly, when the solution 327 is fed
out on the continuous base plate 311, an air in the through-holes
306 is expelled out such that the solution 327 may be easily enter
in the through-hole 306.
[0253] The continuous base plate 311 is further fed in a
solidifying vessel 329, and set in an anti-solvent 330 in the
solidifying vessel 329 such that the porous material may be
shrunken.
[0254] The continuous base plate 311 is fed thereafter into a
drying room 331 by rollers 323c, 323d. In the drying room 331 the
anti-solvent 330 is removed. Thereby, in each through-hole 306 is
formed a dried layer composed of materials for porous material. In
the dried layer, the extremely small holes are formed.
[0255] Then, the continuous base plate 311 is wound by a winding
device 332, and thereafter, the continuous base plate 311 is cut
into base plates 305 having a predetermined size.
[0256] In the present invention, the base plate 305 is not produced
only with a producing method described above. For example, after
being set in the anti-solvent 330, the continuous base plate 311
may be dried in the air for a predetermined time to form a layer,
or washed.
[0257] Further, if the porous material is polymer, such as
polyamide, the anti-solvent 30 may be removed. In this case,
anti-water solution is provided in the through-hole 306, and the
polymer is shrunken in the anti-solvent (water). If the porous
material is other polymer, such as cellulose, after provided in the
through-hole 306, the continuous base plate 311 is dried in the
air. Further, if the porous material is ceramics, a diffusing
solution is prepared from a material which originally has extremely
small holes of predetermined size.
EMBODIMENT 4
[0258] Produce of a Base Plate Having Through-Holes
[0259] A polyesther sheet has a size 80 mm.times.80 mm and a width
of 120 .quadrature.m. A density of the polyesther sheet is 1.0
g/cm.sup.3. Circular holes whose radius is 0.2 mm are formed in the
polyesther sheet with a hole pitch 0.3 mm, and a distance 0.1 mm.
10.times.10 holes construct a unit and 6400 holes are formed in the
polyester sheet. TABLE-US-00004 (2) Supply for porous material
polysulfone (P-3500, UCC Corporations) 15 part by weight
N-methyl-2-pyrrolidone 72 part by weight Polyvinyl pyrrolidone 13
part by weight Water 1.2 part by weight
[0260] Above materials are solved to prepare a solution for
supplying for the porous material. The solution is flown out on the
polyesther sheet with a casting coaster, supplied in the
through-hole. Thereafter, the excess of the solution is removed
with a blade. The polyester sheet is set in an air blowing in 1.2
m/s at 25.degree. C., and humidity of 50%. Then, the polyester
sheet is set in a water of 25.degree. C. to form the extremely
small holes. Thereafter, the polyester sheet is set in diethylene
glycol for 5 minuets, washed in water, and dried. Thus the
biochemical analysis unit 301 is obtained that is constituted of
polyester dissepiments and porous polymer filled area. Herein an
average of radius of the holes is 0.2 .quadrature.m, and a dried
layer is formed to be 120 .quadrature.m in width.
[0261] (5) Estimation of Biochemical Analysis Unit
[0262] A fragment of nucleic acid is supplied in the absorptive
regions 304 of each of the biochemical analysis unit 301.
Thereafter, the biochemical analysis unit 301 is set in an aqueous
solution of radioactive labeling substances to carry out the
hybridization. After withdrawing the biochemical analysis unit from
the aqueous solution, it is washed in water and dried. A stimulable
phosphor sheet is laid on the biochemical analysis unit and
operation of radio autography is carried out in a room temperature.
Then, a radioactive data can be read out from the stimulable
phosphor sheet in high resolution and high sensitivity.
[0263] Further, the absorptive regions 304 may be formed in other
pattern. As shown in FIG. 44A, each line of the respective
absorptive regions 304 is alternatively formed. Furthermore, the
absorptive regions 304 may have, for example, triangle-shape in
FIG. 44B, and tetragonal-shape in FIG. 44C.
[0264] Furthermore, in order to absorb the nucleic acid and the
protein more easily, the absorptive region 305 may be processed so
as to be hydrophilic.
[0265] In FIG. 45, a biochemical analysis unit 351 includes the two
base plates 305 and absorptive regions 354. As shown in FIG. 46,
the absorptive region 354 is retracted from surfaces of the base
plates 305.
[0266] In FIG. 47, an absorptive sheet 361 made of the porous
material is fed from a absorptive sheet roll 361a in an arrowed
direction to a pressing section 364 by a roller 363a. In the
pressing section 364, the two base plates 305 are disposed up- and
downward of the absorptive sheet 361 at a predetermined space. When
a surface of each base plate 305 is uneven, the base plates 305 are
disposed such that the surfaces may confront to each other. The two
base plates 305 are pressed by a pressing device 366a to sandwich
the absorptive sheet 361, and thereafter fed to a cutting section
367 by a roller 363b. In the cutting section 367, cutters 368 cut
off the absorptive sheet roll 361a to form the biochemical analysis
unit 351.
