JP2002323509A - Head for manufacturing micro-array, micro-array manufacturing apparatus using the head, micro-array manufacturing method and micro-array - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a head for manufacturing a micro-array, capable of keeping constant the size and shape of a spot disposed on a substrate. SOLUTION: This head 51 for manufacturing a micro-array is provided with a liquid reservoir member 52 for holding a solution containing an organism sample, and a needle 53 projected from and recessed into the liquid reservoir member 52 to dispose a solution stored in the liquid reservoir part 52 on the substrate 3. When the needle 53 is projected from the liquid reservoir part 52 so that the tip of the needle 53 comes into contact with the substrate 3, the solution held at the tip of the needle 53 and the solution in the liquid reservoir member 52 are communicated with each other. The needle 53 pulls the solution out of the liquid reservoir member 52 and disposes the solution held at the liquid reservoir member 52 on the substrate 3. When the tip of the needle 53 comes into contact with the substrate 3, the solution held at the tip of the needle 53 and the solution in the liquid reservoir member 52 are communicated with each other, whereby the size and shape of the spot disposed on the substrate 3 can be kept constant.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a microarray manufacturing apparatus for arranging a large number of biological samples such as DNA fragments and oligonucleotides on a substrate.

[0002]

2. Description of the Related Art At present, technology development for efficiently analyzing the functions of all genes of various organisms is in progress. A DNA microarray (that is, a DNA chip) is obtained by arranging a large number of spots containing DNA fragments and the like on a glass slide or a silicon substrate, and is very effective for analyzing gene expression, mutation, diversity, and the like.

[0003] The size of a general substrate is 1 to several tens cm.
^{In step 2} , thousands to hundreds of thousands of DNA fragment spots are aligned in this area. The DNA fragment on the substrate is examined using complementary fluorescently labeled DNA. DNA on substrate
Fluorescence is emitted when hybridization occurs between the fragment and the fluorescently labeled DNA. By detecting the spot where the fluorescence is generated by a fluorescence scanner or the like and analyzing the fluorescence image, it is possible to analyze gene expression, mutation, diversity, and the like.

In order to develop the technology of the DNA microarray, a microarray manufacturing device for arranging dense spots of DNA fragments on a substrate is required.

[0005] International publication number WO99 / 36760 includes:
A microarray manufacturing apparatus that arranges DNA fragments prepared in advance on a substrate is disclosed. In this apparatus, as shown in FIG. 18, spots are arranged on a substrate 203 by cooperating with a ring-shaped liquid reservoir member 201 and arrangement pins 202. A solution containing a DNA fragment is held on the inner peripheral surface of the liquid storage member 201. The arrangement pin 202 reciprocates vertically with respect to the liquid storage member 201. When the placement pin 202 exits the liquid storage member 201, the placement pin 2
A solution for forming one spot at the tip of 02 is held. Then, the tip of the arrangement pin 202 is
The solution held at the tip of the placement pin 202 is placed on the substrate by mechanically contacting the top.

[0006] The performance of the microarray manufacturing apparatus is as follows.
In order to quantitatively analyze gene expression and analyze single nucleotide mutations, it is required to have a capability of keeping the size and shape of the spot constant. In the above microarray manufacturing apparatus, the arrangement pin 2
A sharp edge 202 a is provided at the tip of the reference numeral 02, and a fixed volume of the solution is held at the tip of the placement pin 202.

[0007]

However, in the above-described microarray manufacturing apparatus, the solution is held at the tip of the arrangement pin 202 by being separated from the solution held by the liquid storage member 201. Therefore, there is a problem that the volume of the solution held at the tip of the arrangement pin 202 varies, and the size and shape of the spot cannot be kept constant.

Accordingly, the present invention provides a microarray manufacturing head capable of keeping the size and shape of spots arranged on a substrate constant, a microarray manufacturing apparatus using the head, a microarray manufacturing method, and a microarray. Aim.

[0009]

Hereinafter, the present invention will be described. It should be noted that, in order to facilitate understanding of the present invention, reference numerals in the accompanying drawings are added in parentheses.
The present invention is not limited to the illustrated embodiment.

[0010] In order to solve the above problems, the present inventor has proposed:
Using the surface tension of the solution, the solution held in the liquid reservoir and the solution held at the tip of the placement unit were integrated, and the solution was pulled out from the liquid reservoir and placed on the substrate.

That is, according to the first aspect of the present invention, there is provided a liquid reservoir (52) for holding a solution containing a biological sample, and a protruding / retracting part with respect to the liquid reservoir (52), which is stored in the liquid reservoir (52). A microarray producing head (51) comprising: a disposing portion (53) for disposing the solution obtained on the substrate (3), wherein when the tip of the disposing portion (53) contacts the substrate (3), The above-mentioned problem has been solved by a microarray manufacturing head characterized in that the solution held at the tip of the placement section (53) and the solution in the liquid storage section (52) are connected.

According to the present invention, the disposing portion pulls the solution from the liquid reservoir, and disposes the solution held in the liquid reservoir on the substrate. When the tip of the placement section contacts the substrate, the solution held at the tip of the placement section and the solution in the liquid storage section are connected, so that the size and shape of the spot placed on the substrate can be kept constant. Whether or not the solution held at the tip of the disposition portion is connected to the solution in the liquid storage portion is confirmed by watching an image during stamping or the like.

According to a second aspect of the present invention, in the head (51) for producing a microarray according to the first aspect, the outer peripheral surface of the arrangement portion (53) has a rough surface so as to hold a solution. It is characterized by having been done. Here, it is desirable that the entire outer peripheral surface of the arrangement portion (53) is rough, but a part thereof may be rough.

According to the present invention, since the amount of the solution held on the outer peripheral surface of the arrangement portion is stabilized, the size and shape of the spot arranged on the substrate can be kept more constant. When the outer peripheral surface of the arrangement portion is roughened, the shape of the spot can be particularly stabilized to be round. In addition, since a large amount of solution can be held on the outer peripheral surface of the disposition portion, the distance of the solution that can be pulled out from the liquid storage portion also increases.

Further, according to a third aspect of the present invention, in the microarray manufacturing head according to the second aspect, the surface roughness of the outer peripheral surface of the arrangement portion (53) protruding from the liquid reservoir (52) is reduced. The disposition portion (5) in the liquid reservoir portion (52)
3) characterized in that it is rougher than the surface roughness of the outer peripheral surface.

Different kinds of solutions are held in the liquid reservoir. When the liquid reservoir holds a new solution, it is necessary to wash the solution adhering to the inside of the liquid reservoir and the outside of the needle. According to the present invention, since the surface roughness of the arrangement portion in the liquid reservoir that does not contribute to the holding of the solution is smoother than that of the protruding portion, the outside of the arrangement portion can be easily cleaned. In addition, even when the arrangement portion reciprocates while sliding in the liquid reservoir, the arrangement portion smoothly reciprocates.

Further, according to a fourth aspect of the present invention, in the head (51) for producing a microarray according to the second or third aspect, the surface roughness of the outer peripheral surface of the arrangement portion (53) is less than that of the substrate (3). It is characterized in that it is rougher than the surface roughness of the tip of the arrangement portion (53) in contact.

The tip of the arrangement portion mechanically repeatedly contacts the substrate tens of thousands of times. According to the present invention, it is possible to prevent the tip of the arrangement portion from being worn at an early stage.

