JP2021162548A - Fluid handling device - Google Patents

Abstract

To provide a fluid handling device which can generate a droplet more stably.SOLUTION: The fluid handling device includes: a sample flow path for flowing a sample; a dispersion medium flow path for flowing a dispersion medium; a dispersion liquid generation unit connected to the sample flow path and to the dispersion medium flow path, the dispersion liquid generation unit generating a dispersion liquid in which droplets of the sample obtained by breaking the sample by the dispersion medium are dispersed in the dispersion medium; and a dispersion liquid flow path connected to the dispersion liquid generation unit. The dispersion liquid generation unit has a protrusion.SELECTED DRAWING: Figure 5

Description

The present invention relates to a fluid handling device.

In clinical tests, food tests, environmental tests, etc., high-precision analysis of cells and trace amounts of objects to be analyzed such as proteins and nucleic acids may be required. As one of the methods for analyzing a small amount of an object to be analyzed, a method of generating minute droplets having a diameter of 0.1 to 1000 μm from a liquid containing the object to be analyzed and observing or analyzing the droplets is used. be.

The droplets can be generated by flowing a dispersion medium (for example, oil) so as to sandwich the flowing sample and dividing the flowing sample. For example, Patent Document 1 discloses a method of generating droplets by discharging a continuous phase flowing through a microchannel in a direction in which a dispersed phase intersects with each other.

International Publication No. 2002/068104

FIG. 1 shows how droplets are generated by an apparatus as shown in Patent Document 1. In FIG. 1, a sample flowing through the sample flow path 112 is divided by the dispersion medium flowing through the dispersion medium flow path 114 to generate droplets. Here, in a device for generating droplets (fluid handling device), it is generally required to stably generate droplets.

However, in an apparatus as shown in Patent Document 1, for example, as shown in FIG. 2, the dispersion medium flowing through the dispersion medium flow path 114 is flowed so as to be sandwiched between the samples flowing through the sample flow path 112. However, the sample may not be divided and the sample may flow as a laminar flow on the wall surface of the flow path without forming droplets. In particular, when the viscosity of the sample is high, the sample often flows as a laminar flow on the wall surface in this way.

The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a fluid handling device capable of generating droplets more stably.

The present invention provides the following fluid handling devices.
A sample flow path for flowing a sample, a dispersion medium flow path for flowing a dispersion medium, and the sample flow path and the dispersion medium flow path are connected, and the sample is divided by the dispersion medium to divide the sample liquid. It has a dispersion liquid generation unit for generating a dispersion liquid in which droplets are dispersed in the dispersion medium, and a dispersion liquid flow path connected to the dispersion liquid generation unit, and the dispersion liquid generation unit has protrusions. , Liquid handling equipment.

According to the present invention, it is possible to provide a fluid handling device capable of generating droplets more stably.

FIG. 1 shows how droplets are generated in a conventional fluid handling device. FIG. 2 shows a state in which a sample becomes a laminar flow in a conventional fluid handling device and droplets are not generated. FIG. 3A is a plan view of the fluid handling device according to the embodiment of the present invention, and FIG. 3B is a cross-sectional view taken along the line BB shown in FIG. 3A. FIG. 4 is a bottom view of the substrate of the fluid handling device according to the embodiment of the present invention. FIG. 5 shows how droplets are generated in the fluid handling device according to the embodiment of the present invention. 6A to 6I are views showing an example of the shape of the protrusion.

Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings. Note that the dimensions or dimensional ratios shown in the drawings may differ from the actual dimensions or dimensional ratios for the sake of clarity.

(Fluid handling device)
A plan view of the fluid handling device 100 according to the embodiment of the present invention is shown in FIG. 3A, and a cross-sectional view taken along the line BB shown in FIG. 3A is shown in FIG. 3B. Further, a bottom view of the substrate 101 of the fluid handling device 100 is shown in FIG. 4, and an enlarged view of the dispersion liquid generation unit 115 is shown in FIG.

