Patent Description:
There is a demand to capture and comprehensively analyze particles such as cells. For example, particularly in the field of drug discovery, attempts have been made to sort and recover cells at a single cell level to use the sorted cells.

As a method for comprehensively capturing cells, for example, Patent Document <NUM> discloses a substrate in which cells smaller than opening portions are allowed to pass through so that desired cells are held by the opening portions by using a substrate having opening portions of different sizes on an upper surface and a lower surface for the purpose of separating specific cells of different sizes; and a method thereof.

In addition, Patent Document <NUM> discloses, as a substrate for capturing cells and aligning them on a plane, a cell capture substrate that has a plurality of opening portions for isolating and accommodating one cell, and has, on a bottom surface of the opening portions, a plurality of through-holes of a size that does not allow cells to pass through.

In addition, a method in which a large number of single cells are analyzed at the same time by using a microchip having wells with a size that allows only one cell to be accommodated is also known. For example, Patent Document <NUM> discloses a microwell array that has wells with a size that allows only one cell to be accommodated; and a screening method in which cells are cultured in the microwell array, and substances produced from the cells stored in wells are detected. Patent Document <NUM> discloses a cell capture system, a cell sorting apparatus, and a cell removal tool.

Meanwhile, the inventors of the present invention have found that, in a case of capturing particles by using a particle capture device that includes a plurality of recessed portions having a size capable of capturing one particle, the particles may not be captured uniformly. Herein, the phrase "particles not captured uniformly" means that a ratio of the number of recessed portions that capture particles to the total number of recessed portions contained in a unit region on the particle capture device varies from region to region. With such background, the present invention aims to provide a technique for uniformly capturing particles.

In order to achieve the aforementioned objects, in one embodiment, the present invention is a particle capture device (<NUM>) comprising a first substrate (<NUM>) being formed of a layer (10a) in which recessed portions (<NUM>) are patterned and a layer (10b) in which connection holes (<NUM>) are patterned, and having a structure in which a plurality of the recessed portions (<NUM>) are vertically and horizontally disposed at equal intervals, and a second substrate (<NUM>) that is disposed parallel to and facing a first side (<NUM>) of the first substrate (<NUM>), where in the plurality of recessed portions (<NUM>) are open on the second side (<NUM>) of the first substrate (<NUM>) and that have a size capable of capturing one particle (B), the connection holes (<NUM>) connect the first side (<NUM>) to the second side (<NUM>) and have a size allowing a dispersion medium of the particles (B) to move therethrough, a flow path (<NUM>) that has the connection holes (<NUM>) of the first substrate (<NUM>) as an inlet port of the dispersion medium and has an end portion of the first side (<NUM>) of the first substrate (<NUM>) as an outlet port of the dispersion medium is formed between the first substrate (<NUM>) and the second substrate (<NUM>), the total opening area of all the connection holes (<NUM>) included in the particle device is <NUM><NUM> or more and less than <NUM><NUM>, and the cross-sectional area of the flow path (<NUM>) at the outlet port is <NUM> times or more the total opening area of the connection holes (<NUM>), or the total opening area of the connection holes (<NUM>) included in the particle device is <NUM><NUM> or more and <NUM><NUM> or less, and a cross-sectional area of the flow path (<NUM>) at the outlet port is <NUM> times or more the total opening area of the connection holes (<NUM>), a diameter of the particle (B) is <NUM> to <NUM>, an opening area of the connection hole (<NUM>) is the smallest cross-sectional area among cross-sectional areas of a surface, which is parallel to the first substrate, at any position of the connection holes (<NUM>) that connect the first side to the second side.

In one embodiment, the present invention is a particle capture device (<NUM>) including a first substrate (<NUM>) being formed of a layer (10a) in which recessed portions (<NUM>) are patterned and a layer (10b) in which connection holes (<NUM>) are patterned, and having a structure in which a plurality of the recessed portions (<NUM>) are vertically and horizontally disposed at equal intervals, and a second substrate (<NUM>) that is disposed parallel to and facing a first side (<NUM>) of the first substrate (<NUM>), wherein the plurality of recessed portions (<NUM>) are open on the second side (<NUM>) of the first substrate (<NUM>) and have a size capable of capturing one particle (B),the connection holes (<NUM>) connect the first side (<NUM>) to the second side (<NUM>) and have a size allowing a dispersion medium of the particles (B) to move therethrough, , a flow path (<NUM>) that has the connection holes (<NUM>) of the first substrate (<NUM>) as an inlet port of the dispersion medium and has an end portion of the first side (<NUM>) of the first substrate (<NUM>) as an outlet port of the dispersion medium is formed between the first substrate (<NUM>) and the second substrate (<NUM>), a total opening area of all the connection holes (<NUM>) included in the particle capture device is <NUM><NUM> or more, and a distance between the first substrate (<NUM>) and the second substrate (<NUM>) is <NUM> or more, a diameter of the particle (B) is <NUM> to <NUM>, an opening area of the connection hole (<NUM>) is the smallest cross-sectional area among cross-sectional areas of a surface, which is parallel to the first substrate, at any position of the connection holes (<NUM>) that connect the first side to the second side.

According to the present invention, it is possible to provide a technique for uniformly capturing particles.

Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings in some cases. In the drawings, the same or corresponding parts are denoted by the same or corresponding reference numerals, and redundant description is not repeated. In addition, some dimensional ratios in the respective drawings are exaggerated for explanation, and thus do not necessarily correspond to actual dimensional ratios.

In one embodiment, the present invention provides a particle capture device <NUM> comprising a first substrate <NUM> being formed of a layer 10a in which recessed portions <NUM> are patterned and a layer 10b in which connection holes <NUM> are patterned, and having a structure in which a plurality of the recessed portions <NUM> are vertically and horizontally disposed at equal intervals, and a second substrate <NUM> that is disposed parallel to and facing a first side <NUM> of the first substrate <NUM>, wherein the plurality of recessed portions <NUM> are open on the second side <NUM> of the first substrate <NUM> and have a size capable of capturing one particle (B), the connection holes <NUM> connect the first side <NUM> to the second side <NUM> and have a size allowing a dispersion medium of the particles (B) to move therethrough, a flow path <NUM> that has the connection holes <NUM> of the first substrate <NUM> as an inlet port of the dispersion medium and has an end portion of the first side <NUM> of the first substrate <NUM> as an outlet port of the dispersion medium is formed between the first substrate <NUM> and the second substrate <NUM>, the total opening area of the all connection holes <NUM> included in the particle device is <NUM><NUM> or more and less than <NUM><NUM>, and a cross-sectional area of the flow path <NUM> at the outlet port is <NUM> times or more the total opening area of the connection holes <NUM>, or the total opening area of all the connection holes <NUM> included in the particle device is <NUM><NUM> or more and <NUM><NUM> or less, and a cross-sectional area of the flow path (<NUM>) at the outlet port is <NUM> times or more the total opening area of the connection holes <NUM>, a diameter of the particle (B) is <NUM> to <NUM>, an opening area of the connection hole <NUM> is the smallest cross-sectional area among cross-sectional areas of a surface, which is parallel to the first substrate, at any position of the connection holes <NUM> that connect the first side to the second side. As will be described later in Examples, particles can be uniformly captured by the particle capture device of the present embodiment.