According to a fifth aspect of the present invention, in the head for manufacturing a microarray according to any one of the first to fourth aspects, the arrangement portion (53) has a tapered shape whose outer peripheral surface gradually narrows toward a tip. The liquid reservoir (52) is formed in a taper shape in which the inner peripheral surface gradually narrows toward the tip.

According to the present invention, it is easy to connect the solution held in the liquid reservoir to the solution held in the tip of the disposition portion.

Further, as in the invention of claim 6, the outer peripheral surface of the arranging portion may be roughened by grinding or electric discharge machining.

According to the present invention, there is provided a solution storage section (74) for storing a solution containing a biological sample.
A worktable (4) on which a plurality of substrates (3) can be arranged;
A solution holding unit (51) for taking in and holding the solution from the solution storage unit (74) and forming a spot of the solution on the substrate (3); and holding the holding unit (51) with respect to the substrate. Moving means (23, 95) for moving in the direction of approaching / separating to form a spot by using the holding means (51); and holding the holding means (51) in the solution storage section (74), the work table. Conveying means (6, 75) for conveying in the area including (4) and providing two-dimensional coordinates;
A microarray manufacturing apparatus, comprising: a holding section (51) for holding a solution containing a biological sample; a liquid reservoir (52); An arrangement part (53) for arranging the solution stored in (52) on the substrate (3), and when the tip of the arrangement part (53) contacts the substrate (52), the arrangement part (5) is provided.
The solution held at the tip of 3) and the solution in the liquid reservoir (52) are connected to each other, so that the apparatus can also be configured as a microarray manufacturing apparatus.

Further, according to the present invention, the disposing portion (53) is made to protrude and retract from the liquid reservoir (52) for holding a solution containing a biological sample.
A method for preparing a microarray in which the solution stored in 2) is arranged on a substrate (3), wherein the solution held at the tip of the arrangement section (53) and the solution in the liquid storage section (52) remain connected. In this state, the method may be configured as a microarray manufacturing method, wherein the solution stored in the liquid storage section (52) is disposed on the substrate (3).

Furthermore, the present invention provides a microarray in which spots of a solution containing a biological sample are arranged on a substrate (3), wherein the spots of the solution contain a biological sample. The arrangement portion (53) is protruded and retracted with respect to the liquid reservoir portion (52) for holding the solution, and the solution held at the tip of the arrangement portion (53) and the solution in the liquid reservoir portion (52) remain connected. Thus, a microarray formed by arranging the solution stored in the liquid storage section (52) on the substrate (3) can be also configured.

[0025]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Referring to the drawings, a description will be given of a microarray manufacturing apparatus according to an embodiment of the present invention.
FIG. 1 is a plan view showing the microarray manufacturing apparatus of the present embodiment, FIG. 2 is a front view of the microarray manufacturing apparatus taken along the line II-II in FIG. 1, and FIG. FIG. 4 is a right side view of the apparatus, FIG. 4 is a left side view of the apparatus viewed from the direction of line IV-IV in FIG. 2, and FIG.
It is sectional drawing of this apparatus seen from the V line direction.

This apparatus arranges a number of spots of a solution of a biological sample such as a DNA fragment or an oligonucleotide prepared in advance on a substrate made of a slide glass, silicon, or the like. The size of a general substrate is 1 to several tens cm ² , and spots of several thousand to several hundred thousand kinds of DNA fragments are arranged in this area. The spot diameter has a size of, for example, several tens of microns to several hundreds of microns.

As shown in FIG. 1, the microarray manufacturing apparatus has two regions. One is a microarray manufacturing head 51 that holds a solution (hereinafter simply referred to as a head).
Is a stamping area 1 in which a spot of a solution of a biological sample is arranged on the substrate. The other is a cleaning area 2 in which the head 51 after the formation of the spot is cleaned and the cleaned head 51 holds the next solution of a different type. The configuration of the head will be described later.

First, the stamping area will be described. A large number of substrates 3 are placed on the worktable 4 in a matrix. In this embodiment, the substrates 3 are placed in a total of 48 sections in 4 rows vertically and 12 rows horizontally. The number of substrates 3 can be variously changed according to the number of replicas to be manufactured. The substrate 3 is made of a glass slide, silicon, or the like, and the surface of the substrate 3 is subjected to a surface treatment so that a biological sample can be attached thereto.

The worktable 4 is provided with a suction hole corresponding to each substrate, and a conduit of a vacuum device (not shown) is connected to the suction hole. By activating the vacuum device,
Air is sucked from the suction port, and the substrates 3 are fixed to the worktable.

On a part of the work table 4, a test table 5 on which two substrates or dummy substrates for producing a micro array on a trial basis are provided. When the needle of the head 51 holding the solution is suddenly struck against the substrate 3, the needle is struck while the solution is excessively applied.
In order to avoid this, a needle is hit on the substrate 3 on the test table 5, and the solution that has excessively adhered to the needle is dropped.

The head 51 is transported onto the work table 4 and X is used as second transport means for giving the head 51 two-dimensional coordinates.
The Y2-axis transport mechanism 6 is attached. The XY two-axis transport mechanism 6 positions the head 51 by shifting it by, for example, several hundred microns in the X direction or the Y direction from the previously struck position so that a minute spot can be formed on the substrate 3 at a predetermined position. The XY two-axis transport mechanism 6 receives the head 51 up to a transfer position 104 described later,
After the formation of the spot is completed, the head 51 is transported to the transfer position 104 again.

As shown in FIGS. 1 and 4, the XY two-axis transport mechanism 6 includes an X-axis transport mechanism 6X and a Y-axis transport mechanism 6Y. The X-axis moving mechanism 6X has a longitudinal fixed frame 8 extending in the X-axis direction, rails 9, 9 mounted on the fixed frame so as to extend in the X-axis direction, and movably with respect to the rails 9, 9. It includes a linear guide composed of assembled sliders 10, 10, a table 11 guided by the linear guide, and a linear motor 12 for driving the table 11. The linear motor 12 includes a magnet 12a as a secondary side extending in the X-axis direction, and a coil 12b as a primary side attached to the back side of the table 11 so as to face the magnet 12a. On the opposite side of the X-axis transport mechanism 6X with respect to the substrate, a longitudinal fixed frame 13 extending in the X-axis direction, a rail 14 extending on the fixed frame 13 in the X-axis direction, and a rail 14 On the other hand, a linear guide including a slider 15 movably incorporated is provided.

As shown in FIGS. 1 and 2, the Y-axis driving mechanism 6Y includes a longitudinal movable frame 17 provided between the table 11 and the slider 15 driven by the X-axis driving mechanism 6X. 17, a linear guide comprising rails 18 and 18 extended in the X-axis direction and sliders 19 and 19 movably mounted on the rails 18 and 18, and a table 20 guided by the linear guide. And a linear motor 21 for driving the table 20. The linear motor 21 includes a magnet 21a as a secondary side extending in the Y-axis direction, and a coil 21b as a primary side attached to the back side of the table 20 so as to face the magnet 21a.

The XY two-axis transport mechanism 6 supports a Z-axis drive mechanism 23 as moving means. This Z-axis drive mechanism 2
3 moves the head 51 in a Z-axis direction orthogonal to the X-axis and the Y-axis, that is, in a direction approaching / separating from the substrate 3. The Z-axis drive mechanism 23 has a Z1-axis drive mechanism 23Z1 for raising and lowering the entire head 51, and has a Z2-axis drive mechanism 23Z2 for projecting the needle from the liquid reservoir member of the head 51.

