JP2002257694A - Liquid discharge device used in manufacture of probe- support, probe-support manufacturing apparatus using the device, and method of manufacturing probe-support - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method of manufacturing a probe array and an apparatus use d in the manufacture thereof making it possible to surely form respective spots on the support being formed of many kinds of respective probe solution kinds. SOLUTION: A liquid discharge device has liquid discharge parts as many in number as those needed for the manufacture of the probe array, and each of those parts is, constituted such that a group of the spouts thereof composed of a plurality of the same spouts are disposed sharing one liquid receiving part. When the probe solutions are supplied to the support, the same kind of probe solution coming one after another from the plurality of spouts belonging to one and the same group is so controlled that it is seemingly placed one upon another and provided to the same position on the support wherein a spot is formed by the identical probe solution.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a liquid ejecting apparatus used for producing a probe carrier on a carrier, an apparatus for producing a probe carrier using the apparatus, and a method for producing a probe carrier using these apparatuses. .

[0002]

2. Description of the Related Art When analyzing the base sequence of a gene DNA or performing a highly reliable gene diagnosis or the like on multiple items at the same time, selecting a DNA having a target base sequence using a plurality of types of probes. Is required. As a means for providing a plurality of types of probes used for this sorting operation, a DNA microchip has been receiving attention. Also,
In high-throughput screening of drugs and the like and combinatorial chemistry, a large number of target protein and drug solutions (for example, 96 species, 384
Species, 1536 species) and perform an orderly screening. For that purpose, a method for arranging many types of drugs, automated screening technology in that state, dedicated equipment, software for controlling a series of screening operations and statistically processing the results have been developed. Have been.

[0003] These parallel screening operations are basically performed by arranging a large number of known probes as means for selecting a substance to be evaluated, that is, a so-called probe
By using an array, the presence or absence of an action, a reaction, or the like on a probe is detected under the same conditions. Generally, what kind of probe action or reaction is to be used is determined in advance, and therefore, the types of probes mounted on one probe array are, for example, a group of DNA probes having different base sequences, such as Broadly speaking, they are one type of substance. That is, the substances used for the group of probes are, for example, DNA, proteins, and synthesized chemical substances (drugs). In many cases, a probe array composed of a plurality of types of probes forming a group is often used. However, depending on the nature of the screening operation, the probes may be DNA having the same base sequence, protein having the same amino acid sequence, A form in which a number of substances are arranged in an array to form an array may be used. These are mainly used for drug screening and the like.

In a probe array composed of a plurality of types of probes, a group of DNAs having different base sequences, a group of proteins having different amino acid sequences, or a group of different chemical substances is specifically described. In many cases, a plurality of constituents are arranged in an array on a substrate according to a predetermined arrangement order.
Above all, the DNA probe array is used for analysis of the base sequence of gene DNA and, at the same time, for performing highly reliable gene diagnosis on many items.

One of the problems in a probe array comprising a plurality of types of probes forming a group is that as many types of probes as possible, for example, D
That is, mounting the NA probe on one substrate. In other words, how densely the probes can be arranged in an array.

One method of immobilizing a plurality of types of probes in an array on a substrate is described in US Pat. No. 5,424,186 by using a photodegradable protecting group and a carrier using photolithography. A technique for preparing DNA probes having mutually different base sequences in an array by a sequential extension reaction of DNA can be mentioned. Using this technique,
For example, D with more than 10,000 types of different arrangements per cm ²
Manufacture of a DNA probe array equipped with NA is also possible. It should be noted that in this technique, DNA is successively extended by an elongation reaction.
When synthesizing, a photolithography step is performed for each of the four types of bases (A, T, C, G) using a dedicated photomask, and any base is selectively extended to a predetermined portion of the array. As a result, a plurality of types of DNA having a desired base sequence are synthesized on the substrate in a predetermined sequence. Therefore, as the chain length of DNA becomes longer, the cost required for the production becomes higher, and a longer time is required. In addition, since the efficiency of nucleotide synthesis in each extension step is not 100%, the ratio of DNA having a defect in the designed base sequence is not small. Furthermore, in the synthesis, when a photodegradable protecting group is used, the synthesis efficiency is lower than when a normal acid-decomposable protecting group is used. There is also a problem that the ratio of DNA is small.

Further, since a product synthesized directly on a carrier is used as it is, it is of course impossible to remove a DNA having a defective base sequence from a DNA having the designed base sequence by purification and separation. . Other,
In the finally obtained array, there is a problem that the base sequence of DNA synthesized on the substrate cannot be confirmed. This is because if a given base is hardly extended at a certain elongation stage due to a mistake in the process and the product is completely defective, screening using this defective probe array will give an incorrect result. , Which means that there is no way to prevent it. The inability to confirm this base sequence is the biggest and essential problem in this approach.

[0008] As another method different from the above-mentioned method, DNA for a probe is synthesized and purified in advance, and after confirming the base length in some cases, each DNA is supplied to a substrate by a device such as a microdispenser. And the probe
Techniques for manufacturing arrays have also been proposed. PCT Publication No. WO95 / 355O5 discloses that DNA is obtained by using a capillary.
Is described on the membrane. By applying this method, it is possible in principle to produce about 1000 DNA arrays per 1 cm ² . Basically,
This is a method of manufacturing a probe array by supplying a probe solution to a predetermined position on a substrate by using one capillary dispensing device for each probe and repeating the operation. There is no problem if a dedicated capillary is prepared for each probe, but if the same work is to be performed using a small number of capillaries, sufficient capillary should be used when changing the probe type to prevent cross-contamination. Need to be cleaned. Further, it is necessary to control the supply position every time. Therefore, it cannot be said that this method is suitable for manufacturing an array in which various types of probes are arranged at high density. In addition, the probe solution is supplied to the substrate by tapping the tip of the capillary onto the substrate.
The reliability is not perfect.

In addition, 96 wells or 384 wells used especially for high-throughput screening of drugs.
Microdispenser devices are also commercially available, for example, from Robbins Scientific under the trade name HYDRA ^™ , to supply a different drug solution to each well of a microplate of wells. This is basically a two-dimensional arrangement of micro syringes, and the minimum ejection amount is 100 nl. If this is applied to the formation of an array, the density is limited by the minimum ejection amount, and there is a limit in increasing the density.

As another method, DN on a substrate is used.
When performing solid phase synthesis of A, a method of supplying a solution of a substance necessary for synthesis to a substrate by an inkjet method at each elongation step has also been proposed. For example, European Patent Publication EP 0
No. 703 825B1 discloses that a nucleotide monomer and an activator used in solid-phase synthesis of DNA are supplied from separate piezo jet nozzles, respectively, so that DNAs having predetermined base sequences are provided.
A method for solid-phase synthesis of a plurality of species is described. The supply (application) by the ink-jet method has higher reliability such as reproducibility of the supply amount and the nozzle structure can be miniaturized as compared with the supply (application) of the solution using the capillary. It has characteristics suitable for increasing the density of the probe array. However, this method is also basically the application of the sequential elongation reaction of DNA on the substrate, and is the greatest problem in the method described in the aforementioned US Patent (USP) 5,424,186. Problems such as the inability to confirm the base sequence of DNA synthesized on the substrate still remain. Although the complexity of performing a photolithography process using a dedicated mask at each elongation stage is eliminated, the essential requirement for a probe array is that predetermined probes are fixed at each point. , With some problems.
The above-mentioned EP 0,703,825 B1 describes only a method of using a plurality of piezo jet nozzles formed independently. When using this small number of nozzles, the above-mentioned capillary is used. As with the technique, it is not always suitable for high density probe array fabrication.