As shown in FIG. 3B, the fluid handling device 100 according to the embodiment of the present invention is one of the substrate 101 in which the groove and the through hole are formed and the substrate 101 so as to close the opening of the groove and the through hole. It is composed of a film 102 bonded to a surface. As shown in FIGS. 3A to 5, the fluid handling device 100 includes a sample introduction unit 111, a sample flow path 112, a dispersion medium introduction unit 113, a dispersion medium flow path 114, a dispersion liquid generation unit 115, and a dispersion liquid flow path 117. It has a dispersion liquid recovery unit 118. As will be described later, the dispersion liquid generation unit 115 has protrusions 116. The sample introduction unit 111, the dispersion medium introduction unit 113, and the dispersion liquid recovery unit 118 are arbitrary components. Hereinafter, each component will be described so as to follow the flow of the fluid.

The sample introduction unit 111 is an introduction port for introducing a sample into the fluid handling device 100. In the present embodiment, the sample introduction portion 111 is composed of a through hole formed in the substrate 101 and a film 102 that closes one opening of the through hole. The structure of the sample introduction unit 111 is not particularly limited as long as the sample can be introduced into the sample flow path 112. In the present embodiment, there are two sample introduction portions 111, which are bottomed recesses capable of receiving a sample. Further, the shape of the sample introduction portion 111 is not particularly limited. In the present embodiment, the shape of the sample introduction portion 111 is a cylindrical shape.

The sample flow path 112 is connected to the sample introduction unit 111 and is a flow path for flowing the sample introduced into the sample introduction unit 111. In the present embodiment, the sample flow path 112 is composed of a groove formed in the substrate 101 and a film 102 that closes the opening of the groove. The structure of the sample flow path 112 is not particularly limited as long as the sample can flow appropriately. In the present embodiment, there are two sample flow paths 112, which are flow paths extending in the longitudinal direction and the lateral direction of the fluid handling device 100. The upstream end of the sample flow path 112 is connected to the sample introduction unit 111, and the downstream end is connected to the dispersion liquid generation unit 115. Further, in the present embodiment, the two sample flow paths 112 are merged in the middle, and the merged sample flow paths 112 are connected to the dispersion liquid generation unit 115.

The shape of the cross section of the sample flow path 112 is not particularly limited, and may be any shape such as a semicircular shape, a rectangular shape, or a circular shape. The size of the cross section of the sample flow path 112 is also not particularly limited. In the present specification, the "cross section of the flow path" means a cross section in a direction orthogonal to the flow direction of the flow path.

In the above description, the case where the fluid handling device 100 has two sample introduction units 111 and two sample flow paths 112 has been described, but the number of sample introduction units 111 and sample flow paths 112 can be increased as long as the sample can flow. It is not particularly limited, and may be, for example, one for each.

The dispersion medium introduction unit 113 is an introduction port for introducing the dispersion medium (for example, oil) into the fluid handling device 100. In the present embodiment, the fluid handling device 100 is provided with two dispersion medium introduction portions 113, and each dispersion medium introduction portion 113 has a through hole formed in the substrate 101 and one opening of the through hole. It is composed of a film 102 that closes the surface. The structure of the dispersion medium introduction unit 113 is not particularly limited as long as the dispersion medium can be introduced into the dispersion medium flow path 114. In the present embodiment, the dispersion medium introduction unit 113 is a bottomed recess that can receive the dispersion medium. Further, the shape of the dispersion medium introducing portion 113 is not particularly limited. In the present embodiment, the shape of the dispersion medium introduction portion 113 is a cylindrical shape.

The dispersion medium flow path 114 is connected to the dispersion medium introduction unit 113, and is a flow path for flowing the dispersion medium (for example, oil) introduced into the dispersion medium introduction unit 113. In the present embodiment, the fluid handling device 100 is provided with two dispersion medium flow paths 114, and each dispersion medium flow path 114 is a film 102 that closes a groove formed in the substrate 101 and an opening of the groove. Consists of. In the present embodiment, the dispersion medium flow path 114 is a flow path extending in the lateral direction of the fluid handling device 100. The upstream end of one dispersion medium flow path 114 is connected to one dispersion medium introduction unit 113, and the downstream end is connected to the dispersion liquid generation unit 115. Further, the upstream end of the other dispersion medium flow path 114 is connected to the other dispersion medium introduction unit 113, and the downstream end is connected to the dispersion liquid generation unit 115.

The shape of the cross section of the dispersion medium flow path 114 is not particularly limited, and may be any shape such as a semicircular shape, a rectangular shape, or a circular shape. The size of the cross section of the dispersion medium flow path 114 is also not particularly limited.