The Z1-axis driving mechanism 23Z1 is composed of an electric actuator for moving a slider using a feed screw and an electric motor. As shown in FIG. 6, the electric actuator has a highly rigid outer rail 31 having a U-shaped cross section.
And a slider 32 reciprocally movable within the outer rail 31. A nut is integrally provided at the center of the slider 32, and a plurality of circulating balls 33 are provided between both side surfaces of the slider 32 and the inner surface of the outer rail 31.
... are provided. Since this electric actuator has the same rated load in all directions acting on the slider 32, it is suitably used as a drive mechanism in the Z-axis direction in which the head 51 and the like are attached to the slider in an overhang state.

The electric actuator constituting the Z1-axis driving mechanism 23Z1 will be described in detail. The electric actuator includes an outer rail 31 and the outer rail 31.
A slider 32 that is guided so as to be capable of linear movement, a nut 35 provided on the slider 32, and screwed to a screw shaft;
The outer rail 31 has a screw shaft 34 rotatably supported at both ends in the longitudinal direction. An electric motor (not shown) is attached to one end of the outer rail 31. The output shaft of the electric motor is connected to the screw shaft 34 via a joint.

The outer rail 31 has a U-shaped cross section, and a pair of ridges 36, 36 extending in parallel so as to face each other across the recess 31a is provided on the upper surface thereof. Jetty 3
Grooves 37, 37 are formed on the inner surfaces of the grooves 6, 36 over the entire length, and two ball rolling grooves 38, 38 are formed at the upper and lower corners of each groove 37.

The slider 32 includes a block body 32a,
And end plates 32b attached to both end surfaces of the block body 32a. This slider 32
Are inserted into the recesses 31a on the upper surface of the outer rail 31, and are supported so as to be sandwiched between the jetties 36, 36 via balls 33 as rolling elements.

Load rolling grooves facing the ball rolling grooves 38 of the outer rail 31 are formed on both side surfaces of the block body 32a. A plurality of balls 33 are interposed movably between the ball rolling grooves 38 facing each other and the load rolling grooves. In the block body 32a, a ball escape hole for returning a ball rolling in the load area is formed in parallel with the load rolling groove. The block body 32
A return passage for scooping up the balls 33 in the load region and circulating the balls again in the load region is provided in the end plates 32b provided on both sides of the end plate 32a.

At the center of the block body 32a, a screw shaft 3
4 is provided with a nut to be screwed. A helical load rolling groove corresponding to the helical ball rolling groove formed on the screw shaft 34 is formed in the nut. A plurality of balls as rolling elements are interposed between the spiral ball rolling grooves and the load rolling grooves so as to freely roll. The nut is provided with a return tube for circulating a ball rolling in the load area.

As shown in FIGS. 1, 2 and 5, a table 41 is mounted on the slider of the Z1-axis driving mechanism 23Z1, and the Z-axis moving mechanism 23Z2 is mounted on the table 41.
Is attached. The Z2-axis drive mechanism 23Z2
It is composed of an electric actuator having the same configuration as the one-axis drive mechanism 23Z1, and is smaller than the Z1-axis drive mechanism 23Z1. An L-shaped arm 42 for raising and lowering the needle of the head 51 is attached to the slider of the Z2-axis moving mechanism 23Z2. The L-shaped arm 42 can be inserted into the head 51 by an air cylinder (not shown) (see FIG. 7). Connect the tip of the L-shaped arm 42 to the head 5
The needle is projected from the liquid reservoir member of the head 51 by lowering the inserted L-shaped arm 42 by the Z2-axis moving mechanism 23Z2.

The table 41 of the Z1-axis drive mechanism 23Z1 is provided with a Θ-axis rotation mechanism 43 as attitude changing means for changing the attitude of the head 51. The Θ-axis rotating mechanism 43 rotates the head 51 in a horizontal plane. The Θ-axis rotation mechanism 43 includes an electric motor 44 attached to the table 41 and a substantially cylindrical chuck portion 45 supported on the table 41 so as to be rotatable around the Z-axis. The chuck portion 45 is connected to the electric motor 44 via a joint. The chuck portion 45 detachably holds the head 51.

FIG. 7 shows the chuck section 45 and the head 51. As shown in FIG. 3A, a fitting convex portion 45a that fits into the head 51 is formed below the chuck portion 45, and the convex portion 45a is rotatable at equal intervals in the circumferential direction. Claws 46 are provided. The claws 46 are rotated by an air cylinder (not shown). Insert the fitting projection 45a of the chuck portion 45 into the fitting recess 51a of the head 51, and
When 6 ... are simultaneously opened so that they protrude to the side, claws 46 ...
Is hooked on the pin 51b provided in the fitting concave portion 51a of the head 51. Thus, the chuck 45 holds the head 51. When the claws 46 are closed inward, the claws 46 are closed.
The engagement between the pin 51b and the head 51 is released, and the head 51 is removed from the chuck portion 45. A plurality of positioning taper pins 51c are provided on the upper surface of the head 51 so that the head 51 can be positioned with respect to the chuck portion 45.

FIG. 7B shows a state where the tip of the L-shaped arm 42 is inserted into the head 51. The needle 53 protrudes from the liquid storage member 52 of the head 51 by lowering the inserted L-shaped arm 42 by the Z2-axis moving mechanism 23Z2.

As shown in FIG. 2, the work table 4 is provided with a photographing element 67 (for example, a CCD camera) as detecting means for detecting the attitude and position of the head 51 from below. The replaced head 51 is first conveyed above the imaging element 67. A mark indicating the position is attached to the head 51, and the image sensor 67 detects the mark. Information on the attitude and position of the head 51 detected by the imaging element 67 is input to a control device as control means. Based on the information on the attitude and position of the head 51, the control device controls the Θ-axis rotation mechanism 43 and the XY2 as the attitude means so as to always maintain a constant attitude and position even when the head 51 is replaced.
The shaft transport mechanism 6 is operated.

The controller operates the ５１-axis rotation mechanism 43 to rotate the head 51 around the Z axis, thereby changing the attitude of the head 51. Further, the control device operates the XY two-axis transport mechanism 6 to rotate the head 51 around the Z axis, thereby
The position of 1 changes. Thus, the replaced head 5
By correcting the attitude and position of the head 51 to the same attitude and position as those of the head 51 before the replacement, a spot of the solution can be accurately formed on the substrate 3. The Θ-axis rotation mechanism 43 is provided with an encoder as angle detection means for detecting the rotation angle of the electric motor 44. The rotation angle of the electric motor 44 is feedback-controlled so that the Θ-axis rotation mechanism 43 rotates by a predetermined angle.

Further, the XY biaxial transport mechanism 6 is formed so that a spot can be formed at a predetermined position with respect to the substrate 3.
A board photographing element 68 (for example, a CCD camera) for detecting the position of the board 3 attached to the work table 4, and a spot photographing element 69 for detecting a situation of a spot formed on the board.
(For example, a CCD camera).

FIGS. 8 and 9 show a head 51 as a holding means. The head 51 includes a cylindrical chucked portion 54 attached to the chuck portion 45 and the chucked portion 5.
4, a substantially rectangular upper plate 55 fixed to the lower surface of
A substantially rectangular lower plate 57 as a base portion is generally provided on the upper plate 55 via a plurality of columns 56.