A particle capture device <NUM> of the present embodiment comprises a first substrate <NUM> being formed of a layer 10a in which recessed portions <NUM> are patterned and a layer 10b in which connection holes <NUM> are patterned, and having a structure in which a plurality of the recessed portions <NUM> are vertically and horizontally disposed at equal intervals; and a second substrate <NUM> that is disposed parallel to and facing a first side <NUM> of the first substrate <NUM>, wherein the plurality of recessed portions <NUM> are open on the second side <NUM> of the first substrate <NUM> and have a size capable of capturing one particle (B), the connection holes <NUM> connect the first side <NUM> to the second side <NUM> and have a size allowing a dispersion medium of the particles (B) to move therethrough, a flow path <NUM> that has the connection holes <NUM> of the first substrate <NUM> as an inlet port of the dispersion medium and has an end portion of the first side <NUM> of the first substrate <NUM> as an outlet port of the dispersion medium is formed between the first substrate <NUM> and the second substrate <NUM>, the total opening area of the all connection holes <NUM> included in the particle capture device may be <NUM><NUM> or more, and a distance between the first substrate and the second substrate may be <NUM> or more, a diameter of the particle (B) is <NUM> to <NUM>, an opening area of the connection hole <NUM> is the smallest cross-sectional area among cross-sectional areas of a surface, which is parallel to the first substrate, at any position of the connection holes (<NUM> that connect the first side to the second side. As will be described later in Examples, particles can also be uniformly captured by such a particle capture device of the present embodiment.

<FIG>, <FIG>, <FIG>, <FIG>, and <FIG> are schematic views showing an example of the particle capture device of the present embodiment. <FIG> is a front cross-sectional view, and <FIG> is a top view. In addition, <FIG> and <FIG> are perspective views showing an example of the particle capture device. Furthermore, <FIG> is a front cross-sectional view, and <FIG> is a top view. Furthermore, <FIG> is a front cross-sectional view, and <FIG> is a top view.

A particle capture device <NUM> of the present embodiment includes a first substrate <NUM> being formed of a layer 10a in which recessed portions <NUM> are patterned and a layer 10b in which connection holes <NUM> are patterned, and having a structure in which a plurality of the recessed portions <NUM> are vertically and horizontally disposed at equal intervals; and a second substrate <NUM> that is disposed parallel to and facing a first side <NUM> of the first substrate <NUM>. In addition, the plurality of recessed portions <NUM> are open on the second side <NUM> of the first substrate <NUM> and have a size capable of capturing one particle (B). Furthermore, the connection holes <NUM> connect the first side <NUM> to the second side <NUM> and have a size allowing a dispersion medium of the particles (B) to move therethrough. Furthermore, a flow path <NUM> that has the connection holes <NUM> of the first substrate <NUM> as an inlet port of the dispersion medium and has end portions 11a and 11b of the first side <NUM> of the first substrate <NUM> as an outlet port of the dispersion medium is formed between the first substrate <NUM> and the second substrate <NUM>. Furthermore, in a case where the total opening area of all the connection holes <NUM> included in the particle device is <NUM><NUM> or more and less than <NUM><NUM>, for example, <NUM> to <NUM><NUM>, the total cross-sectional area of the flow path <NUM> at the outlet ports 11a and 11b is <NUM> times or more the total opening area of the connection holes <NUM>. Furthermore, in a case where the total opening area of all the connection holes <NUM> included in the particle device is <NUM><NUM> or more and <NUM><NUM> or less, for example, <NUM> to <NUM><NUM>, for example, <NUM> to <NUM><NUM>, for example, <NUM> to <NUM><NUM>, and for example, <NUM> to <NUM><NUM>, the total cross-sectional area of the flow path <NUM> at the outlet ports 11a and 11b is <NUM> times or more the total opening area of the connection holes <NUM>. Furthermore, a diameter of the particle (B) is <NUM> to <NUM>, and an opening area of the connection hole <NUM> is the smallest cross-sectional area among cross-sectional areas of a surface, which is parallel to the first substrate, at any position of the connection holes <NUM> that connect the first side to the second side.

In the particle capture device (<NUM>) of the present embodiment, the distance between the first substrate <NUM> and the second substrate <NUM> may be <NUM> or more.

In a case of the particle capture device shown in <FIG>, an area of the outlet port is the total cross-sectional area of the flow path <NUM> at the end portions (11a and 11b) of the first side <NUM> of the first substrate <NUM>.

As will be described later in Examples, in the particle capture device <NUM> of the present embodiment, in a case where the total opening area of all the connection holes <NUM> included in the particle device is <NUM><NUM> or more and less than <NUM><NUM>, the cross-sectional area of the flow path <NUM> at the outlet port is <NUM> times or more the total opening area of the connection holes <NUM>. Therefore, particles can be uniformly captured. In addition, in the particle capture device of the present embodiment, in a case where the total opening area of all the connection holes <NUM> included in the particle device is <NUM><NUM> or more and <NUM><NUM> or less, the cross-sectional area of the flow path <NUM> at the outlet port is <NUM> times or more the total opening area of the connection holes <NUM>. Therefore, particles (B) with a diameter of <NUM> to <NUM>, can be uniformly captured. Furthermore, in the particle capture device of the present embodiment, the distance between the first substrate <NUM> and the second substrate <NUM> may be <NUM> or more. Therefore, particles can be uniformly captured.