Japanese Patent Application Laid-Open No. 11-187900 discloses a method in which a liquid containing a probe is attached to a solid phase as a droplet using a bubble jet (registered trademark) head to form a spot containing a probe on the solid phase. However, since the ink jet head used is a head for a general printer, it cannot be said that the structure is optimal for manufacturing the probe array. Hereinafter, this point will be described in detail.

A conventional ink jet head is a technique developed for printing characters and images. Therefore, the solution used is one color (black) ink for monochrome (generally black) printing, and generally, for color printing,
The three primary colors of ink, namely, yellow (Y), cyan (C), and magenta (M) are used. In the case of color printing, black or Y, M, C,
May be used, but at most ten or more types of inks are not used.

Further, since a large amount of ink is used for printing on paper, a conventional ink jet printing head has a tank (reservoir) for filling ink having a sufficient capacity, and ink is supplied to a nozzle. A guide channel and a nozzle for discharging ink are provided.

On the other hand, as described above, it is desired that a liquid ejection apparatus for manufacturing a probe array ejects as many kinds of liquids as possible. Therefore,
It is desirable to provide a liquid ejection device in which storage units (reservoirs) for storing the probe solution are provided in a number corresponding to a large number of types of probes required for manufacturing the probe array, and discharge ports corresponding to the respective storage units are arranged.

In a liquid ejection apparatus for manufacturing a probe array, a liquid is not consumed as much as when printing on paper, so that a relatively small reservoir volume is sufficient.

Furthermore, a conventional general ink jet printer
In a printing head, it is necessary to discharge a desired ink to a desired position on a paper surface in order to form a character or an image. Therefore, a head configuration is adopted in which each nozzle can be independently selected at an arbitrary timing. A power transistor and a logic circuit required for discharging ink (liquid) from a desired nozzle may be provided outside the head or inside the head.

As the ink jet system, there are a bubble jet system in which a liquid is discharged by thermal energy generated from a heater, and a piezo ink jet system in which a liquid is discharged by deformation of an element generated by applying a voltage to a piezo element. Among them, the bubble jet method has a simpler structure than the piezo ink jet, and is suitable for downsizing the head and increasing the number of nozzles.

[0018]

As described above, the method of manufacturing a probe array using a liquid ejection apparatus is characterized in that a small amount of probe droplets is arranged on a substrate at a high density. Are better.

In such a probe array that achieves a high-density array of a large number of fine dot-shaped probe spots, a necessary probe is required to further improve the yield rate of the obtained probe array, that is, the production yield. It is necessary to verify whether or not spots are formed on the substrate.

However, when a large number of probe spots are formed, particularly when the type of solution ranges from 1,000 to 10,000, it takes a great deal of effort to test whether all of the desired probe spots are formed on the substrate. Or
Often it is necessary to use special equipment.

That is, there is a possibility that a spot of the probe is not formed on the substrate due to irregular discharge or non-discharge from each nozzle of the liquid discharge device due to dust clogging, disconnection, mixing of bubbles, and the like. Further, in the case of such a liquid discharge apparatus in which a very large number of nozzles are integrally formed on a substrate, even if one nozzle is defective, the entire apparatus is defective, and the yield of the manufacturing apparatus itself is poor. There is a problem that productivity is low. Furthermore, even if the apparatus itself is not defective, if the ejection failure occurs for any reason, the probe array manufactured by the apparatus will have a defective quality part, and such a defective product will be rejected. The occurrence causes a decrease in the manufacturing yield of the probe array itself.

The present invention solves the above-mentioned problems in the manufacture of a probe carrier such as a probe array in which probe spots are formed on a substrate, and an object of the present invention is to form each probe solution from a variety of probe solution types. It is an object of the present invention to provide a method for producing a probe array capable of reliably forming spots formed on a carrier and an apparatus used for the same.

[0023]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies in order to solve the above problems, and as a result, provided a plurality of discharge ports for discharging the same probe solution to one liquid storage section. By forming one spot of the probe on the carrier by overlapping a plurality of probe solutions including the same probe sequentially discharged from each discharge port, even if the discharge from one discharge port is irregular, It was found that a spot was formed even if it was present, and that the amount of the probe could be within an allowable range. Thus, even if the mechanism for discharging from one discharge port is defective in the manufacturing process of the liquid discharge device, it is not necessary to make the entire substrate defective, and the production yield of the liquid discharge device can be significantly improved. confirmed. Furthermore, it has been found that the use of such a liquid ejection apparatus can improve the production yield of the probe carrier itself such as a probe array.

Further, the present inventors preferably improve the arrangement density of the discharge ports by using a liquid discharge method in which the probe solution is heated and boiled, and the liquid is discharged at the pressure. It has been found that the above problems can be solved without increasing the size of the liquid ejection device and the probe carrier manufacturing device. In addition, by using a liquid ejection method characterized in that bubbles generated by heating the solution communicate with the outside air, it is possible to accurately reproduce the amount of liquid ejected at a time in the range of 0.1 pl to 50 pl Is possible,
It has been found that it is suitable for the above purpose.

The present invention has been made based on the above findings by the present inventors.

A liquid discharging apparatus according to the present invention is a liquid discharging apparatus used for manufacturing a probe carrier having a plurality of types of probes disposed on a carrier, and a liquid storing section for storing a probe solution containing the probes. A plurality of discharge ports for discharging the probe solution supplied from the liquid storage section, a liquid path commonly communicating the liquid storage section and the plurality of discharge ports, and each of the plurality of discharge ports And a discharge energy generating means that enables independent discharge of the probe solution by each of the plurality of discharge ports. The liquid ejecting apparatus is characterized in that the liquid ejecting apparatus is provided with a liquid ejecting apparatus.

[0027] The apparatus for manufacturing a probe carrier according to the present invention includes a liquid ejection device having the above-described structure, and a carrier holding means for holding the carrier and moving the carrier relative to the liquid ejection device. It is characterized by having.

Further, according to the method for manufacturing a probe carrier of the present invention, in the method for manufacturing a probe carrier in which spots of a plurality of types of probes are arranged on the carrier, the liquid ejecting apparatus is moved relative to the carrier. A step of discharging the solutions of the plurality of types of probes to the carrier in accordance with information on the arrangement positions of the probes and fixing the carriers, wherein the liquid discharging device is configured to store a probe solution; A discharge port group including a plurality of discharge ports provided in common with each other, a liquid path for commonly connecting the liquid storage portion and the plurality of discharge ports, and a plurality of discharge ports. And a discharge energy generating means that enables independent discharge of the probe solution from each of the plurality of discharge ports. And the step of forming the probe solution spot moves a group of discharge ports provided in common to the liquid storage portion relative to the carrier, and Driving the ejection energy generating means corresponding to these outlets such that the same type of probe solution adheres to the same spot forming position on the carrier from the plurality of outlets constituting the outlet group. This is a method for producing a probe carrier.

It is preferable that the number of discharge ports forming one discharge port group in the liquid discharge apparatus used in the present invention is 10 or more.

The volume of the probe solution discharged from each of the plurality of discharge ports at one time is preferably in the range of 0.1 pl to 50 pl.