The lower plate 57 has a liquid reservoir member 52 as a liquid reservoir for holding a solution to be supplied to the substrates 3.
... are attached vertically and horizontally parallel to each other. A needle 53 (also referred to as a pin) as an arrangement portion is accommodated in the liquid storage members 52. The needle 53 is guided by a plurality of needle bushes 66 fixed to the lower plate 57 so as to be able to reciprocate in the vertical direction. In this embodiment, a total of 48 liquid reservoir members 52... And needles 53...
.. Can be variously set depending on the number of substrates 3... On which spots can be simultaneously formed.

The lower plate 57 is provided with a plurality of needles 53... The space 58 for supplying the cleaning liquid etc.
As shown in FIG.
2 ... communicates with everything.

Between the upper plate 55 and the lower plate 57, the intermediate plate 59 is slidable with respect to the support.
Is provided. A connecting portion 60 is provided on the lower surface of the intermediate plate 59.
A needle support plate 61 is fixed via the needle support plate 61, and the plurality of needles 53 are supported by the needle support plate 61. A flange 53d to be mounted on the upper surface of the needle support plate 61 is formed above the needle 53, and a coil spring 62 is interposed between the flange 53d and the intermediate plate 59. The coil springs 62 are compressed and deformed when the needles 53 come into contact with the substrate 3, and adjust the load applied from the needles 53 to the substrate 3. The intermediate plate 59 is provided with a bush 63 for guiding the sliding movement of the intermediate plate 59 with respect to the column 56. A coil spring 64 for raising the needle 53 between the intermediate plate 59 and the lower plate 57 and retracting the needle 53 into the liquid storage member 52.
Is provided.

FIG. 11 shows a state where the needles 53 are lowered. When the intermediate plate 59 is lowered as shown in this figure, the needles 53 are also lowered together with the intermediate plate 59, and the needles 53 project from the lower ends of the liquid storage members 52. When the needles 53 contact the substrate 3, the coil springs 62 are compressed and deformed so that no excessive load is applied to the substrate 3 from the needles 53.

The operation of the head 51 by each drive mechanism will be described. First, the head 51 is positioned by the XY biaxial transport mechanism 6 in the X and Y directions above the substrate 3. Next, the head 51 is moved by the Z1-axis moving mechanism 23Z1.
The whole is lowered, and the head 51 is positioned at a predetermined distance from the substrate in the Z direction. Next, the Z2 axis moving mechanism 23Z
The two L-shaped arms 42 are connected to the intermediate plate 59 in the head 51.
It is advanced upward. L by the Z2 axis moving mechanism 23Z2
When the arm 42 is lowered, the intermediate plate 59 is pushed down by the L-arm 42, whereby the needle 5 is moved.
3 protrudes from the liquid storage member 52. On the other hand, when the L-shaped arm 42 is raised by the Z2-axis moving mechanism 23Z2, the intermediate plate 59 is raised by the restoring force of the coil spring 64, whereby the needle 53 is retracted into the liquid storage member 52.

FIG. 12 shows a liquid storage member 52 for holding a solution.
And a needle 53. The liquid storage member 52 is formed in a tapered tapered tube shape, and a needle 53 is stored in the tapered internal space together with the solution. The lower part of the liquid reservoir member 52, which is the narrowest, also guides the vertical movement of the needle 53.

The distal end portion 53a of the needle 53 also has a tapered outer peripheral surface. Further, the distal end surface 53b of the needle 53 that contacts the substrate 3 is formed as a circular or polygonal flat surface. The outer peripheral surface of the distal end portion 53a is the outer peripheral surface of the straight portion 53c and the distal end surface 53b of the needle 53.
In comparison with the above, the surface roughness is made rough so that the solution can be held. This surface roughness is such that when the needle 53 projects a predetermined amount from the liquid reservoir member 52 and the distal end surface 53b of the needle 53 comes into contact with the substrate 3, the solution held on the distal end surface 53b and the solution in the liquid reservoir member 52 are separated. Set to connect. Further, this surface roughness is formed by grinding or electric discharge machining. For example, in the case of grinding, the outer peripheral surface of the tip 53a is roughened by moving the grindstone in the longitudinal direction of the needle 53.

FIGS. 13A to 13E show the liquid storage member 52.
FIG. 4 is a process chart showing a method of arranging a solution stored in the substrate 3 on a substrate 3. FIGS. 6A to 6E show the liquid storage member 52.
The needle 53 is in the Z-axis direction (that is, in the vertical direction)
Shows the state of the solution when moving to.

First, as shown in FIG. 7A, the liquid storage member 52 is positioned above the substrate 3. Next, as shown in (b) and (c) in the figure, the needle 53 is gradually lowered with respect to the liquid storage member 52. Next, the needle 53 is made to protrude from the liquid storage member 52 as shown in FIG. At this time, due to the surface tension of the solution,
The solution in 2 is pulled out. And the needle 53
Is brought into contact with the substrate 3. When the distal end face 53b of the needle 53 comes into mechanical contact with the substrate 3, the solution moves from the distal end face 53b of the needle 53 to the substrate 3, and the substrate 3
The solution is placed on top. At this time, the solution held at the tip of the needle 53 and the solution in the liquid storage member 52 are connected. Then, as shown in (e) in the figure, when the needle 53 is retracted from the substrate 3, a solution spot is formed on the substrate 3.

As described above, the solution held by the liquid storage member 52 and the solution held at the tip of the needle 53 are integrated, and the solution is pulled out from the liquid storage member 52 by utilizing the surface tension of the solution to form a substrate. By arranging the spots on the substrate 3, the size and shape of the spots arranged on the substrate 3 can be kept constant. Further, by making the outer peripheral surface of the needle 53 rough, the amount of the solution held on the outer peripheral surface of the needle 53 is stabilized.
For this reason, the size and shape of the spot arranged on the substrate 3 can be kept more constant.

FIG. 14 shows another example of the needle 53.
In this example, a needle 53 projecting from the liquid storage member 52
The surface roughness of the outer peripheral surface 53d of the needle 53 in the liquid reservoir member 52 is larger than the surface roughness of the outer peripheral surface 53c of the needle 53. Since different types of solutions are held in the liquid storage member 52, it is necessary to clean the solution attached to the inside of the liquid storage member 52 and the outside of the needle 53 when the liquid storage member 52 holds a new solution. By making the surface roughness of the needle 53 in the liquid reservoir member 52 that does not contribute to holding the solution smoother than the protruding portion, the outside of the needle 53 can be easily cleaned. Also, when the needle 53 reciprocates while sliding within the liquid reservoir member 52, the needle 53 reciprocates smoothly.

Next, the cleaning area will be described. In this cleaning area, the head 51 after the formation of the spot is subjected to ultrasonic cleaning, followed by rinsing and drying. The washed head 51 holds a new solution of the next biological sample.

As shown in FIG. 1, an ultrasonic cleaning section 71 as a cleaning section for ultrasonically cleaning the head 51 and a rinsing section as a cleaning section for rinsing the head 51 are provided on the cleaning table 96. A washing unit 72, a drying unit 73 for drying the head 51, and a solution storage unit 74 for storing a solution containing a biological sample are provided. The head 51 is transported between the ultrasonic cleaning section 71, the rinsing section 72, the drying section 73, and the solution storage section 74 on the cleaning table 96.
An XY two-axis transport mechanism 75 is provided as a first transport unit that gives two-dimensional coordinates to the XY coordinate system.