As will be described later in Examples, examples of cases in which particles cannot be uniformly captured include a case in which a particle capturing ratio is low at the center portion of the particle capture device, and a particle capturing ratio is high at the end portions (portions close to the outlet ports) of the particle capture device; and the like. More specifically, photographs shown in <FIG> are examples thereof. In the present specification, a particle capturing ratio refers to a ratio of the total number of recessed portions contained in a unit area to the number of recessed portion that have captured particles. In addition, a unit area is not particularly limited, and may be, for example, one field of view when observed with a microscope.

Meanwhile, in the particle capture device of the present embodiment, variations between a particle capturing ratio at the center portion of the particle capture device and a particle capturing ratio at the end portion of the particle capture device are small. Therefore, according to the particle capture device of the present embodiment, particles can be uniformly captured over the whole particle capture device. In the present specification, the phrase "particle capturing ratio being uniform" is synonymous with the phrase "variations in capturing rate being small," and means that a ratio of particle capturing ratios between any regions of the particle capture device is, for example, <NUM> or more, is preferably <NUM> or more, and is more preferably <NUM> or more.

In the devices of the related art, capture of particles such as cells in the recessed portion is performed by free fall due to a weight of the particles or by a forced fall due to a centrifugal force, but a low capturing rate is a problem. On the other hand, according to the particle capture device of the present embodiment, because a flow of a liquid from the recessed portion <NUM> to the connection holes <NUM> can be generated, particles are easily captured in the recessed portion due to the flow of the liquid, and therefore a capturing rate tends to be improved.

In addition, in the devices of the related art, when attempting to recover captured particles such as cells, it is difficult to create a flow of a liquid by which particles themselves are swept away by suction from a recessed portion, and a low success rate of recovery of target particles is a problem. On the other hand, according to the particle capture device of the present embodiment, because a flow of a liquid from the flow path <NUM> to an opening portion of the recessed portion <NUM> can be generated through the connection holes <NUM> of the recessed portion <NUM>, a success rate of recovery of particles tends to be improved compared to the devices of the related art.

In the particle capture device of the present embodiment, the particles are not particularly limited, and examples thereof include cells, cell clusters, resin particles, metal particles, glass particles, ceramic particles, and the like. The diameter of the particles is of <NUM> to <NUM>, for example, about <NUM> to <NUM>, for example, about <NUM> to <NUM>, and for example, about <NUM> to <NUM>. In the present specification, the diameter of particles refers to the diameter of a circle having the same area as a particle-projected area.

When capturing particles, the particles that are in a state of being suspended in a dispersion medium are supplied from the second side <NUM> of the first substrate <NUM>. The dispersion medium is not particularly limited, and examples thereof include water, a buffer solution, an isotonic solution, a culture medium, and the like, and these can be appropriately used according to the purpose.

As shown in <FIG>, the first substrate <NUM> is formed of a layer 10a in which the recessed portions <NUM> are patterned, and a layer 10b in which the connection holes <NUM> are patterned. For example, as shown in <FIG>, the first substrate <NUM> has a structure in which a plurality of the recessed portions <NUM> are vertically and horizontally disposed at equal intervals.

In <FIG>, B represents one particle. As shown in <FIG>, a shape of the recessed portion <NUM> is not particularly limited as long as one particle can be captured thereby. A shape of the recessed portion <NUM> may be a cylindrical shape, may be a polyhedron (for example, a rectangular parallelepiped, a hexagonal prism, an octagonal prism, and the like) constituted by a plurality of surfaces, may be an inverted truncated cone, may be an inverted truncated pyramid (inverted truncated triangle, inverted truncated square, inverted truncated pentagon, inverted truncated hexagon, or inverted truncated polygon having seven or more corners), or may be a combination shape of two or more of these shapes.

A shape of the recessed portion <NUM> may be, for example, a shape in which a part of the recessed portion is a cylindrical shape and the rest thereof is an inverted truncated cone shape. In a case where a shape of the recessed portion <NUM> is a cylindrical shape or a rectangular parallelepiped, a bottom part of the recessed portion <NUM> is generally flat, but may be a curved surface (a convex surface or concave surface).

The dimensions of the recessed portion <NUM> is determined in consideration of a suitable ratio of the diameter of particles (B) of <NUM> to <NUM> to be captured in the recessed portion <NUM> to the dimensions of the recessed portion <NUM>. The recessed portions <NUM> are patterned so that a plurality of recessed portions <NUM> are vertically and horizontally disposed at equal intervals.

In addition, a shape and the dimensions of the recessed portion <NUM> are appropriately determined in consideration of the type (a shape, dimensions, and the like of a particle) of particles to be captured by the recessed portion <NUM> so that one particle is captured by one recessed portion <NUM>.

In order to capture one particle with one recessed portion <NUM>, the diameter of the largest circle that is in internal contact with a planar shape of the recessed portion <NUM> is preferably within a range of <NUM> to <NUM> times, is more preferably within a range of <NUM> to <NUM> times, and is even more preferably within a range of <NUM> to <NUM> times the diameter of particles to be captured by the recessed portion <NUM>.

In addition, a depth of the recessed portion <NUM> is preferably within a range of <NUM> to <NUM> times, is more preferably within a range of <NUM> to <NUM> times, and even more preferably within a range of <NUM> to <NUM> times the diameter of particles to be captured by the recessed portion <NUM>.

For example, in a case where particles to be captured are substantially spherical with a diameter of about <NUM> to <NUM>, the thickness of the first substrate <NUM>, the number of the recessed portions <NUM>, and dimensions of the recessed portion <NUM> are preferably as follows.

Firstly, the thickness of the first substrate <NUM> is preferably <NUM> to <NUM>, and is more preferably <NUM> to <NUM>. In addition, the number of the recessed portions <NUM> included in the first substrate <NUM> is not particularly limited, but is preferably within a range of, for example, <NUM>,<NUM> to <NUM>,<NUM>,<NUM> per <NUM><NUM>. Furthermore, an opening ratio of the recessed portion <NUM> is less than <NUM>% in some cases due to technical problems in manufacturing. The opening ratio of the recessed portion <NUM> is preferably, for example, within a range of <NUM> to <NUM>%.

In addition, for example, in a case where the recessed portion <NUM> is cylindrical, the size of the recessed portion <NUM> is preferably <NUM> to <NUM> in diameter, is more preferably <NUM> to <NUM> in diameter, and is even more preferably <NUM> to <NUM> in diameter. Furthermore, a depth of the recessed portion <NUM> is preferably <NUM> to <NUM>, is more preferably <NUM> to <NUM>, is even more preferably <NUM> to <NUM>, and is particularly preferably <NUM> to <NUM>. A case in which a depth of the recessed portion <NUM> is <NUM> or more is preferable from the viewpoint of easy capture of particles and practical use. Furthermore, a case in which the depth of the recessed part <NUM> is <NUM> or less is preferable from the viewpoint of a low probability of capture of a plurality of particles.