[0267] The pressing devices 366a are heated and press the two base
plates 305 to the absorptive sheet 361 in thermo compression. As
shown in FIG. 48, the base plates 305 sandwich the absorptive sheet
361 thereby. The thermal compression is adequate when the base
plate 305 is formed of at least one of metals and ceramics. The
pressure and the temperature applied for the thermo compression may
be changed corresponding sorts and thickness of the base plates 305
and the absorptive sheets 361, and is usually 10-500 kg/cm.sup.2,
preferably 50-200 kg/cm.sup.2.
[0268] In order to form the biochemical analysis unit 351, a
solvent may be used. As shown in FIG. 49, there are a solvent
applying section 374 between the absorptive sheet roll 361a and the
pressing section 364, and a drying section 379 between the pressing
section 364 and the cutting section 367.
[0269] After fed by a roller 373a, the absorptive sheet 361 is set
in a solvent in a vessel 375 provided in the solvent applying
section 374. Then the absorptive sheet 361 is fed to the pressing
section 364 by rollers 373b, 373c, 373d. After thermal compression
in the pressing section 364, the pair of the two base plates 305
sandwiching the absorptive sheet 361 is fed in a drying room 380 by
a roller 373e. In the drying room 380, an air blow is applied to
the pair of the base plates 305 to dry the solvent remaining in the
extremely small holes of the absorptive sheet 361. Thereafter, the
pair of the base plates 305 is fed in the cutting section 367 to
obtain the biochemical analysis unit 351.
[0270] As the solvent may be used materials which can solve the
base plate 305 but not the absorptive sheet 361. Such material must
be decided corresponding to sorts of the base plates 305 and the
absorptive sheet 361, and there are for example, acetone,
methylethylketone, DMSO (dimethyl sulfoxyde), DMF (dimethyl
formamide), methylene chloride, N-methyl-2-piloridrine, chloroform,
trichloroethane, benzene, toluene, and the like.
[0271] Further, in order to absorb the nucleic acid and the protein
more easily, the absorptive region 354 may be processed so as to be
hydrophilic.
EMBODIMENT 4
[0272] (1) Produce of Base Plate
[0273] Two base plates coated with nickel are prepared for an
electro coating method. Each base plate has a size 80 mm.times.80
mm and a width of 120 .quadrature.m. A density of the base plate is
8.8 g/cm.sup.3. Circular holes whose radius is 0.2 mm are arranged
with a hole pitch 0.3 mm and a distance 0.1 mm. 10.times.10 holes
construct a unit and 6400 holes. TABLE-US-00005 (2) Supply for
porous material Nylon-6 (Polysciences Corporation) 14 part by
weight Formic acid 66 part by weight Water 20 part by weight
[0274] Above materials are solved to prepare a solution for forming
porous structure. The solution is doped on the polyesther sheet
with a casting coaster, supplied in the through-hole. Thereafter,
the excess of the solution is removed with a blade. The base plate
is set in 40% formic acid aqueous solution to form the extremely
small holes. Thereafter, the base plate is washed in water and
dried. Thus the biochemical analysis unit is obtained that is
constructed of polyester dissepiments and a porous polymer area.
Herein an average of radius of the holes is 0.5 .mu.m, and a dried
layer is formed to be 160 .mu.m in width.
[0275] (3) Prepare of Porous Material TABLE-US-00006 (3) Prepare of
porous material Nylon-6 15 part by weight Formic acid 83 part by
weight Water 2 part by weight
[0276] Above materials are mixed in a room temperature for three
hours. The mixture is warmed at 50.degree. C. for one hour and
cooled to prepare a polymer solution. The polymer solution is
applied and dried to form a porous material sheet. Thereafter, the
porous material sheet is set in 20%-formic acid solution to form
the extremely small holes. The average of the diameter of the small
holes is 0.45 .mu.m.
[0277] (4) Unitizing Through Pressing
[0278] The porous material is sandwiched between the two base
plates, and they are pressed under 50 kg/cm.sup.2 and in
150.degree. C. Thereafter, the excess of the porous material is cut
off to obtain a biochemical analysis unit.
[0279] (5) Estimation of Biochemical Analysis Unit
[0280] A fragment of nucleic acid is supplied in porous material of
each of the biochemical analysis unit. Thereafter, the biochemical
analysis unit is set in an aqueous solution of radioactive labeling
substances to carry out the hybridization. After withdrawing the
biochemical analysis unit from the aqueous solution, it is washed
in water and dried. A stimulable phosphor sheet is laid on the
biochemical analysis unit and operation of radio autography is
carried out in a room temperature. Then, a radioactive data can be
read out from the stimulable phosphor sheet in high resolution and
high sensitivity.
[0281] Further, the absorptive regions 354 may be formed in other
pattern. As shown in FIG. 50A, each line of the respective
absorptive regions 354 is alternatively formed. Furthermore, the
absorptive regions 354 may have, for example, triangle-shape in
FIG. 50B, and tetragonal-shape in FIG. 50C.
[0282] Various changes and modifications are possible in the
present invention and may be understood to be within the present
invention.
* * * * *