In the above description, the case where the fluid handling device 100 has two dispersion medium introduction units 113 and two dispersion medium flow paths 114 has been described, but the number of the dispersion medium introduction units 113 and the dispersion medium flow paths 114 is based on the sample. There is no particular limitation as long as it can be divided, and for example, each may be one.

The dispersion liquid generation unit 115 is connected to the sample flow path 112 and the dispersion medium flow path 114, and divides the sample flowing through the sample flow path 112 by the dispersion medium flowing through the dispersion medium flow path 114 to generate droplets of the sample. A dispersion liquid dispersed in a dispersion medium is produced. The dispersion liquid generation unit 115 is configured by connecting the dispersion medium flow path 114 to the sample flow path 112. In the present embodiment, the dispersion medium flow paths 114 are connected from the left and right sides of the sample flow path 112, and the sample flowing through the sample flow path 112 is divided by the dispersion medium flowing from both the left and right sides, so that the sample can be sampled. Droplets are generated (see FIG. 5).

The size of the opening (downstream end of the sample flow path 112) of the sample flow path 112 in the dispersion liquid generation unit 115 affects the size of the droplet, and in general, the diameter of the droplet is the diameter of the sample flow path 112. It is substantially the same as the opening of the sample flow path 112. Therefore, the size (depth and width) of the opening of the sample flow path 112 is appropriately selected according to the desired diameter of the droplet.

The size of the opening (downstream end of the dispersion medium flow path 114) of the dispersion medium flow path 114 in the dispersion liquid generation unit 115 affects the size, number, production yield, and the like of the droplets. Therefore, the size (depth and width) of the opening of the dispersion medium flow path 114 is appropriately selected according to the type of sample and the like.

The dispersion liquid generation unit 115 has protrusions 116. The protrusion 116 allows the sample flowing through the sample flow path 112 to flow while being clinging to the surface of the protrusion 116. As a result, the protrusion 116 directs the flow of the sample, suppresses the sample from flowing so as to adhere to the wall of the dispersion liquid flow path 117, and stably generates droplets.

A part of the protrusion 116 may be arranged outside the dispersion liquid generation unit 115 (for example, inside the sample flow path 112), but at least a part of the protrusion 116 is arranged in the dispersion liquid generation unit 115. Further, it is preferable that the portion on the upstream side (sample flow path 112 side) of the protrusion 116 is at least at a position where the sample flowing through the sample flow path 112 comes into contact with the portion. When the sample comes into contact with the portion on the upstream side of the protrusion 116, the sample then flows so as to cling to the side surface of the protrusion 116, and the flow of the sample is directed. On the other hand, it is preferable that the end portion of the protrusion 116 on the downstream side (dispersion liquid flow path 117 side) is located inside the flow path width (or extension line of the flow path width) of the dispersion liquid flow path 117. Since the downstream end of the protrusion 116 is located within the flow path width of the dispersion liquid flow path 117, it is possible to prevent the sample from flowing so as to adhere to the wall of the dispersion liquid flow path 117.

The shape of the protrusion 116 is not particularly limited as long as the sample can flow so as to cling to the surface thereof and the flow of the sample can be directed. The protrusions 116 are preferably symmetrical when viewed in a plan view, for example, as shown in FIGS. 4 and 5. More specifically, the protrusion 116 is the center of the sample flow path 112 in the width direction at the connection portion between the sample flow path 112 and the dispersion liquid generation unit 115 (the opening of the sample flow path 112 in the dispersion liquid generation unit 115). For the line connecting the center of the dispersion liquid flow path 117 in the width direction at the connection portion between the dispersion liquid flow path 117 and the dispersion liquid generation unit 115 (the opening of the dispersion liquid flow path 117 in the dispersion liquid generation unit 115). It is preferably line symmetric. Further, it is preferable that the protrusion 116 includes a taber portion for facilitating the merging of the samples flowing to the left and right of the protrusion 116 on the downstream side. The “tapered portion” means a portion whose width becomes narrower from the upstream side (sample flow path 112 side) to the downstream side (dispersion liquid flow path 117 side). The tapered portion preferably has a tapered shape that narrows toward the center of the flow path width of the dispersion liquid flow path 117. By doing so, it is suppressed that the sample flows through the center of the flow path and the sample flows so as to adhere to the wall of the dispersion liquid flow path 117.