Dimensions of the connection holes <NUM> can be appropriately determined in consideration of the diameter of particles to be captured by the recessed portion <NUM>, dimensions of the recessed portion <NUM>, characteristics of a dispersion medium for moving particles through the connection holes <NUM>, and the like. The connection holes <NUM> are preferably patterned so that a form, diameter of holes, density, and the like thereof are controlled. A case in which the connection holes are controlled is preferable, because it is then easy to ensure uniformity of a permeation amount of the dispersion medium of particles. However, the connection holes <NUM> are not limited to holes produced by patterning, and for example, it is also possible to use holes formed by using a porous material such as a porous film.

In detail, the number, position, shape, size, and the like of the connection holes <NUM> are not particularly limited as long as the size thereof is a size that enables capturing of particles (storing in the inside of the recessed portion <NUM>) without allowing the particles to pass through, and moving of a dispersion medium.

For example, as shown in <FIG>, in a case where the recessed portion <NUM> is cylindrical, a plurality of cylindrical connection holes <NUM> having a diameter smaller than the diameter of the recessed portion <NUM> may be provided at a bottom part of the recessed portion <NUM>. In addition, as shown in <FIG>, in a case where the recessed portion <NUM> is cylindrical, connection holes having a shape shown as 14a to 14d of <FIG> may be provided at a bottom part of the recessed portion <NUM>.

For example, in a case where particles to be captured are substantially spherical with a diameter of about <NUM> to <NUM>, and the connection holes <NUM> are cylindrical, the diameter of the connection holes <NUM> is preferably <NUM> to <NUM>, is more preferably <NUM> to <NUM>, and is even more preferably <NUM> to <NUM>. In a case where the connection holes <NUM> has a palisading shape, a width thereof is preferably <NUM> to <NUM>, is more preferably <NUM> to <NUM>, and is even more preferably <NUM> to <NUM>. In a case where the connection holes <NUM> have a lattice shape, a first side is preferably <NUM> to <NUM>, is more preferably <NUM> to <NUM>, and is even more preferably <NUM> to <NUM>.

For example, in a case where the connection holes <NUM> are cylindrical, cross-sectional areas of surfaces, which are parallel to the first substrate of the connection holes <NUM> are constant throughout all the connection holes <NUM>. In this case, a cross-sectional area of a surface, which is parallel to the first substrate, at any position of the connection holes <NUM> may be regarded as an opening area of the connection port <NUM>.

In addition, in a case where cross-sectional areas of surfaces, which are parallel to the first substrate of the connection holes <NUM> are not constant, as an opening area of the connection port <NUM>, the smallest cross-sectional area among cross-sectional areas of surfaces parallel to the first substrate may be regarded as an opening area of the connection port <NUM>.

The total opening area of the connection holes <NUM> is an area obtained by totaling opening areas of all the connection holes <NUM> included in the particle capture device of the present embodiment.

As shown in <FIG>, the particle capture device <NUM> of the present embodiment includes the second substrate <NUM> that is disposed parallel to and facing the first side <NUM> of the first substrate <NUM>. In addition, the flow path <NUM> that has the connection holes <NUM> of the first substrate <NUM> as an inlet port and has the end portions 11a and 11b of the first side <NUM> of the first substrate <NUM> as an outlet port is formed between the first substrate <NUM> and the second substrate <NUM>.

As shown in <FIG>, pillars <NUM> that support the first substrate <NUM> may be present between the first substrate <NUM> and the second substrate <NUM>. In a case where the pillars <NUM> are present, the number, position, shape, size, and the like of the pillars <NUM> are not particularly limited as long as the first substrate <NUM> can be supported and the object of the present invention can be achieved thereby.

In the particle capture device of the present embodiment, an area of the outlet port may be larger than the total opening area of the connection holes <NUM>. As described above, in the case of the particle capture device shown in <FIG>, the area of the outlet port is the total cross-sectional area of the flow path <NUM> at the end portions (11a and 11b) of the first side <NUM> of the first substrate <NUM>.

In addition, in a case where the connection holes <NUM> are formed by using a porous material such as a porous film, an opening area of the connection holes <NUM> can be determined based on a void volume of the porous material. More specifically, for example, a product of the total opening area of the recessed portion <NUM> and a void volume of the porous material that forms the connection holes <NUM> may be regarded as the total opening area of the connection holes <NUM>.

In the particle capture device of the present embodiment, an area of the outlet port may be <NUM> times or more, may be <NUM> times or more, may be <NUM> times or more, may be <NUM> times or more, may be <NUM> times or more, may be <NUM> times or more, or may be <NUM> times or more the total opening area of the connection holes <NUM>. The upper limit to an area of the outlet port is not particularly limited, but it is practical to set the upper limit to, for example, about <NUM> times the total opening area of the connection holes <NUM>.

As will be described later in Examples, in a case where an area of the outlet port is larger than the total opening area of the connection holes <NUM>, particles tend to be more uniformly captured.

In addition, for example, in a case where particles to be captured are substantially spherical with a diameter of about <NUM> to <NUM>, the distance between the first substrate <NUM> and the second substrate <NUM> may be, for example, <NUM> or more, may be, for example, <NUM> or more, may be, for example, <NUM> or more, may be, for example, <NUM> or more, may be, for example, <NUM> or more, and may be, for example, <NUM> or more. The upper limit of the distance between the first substrate <NUM> and the second substrate <NUM> is not limited from the viewpoint of a performance of the particle capture device, but is preferably <NUM> or less in consideration of practicability and the like (the amount of a dispersion medium used, the size of a microscope for observation, and the like).

As will be described later in Examples, when the distance between the first substrate <NUM> and the second substrate <NUM> is within the above-mentioned range, particles tend to be more uniformly captured.

A material of the particle capture device of the present embodiment is not particularly limited, and is preferably a transparent material from the viewpoint of easiness of observation of particles. In addition, in a case where captured particles are observed by fluorescent observation as an index, a material is preferably a material with low autofluorescence.

As a specific material of the first substrate <NUM> and the second substrate <NUM>, it is possible to use, for example, glass, and a general resin that is transparent and has low autofluorescence, such as polyethylene terephthalate (PET), polymethyl methacrylate (PMMA), polycarbonate (PC), cycloolefin polymer (COP), and epoxy.