Further, it is preferable that all of the discharge ports form a discharge port group arranged one-dimensionally or two-dimensionally on a discharge port formation surface on the substrate.

Further, the flow path extends linearly in a direction perpendicular to the discharge port forming surface, and the plurality of discharge ports commonly communicating with the one liquid storage portion are provided in the flow path. Are preferably arranged on an arc at an equal distance from the intersection of the central axis of the nozzle and the discharge port forming surface.

Further, it is preferable that the liquid discharge energy generating element is a heater element that generates thermal energy, heats the probe solution to boil, and discharges the probe solution from the discharge port with the pressure.

Each of the liquid discharge sections is provided with a heater element provided on a front surface of the substrate, a probe solution flow path provided at a position corresponding to the heater element, and a communication with the flow path. A discharge port for discharging the probe solution supplied from the flow path by the heat generated by the heater element, and a liquid storage unit provided on the back surface side of the substrate and communicating with the flow path; A discharge port, a flow path, and a liquid storage section are formed in a chip having a path formed through the substrate, and the heater element is connected at both ends to first and second wirings insulated from each other. It is preferable to be driven by an electric signal applied via the first and second wirings.

Further, in the liquid discharge section, when the probe solution is discharged from the discharge port by driving the heater element, bubbles are generated in the probe solution in the flow path, and the bubbles pass through the discharge port. It is preferable to have a structure that communicates with the outside air.

According to the present invention, even if one discharge port has a defect in the manufacturing process of the liquid discharge device, it is not necessary to make the entire device defective, and the yield of the liquid discharge device can be significantly improved. confirmed.

Further, according to the probe array manufacturing method of the present invention using the apparatus for manufacturing a probe carrier using the liquid discharging apparatus as a liquid discharging means, the spot of a predetermined probe is reliably formed on the carrier. Therefore, the quality check after the production of the probe carrier can be omitted or greatly simplified, and the production yield of the probe carrier can be improved and the production process can be simplified.

[0038]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS A liquid ejection apparatus according to the present invention comprises:
A liquid storage section for storing the probe solution, a plurality of discharge ports for discharging the probe solution supplied from the liquid storage section, and a liquid path for commonly communicating the plurality of discharge ports to the liquid storage section. And a discharge energy generation means provided corresponding to each of the plurality of discharge ports, and discharge energy generating means for enabling independent discharge of the probe solution by each of the plurality of discharge ports. Having.

That is, the liquid ejecting apparatus according to the present invention, when producing a probe carrier in which a plurality of types of probe spots are formed on a carrier, supplies the same probe solution from a plurality of ejection ports forming one ejection port group. The number of discharge ports corresponds to the number of discharge ports, and the carrier can be sequentially discharged to the same position on the carrier.

By using the liquid discharging apparatus having such a configuration, when manufacturing a probe carrier such as a two-dimensional probe array, each of the separately prepared probe solutions is discharged and applied to the carrier in a desired liquid amount. This makes it possible to achieve various types of probes with high density.

Further, according to the configuration in which a plurality of discharge ports are provided corresponding to one liquid storage portion, one of the plurality of discharge ports is provided.
Even when a discharge failure occurs in the discharge of the liquid from one of the liquids, the provision of the probe solution to the carrier is guaranteed by the discharge from the other discharge ports, and more reliable formation of the probe spot can be achieved.

Hereinafter, the method and apparatus for producing a probe carrier of the present invention will be described in more detail.
In particular, a case where a liquid ejection method using thermal energy as ejection energy is used as a representative example will be described focusing on a step of ejecting and applying a desired amount of liquid to each probe and a liquid ejection apparatus used therefor.

The amount of the probe solution discharged from one discharge port at a time is determined in consideration of various factors such as the viscosity of the probe solution, the affinity between the probe solution and the carrier, and the reactivity between the probe and the carrier. It is appropriately selected according to the size and shape of each dot spot constituting the probe carrier to be formed. Generally, an aqueous solvent is used for the probe solution.In the method of the present invention, the probe solution discharged from each discharge port at a time generally has a volume of 0.1 picoliter to 100 picoliter. It is preferable to select a range and design and adjust the discharge port diameter and the like according to the liquid amount.

The area occupied by the array unit (unit area where one spot is formed) to which the probe solution is applied is from 0.01 (for example, 0.1 μm × 0.1 μ) μm ² to 40,000 (for example, 200 μm × 200 μm) μm ^2. Generally, this depends on the size of the array itself and the density of the array matrix.

The size and capacity of the liquid storage unit when used is also appropriately selected depending on the amount of the probe solution discharged from the discharge port at one time and the number of arrays to be prepared. In addition, since the amount of the probe solution to be discharged at one time from the setting of the discharge port diameter is naturally within a certain range, a plurality of liquid discharge portions of the liquid discharge device are processed by processing a substrate made of semiconductor such as silicon or glass. In the case of forming an integrated chip, a size capable of integrally forming the liquid storage portion on the back surface of the substrate facing the discharge port may be sufficient as described later (see FIGS. 4 and 5).

On the other hand, when the amount of the probe solution discharged from the discharge port at a time is relatively large and the number of arrays required to be manufactured is large, the probe solution is added to the liquid storage unit integrally formed on the substrate each time. By doing so, it is possible to use a method that covers the amount of solution required when manufacturing the total number of arrays. Separately, a configuration may be adopted in which a liquid storage unit for increasing the amount can be connected to the liquid storage unit disposed on the back side of the substrate. At that time, the addition of the probe solution is performed via the liquid storage portion for increasing the volume, and the shape itself of the liquid storage portion on the substrate side may be set so that the supply of the probe solution can be easily performed, if necessary. it can.

For each probe used in the manufacture of this probe carrier, a liquid discharge section is formed by associating a pair of liquid storage sections with a plurality of discharge ports, and the discharge ports arranged in the plurality of liquid discharge sections are formed as follows. Preferably, the discharge port surfaces are formed in a one-dimensional or two-dimensional array. Therefore, the number of liquid ejection sections having a pair of liquid storage sections and a plurality of ejection ports is not particularly limited, and is selected according to a required probe type in an array or the like. . The diameter of the dot spots, the number of spots, the applied density thereof, or the overall arrangement pattern shape in an array or the like, and furthermore, the total number of liquid ejection parts is basically determined by the number of required probe types. It is determined. In the present invention, the total number of ejection ports provided on one ejection port formation surface is:
Total number of ejection ports = (number of liquid ejection sections) × (number of ejection ports of liquid ejection section).

In the method of the present invention, generally, probes arranged on a carrier in a pattern such as a two-dimensional array form include:
The types in the large meaning are the same types. That is,
In the method of the present invention, the type of each probe itself is not particularly limited as long as each probe can be discharged from the liquid discharge device as a solution. On the other hand, the method of the present invention is applied to a material that can be fixed on a substrate after being discharged and applied as a solution on a carrier.

The probe immobilized on the carrier can be specifically recognized by a specific target (target).
Often called ligands. Further, the probe includes an oligonucleotide, a polynucleotide, or another polymer that can be recognized by a specific target. The term "probe" refers to a probe molecule itself having a probe function such as an individual polynucleotide molecule, and a probe having the same probe function such as a polynucleotide having the same sequence immobilized on a carrier surface in a dispersed state or the like. It may mean a population of molecules. Also, a probe may be capable of binding, or become capable of binding, to a target as part of a ligand-antiligand pair. Probes and targets in the present invention can include bases as found in nature, or analogs thereof.