Further, the portion on the upstream side (sample flow path 112 side) of the protrusion 116 preferably has a large surface area to some extent in order to increase the amount of the sample clinging to the surface of the protrusion 116 and direct the flow of the sample. On the other hand, the portion on the downstream side (dispersion liquid flow path 117 side) of the protrusion 116 preferably has a tapered portion for merging the samples flowing around the protrusion 116. As a result, the downstream side of the protrusion 116 preferably has a relatively smaller surface area than the upstream side. Further, as a result, it is preferable that the protrusion 116 as a whole has a tapered shape that tapers from upstream to downstream when viewed in a plan view. Specifically, the protrusion 116 has a water droplet shape in a plan view as shown in FIGS. 4 and 5, for example. Other examples of the shape of the protrusion 116 when viewed in a plan view are shown in FIGS. 6A to 6I.

Further, it is preferable that there is no sudden change in angle between the upstream portion and the downstream portion of the protrusion 116 in order to facilitate the flow of the sample along the surface thereof. The space between the upstream portion and the downstream portion of the protrusion 116 is preferably, for example, a smooth curved surface or a flat surface. Further, the protrusion 116 is preferably elongated from the viewpoint of directing the flow of the sample. Specifically, the length in the direction in which the fluid flows (the length in the direction perpendicular to the flow path width) rather than the length in the direction of the flow path width (the length in the direction of the sample flow path width or the dispersion liquid flow path width). ) Is preferably longer.

Further, when the fluid handling device 100 is viewed in a plan view, at least a part of the protrusion 116 is in the connection portion between the sample flow path 112 and the dispersion liquid generation unit 115 (the opening of the sample flow path 112 in the dispersion liquid generation unit 115). The width of the dispersion liquid flow path 117 at the center in the width direction of the sample flow path 112 and the connection portion between the dispersion liquid flow path 117 and the dispersion liquid generation unit 115 (the opening of the dispersion liquid flow path 117 in the dispersion liquid generation unit 115). It is preferably located on a line connecting the center of the direction. Specifically, it is preferable that the axis of symmetry of the protrusion 116, which is axisymmetric when viewed in a plan view, is located on the above line. By doing so, the sample can flow in the center of the flow path, and the flow of the sample so as to adhere to the wall of the dispersion liquid flow path 117 can be suppressed.

The three-dimensional shape of the protrusion 116 is not particularly limited, and examples of the three-dimensional shape of the protrusion 116 include a pillar, a cone, and the like. That is, the horizontal cross section of the protrusion 116 may be the same or different from the bottom to the top of the protrusion.

The height of the protrusion 116 is not particularly limited. The height of the protrusion 116 may be, for example, the same as the height of the flow path when the dispersion liquid flow path 117 is viewed in cross section, or about 80% to 50% of the height of the flow path.

The protrusion 116 is preferably a structure that protrudes from the substrate 101 (bottom surface of the groove) from the viewpoint of ease of manufacture. Further, the protrusion 116 may be a structure protruding from the film 102 side.

The dispersion liquid flow path 117 is connected to the dispersion liquid generation unit 115, and is a flow path for flowing the dispersion liquid containing the droplets generated by the dispersion liquid generation unit 115. In the present embodiment, the dispersion liquid flow path 117 is composed of a groove formed in the substrate 101 and a film 102 that closes the opening of the groove. The structure of the dispersion liquid flow path 117 is not particularly limited as long as the droplets can flow appropriately. In the present embodiment, the dispersion liquid flow path 117 is a flow path that extends in the longitudinal direction of the fluid handling device 100 continuously with the sample flow path 112. The upstream end of the dispersion liquid flow path 117 is connected to the dispersion liquid generation unit 115, and the downstream end is connected to the dispersion liquid recovery unit 118.

The shape of the cross section of the dispersion liquid flow path 117 is not particularly limited, and may be any shape such as a semicircular shape, a rectangular shape, and a circular shape. The size (depth and width) of the cross section of the dispersion liquid flow path 117 is preferably equal to or larger than the size (depth and width) of the cross section of the sample flow path 112 so as not to hinder the movement of the droplets.