In addition, in a case of capturing cells as particles, it is preferable that a material of the particle capture device of the present embodiment have no cell cytotoxicity and low cell adhesiveness.

The material of the particle capture device of the present embodiment is preferably polymerized by using a curable resin composition which is easy to microfabricate (hereinafter will be referred to as a "photosensitive resin composition") from the viewpoint of formation of the recessed portions <NUM> having a size capable of capturing one particle, and the connection holes <NUM> having a size allowing a dispersion medium to move therethrough.

A curable resin composition has properties of being crosslinked and cured by irradiation with active energy rays such as ultraviolet rays, and is preferably a curable resin composition which is used for a negative-type photoresist, a negative-type dry film resist, or molding of a micro resin having a fine structure. Hereinafter, a cured product obtained by curing a curable resin composition into a desired shape by photolithography will be referred to as a resin pattern in some cases.

In a case where the curable resin composition is used for applications such as micro resin molding, firstly, the curable resin composition is applied to a surface of a substrate on which a resin pattern is to be formed, and a solvent component contained in the curable resin composition is volatilized to produce a resin film. Next, a photomask that becomes a shape of a pattern to be formed is placed on a surface of the resin film, and is irradiated with active energy rays such as ultraviolet rays. Thereafter, a resin pattern is formed on a surface of a substrate by subjecting it to a developing process and, if necessary, a post-baking process. This resin pattern can be used for the particle capture device of the present embodiment.

As such a curable resin composition, for example, it is possible to adopt a resin composition generally used for micro resin molding, such as a photocurable composition which contains an epoxy functional novolak resin, a cationic photopolymerization initiator such as a triarylsulfonium salt, and a diluent capable of reacting with epoxy functional groups, and which is completely cured to become a resin that is unlikely to be peeled off; a photocurable composition which contains a multifunctional bisphenol-A formaldehyde novolak resin, triphenylsulfonium hexafluoroantimonate that is an acid generator, and PGMEA that is a solvent, and which becomes a resin that can form a thick film; and the like.

In addition, when a photosensitive (curable) resin composition is prepared by combining an epoxy resin and a specific acid generator, and a resin pattern is formed by using this curable resin composition, it is possible to form, with high sensitivity, a resin pattern which has a small volume shrinkage at the time of heating and curing, and has a shape in which the aspect ratio is high.

Examples of curable (photosensitive) resin compositions include a photosensitive resin composition containing a polyfunctional epoxy resin (a) and a cationic polymerization initiator (b).

A polyfunctional epoxy resin used in the present embodiment may be any epoxy resin as long as it is an epoxy resin that has two or more epoxy groups in one molecule, and contains a number of epoxy groups, which is sufficient to cure a resin film formed of a curable resin composition, in one molecule. As such a polyfunctional epoxy resin, a phenol novolac-type epoxy resin, an ortho cresol novolac-type epoxy resin, a triphenyl novolac-type epoxy resin, and a bisphenol A novolac-type epoxy resin are preferable.

A functionality, which is the number of epoxy groups contained in one molecule of the polyfunctional epoxy resin, is preferably <NUM> or more, and is more preferably <NUM> to <NUM>. A case in which the functionality of the polyfunctional epoxy resin is <NUM> or more is preferable because it is then possible to form a resin pattern in which an aspect ratio and resolution are high, and a case in which the functionality of the polyfunctional epoxy resin is <NUM> or less is preferable because it is then easy to control resin synthesis, and it is possible to suppress an excessive increase in internal stress of a resin pattern.

The mass average molecular weight of the polyfunctional epoxy resin is preferably <NUM> to <NUM>,<NUM>, and is more preferably <NUM> to <NUM>,<NUM>. A case in which a mass average molecular weight of the polyfunctional epoxy resin is <NUM> or more is preferable from the viewpoint of enabling suppression of a heat flow which may occur before a curable resin composition is cured by irradiation with active energy rays, and a case in which a mass average molecular weight of the polyfunctional epoxy resin is <NUM> or less is preferable from the viewpoint of enabling obtaining of an appropriate dissolution rate at the time of patterning development.

The amount of the polyfunctional epoxy resin in the photosensitive resin composition is preferably <NUM> to <NUM>% by mass, and is more preferably <NUM> to <NUM>% by mass with respect to the total solid content. Accordingly, when the polyfunctional epoxy resin is coated on a substrate, a photosensitive resin film having appropriate hardness is obtained with high sensitivity.

Next, the cationic polymerization initiator will be described. The cationic polymerization initiator is a compound in which cations are generated upon receiving irradiation with excimer laser light such as ultraviolet rays, far ultraviolet rays, KrF, and ArF, and active energy rays such as X-rays and electron beams, and these cations become a polymerization initiator.

Examples of such cationic polymerization initiators include.

The amount of the cationic polymerization initiator in the curable resin composition is preferably <NUM> to <NUM>% by mass, and is more preferably <NUM> to <NUM>% by mass. A case in which the amount of the cationic polymerization initiator in the curable resin composition is <NUM>% by mass or more is preferable, because then a curing time of the curable resin composition upon exposure to active energy rays can be appropriately set. In addition, a case in which the amount of the cationic polymerization initiator in the curable resin composition is <NUM> mass% or less is preferable, because then developability after exposure to active energy rays can be made favorable. The above-mentioned content is a content in a case where the curable resin composition does not contain a solvent component to be described later. Accordingly, in a case where the curable resin composition contains a solvent component to be described later, this is sufficient as long as the amount of the cationic polymerization initiator after removing a mass of a solvent component is within the above-mentioned range. Furthermore, it is obvious to those skilled in the art that these details of the curable resin composition can be realized based on methods known to those skilled in the art which are described in <CIT> and <CIT>.

In the particle capture device of the present embodiment, a shape of the first substrate <NUM>, a shape of the second substrate <NUM>, and the arrangement of the first substrate <NUM> and the second substrate <NUM> are not limited to those shown in <FIG>. For example, in <FIG>, although the first substrate <NUM> and the second substrate <NUM> are both rectangular, the first substrate <NUM> and the second substrate <NUM> may be, for example, circular or may be a polygon such as a triangle, pentagon, hexagon, heptagon, or octagon.