The probe used for the probe carrier produced by the method of the present invention is appropriately selected depending on the purpose of use. However, in carrying out the method of the present invention suitably, Probes include DNA, RN
A, cDNA (complementary DNA), PNA,
Oligonucleotides, polynucleotides, other nucleic acids, oligopeptides, polypeptides, proteins, enzymes, substrates for enzymes, antibodies, epitopes for antibodies, antigens, hormones, hormone receptors, ligands,
It is preferably any of a ligand receptor, an oligosaccharide, and a polysaccharide, and two or more of these can be used in combination as needed.

In the present invention, a plurality of these probes, each of which is fixed on the surface of the carrier as an independent region, for example, a dot spot, is referred to as a probe carrier. Many probe spots are arranged in a plane. ,
That is, a probe arrayed in a two-dimensional array
An array. The probe carrier includes a test plate or chip generally called a DNA macro array, a DNA chip, or a probe array.

On the other hand, in the present invention, the probe has a structure capable of binding to the surface of the carrier, and it is desirable that the probe is fixed on the carrier via the structure capable of binding. At this time, the structure of the probe capable of binding to the carrier surface includes an amino group, a sulfhydryl group, a carboxyl group, a hydroxyl group, and an acid halide (haloformyl group;
-COX), halide compound (-X), aziridine, maleimide group, succinimide, isothiocyanate, sulfonyl chloride (-SO ₂ Cl), aldehyde (formyl group; -CHO), hydrazine, organic functional groups such as iodoacetamide It is preferably formed by a treatment to be introduced.

In the method of manufacturing a probe carrier according to the present invention, a plurality of types of probes prepared separately in advance are used as a solution in the manufacture of the probe carrier, and the solution is supplied to each well on the carrier by discharging using a liquid discharging device. By doing so, it is possible to achieve various types of densification in the probe carrier.

[0054]

The present invention will be described more specifically with reference to the following examples. It should be noted that, although the example shown here is an example of a preferred embodiment of the present invention, the present invention
It is not limited by these examples.

First, a description will be given of an apparatus for manufacturing a probe array using a liquid discharge apparatus in which discharge ports used in the step of discharging and applying a probe solution are arranged in a two-dimensional array and thermal energy is used for discharging liquid.

(Structure of Liquid Discharge Apparatus for Discharging Probe Solution) (Example 1) FIG. 1 is a schematic plan view showing a structure of a discharge port forming surface of an example of a liquid discharge apparatus. This liquid ejecting apparatus has a structure including a chip in which a number of liquid ejecting sections are arranged on a substrate made of silicon. As will be described later in detail, in this embodiment, a plurality of the chips are used to form one liquid discharge device, which is used as a liquid discharge unit (liquid discharge unit) of a probe array manufacturing device. Most of the functions of the liquid ejection device depend on the configuration of the chip.

FIG. 1 is a view for explaining a basic configuration of a liquid discharge apparatus used in the present invention, and shows a configuration in which each liquid discharge section has one discharge port (nozzle) for convenience. In the liquid ejection apparatus used in the present invention, an enlarged view of the vicinity of the nozzle in FIG. 2 (corresponding to a portion surrounded by a circle in FIG. 1)
As shown in (1), a configuration in which two or more sets (10 sets in this embodiment) each including one heater element and one nozzle are arranged for one liquid storage portion (reservoir) is preferably used.

1 and 2, reference numeral 1 denotes a silicon substrate;
2 is a heater made of TaN, TaSiN, TaAl or the like;
3 is a first wiring made of aluminum or the like, 4 is a second wiring made of aluminum or the like, 5 is a pad for making electrical contact between the head and the outside, 6 is a nozzle, 7 is a flow path, 8
Is a supply port for supplying a liquid from the back surface of the substrate to the surface of the substrate. As will be described later, the supply port is formed by anisotropic etching of silicon. At this time, the back surface of the substrate 1 has a quadrangular pyramid-shaped opening whose edge extends to a portion indicated by 9 (dotted line). are doing. The supply port also serves as a liquid reservoir. In this configuration, the supply port, the flow path (see FIGS. 3 and 4 described later), the heater element, and the nozzle form individually independent liquid ejection units.

The direction indicated by the white arrow in FIG. 1 will be described later in detail, but is the direction in which the liquid ejecting apparatus moves when the liquid ejecting apparatus is mounted on the probe array manufacturing apparatus as a liquid ejecting unit. Described as the main scanning direction.

As shown in FIG. 2, in this embodiment, ten nozzles and heaters correspond to one supply port. Adjacent pairs of nozzles and heaters in the same liquid ejection section are separated by partition walls (not shown) and are arranged at intervals of 42.5 μm (600 dpi). Each heater is coupled to a different set of first and second wires, and a total of 10 wires are connected to the outside through 10 sets of pads (omitted) at the end of the substrate. With this wiring, a plurality of nozzles provided in the same liquid discharge unit can discharge liquid independently of each other.

In FIG. 1, eight nozzles arranged in the horizontal direction with an adjacent nozzle group interval of 1.27 mm (corresponding to 20 dpi) are shown in FIG. 1 in five rows in a vertical direction and an offset of 100 dpi (a shift in the horizontal direction). ). Also, the interval between adjacent nozzle rows is set to 100 dpi.

Each nozzle interval and each nozzle row interval in the configuration shown in FIG. 2 are also set in accordance with the embodiment of FIG.
In the case where the configuration shown in FIG. 2 is adopted, the interval between the vertically adjacent nozzle rows in FIG. 1 is based on, for example, the center position of ten nozzles provided vertically close in the same liquid ejection unit. Can be set.

In the configuration shown in FIG. 2, 80 heaters included in the horizontal nozzle row are connected by ten sets of first and second wirings. The length of the chip in the long side direction is about 12 mm, and the length in the short side direction is about 9 mm. The number of nozzles in one chip is 400. FIG.
FIG. 4 shows a cross-sectional view taken along line A ′. FIG. 4 is a cross-sectional view taken along line BB ′ of FIG. FIG. 5 shows a schematic diagram of the back surface of the semiconductor chip (corresponding to the back surface of the semiconductor chip shown in FIG. 1).

In FIGS. 3 and 4, those having the same numbers as those used in FIGS. 1 and 2 indicate the same ones. Reference numeral 10 denotes an insulating film, 11 denotes a protective film, 12 denotes a nozzle material, and 13 denotes a cavitation-resistant film made of Ta or the like. The insulating film 10 may be any of a thermal oxide film formed by thermally oxidizing a silicon substrate, an oxide film and a nitride film formed by CVD. The protective film 11 is an oxide film formed by CVD,
Any film such as a nitride film may be used. The nozzle material 12 forming the nozzle 6 and the flow path 7 is formed by extending a semiconductor process using photolithography technology even if a nozzle material having a nozzle and a flow path is pasted on a semiconductor substrate in advance. May be.

In particular, when a chip needs to be manufactured with a larger area, a method of attaching a nozzle material having a nozzle and a flow path to a substrate has a large area because the nozzle material has a large area. Since there are problems such as warpage and positional deviation and it becomes difficult to manufacture a chip, a manufacturing method of laminating a nozzle material on a substrate using photolithography technology is desired. As a method of forming a nozzle using photolithography, for example, there is a method described in JP-A-62-264957.