The XY two-axis transport mechanism 75 includes an X-axis transport mechanism 75X and a Y-axis transport mechanism 75Y.

As shown in FIGS. 1 and 3, the X-axis moving mechanism 75X includes a longitudinal fixed frame 81 extending in the X-axis direction.
And a linear guide including rails 82, 82 mounted on the fixed frame 81 in the X-axis direction and sliders 83, 83 movably assembled to the rails 82, 82, and the linear guide. It has a table 84 to be guided and a feed screw 85 for driving the table 84. The feed screw, a ball screw nut attached to the lower surface of the table, screwed with the ball screw nut,
A screw shaft 85a extending in the X-axis direction;
and an electric motor 86 for rotating a. The screw shaft 85a and the electric motor 86 are connected via a winding transmission.

The Y-axis driving mechanism 75Y is an X-axis driving mechanism 75
A longitudinal movable frame 87 fixed on a table 84 driven by X, a rail 88 extending and attached to the movable frame 87 in the X-axis direction, and a slider 89 movably incorporated with respect to the rail 88 , A table 90 guided by the linear guide, and a feed screw 91 for driving the table 90. The feed screw 91 includes a ball screw nut attached to the lower surface of the table 90, a screw shaft 91a screwed to the ball screw nut and extended in the X-axis direction, and an electric motor 92 for rotating the screw shaft 91a. It is composed of The screw shaft 91a and the electric motor 92 are connected via a winding transmission.

As shown in FIGS. 1 and 2, the XY two-axis transport mechanism 75 is provided with a Z-axis drive mechanism 95 as moving means. The Z-axis drive mechanism 95 moves the head 51 in a Z-axis direction orthogonal to the X-axis and the Y-axis, that is, in a direction orthogonal to the washing table 96. This Z-axis drive mechanism 95
Like the Z-axis drive mechanism 23 in the stamping area,
It has a Z1-axis drive mechanism 95Z1 and a Z2-axis drive mechanism 95Z2. Then, the ultrasonic cleaning unit 71 and the rinsing cleaning unit 7
2. The needle 53 can be protruded from the liquid storage member 52 at any position of the drying section 73 and the solution storage section 74.

The Z1-axis driving mechanism 95Z1 is composed of an electric actuator for moving a block using a feed screw and an electric motor, similarly to the Z1-axis driving mechanism 23Z1 in the stamping area. As shown in FIG. 6, the electric actuator includes a highly rigid outer rail 31 having a U-shaped cross-sectional shape, and a slider 32 assembled in the outer rail 31 so as to be able to reciprocate. A nut is integrally provided at the center of the slider 32, and a plurality of circulating balls 33 are provided between both side surfaces of the slider 32 and the inner surface of the outer rail 31. Since this electric actuator has the same rated load in all directions acting on the slider 32, it is suitably used as a drive mechanism in the Z-axis direction for attaching a head or the like to the slider in an overhang state.

A Z2-axis moving mechanism 95Z2 is attached to the table 97 of the Z1-axis driving mechanism 95Z1. The Z2-axis drive mechanism 95Z2 is composed of an electric actuator having the same configuration as the Z1-axis drive mechanism 95Z1, and is smaller than the Z1-axis drive mechanism 95Z1. An L-shaped arm 99 for raising and lowering the needle 53 of the head 51 is attached to the table 98 of the Z2-axis moving mechanism 95Z2. The L-shaped arm 99 can be inserted into the head 51 by an air cylinder (not shown). L-shaped arm 9
9 is inserted into the head, and the inserted L-shaped arm 99 is lowered by the Z2-axis moving mechanism 95Z2 so that the needle 5 is removed from the liquid storage member 52 of the head 51.
3 protrudes.

A turning motor 100 as a turning portion is attached to the table 97 of the Z1-axis driving mechanism, and a disk 101 that turns in a horizontal plane is attached to the output shaft of the turning motor 100. 1 on the lower surface of the disk 101
A pair of clamps 102, 102 as gripping portions capable of gripping the head 51 at intervals of 80 degrees are attached.
The clamps 102, 102 are opened and closed by an air cylinder (not shown) or the like, and sandwich a flat portion 103 (see FIGS. 8 and 9) formed on the outer periphery of the head 51.

The head 51 transported by the XY biaxial transport mechanism 75 in the cleaning area has the same configuration as the head 51 transported by the biaxial transport mechanism 6 in the stamping area. Description is omitted.

The turning motor 100 turns by 180 degrees so that the XY two-axis transfer mechanism 6 in the stamping area is rotated.
Of the head 51 to the XY two-axis transport mechanism 75 in the cleaning area, and the head 51 from the XY two-axis transport mechanism 75 in the cleaning area to the XY two-axis transport mechanism 6 in the stamping area
Is delivered.

Specifically, as shown in FIGS. 1 and 2,
First, the XY two-axis transport mechanism 6 in the stamping area transports the head 51 after forming the spot to the transfer position 104. On the other hand, the XY two-axis transport mechanism 75 in the cleaning area transports the head 51 holding the new solution to the copy position 105 shifted from the transfer position 104 by 180 degrees.
At this time, an empty clamp that does not grip the head is located at the transfer position 104. Next, the clamp 102 of the XY two-axis transport mechanism 75 in the cleaning area grips the head 51 after the spot transported to the transfer position 104. Thus, the head is transferred from the XY two-axis transport mechanism 6 in the stamping area to the XY two-axis transport mechanism 75 in the cleaning area. Next, the turning motor 100 turns the disk 101 by 180 degrees, and the head 51 after the spot formation is moved to the holding position 105.
And the head 51 holding the new solution is positioned at the transfer position 104. Next, the chuck section 45 of the XY biaxial transport mechanism 75 in the stamping area grips the head 51 holding a new solution. As a result, the XY two-axis transport mechanism 75 in the cleaning area
The head is delivered to the shaft transport mechanism 6.

As described above, the heads 51 can be transferred between the XY two-axis transport mechanism 6 in the stamping area and the XY two-axis transport mechanism 75 in the cleaning area, so that one head 51 forms a spot on the substrate 3. During the operation, the other head 51 can be cleaned or the like. Except for the moment when the XY two-axis transport mechanism 6 in the stamping area and the XY two-axis transport mechanism 75 in the cleaning area transfer the heads 51 and 51 to each other, the operation of forming a spot on the substrate can be continued without interruption. A microarray can be prepared in an appropriate manner. Further, since the heads 51 and 51 are directly transferred between the XY two-axis transport mechanism 6 in the stamping area and the XY two-axis transport mechanism 75 in the cleaning area without temporarily placing the head 51 on the apparatus, wasteful waiting time is generated. No,
Delivery work can be performed more efficiently.

In the above embodiment, the pair of clamps 102 and 102 and the turning motor 100 are connected to the X in the cleaning area.
Although provided on the Y2-axis transport mechanism 75 side, it may be provided on the XY 2-axis transport mechanism 6 side of the stamping area. If a short waiting time is allowed, a turntable may be provided on the apparatus, and the head 51 may be transferred via the turntable.

After the spot formation, the head in the cleaning area
The wafer is transported to the ultrasonic cleaning unit 71 by the Y2-axis transport mechanism 75. In the ultrasonic cleaning section 71, the liquid storage member 52 is immersed in pure water subjected to ultrasonic vibration to clean the outside thereof. In the ultrasonic cleaning section 71, it is desirable that the outside of the needle 53 is also cleaned while the needle 53 is projected from the liquid reservoir member 52.