In addition, in <FIG>, the first substrate <NUM> is disposed at the center of the second substrate <NUM>, and outlet ports are present at two positions of 11a and 11b, but, for example, the first substrate <NUM> may be disposed at a position such that one end thereof is aligned with the second substrate <NUM>, and only one of the outlet ports 11a and <NUM>1b may be present.

<FIG> are schematic views showing an example of the particle capture device of the present embodiment. <FIG> is a front cross-sectional view, and <FIG> is a top view.

A particle capture device <NUM> includes a first substrate <NUM> and a second substrate <NUM> that is disposed parallel to and facing a first side <NUM> of the first substrate <NUM>. In addition, the first substrate <NUM> has a plurality of recessed portions <NUM> that are open on ae second side <NUM> of the first substrate <NUM> and that have a size capable of capturing one particle. Furthermore, the recessed portion <NUM> has connection holes <NUM> that connect the first side <NUM> to the second side <NUM> and that have a size allowing a dispersion medium of the particles to move therethrough. Furthermore, a flow path <NUM> that has the connection holes <NUM> of the first substrate <NUM> as an inlet port of the dispersion medium and has an end portion 11a of the first side <NUM> of the first substrate <NUM> as an outlet port of the dispersion medium is formed between the first substrate <NUM> and the second substrate <NUM>. Furthermore, an area of the outlet port 11a is <NUM> times or more the total opening area of the recessed portion <NUM>. Furthermore, the relative position between the first substrate <NUM> and the second substrate <NUM> is determined by a holding member <NUM>. In the particle capture device <NUM>, a configuration in which the substrate <NUM> is held on the substrate <NUM> by adding pillars or the like to a lower portion of the substrate <NUM>, instead of the holding member <NUM> may be adopted.

In the particle capture device shown in <FIG>, a planar shape of the first substrate <NUM> is circular. A planar shape of the second substrate <NUM> is also circular. For this reason, a shape of the particle capture device shown in <FIG> is similar to a Petri dish having two layers.

In a case of the particle capture device shown in <FIG>, the end portion 11a of the first side <NUM> of the first substrate <NUM> is a circumference of the circular first substrate <NUM>. Accordingly, in the particle capture device shown in <FIG>, an area of the outlet port is a cross-sectional area of the flow path <NUM> at a circumference 11a of the first substrate <NUM>.

A particle capture device <NUM> includes a first substrate <NUM> and a second substrate <NUM> that is disposed parallel to and facing a first side <NUM> of the first substrate <NUM>. In addition, the first substrate <NUM> has a plurality of recessed portions <NUM> that are open on a second side <NUM> of the first substrate <NUM> and that have a size capable of capturing one particle. Furthermore, the recessed portion <NUM> has connection holes <NUM> that connect the first side <NUM> to the second side <NUM> and that have a size allowing a dispersion medium of the particles to move therethrough. Furthermore, a flow path <NUM> that has the connection holes <NUM> of the first substrate <NUM> as an inlet port of the dispersion medium and has end portions 11a, 11b, 11c, and 11d of the first side <NUM> of the first substrate <NUM> as an outlet port of the dispersion medium is formed between the first substrate <NUM> and the second substrate <NUM>. Furthermore, the total area of the outlet ports 11a, 11b, 11c, and 11d is <NUM> times or more the total opening area of the recessed portion <NUM>. Furthermore, a relative position between the first substrate <NUM> and the second substrate <NUM> is determined by a holding member <NUM>. In the particle capture device <NUM>, a configuration in which the substrate <NUM> is held on the substrate <NUM> by adding pillars or the like to a lower portion of the substrate <NUM>, instead of the holding member <NUM> may be adopted.

In the particle capture device shown in <FIG>, a planar shape of the first substrate <NUM> is rectangular. A planar shape of the second substrate <NUM> is circular.

In a case of the particle capture device shown in <FIG>, each of the end portions 11a, 11b, 11c, and 11d of the first side <NUM> of the first substrate <NUM> forms first side of an outer circumference of the rectangular first substrate <NUM>. Accordingly, in the particle capture device shown in <FIG>, the area of the outlet port is the total cross-sectional area of the flow path <NUM> at the sides 11a, 11b, 11c, and 11d of the first substrate <NUM>.

A plurality of the particle capture devices described above may be connected together. For example, a plurality of particle capture devices <NUM> or <NUM> described above may be connected together to form shapes such as a <NUM>-well plate, <NUM>-well plate, <NUM>-well plate, <NUM>-well plate, <NUM>-well plate, <NUM>-well plate, and <NUM>-well plate. In particular, in a case of capturing particles which are cells, the size of the particle capture device is preferably produced to be a size according to the SBS standard, a slide glass size, or a Petri dish size, which are widely used for cell culture and the like, from the viewpoint of practical use.

The present disclosure describes a method for manufacturing the particle capture device described above. The manufacturing method of the present embodiment includes a process <NUM> in which a dissolvable base film is formed on a first support, a first curable resin composition is applied on the base film to form a first curable resin film, connection holes are patterned on the first curable resin film, and a support layer on which connection holes are patterned is obtained; a process <NUM> in which a second curable resin composition is applied on the support layer to form a second curable resin film, recessed portions are patterned on the second curable resin film, and a first substrate on which recessed portions are patterned is obtained; a process <NUM> in which the base film is dissolved to peel off the first substrate from the first support; and a process <NUM> in which the first substrate and a second substrate are bonded. The bonded product of the first substrate and the second substrate is the particle capture device.

In the manufacturing method described in the present disclosure, the second substrate may have pillars. In this case, the manufacturing method described in the present disclosure may include, before the process <NUM>, a process a in which a third curable resin composition is applied on the second substrate to form a third curable resin film, pillars are patterned on the third curable resin film, and a second substrate on which the pillars are patterned is obtained.

In the present process, for example, as shown in <FIG>, a dissolvable base film <NUM> is formed on a first support <NUM>, a first curable resin composition is applied to the base film <NUM> to form a first curable resin film 10B, the first curable resin film 10B is exposed and then developed, and a layer 10b on which connection holes <NUM> are patterned as shown in as shown in <FIG> is obtained.

A method for patterning the connection holes <NUM> is not limited to exposure and development, and an imprint method, a method using a directed self assembly (DSA) technique, and the like may be adopted. In addition, as a method for curing the first curable resin film 10B, known methods may be adopted instead of exposure.