The dispersion liquid recovery unit 118 is connected to the dispersion liquid flow path 117 and is an outlet for recovering the dispersion liquid containing droplets. In the present embodiment, the dispersion liquid recovery unit 118 is composed of a through hole formed in the substrate 101 and a film 102 that closes one opening of the through hole. The structure of the dispersion liquid recovery unit 118 is not particularly limited as long as the dispersion liquid containing droplets can be recovered. In the present embodiment, the dispersion liquid recovery unit 118 is a bottomed recess capable of accommodating the dispersion liquid. Further, the shape of the dispersion liquid recovery unit 118 is not particularly limited. In the present embodiment, the shape of the dispersion liquid recovery unit 118 is a cylindrical shape. The size of the dispersion liquid recovery unit 118 may be appropriately set according to the amount of the dispersion liquid to be recovered.

(Fluid handling method)
Next, a method of generating and collecting droplets of a sample using the fluid handling device 100 according to the present embodiment (fluid handling method) will be described.

First, a sample is introduced into the sample introduction unit 111, and a dispersion medium (for example, oil) is introduced into the two dispersion medium introduction units 113.

The sample is, for example, a liquid to be sorted as a droplet, or a liquid containing an object to be sorted by encapsulating the sample in the droplet. Examples of samples include liquids containing cells, proteins, nucleic acids, etc. In addition, the sample may contain a dispersion solvent for dispersing the subject to be sorted such as the above-mentioned cells, proteins, nucleic acids and the like.

The dispersion medium is not particularly limited as long as it has low compatibility with the sample and can divide the sample flowing through the sample flow path 112 in the dispersion liquid generation unit 115.

The sample flows through the sample flow path 112 by being pressurized by the sample introduction section 111, and the dispersion medium flows through the dispersion medium flow path 114 by being pressurized by the dispersion medium introduction section 113. Alternatively, the sample and the dispersion medium may be taken into the sample flow path 112 and the dispersion medium flow path 114 by reducing the pressure in the dispersion liquid recovery unit 118.

As shown in FIG. 5, in the dispersion liquid generation unit 115, the sample flowing from the sample flow path 112 flows so as to cling to the protrusion 116. Then, the sample is divided by the dispersion medium flowing through the two dispersion medium flow paths 114. As a result, the sample becomes droplets surrounded by a dispersion medium, and a dispersion liquid in which the sample droplets are dispersed in the dispersion medium is generated.

The sample flows so as to cling to the protrusion 116 as described above. As a result, as shown in FIG. 2, it is suppressed that the sample adheres to the wall of the dispersion liquid flow path 117 and flows, and that droplets are not generated is suppressed.

(effect)
According to the fluid handling apparatus according to the present invention, droplets can be generated more stably. In particular, when the viscosity is high, the sample tends to flow so as to adhere to the wall of the dispersion liquid flow path 117. Therefore, the fluid handling device according to the present invention is particularly useful when the viscosity of the sample is high.

The fluid handling device and the fluid handling method of the present invention can be applied to, for example, clinical tests, food tests, environmental tests, and the like.

100 Fluid handling device 101 Substrate 102 Film 111 Sample introduction part 112 Sample flow path 113 Dispersion medium introduction part 114 Dispersion medium flow path 115 Dispersion liquid generation part 116 Protrusion 117 Dispersion liquid flow path 118 Dispersion liquid recovery part

Claims (5)

A sample flow path for flowing the sample and
A dispersion medium flow path for flowing the dispersion medium and
A dispersion liquid generation unit connected to the sample flow path and the dispersion medium flow path and for dividing the sample with the dispersion medium to generate a dispersion liquid in which droplets of the sample are dispersed in the dispersion medium.
The dispersion liquid flow path connected to the dispersion liquid generation unit and
Have,
The dispersion liquid generating portion has protrusions.
Fluid handling device. When the fluid handling device is viewed in a plan view, at least a part of the protrusions includes the center in the width direction of the sample flow path at the connection portion between the sample flow path and the dispersion liquid generation part, and the dispersion liquid flow path. The fluid handling device according to claim 1, which is located on a line connecting the center of the dispersion liquid flow path in the width direction at the connection portion with the dispersion liquid generation unit. The fluid handling device according to claim 2, wherein the protrusions are line-symmetric with respect to the line. The fluid handling apparatus according to any one of claims 1 to 3, wherein the protrusion includes a tapered portion whose width becomes narrower from the sample flow path side toward the dispersion liquid flow path side. The fluid handling device according to any one of claims 1 to 4, wherein the protrusion is a pillar or a cone.

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