The head 51 after the ultrasonic cleaning is transported to the rinse cleaning section 72 by the XY biaxial transport mechanism 75. The rinse cleaning section 72 cleans the inside and outside of the liquid storage member 52 and the outside of the needle 53.

The head 51 is incorporated in a pure water tank storing ultrapure water as a cleaning liquid, and the outside of the liquid reservoir 52 is cleaned by immersing the liquid reservoir 52 in ultrapure water. Also, by incorporating the head 51 into a pure water tank, a pure water supply pipe 108 (see FIG. 8) provided in the pure water tank is connected to the head 51, and the pure water supply pipe 108 and the supply space 58 for cleaning liquid and the like communicate. . As shown in FIG.
The first lower plate 57 is provided with a space 58 for supplying a cleaning liquid or the like corresponding to the rear end of the liquid storage member 52. The cleaning liquid supply space 58 is a wide single space extending over each liquid storage member 52. When pure water with pressure is supplied from the pure water supply pipe 108, the pure water spreads in this single space. The pure water filling the single space is supplied to each liquid storage member 52.

By applying pressure to the inside of the liquid storage member 52 for cleaning, the cleaning time can be shortened, for example, as compared with a case where the solution is dropped without applying pressure. Further, by forming a single space extending over the plurality of liquid storage members 52, the pressure loss of pure water supplied into the plurality of liquid storage members 52 is reduced, and the pressure loss between the liquid storage members 52 is reduced. Becomes substantially equal. Therefore, the plurality of liquid storage members 52
. And the outside of the plurality of needles 53 can be washed by applying a substantially uniform pressure.

As shown in FIG. 1, the head 51 after the rinsing and cleaning is transported to the drying unit 73 by the XY biaxial transport mechanism 75. In the drying section 73, the inside and outside of the liquid storage member 52 and the outside of the needle 53 are dried.

FIGS. 15 to 17 show the drying unit 73. The drying unit 73 has a substantially rectangular parallelepiped drying tank 111 whose upper part is open. The head 51 is incorporated in an upper space of the drying tank 111, and the upper part of the drying tank 111 is
Is closed by the lower plate 57. A plurality of nozzles 112, 1 for blowing compressed air obliquely to the wall surfaces are provided on both opposing walls 111a, 111a of the drying tank 111.
12 are provided. Each nozzle 112 jets air slightly downward from the horizontal direction. On a plane, both walls 11
The angle α at which the walls 1a and 111a intersect with the direction in which the air is ejected from each nozzle 112 is approximately 45 degrees. Further, the nozzle 112 is disposed symmetrically with respect to the liquid reservoir member.

The nozzles 112 are provided with air supply passages 113.
Is connected. The nozzle 112 and the air supply passage 113 are made of two plastic plate members 114 and 115.
Are formed together. An air supply passage 113 having a substantially semicircular cross section along the plate 114 is formed in the outer plate 114.
Is formed. The inner plate member 115 has nozzles 112.
A hole is formed obliquely with respect to the plate material 115 so as to constitute the above. When the outer plate 114 and the inner plate 115 are overlapped, the nozzle 112 and the air supply passage 113
Is formed.

An exhaust port 116 is provided on the downstream wall 111b of the flow, which intersects with both walls 111a, 111a. At the bottom of the drying tank 111, outlets 117, 117 for discharging the mist-like cleaning water removed from the liquid storage member 52 and the needle 53 are provided. Drying tank 111
Inside, an air pipe 118 for drying the inside of the liquid reservoir member 52 is provided. The head 51 is connected to the drying tank 111
, The air pipe 118 communicates with the cleaning liquid etc. supply space 58 (see FIG. 8). Since the cleaning liquid supply space 58 is a wide single space extending over the plurality of liquid storage members 52, when compressed air is supplied from the air pipe 118, each of the liquid storage members 52 passes through the cleaning liquid supply space 58. Dry air is supplied inside the.

The flow of the air jet is controlled by the two walls 111a, 11a.
By providing an exhaust port 116 at an angle with respect to the wall surface of 1a and at the downstream side of the flow, a directional flow of air is generated in the drying tank 111, and the air causes a flow from the surface of the liquid storage member 52 or the needle 53. The cleaning solution mixed with the blown-off solution rides on this flow and all of the drying solution
It is discharged outside. Therefore, reattachment of the cleaning liquid is prevented.

On the other hand, if the air is simply jetted to the liquid reservoir member 52 or the needle 53 without providing the exhaust port 116, the residual cleaning liquid scattered with the air bounces off the wall surface of the drying tank 111, etc. There is a possibility that the residual cleaning liquid may adhere to the liquid storage member 52 or the needle 53 again. In the case of reattachment, not only the drying is not performed efficiently but also the possibility that a new solution becomes turbid in the reattached cleaning liquid is inevitable.

A liquid reservoir member 52 and a needle 53 are arranged in the head 51 in a vertical and horizontal direction in parallel with each other. By making the flow of the air jet oblique to the wall surfaces of both walls 111a, 111a,
Air can easily reach the shadowed area when viewed from the wall side. Therefore, the plurality of liquid storage members 52 and the needles 53 can be uniformly dried.

As shown in FIGS. 1 and 2, the dried head 51 is moved by the XY biaxial transport mechanism 75 to the solution storage section 7.
4 is carried. The solution storage unit 74 includes a plurality of titer plates 121 serving as solution holding plates for storing a solution.
Are stored, and the cassette 122
The titer plate 121 from the loading position 1
32, and a plate transport mechanism 123 for transporting the sheet to the P. 32. In the solution storage section 74, the head 51 after the cleaning is filled with a new biological sample solution. The operation of immersing the head 51 in the solution and sucking the solution is called loading.

A plurality of (for example, 384) recesses are arranged in each titer plate 121, and a solution of a biological sample is stored in the recesses. For example, assuming that the head has 48 reservoir members, one titer plate requires 8 reservoirs.
Can be loaded times. The plurality of recesses may be filled with the same type of solution, or may be filled with different types of solutions.

A plurality of (for example, ten) titer plates 121 are stored in the cassette 122 at equal intervals in the Z-axis direction (that is, in the vertical direction). Two sets of cassettes 122 are provided above and below the washing table 96, and this apparatus stores a total of 20 titer plates 121. An opening for taking in and out the titer plate 121 is formed on the side of the transport mechanism 123 of the cassette 122. Further, a handle 125 for grasping by hand is provided on the upper surface of the cassette 122.

The cassette 122 is mounted on a cassette support 124 slidably mounted on the apparatus. The cassette support 124 is manually pulled out, the cassette 122 is placed on the cassette support 124, and the cassette support 124 is manually returned to the original position, whereby the cassette 122 is incorporated into the apparatus.

The plate transport mechanism 123 includes a Z-axis drive mechanism 123Z, a Y-axis drive mechanism 123Y, and an X-axis drive mechanism 123.
X. The Z-axis drive mechanism 123Z has the same configuration as the above-described electric actuator that moves the slider using a feed screw and an electric motor. The Z-axis driving mechanism 123Z is provided between the upper end titer plate 121 and the lower end titer plate 121.
Is moved up and down.