Examples of the first support include a substrate for electronic components, a support obtained by forming a predetermined wiring pattern on this substrate, and the like. More specific examples thereof include a silicon wafer, a metal substrate such as copper, chromium, iron, and aluminum, a glass substrate, and the like. As a material of a wiring pattern, it is possible to use, for example, copper, aluminum, nickel, gold, or the like. Examples of the first curable resin composition include the above-described curable (photosensitive) resin composition.

For the base film <NUM>, it is possible to use polyvinyl alcohol resin, dextrin, gelatin, glue, casein, shellac, gum arabic, starch, protein, a polyacrylic acid amide, sodium polyacrylate, polyvinyl methyl ether, a styrenic elastomer, a copolymer of methyl vinyl ether and maleic acid anhydride, a copolymer of vinyl acetate and itaconic acid, polyvinyl pyrrolidone, acetyl cellulose, hydroxyethyl cellulose, sodium alginate, and the like. These materials may be a combination of a plurality of materials soluble in the same kind of liquid. From the viewpoint of hardess and flexibility of the base film, a material of the base film may contain, for example, a rubber component such as mannan, xanthan gum, or guar gum.

In the present process, for example, as shown in <FIG>, a second curable resin composition is applied on the layer 10b to form a second curable resin film 10A, the second curable resin film 10A is exposed and then developed, and a first substrate <NUM> in which the recessed portions <NUM> are patterned on the layer 10b is obtained.

Examples of the second curable resin composition include the above-described curable (photosensitive) resin composition. A method for patterning the recessed portions <NUM> is not limited to exposure and development, and an imprint method, a method using a directed self assembly (DSA) technique, and the like may be adopted. In addition, as a method for curing the second curable resin composition, known methods may be adopted instead of exposure.

In the present process, for example, the base film <NUM> is dissolved by immersing the whole substrate in a release agent (for example, <NUM>-methyl-<NUM>-isopropylcyclohexane (p-menthane)), and the first substrate <NUM> is peeled off from the first support <NUM>.

In the present process, the first substrate <NUM> shown in <FIG> which is obtained in the above-described process, and the second substrate <NUM> shown in <FIG> are bonded. At the time of bonding, the layer 10b is joined to face the second substrate <NUM>. When bonding, the curable resin composition may be used as an adhesive. As shown in <FIG>, the second substrate <NUM> may have a pillar <NUM>.

In the present process, as shown in <FIG>, for example, a third curable resin composition is applied on a second support <NUM> to form a third curable resin film 22A, the third curable resin film 22A is exposed and then developed, and a pillar pattern <NUM> as shown in <FIG> is formed.

The formation of the pillar pattern <NUM> is optional, and the present process may not be present. In addition, as a method for curing the third curable resin composition, known methods may be adopted instead of exposure. For example, a substrate for electronic components can be used as the support <NUM>, but from the viewpoint of easy observation of captured particles, a transparent substrate is preferable, and specifically, it is preferable to adopt a glass substrate. Examples of the third curable resin composition include the above-described curable (photosensitive) resin composition.

The present disclosure describes a method for capturing particles which includes a process of supplying particles to the inlet port of the particle capture device described above and allowing a dispersion medium to flow out of the outlet port. The capturing method described in the present disclosure can be said to be a method for capturing particles uniformly, a method for producing uniformly captured particles, and the like.

In the method for capturing particles described in the present disclosure, particles supplied from the inlet port of the particle capture device described above are captured by the recessed portions <NUM> provided in the first substrate <NUM>. In addition, a dispersion medium of the particles moves through the connection holes <NUM>, passes through the flow path <NUM>, and is discharged from the outlet port.

In the method for capturing particles described in the present disclosure, particles can be uniformly captured by using the particle capture device described above.

The terms used in the present specification are used to describe specific embodiments and should not be understood to limit the invention. Unless otherwise specified, the terms used in the present specification (including technical terms and scientific terms) are interpreted to have the same meaning as those commonly understood by those in the skilled art in the technical field to which the present invention belongs, and therefore should not be idealized or interpreted in an overly formal sense.

The term "containing" used in the present specification is intended to mean that the described items (members, processes, elements, numbers, and the like) are present, and the term does not exclude the existence of other items (members, processes, elements, numbers, and the like), except when the context needs to be understood in clearly different ways.

In the specification and the scope of claims, unless otherwise specified explicitly and unless there is a contradiction in the contexts, it is intended that for each of nouns described in the present specification and the scope of the claims, one or more than one objects may be present.

Hereinafter, the present invention will be described in more detail using Examples, but it is not limited to the following examples.

A base agent was applied on a silicon substrate with a spin coater (<NUM> rpm, <NUM> seconds), and prebaked on a hot plate at <NUM> for <NUM> minute and <NUM> for <NUM> minutes to form a base film.

A photosensitive resin composition (refer to <CIT> and <CIT>) was applied on the base film with a spin coater (<NUM> rpm, <NUM> seconds), and prebaked on a hot plate for <NUM> minutes at <NUM>. Thereafter, pattern exposure (GHI rays, <NUM> mJ) was performed using a mirror projection mask aligner (type "MPA-600FA," manufactured by Canon), and heating was performed at <NUM> for <NUM> minutes with a hot plate after exposure. Thereafter, development treatment was performed for <NUM> seconds by an immersion method using propylene glycol monomethyl ether acetate (PGMEA). Subsequently, a resin pattern as the whole substrate after development was post-baked for <NUM> minute at <NUM> using an oven, and therefore a cylindrical connection hole resin pattern was obtained.

On the connection hole resin pattern obtained above, the photosensitive resin composition was applied with a spin coater (<NUM> rpm, <NUM> seconds), and prebaked on a hot plate for <NUM> minutes at <NUM>. Thereafter, pattern exposure (GHI rays, <NUM> mJ) was performed using a mirror projection mask aligner (type "MPA-600FA," manufactured by Canon), and heating was performed at <NUM> for <NUM> minutes with a hot plate after exposure. Thereafter, development treatment was performed for <NUM> minutes by an immersion method using PGMEA. Subsequently, a resin pattern of the whole substrate after development was post-baked for <NUM> minute at <NUM> using an oven, and therefore a recessed portion pattern was obtained. The recessed portion had a cylindrical shape with a diameter of <NUM>.

The first substrate on which the recessed portions obtained as above were patterned was immersed in a release agent to dissolve the above-mentioned base film, thereby peeling off the first substrate in which the recessed portion pattern was formed on the connection hole resin pattern from the silicon substrate.