The supply port 7 is formed by anisotropic etching of silicon using a TMAH solution, and opens at an angle of 54.7 ° with respect to the substrate surface as shown in FIG. The shape of the supply port is a truncated square pyramid as shown in FIG. In this prototype, the width of the supply port on the substrate surface was set to 100 μm as shown in FIG. 3, and the thickness of the silicon substrate 1 was 625 μm, so the width on the back surface of the supply port was about 1 mm. Becomes Further, as can be seen from FIG. 2, the long side of the supply port is 42 μm × 10 = 420 μm.

In the conventional ink jet head for printing, the main purpose of the supply port is to guide the ink from the connection portion with the ink tank connected to the back surface of the substrate to the heater portion. In the apparatus described above, the supply port can be used as a liquid reservoir because the total amount of liquid discharge is small.

With a supply port of the above dimensions, the volume is about 0.23
μl, and in this embodiment, the total discharge amount from the ten nozzles is 24 pl, so this volume corresponds to an amount that can produce about 9600 probe arrays.

When the chip is viewed from the back, the supply port is as shown in FIG.
The shape shown in FIG. As shown in FIG. 4, the liquid is guided from the supply port 8 to the substrate surface from the back surface of the substrate, and is guided to the nozzle 6 through the flow path 7. That is, a path penetrating the substrate is formed by the supply port (liquid reservoir), the flow path, and the nozzle.

When a voltage is applied to both ends of the heater, the liquid near the heater is overheated to cause film bubbling, and the liquid is discharged as shown in FIG. The amount of liquid discharged from the nozzle was 2.4 pl. 24 heaters are required to obtain this volume
μm × 24 μm, and the nozzle was 11 μmφ.

In order to discharge the liquid stably, it is essential to cause stable film bubbling. In order to cause stable film foaming, it is desirable that a voltage pulse of 0.1 to 5 μs be applied to the heater. Further, in order to precisely control the amount of each probe included in the probe array, the amount of droplets ejected from the nozzle is stable, as disclosed in JP-A-4-10940, JP-A-4-10941, As described in JP-A No. 4-10942, a system in which bubbles generated by overheating by a heater communicate with the outside air is preferable.

FIG. 8 is a schematic view of a liquid ejection apparatus in which a plurality of chips are arranged in parallel. In FIG. 8, reference numeral 21 denotes a liquid ejection apparatus having a portion in which 25 chips are arranged in parallel,
Reference numeral 22 denotes the chip described with reference to FIGS. 1 to 7, and reference numeral 23 denotes a nozzle. In FIG. 8, the tip 22 shows only the nozzle 23 for clarification. In this liquid ejecting apparatus, the chips 22 are arranged in 5 rows and 5 columns and each chip has 80 nozzles. Therefore, one unit has a total of 2000 nozzles. The liquid ejection device according to the present invention can be configured by using the chip illustrated in FIG. 2 as the chip illustrated in FIG.

FIG. 9 shows an example of a configuration in which a plurality of chips are arranged in parallel. As shown in FIG. 9, a large number of windows 22 are fixed by inserting and inserting chips 22 into the respective openings using a window frame-shaped fixing frame 24 having openings 25 formed of alumina, resin, or the like. The liquid ejection device in which the chips are arranged in parallel can be obtained. The pads of each chip are electrically connected to the outside of the head by a flexible wiring board (not shown) arranged on the frame 24. The solution is injected into the supply port 8.

(Structure of Probe Array Manufacturing Apparatus) FIG.
FIG. 0 shows a schematic diagram of a structure of a main part of an example of a probe array manufacturing apparatus using a liquid ejection device as a liquid ejection unit. In FIG. 10, reference numeral 22 denotes a shaft for guiding the movement of the liquid discharge unit 31 substantially in parallel, and 32 denotes a probe
A stage on which a carrier for manufacturing an array is fixed, and 33 is a carrier on which a probe array is formed (a glass substrate is used in this example).

The unit moves in the X direction in FIG. 10, and the stage moves in the Y direction. By these operations, the unit can move two-dimensionally relative to the stage. FIG. 10 shows a structure in which a glass substrate serving as a plurality of probe arrays is fixed and a probe is provided. However, a probe array is manufactured on a glass substrate serving as one large probe array, and thereafter, The glass substrate may be cut to obtain a probe array.

(Method of Applying Probe Solution Using Liquid Discharge Unit) Next, a method of manufacturing a probe array will be described. FIG. 11 is a schematic diagram for explaining a method for applying a probe solution using the probe array manufacturing apparatus. FIG.
Reference numerals 41 to 42 denote chips, and reference numeral 33 denotes a carrier made of glass or the like for manufacturing a probe array. In FIG. 11, since the surface on which the probe array is formed is drawn facing up, the arrangement of the nozzles of the chip and the main scanning direction are as follows.
Actually, the left and right sides are opposite to those shown in FIG.

In FIG. 11, reference numeral 41 denotes a chip indicated by "1" in FIG. 8, and reference numeral 42 denotes a chip indicated by "2" in FIG. In each chip, as shown in FIG. 1, six rows of nozzles from eight liquid ejection units arranged in the horizontal direction are offset in parallel (with a predetermined gap) in the vertical direction. Having a configuration. Each heater in one nozzle example is shown in FIG.
As shown in FIG. 2, since the electrodes are independently connected to the pair of first and second aluminum wirings, by applying a voltage pulse between a pair of pads connected to these wirings, The probe solution can be discharged from the nozzle. In the configuration of FIG. 2, the first ejection ports provided in each liquid ejection unit are simultaneously driven, and the second to tenth nozzles are simultaneously sequentially driven.

In FIGS. 8 to 11, the numerals 1, 2, 3, 4, 5 and A, B,
C, D, E, F, G, and H are displayed to indicate the distinction between the nozzle rows. In FIG. 2, ten nozzles are provided in the same liquid ejection unit, but in FIG. 11, the number of nozzles arranged in the same liquid ejection unit is simplified to three.

First, in FIG. 11, 1A, 1B, 1C,
Eight spots indicated by 1D, 1E, 1F, 1G, and 1H are formed. Next, the head is set to 0.04 mm in the main scanning direction.
(Equivalent to 600dpi) First nozzle row 1
Are discharged from the second nozzle of 1A, 1A, 1
8 indicated by B, 1C, 1D, 1E, 1F, 1G, 1H
A spot with the same probe solution is formed over the two spots. The discharge interval between the first nozzle and the second nozzle is 1/25/600 seconds (67 μs), assuming that the moving speed of the head is, for example, 25 inches per second. And the spot by the second droplet completely match. By repeating the ejection of the third to tenth nozzles one after another in this manner,
The above eight spots are completed. Next, at the timing when the head moves 1.27 mm (corresponding to 20 dpi) in the main scanning direction, ejection is sequentially performed from the ten nozzles of the second nozzle row 2 of the first chip, and 2A, 2B, 2C, 2
Eight spots indicated by D, 2E, 2F, 2G, and 2H are arranged in a line on the probe array.
Subsequently, in the same manner, the third to fifth nozzle rows 3 to
5 sequentially, and the first of the probe array 33
A row of 40 probe groups (shown by black circles in FIG. 11) is arranged.