The X-axis moving mechanism 123X is attached to the table 127 of the Z-axis driving mechanism 123Z. The X-axis moving mechanism 123X is composed of a so-called rodless cylinder.
The rodless cylinder includes a track rail 128 extending in the X-axis direction, and a table 129 that can slide the track rail 128.
9 is moved in the X-axis direction. At both ends of the track rail 128, stoppers for positioning the table 129 are provided.

The Y-axis moving mechanism 123Y is attached to the table 129 of the X-axis moving mechanism 123X. This Y-axis moving mechanism 123Y also comprises a so-called rodless cylinder,
The table 130 is moved in the Y-axis direction, and the table 130 is positioned at two positions in the Y-axis direction. A support plate 126 that supports the titer plate 121 is attached to the table 130 of the Y-axis moving mechanism 123Y.

The table 130 has a suction cup 131 for removing a cover from the titer plate 121.
Is attached. The titer plate 121 is covered with a cover to prevent evaporation of the water content of the solution. Since this cover is in the way during loading, the cover is
And is retracted upward by a moving mechanism such as an electric actuator (not shown).

The operation of the plate transport mechanism 123 for taking out the target titer plate 121 from the plurality of titer plates 121 will be described.

First, the plate transport mechanism 123 moves the support plate 126 in the Z-axis direction by the Z-axis drive mechanism 123Z, and positions the support plate 126 slightly below the target titer plate 121. Next, the X-axis drive mechanism 123
X is driven to insert the support plate 126 into the cassette 122. Next, the Z-axis drive mechanism 123Z is driven again, and the support plate 1
26 is raised slightly, and the titer plate 121 is lifted. Then, the X-axis driving mechanism 123X is driven again to pull out the titer plate 121 from the cassette 122.
Then, the titer plate 121 is transported to the load position 132. The operation of the transport mechanism is executed by a control device (not shown).

When the titer plate 121 is in the load position 13
After being transported to 2, the head 51 after cleaning and drying is also transported to the load position by the two-dimensional transport mechanism 75. At the load position 132, the solution is sucked by immersing the liquid reservoir member 52 in the solution of the biological sample.

The method for sucking the solution will be described. First, the liquid storage member 52 is inserted into the concave portion in the titer plate 121, and the tip of the liquid storage member 52 is immersed in the solution. Next, when the needle 53 is raised with the position of the liquid reservoir 52 fixed, the solution is pulled up in accordance with the rise of the needle 53, and the liquid is filled in the liquid reservoir 52. When the liquid storage member 52 and the needle 53 are pulled up from this state, the solution filled in the liquid storage member is held as it is.

On the washing table 96, a head place 135 is provided. The head 51 is first placed in the head storage 135. The operation of the apparatus starts when the XY two-axis transport mechanism 75 in the cleaning area goes to pick up the head 51 placed in the head storage 135.

Next, the overall operation of the microarray manufacturing apparatus of the present embodiment will be described according to the procedure for manufacturing a microarray. In the following steps, the head 51 is moved to a predetermined position by appropriately operating the XY two-axis transport mechanism 6 and the Z-axis drive mechanism 23 in the stamping area and the XY two-axis transport mechanism 75 and the Z-axis drive mechanism 95 in the cleaning area. Are sequentially positioned. Such control is performed by a control device (not shown).

First, as a preparation stage, a plurality of substrates 3 are arranged in a stamping area, and a vacuum device is operated to
… Suction and fix. A substrate or a dummy substrate for forming a microarray on a test basis is fixed to the test table 5. On the other hand, the cassette 12 of the solution storage section 74 in the cleaning area
2 accommodate a plurality of titer plates 121.
In each of the recesses of the titer plates 121, for example, a solution of a plurality of types of DNA fragments is put.

Next, the XY two-axis transport mechanism 75 in the cleaning area goes to pick up the head 51 placed on the head place 135. Here, of the pair of clamps 102, only one clamp 102 grips the head 51.

Next, the XY two-axis transport mechanism 75 transports the gripped head 51 to the load position 132. Here, a loading step of sucking the solution into the liquid storage member 52 is performed. The plate transport mechanism 123 transports the titer plate 121 containing the required solution to the load position 132 before the head 51 is transported to the load position 132.
The XY two-axis transport mechanism 75 moves the head 51 to the load position 132
After the transfer, the Z-axis drive mechanism 123Z in the cleaning area
The liquid storage member 52 is moved so that the liquid storage member 52 sucks the solution.
Then, the needle 53 is moved up and down.

Next, the XY two-axis transport mechanism 75 in the cleaning area
Transports the head 51 holding the solution to the transfer position 104.

Next, the XY two-axis transport mechanism 6 in the stamping area transports the empty chuck portion 45 to the transfer position 104. Then, the Z1-axis driving mechanism in the stamping area moves down the chuck unit 45, and the chuck unit 45 grips the head holding the solution. Thus, the head is transferred from the XY two-axis transport mechanism 75 in the cleaning area to the XY two-axis transport mechanism 6 in the stamping area.

Next, the XY two-axis transport mechanism 6 in the stamping area transports the head 51 to the test table 5. In the test table 5, a test step of adjusting the amount of the solution adhering to the needle 53 is performed. In the test step, the Z-axis drive mechanism in the stamping area strikes the needle 53 on the substrate 3 and drops the solution that has excessively adhered to the needle 53.

After the test process is completed, a stamping process for forming a spot on the substrate 3 is performed. In this stamping step, first, the XY biaxial transport mechanism 6 in the stamping area moves the head 51 to the spot forming position on the substrate 3. Then, the Z1-axis driving mechanism 2 in the stamping area
3Z1 descends the head 51, and positions the head 51 slightly above the substrate 3. Next, the Z2 axis driving mechanism 23Z2 in the stamping area causes the needle 53 to protrude from the liquid storage member 52, and strikes the needle 53 on the substrate 3.

After forming a spot on a predetermined substrate, the XY biaxial transport mechanism in the stamping area moves the head to the next substrate. Then, the above-described stamping step is repeated again.

While the XY biaxial transport mechanism 6 in the stamping area repeats the stamping process, the XY in the cleaning area
The biaxial transport mechanism 75 grips the remaining head 51 placed on the head storage 135 and transports the remaining head 51 to the load position 132.
At the loading position 132, a loading step of sucking the solution into the liquid storage member 52 is performed. Then, XY of the cleaning area
The biaxial transport mechanism 75 transports the head 51 holding the solution to the copy position 105. At this time, the transfer position 104
An empty clamp 102 that does not grip the head is located at the position.

After forming spots on all the substrates 3 on the worktable 4, the XY two-axis transport mechanism 6 in the stamping area transfers the head 51 after forming the spots to the transfer position 10
To 4. Then, the heads 51, 51 gripped between the XY two-axis transport mechanism 6 in the stamping area and the XY two-axis transport mechanism 75 in the cleaning area are transferred to each other.

The delivery step will be described. First, the empty clamp 102 provided in the XY two-axis transport mechanism 75 in the cleaning area grips the spot-formed head 51 transported to the transfer position 104. As a result, the XY two-axis transport mechanism 6 in the stamping area moves the XY 2
The head 51 after spot formation is transferred to the shaft transport mechanism 75. Next, the turning motor 100 positions the head 51 after spot formation at the standby position 105 and positions the head 51 holding a new solution at the transfer position 104. Next, the chuck 45 provided in the XY two-axis transport mechanism 6 in the stamping area has the head 5 holding a new solution.
1 is gripped. As a result, the head 51 is transferred from the XY two-axis transport mechanism 75 in the cleaning area to the XY two-axis transport mechanism 6 in the stamping area.