The photosensitive resin composition was applied on a glass substrate with a spin coater (<NUM> rpm, <NUM> seconds), and prebaked on a hot plate for <NUM> minutes at <NUM>. Thereafter, pattern exposure (soft contact, GHI ray, <NUM> mJ) was performed using a parallel light exposure machine (manufactured by Hakuto Co. , model number MAT-<NUM>), and heating was performed at <NUM> for <NUM> minutes with a hot plate after exposure. Thereafter, development treatment was performed for <NUM> minutes by an immersion method using PGMEA. Subsequently, a resin pattern of the whole substrate after development was post-baked for <NUM> minute at <NUM> using an oven, and therefore a resin pattern was formed on the second substrate. A resin pattern defines the distance between the first substrate and the second substrate (hereinafter referred to as a "flow path height") in a case where the first substrate and the second substrate were bonded in a process to be described later. A resin pattern in which the distance between the first substrate and the second substrate was <NUM> was produced. In addition, in a case where a flow path height was high (for example, <NUM> or more), the above-described application process with a spin coater was repeatedly performed until the height became a target height.

An adhesive was applied to a top portion of the second substrate resin pattern obtained above, and prebaked at <NUM> for <NUM> minute. Thereafter, the first substrate obtained above was bonded to the second substrate such that a connection hole pattern was on the bottom. Exposure (soft contact, GHI ray, <NUM> mJ) was performed using a parallel light exposure machine (manufactured by Hakuto Co. , model number MAT-<NUM>), and heating was performed at <NUM> for <NUM> minutes and <NUM> for <NUM> minute with a hot plate after exposure. An adhesive was cured to bond the first substrate and the second substrate. Therefore, a particle capture device of Example <NUM> which has a shape shown in <FIG> was obtained.

The thickness of the first substrate was <NUM>, a pitch between recessed portions was <NUM>, and the diameter of cylindrical connection holes was <NUM>. The diameter of the recessed portions was <NUM>, and the distance between the first substrate and the second substrate was <NUM>. In addition, the size of the particle capture device was a length of <NUM> and a width of <NUM> in a plan view, which was a rectangular shape, and the thickness thereof was <NUM>.

In the particle capture device of Example <NUM>, an area of an outlet port was <NUM><NUM>. The area of an outlet port was the total cross-sectional area of the flow path <NUM> at two places of 11a and 11b shown in <FIG>. In addition, the total opening area of the connection holes was <NUM><NUM>. Accordingly, the area of the outlet port was about <NUM> times the total opening area of the connection holes.

Particle capture devices of Examples <NUM> to <NUM> and Comparative Examples <NUM> and <NUM> were produced in the same manner as in Example <NUM>, except that the shape of the device, the diameter of the recessed portions, the height of the flow path, the total opening areas of recessed portions and connection holes, and the area of the outlet port were changed as shown in Table <NUM>.

A particle capture device of which the device shape was a rectangle had a rectangular shape in which the length was <NUM> and a width was <NUM> in a plan view, and the thickness thereof was <NUM>. In addition, a particle capture device of which a device shape was a circular shape had a circular shape in which the outer diameter was <NUM>, and the thickness thereof was <NUM>.

Namalwa cells suspended in a culture medium were introduced into and captured in the particle capture devices of Examples <NUM> to <NUM> and Comparative Examples <NUM> and <NUM>. Namalwa cells were stained with Calcein-AM (manufactured by DOJINDO LABORATORIES) in advance. The number of Namalwa cells introduced into the particle capture device was equal to the number of recessed portions of each of the particle capture devices.

Subsequently, fluorescence microscope observation (object lens magnification of <NUM>×, model "BZ-<NUM>," KEYENCE CORPORATION) was performed on a center portion and an end portion of the particle capture device, and the number of captured cells in one field of view was measured. The measurement results of the particle capture devices of Examples <NUM> to <NUM> and Comparative Examples <NUM> and <NUM> are shown in Table <NUM>.

In Table <NUM>, an "area ratio" indicates a ratio of the area of the outlet port to the total opening area of the connection holes of the particle capture device. In addition, a "cell number ratio" indicates a ratio of the number of cells in the center portion to the number of cells in the end portion of the particle capture device in one field of view when observed with a fluorescence microscope. This value is identical to the ratio of a capturing rate of cells in the center portion to a capturing rate of cells in the end portion of the particle capture device.

Furthermore, <FIG> is a photograph which shows the results of performing fluorescence microscope observation on the center portion and the end portion of the particle capture device, after capturing Namalwa cells with the particle capture device of Comparative Example <NUM> as an example. As shown in <FIG>, in the particle capture device of Comparative Example <NUM>, a capturing rate of cells differed depending on the position of the particle capture device.

Claim 1:
A particle capture device (<NUM>) comprising:
a first substrate (<NUM>) being formed of a layer (10a) in which recessed portions (<NUM>) are patterned and a layer (10b) in which connection holes (<NUM>) are patterned, and having a structure in which a plurality of the recessed portions (<NUM>) are vertically and horizontally disposed at equal intervals; and
a second substrate (<NUM>) that is disposed parallel to and facing a first side (<NUM>) of the first substrate (<NUM>),
wherein the plurality of recessed portions (<NUM>) are open on the second side (<NUM>) of the first substrate (<NUM>) and have a size capable of capturing one particle (B),
the connection holes (<NUM>) connect the first side (<NUM>) to the second side (<NUM>) and have a size allowing a dispersion medium of the particles (B) to move therethrough,
a flow path (<NUM>) that has the connection holes (<NUM>) of the first substrate (<NUM>) as an inlet port of the dispersion medium and has an end portion of the first side (<NUM>) of the first substrate (<NUM>) as an outlet port of the dispersion medium is formed between the first substrate (<NUM>) and the second substrate (<NUM>),
a total opening area of all the connection holes (<NUM>) included in the particle device is <NUM><NUM> or more and less than <NUM><NUM>, and a cross-sectional area of the flow path (<NUM>) at the outlet port is <NUM> times or more the total opening area of the connection holes (<NUM>), or
a total opening area of all the connection holes (<NUM>) included in the particle device is <NUM><NUM> or more and <NUM><NUM> or less, and a cross-sectional area of the flow path (<NUM>) at the outlet port is <NUM> times or more the total opening area of the connection holes (<NUM>),
a diameter of the particle (B) is <NUM> to <NUM>,
an opening area of the connection hole (<NUM>) is the smallest cross-sectional area among cross-sectional areas of a surface, which is parallel to the first substrate, at any position of the connection holes (<NUM>) that connect the first side to the second side.