At this time, the distance between the centers of adjacent probes is 254 μm (corresponding to 100 dpi). That is, the 40 types of liquids discharged from the first chip form the first row of probe groups in the probe array. This situation is schematically shown at 43 in FIG. (Only 5 spots of 1A to 5A out of 40 spots are shown.)
Next, the liquid was discharged from the second chip by the same operation, and the probes in the second row (shown by white circles in FIG. 11) of the probe array were arranged. At this time, the center-to-center distance between the first row of probe groups made from the first chip and the second row of probe groups made from the second chip is 254 μm (corresponding to 100 dpi). The drive timing was adjusted so that

Further, the third to twenty-fifth operations are performed by the same operation.
A droplet was ejected from the chip of No. 1 to produce a probe array. (Spot surrounded by a dotted line in FIG. 11) As described above, a probe array of 40 rows and 25 columns of 100 dpi can be manufactured from the head shown in FIG.

Further, since one spot is formed by ten droplets, even if one nozzle breaks down due to dust, heater disconnection, etc., the amount of probe forming the spot is reduced by 10%. This alone does not cause a problem in the quality of the probe array. Further, it can be easily understood from the above description that a probe array requiring a larger number of probes can be manufactured by a similar configuration.

The case where silicon is used as a chip constituting a head has been described above. However, as described above, the present invention has a simple structure including a heater and wiring connected to the heater. In the embodiment in which the head can be manufactured using a less expensive substrate such as a glass substrate without using it, the case where the semiconductor chip having 400 nozzles is arranged in 5 rows and 5 columns to form the head is described. However, it is possible to freely select that the number of nozzles and the arrangement of the arrangement are limited to the configuration shown in the embodiment.

Using the semiconductor chip described in the embodiment,
When a head with a one-dimensional array such as one row and 25 columns is manufactured,
Since the probe array can be created only by the main scanning, the structure of the probe array manufacturing apparatus can have a simpler structure than the structure shown in FIG.

(Embodiment 2) FIG. 12 is a schematic view showing another example of a chip constituting a liquid ejection apparatus according to the present invention. Figure 1
2 is an enlarged view near the nozzle, corresponding to FIG. 2, and the same numbers indicate the same parts.

As shown in FIG. 12, ten nozzles and heaters are provided for one supply port in this embodiment.
5 on each side. Adjacent nozzles and heaters are separated by partition walls (not shown)
They are arranged at intervals of 42.5 μm (600 dpi). The interval between the two nozzle rows arranged with the center axis of the flow path interposed therebetween is 254 μm (6
/ 600dpi). Each heater is associated with a different set of first and second wires and
Ten sets of wiring are connected to the outside via ten sets of pads (omitted) at the end of the board. The arrangement of the liquid ejection units is performed according to the configuration of FIG. That is, the ten nozzle groups provided in the same liquid ejection unit are arranged such that adjacent nozzle group intervals in the horizontal direction in FIG.
A row composed of eight nozzle groups arranged at 1.27 mm (equivalent to 20 dpi) is formed. Also, in FIG. 1, the five nozzle group rows that are arranged in the vertical direction are arranged with a 100 dpi offset (with a shift in the horizontal direction). The interval between the nozzle groups adjacent vertically is also set to 100 dpi based on the center of each nozzle group.

The supply port has a truncated quadrangular pyramid shape as shown in FIG. In this prototype, the width of the supply port on the substrate surface was set to 100 μm as shown in FIG. 3, and the thickness of the silicon substrate 1 was 625 μm, so the width on the back surface of the supply port was about 1 mm. Becomes Also, as can be seen from FIG. 2, the long side of the supply port is 42 μm × 5 = 210 μm, which is shorter than in the first embodiment. As a result, the length of the chip in the long side direction can be reduced to about 12 mm, and the length in the short side direction can be reduced to about 8 mm.

(Method of Applying Probe Solution Using Liquid Discharge Apparatus) When this head and apparatus are used, first, one side of two nozzle rows in the same liquid discharge section is used for 1000 times as in the first embodiment. After forming the number of spots, returning the head and substrate to the origin, offset by 254 μm in the sub-scanning direction, and using the remaining rows, further discharge the probe solution onto the already formed spots, and To obtain the amount of the probe. According to this method, the time interval from the ejection of the first row to the ejection of the remaining rows is 1 inch in 2.5 inches × 5 reciprocations even if the main scanning speed is 25 inches per second, and the solution by the earlier ejection is the substrate. Therefore, overflow due to subsequent ejection does not occur, and the diameter of the spot formed can be kept small even when a relatively large ejection amount is used.

(Embodiment 3) FIG. 13 is a schematic view showing another example of a semiconductor chip constituting a liquid ejecting apparatus according to the present invention. FIG. 13 is an enlarged view of the vicinity of the nozzle and corresponds to FIG. 2, and the same numbers indicate the same parts.

As shown in FIG. 13, in this embodiment, ten nozzles and heaters are arranged for one supply port on a circumference centered on the supply port. That is, they are arranged on a circumference centered on the central axis of a liquid path extending perpendicularly to the substrate from the supply port. A portion including a pair of adjacent nozzles and a heater is separated by a partition (not shown), and is arranged at an interval of 85 μm (300 dpi). The diameter of the circle forming the arrangement orbit of the discharge ports is 85 μm × 9 / π = 0.24 mm. Each heater is coupled to a different set of first and second wires, and a total of 10 wires are connected to the outside through 10 sets of pads (omitted) at the end of the substrate. As shown in FIG. 1, the chip forms a row composed of eight nozzle groups arranged in the horizontal direction in FIG. 1 with an adjacent nozzle group spacing of 1.27 mm (corresponding to 20 dpi), and this row has five vertical rows. In parallel with each other at a 100 dpi offset (lateral deviation). Also, the interval between adjacent nozzle groups in the vertical direction is 100 dpi with respect to the center of each nozzle group.
Is set to

The supply port has a truncated quadrangular pyramid shape as shown in FIG. In this prototype, the width of the supply port on the substrate surface was set to 100 μm as shown in FIG. 3, and the thickness of the silicon substrate 1 was 625 μm, so the width on the back surface of the supply port was about 1 mm. Becomes Further, as can be seen from FIG. 13, the supply port is 100 μm × 100 μm, which is shorter than in the second embodiment. As a result, the length of the chip in the long side direction can be reduced to about 12 mm, and the length in the short side direction can be reduced to about 7 mm.

In this arrangement, the nozzle interval is 85
Since it is as large as μm, it is possible to arrange a larger heater and discharge port, and it is possible to obtain a relatively large discharge amount. Furthermore, if you increase the diameter of the circumference,
More nozzles can be arranged on the circumference, and the stability of the probe amount can be further improved. When the circumference is increased, the distance between the supply port and the discharge port increases, so that the flow resistance of the nozzle increases and the response frequency decreases.
This is not a problem because the nozzle discharges only once per nozzle.

(Method of Applying Probe Solution Using Liquid Discharge Apparatus) When this head and apparatus are used, first, main scanning and sub-scanning are performed simultaneously, and the relative movement between the substrate and the head is the same as that of the nozzle arrangement. By performing the movement, the probe solution sequentially discharged from the nozzles on the circumference is driven so as to land on the same point on the substrate. Thereafter, the probe array is completed by moving in the main scanning direction by 1.27 mm and repeating a circular motion.