The XY biaxial transport mechanism 6 in the stamping area after the transfer step transports the head 51 onto the substrate again. Then, the test step and the stamping step are performed.

The XY two-axis transport mechanism 75 in the cleaning area after the transfer step executes the cleaning step at the same time that the XY two-axis transport mechanism 6 in the stamping area executes the test step and the stamping step. In this cleaning step, first, the head 51 after the formation of the spot is conveyed to the ultrasonic cleaning section 71, and the outside of the liquid storage member 52 is ultrasonically cleaned. Thereafter, the head 51 is conveyed to the rinsing section 72, and the inside and outside of the liquid reservoir member 52 and the needle 53 are rinsed.
Thereafter, the head 51 is transported to the drying unit 73, and the liquid storage member 5
2 and the needle 53 are dried.

The XY two-axis transport mechanism 75 in the cleaning area transports the cleaned head 51 to the load position 132 again. At this loading position, a loading step for sucking a new solution into the head 51 after cleaning is performed again.

Thereafter, the XY two-axis transport mechanism 6 in the stamping area sequentially executes the head transfer step, the test step, and the stamping step. on the other hand,
The XY two-axis transport mechanism 75 in the cleaning area sequentially executes the head transfer step, the cleaning step, and the loading step.

As described above, while one of the heads 51 conveyed by the XY biaxial conveying mechanism 6 in the stamping area forms a spot on the substrate 3,.
The other head 51 transported by the biaxial transport mechanism 75
By washing and drying, the stamping step of forming spots on the substrate 3 can be continued without interruption, and a microarray can be manufactured extremely efficiently.

In the above embodiment, the holding means (head) provided with the needle and the liquid storage member has been described, but a holding means having only the needle is also applicable.

[0116]

As described above, according to the present invention, the solution held in the liquid reservoir and the solution held at the tip of the placement portion are integrated by utilizing the surface tension of the solution, and The solution was pulled out of the substrate and placed on the substrate. Then, when the arrangement portion protrudes from the liquid reservoir portion and the tip of the arrangement portion contacts the substrate, the solution held at the distal end of the arrangement portion and the solution in the liquid reservoir portion are connected. For this reason, the size and shape of the spot arranged on the substrate can be kept constant.

[Brief description of the drawings]

FIG. 1 is a plan view showing a microarray manufacturing apparatus according to a first embodiment of the present invention.

FIG. 2 is a front view of the microarray manufacturing apparatus as viewed in the direction of the line II-II in FIG.

FIG. 3 is a right side view of the microarray manufacturing apparatus as viewed from the line III-III in FIG. 2;

FIG. 4 is a left side view of the microarray manufacturing apparatus as viewed from the direction of line IV-IV in FIG. 2;

FIG. 5 is a cross-sectional view of the microarray manufacturing apparatus as viewed from the line VV in FIG. 1;

FIG. 6 is a perspective view showing an electric actuator.

FIG. 7 is a view showing a chuck portion and a head ((A) in the figure shows a state where the needle is raised, and (B) in the figure shows a state where the needle is lowered).

FIG. 8 is a front view of a head.

FIG. 9 is a right side view of the head as viewed from the direction of line IX-IX in FIG. 8;

FIG. 10 is a bottom view of the head as seen from the line XX in FIG. 8;

FIG. 11 is a front view of the head showing a state where the needle protrudes from the liquid storage member.

FIG. 12 is a detailed view showing a liquid storage member and a needle.

FIG. 13 is a process chart showing a method of arranging a solution stored in a liquid storage member on a substrate.

FIG. 14 is a detailed view showing another example of the liquid reservoir member and the needle.

FIG. 15 is a sectional view showing a drying unit.

FIG. 16 is a plan view of the drying unit as viewed from the direction of the line XVI-XVI in FIG. 15;

FIG. 17 is a cross-sectional view of the drying unit viewed from the direction of the line XVII-XVII in FIG. 15;

FIG. 18 is a diagram showing a conventional microarray manufacturing apparatus.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 3 ... Board | substrate 4 ... Work table 6 ... XY two-axis conveyance mechanism (transportation means) of a stamping area 23,95 ... Z-axis drive mechanism (movement means) 51 ... Head (holding means) 52 ... Liquid storage member (liquid storage part) 53 … Needle (arrangement part) 74… Solution storage part 75… XY two-axis transport mechanism (transportation means) in the washing area

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) G01N 33/53 G01N 33/566 33/566 C12N 15/00 F

Claims (9)

[Claims] 1. A microarray production system comprising: a liquid reservoir for holding a solution containing a biological sample; and a disposing portion that protrudes and retracts from the liquid reservoir and disposes the solution stored in the liquid reservoir on a substrate. A head for producing a microarray, wherein a solution held at a tip of the disposition portion and a solution in the liquid reservoir portion are connected when the tip of the disposition portion contacts the substrate. 2. The microarray manufacturing head according to claim 1, wherein an outer peripheral surface of the arrangement portion is roughened so as to hold a solution. 3. The liquid ejection head according to claim 2, wherein the surface roughness of the outer peripheral surface of the arrangement portion protruding from the liquid reservoir portion is larger than the surface roughness of the outer peripheral surface of the arrangement portion in the liquid reservoir portion. The microarray production head according to the above. 4. The head for producing a microarray according to claim 2, wherein a surface roughness of an outer peripheral surface of the arrangement portion is larger than a surface roughness of a tip end of the arrangement portion in contact with the substrate. . 5. The disposing portion is formed in a taper whose outer peripheral surface gradually narrows toward a tip, and the liquid reservoir is formed in a taper whose inner peripheral surface gradually narrows toward a tip. The head for producing a microarray according to any one of claims 1 to 4, wherein: 6. The microarray producing head according to claim 2, wherein an outer peripheral surface of the arrangement portion is roughened by grinding stone processing or electric discharge machining. 7. A solution storage section for storing a solution containing a biological sample, a worktable on which a plurality of substrates can be arranged, and taking and holding the solution from the solution storage section, forming a spot of the solution on the substrate. A solution holding means for forming, a moving means for moving the holding means in the direction of approaching / separating from the substrate, and forming the spot by the holding means; and A transport unit that transports in a region including the work table and provides two-dimensional coordinates, wherein the holding unit includes: a liquid reservoir that holds a solution containing a biological sample; and the liquid reservoir. And an arrangement part for disposing the solution stored in the liquid storage part on the substrate, wherein the arrangement part is held at the tip of the arrangement part when the tip of the arrangement part contacts the substrate. Solution and the solution A microarray manufacturing device, wherein the solution in the reservoir is connected. 8. A microarray manufacturing method comprising: disposing an arrangement portion in and out of a liquid storage portion for holding a solution containing a biological sample; and disposing the solution stored in the liquid storage portion on a substrate. A method for producing a microarray, comprising: disposing a solution stored in a liquid reservoir on a substrate while a solution held at a tip and a solution in the liquid reservoir are connected. 9. A microarray in which spots of a solution containing a biological sample are arranged on a substrate, wherein the spots of the solution have an arrangement part protruding and retracting with respect to a liquid reservoir part holding a solution containing the biological sample. A microarray formed by arranging a solution stored in the liquid reservoir on a substrate in a state where the solution held at the tip of the disposition part and the solution in the liquid reservoir are connected.