Example 4 (Production of DNA Array Using Liquid Discharge Apparatus) 25.4
The fused quartz substrates mm × 25.4mm × 0.5mm ^t 1
% Ultrasonic cleaning GP-III (Branson) for 20 minutes, followed by ultrasonic cleaning with tap water and running water cleaning as appropriate. Next, it was immersed in 1N NaCl at 80 ° C. for 20 minutes, washed with running water (tap water), washed with ultrapure water, ultrasonic, and washed with running water (ultra pure water).

Then, purified by distillation under reduced pressure, the following formula (I):

[0096]

Embedded image Aqueous solution containing 1% aminosilane coupling agent (KBM-603: Compound I, manufactured by Shin-Etsu Chemical Co., Ltd.) was stirred at room temperature for 1 hour to hydrolyze the methoxy group. Next, the substrate was immediately immersed in the silane coupling agent aqueous solution after washing, and immersed at room temperature for 1 hour. Thereafter, the substrate was washed with running water (ultra pure water), dried by blowing nitrogen gas, and then heated and fixed in an oven at 120 ° C. for 1 hour.

After cooling, the following formula (II):

[0098]

Embedded image N- (6-maleimidoca proxy) succinimide (E
The substrate was immersed in a 0.3% solution of MCS (compound II) (ethanol: dimethylsulfoxide = 1: 1) at room temperature for 2 hours to react EMCS with amino groups of the aminosilane coupling agent. After the completion of the reaction, the resultant was washed once with ethanol: dimethylsulfoxide = 1: 1 and three times with ethanol, and dried by blowing nitrogen gas. 5'-ATGAACCGGAGGCCCATC-3 '(SEQ ID NO: 1) 3'-TACTTGGCCTCCGGGTAG-5' (SEQ ID NO: 2) having a nucleotide sequence complementary to the above nucleotide sequence, and 5 ' An oligonucleotide (Compound III Vex, Inc.) having a mercapto group (SH group: also referred to as a sulfhydryl group) capable of reacting with a finally purified maleimide group on the substrate surface via a linker at the terminal is used in this Example. The probe was used for verification. Formula (III):

[0099]

Embedded image Oligonucleotides (compounds) into which mercapto groups have been introduced
III) is a solvent for discharging with a ZJB head, that is, glycerin 7.5 wt%, urea 7.5 wt%, thiodiglycol 7.5 wt%, general formula (IV):

[0100]

Embedded image Acetylene alcohol (for example, trade name: acetylenol EH Kawaken Fine Chemical Co., Ltd.) 1
It was dissolved in an aqueous solution containing wt% so that the absorbance became 1.0. This oligonucleotide solution was supplied to the solution reservoir of the liquid ejecting apparatus prepared in Example 1 using a microdispenser. Before filling the final DNA solution, each solution reservoir and nozzle were washed with a solvent of the above composition in advance for the purpose of adapting the prepared head to the solvent, and if necessary, the oligonucleotide solution. And the removal of the liquid by vacuum suction was repeated as appropriate.

Thereafter, the oligonucleotide solution was placed on the substrate treated with the above-described maleimide group by 10 nozzles connected to these from 10 reservoirs at 10 positions on the substrate, and 2.4 pl of the oligonucleotide solution was respectively placed at 10 positions on the substrate. One drop
It was ejected so as to be supplied by 0 drops.

The solvent having the above-mentioned composition has a high moisturizing property, and is dried and concentrated in the solution reservoir, and the droplet of the oligonucleotide solution applied on the substrate is fixed in the next step by reaction with the substrate surface. Before being dried, it can be prevented from drying and solidifying.

The substrate to which the solution of the oligonucleotide (compound III) of formula (III) was applied was kept in a 100% humidity chamber at room temperature for 1 hour, and the mercapto group of the oligonucleotide and the maleimide group on the substrate were Was performed. After removal, the substrate was washed in running water (ultra pure water) for about 30 seconds to remove unreacted oligonucleotide.

Next, on the substrate on which the dots on which the oligonucleotides were fixed were formed, BSA (bovine serum) was added to 50 mM phosphate buffer (pH = 7.0, containing 1 M NaCl) in order to perform a blocking treatment on the surface other than the dots. (Albumin Sigma-Aldrich Japan) was immersed for 1 hour in a blocking solution in which it was dissolved at a concentration of 2%, and then appropriately washed with the above 50 mM phosphate buffer.
Stored in mM phosphate buffer.

(DN by hybridization reaction)
Evaluation of probe A) As a model target DNA, formula (V):

[0106]

Embedded image With a probe on a substrate prepared using a DNA molecule having the above sequence, ie, a compound V (purchased from Vex Co., Ltd.) having the above sequence and having tetramethylrhodamine bound to the 5 ′ end as a fluorescent label. The reaction was performed.

In this hybridization reaction, a phosphate buffer (10 mM phosphate buffer pH = 7.0, containing 50 mM NaCl) containing Compound V at a concentration of 5 nM was used.
ml and performed in a hybrid pack. The substrate was sealed together with the model target DNA solution in a hybrid pack, heated to 70 ° C. in a thermostat, cooled to 50 ° C., and left in that state for 10 hours.

Next, the substrate was taken out of the hybrid pack and washed with a hybridization buffer in order to remove unreacted target DNA. After washing, the substrate was placed on a slide glass while being covered with a buffer solution, covered with a cover glass, and the fluorescence from the fluorescent label was observed. The fluorescence microscope used for this observation was ECLIPSE E80
0 (Nikon Corporation) with a 20 × objective lens (plan apochromat) and a fluorescent filter (Y-2E / C). Images captured with a fluorescence microscope were captured using a CCD camera with an image intensifier (C2400-87 Hamamatsu Photonics KK) and an image processing device (Argus50 Hamamatsu Photonics KK).

On the basis of the recorded images, fluorescence was observed for all of the dots on which the compound III was fixed, formed in a two-dimensional array on the substrate. Their fluorescence intensity was within plus or minus 10%.

[0110]

As described above, in manufacturing a probe array, a liquid ejecting apparatus in which nozzle groups are arranged two-dimensionally is used, and one type of probe solution is discharged from a plurality of nozzles to form a single probe solution on a substrate. By forming two spots, it is possible to reduce the influence of irregular ejection of the droplet ejection nozzle. Further, depending on the nozzle arrangement method, more nozzles can be arranged without increasing the size of the substrate. In addition, by using a bubble jet method as a droplet jetting method, a high-density multiple nozzle arrangement can be performed.
Further, a more stable droplet amount can be obtained by a discharge method in which bubbles communicate with the outside air.

[0111]

[Sequence list]

 SEQUENCE LISTING <110> Canon INC. <120> A device preparing a probe array, a machine using the device and a method for preparing a probe array <130> 4396100 <151> 2000-09-19 <160> 6 <210> 1 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Base Oligonucleotide for preparation of a probe <400> 1 atgaaccgga ggcccatc 18 <210> 2 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Oligonucleotide probe for hybridization assay <400> 2 tacttggcct ccgggtag

[Brief description of the drawings]

FIG. 1 is a schematic view of a semiconductor chip constituting a liquid ejecting apparatus according to the present invention.

FIG. 2 is an enlarged view of the vicinity of a nozzle in FIG.

FIG. 3 is a sectional view taken along line AA ′ of FIG. 1;

FIG. 4 is a sectional view taken along line BB ′ of FIG. 1;

FIG. 5 is a schematic diagram of the back surface of a semiconductor chip constituting the liquid ejecting apparatus (corresponding to the back surface of the semiconductor chip shown in FIG. 1).

FIG. 6 is a schematic diagram for explaining a shape of a liquid supply port (reservoir) of a semiconductor chip constituting the liquid ejecting apparatus.

FIG. 7 is a schematic diagram for explaining ejection of liquid by the liquid ejecting apparatus.

FIG. 8 is a schematic diagram of a liquid ejecting apparatus.

FIG. 9 is a schematic view of a thermal liquid ejecting apparatus.

FIG. 10 is a schematic diagram of a structure of a probe array manufacturing apparatus.

FIG. 11 is a schematic view of a probe array manufacturing method.

FIG. 12 is a schematic view of a second embodiment of the liquid ejecting apparatus.

FIG. 13 is a schematic view of a third embodiment of the liquid ejecting apparatus.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI Theme coat ゛ (Reference) G01N 33/566 B41J 3/04 103B 35/10 C12N 15/00 ZNAF 37/00 102 G01N 35/06 JF Term (reference) 2C057 AF99 AG14 AG16 AG46 AG91 AH20 AN01 BA04 BA13 2G052 AA28 AB20 AD26 CA08 CA30 DA01 DA08 EB11 EC14 HC07 HC34 JA09 JA13 JA16 2G058 AA09 CC02 EA11 EA14 EB00 ED02 ED11 ED20 CA11 A11A11A01A11 A01A11 CAB BB20 CC03 CC08 FA12 FA15

Claims (20)

[The claims] 1. A liquid ejecting apparatus used for manufacturing a probe carrier having a plurality of types of probes arranged on a carrier, comprising: a liquid storage section for storing a probe solution containing the probe; and a supply from the liquid storage section. A plurality of outlets for discharging the probe solution, and a liquid path for commonly communicating the plurality of outlets with the liquid storage unit, provided corresponding to each of the plurality of outlets, And a discharge energy generating means that enables independent discharge of the probe solution by each of the plurality of discharge ports, so that the same type of probe solution is applied to the same position of the carrier. A liquid discharge device characterized by the above-mentioned. 2. The method according to claim 1, wherein the number of discharge ports forming the discharge port group is one.
The method for producing a probe carrier according to claim 1, wherein the number is 0 or more. 3. The liquid ejection apparatus according to claim 1, wherein a volume of the probe solution ejected from each of the plurality of ejection ports at one time is in a range of 0.1 pl to 50 pl. 4. The liquid according to claim 1, wherein all of the discharge ports form a discharge port group arranged one-dimensionally or two-dimensionally on a discharge port formation surface on a substrate. Discharge device. 5. A flow path, wherein the flow path extends linearly in a direction perpendicular to the discharge port forming surface, and a plurality of discharge ports commonly communicating with the one liquid storage portion are provided in the flow path. 5. The liquid discharge device according to claim 4, wherein the liquid discharge devices are arranged on a circular arc at an equal distance around an intersection between the central axis of the nozzle and the discharge port forming surface. 6. The heater element according to claim 1, wherein the liquid discharge energy generating element is a heater element that generates thermal energy, heats the probe solution to boil, and discharges the probe solution at the pressure from the discharge port. A liquid ejection device according to claim 1. 7. Each of the liquid discharge units is provided with a heater element provided on a front surface of a substrate, a flow path of a probe solution provided at a position corresponding to the heater element, and communicating with the flow path. A discharge port for discharging the probe solution supplied from the flow path by the heat generated by the heater element, and a liquid storage unit provided on the back surface side of the substrate and communicating with the flow path; A discharge port, a flow path, and a liquid storage portion are formed in a chip having a path formed through the substrate. The heater element is connected at both ends to first and second wirings insulated from each other. The liquid ejecting apparatus according to claim 6, wherein the liquid ejecting apparatus is driven by an electric signal applied through the first and second wirings. 8. The liquid ejecting section, when driving the heater element to eject the probe solution from the ejection port, generates bubbles in the probe solution in the flow path, and the bubbles pass through the ejection port. The liquid ejection device according to claim 7, having a structure communicating with outside air. 9. A liquid ejecting apparatus according to claim 1, further comprising: carrier holding means for holding the carrier and moving the carrier relatively to the liquid ejecting apparatus. An apparatus for manufacturing a probe carrier. 10. A method of manufacturing a probe carrier in which spots of a plurality of types of probes are arranged on a carrier, wherein the liquid ejection device is moved relatively to the carrier.
A step of discharging the solutions of the plurality of types of probes to the carrier in accordance with information on the arrangement positions of the probes and fixing the carriers, wherein the liquid discharging device includes: a liquid storage unit that stores a probe solution; A discharge port group consisting of a plurality of discharge ports provided in common with the unit, a liquid path for commonly communicating the plurality of discharge ports with the liquid storage unit, and a plurality of discharge ports. A plurality of liquid discharge units provided correspondingly and having discharge energy generating means for enabling independent discharge of the probe solution by each of the plurality of discharge ports, the number of which corresponds to at least the plurality of types of probe solutions. And wherein the step of forming the probe solution spot moves a group of discharge ports provided in common to the liquid storage portion relative to the carrier, thereby forming the group of discharge ports. Producing a probe carrier, the method comprising: driving a discharge energy generating means corresponding to these discharge ports so that the same type of probe solution adheres to the same spot forming position on the carrier from a plurality of discharge ports. Method. 11. The method according to claim 10, wherein the number of the discharge ports forming the discharge port group is 10 or more. 12. The method according to claim 10, wherein a volume of the probe solution discharged from each of the plurality of discharge ports at one time is in a range of 0.1 pl to 50 pl. 13. The manufacturing method according to claim 10, wherein all of the discharge ports form a discharge port group arranged one-dimensionally or two-dimensionally on a discharge port formation surface on a substrate. Method. 14. A flow path, wherein the flow path extends linearly in a direction perpendicular to the discharge port forming surface, and a plurality of discharge ports commonly communicating with the one liquid storage portion are provided in the flow path. 14. The manufacturing method according to claim 13, wherein the nozzles are arranged on a circular arc equidistant from an intersection between the central axis of the nozzles and the discharge port forming surface. 15. The liquid discharge energy generating element according to claim 15,
The manufacturing method according to any one of claims 10 to 14, wherein the heater element is a heater element that generates heat energy, heats the probe solution to boil, and discharges the probe solution from the discharge port at the pressure. 16. Each of the liquid ejection sections is provided with a heater element provided on a front surface of a substrate, a probe solution flow path provided at a position corresponding to the heater element, and communicating with the flow path. A discharge port for discharging the probe solution supplied from the flow path by the heat generated by the heater element, and a liquid storage unit provided on the back side of the substrate and communicating with the flow path,
These discharge ports, flow paths and liquid storage sections are formed in a chip forming a path penetrating the substrate, and both ends of the heater element are connected to first and second wirings insulated from each other. 16. The manufacturing method according to claim 15, wherein the driving method is driven by an electric signal applied through the first and second wirings. 17. The liquid ejecting section, when driving the heater element to eject the probe solution from the ejection port, generates bubbles in the probe solution in the flow path, and the bubbles pass through the ejection port. 2. A structure having a structure for communicating with outside air.
7. The production method according to 6. 18. The liquid ejecting apparatus according to claim 1, wherein the probe is a substance that specifically recognizes a target substance. 19. The apparatus according to claim 9, wherein the probe is a substance that specifically recognizes a target substance. 20. The method according to claim 10, wherein the probe is a substance that specifically recognizes a target substance.