Two-liquid confluence type dilution device in a microchannel and dilution channel device using the same

Abstract

A two-liquid confluence type dilution device is provided in which two liquids can start flowing in simultaneously during mixing, and one liquid does not invade the other liquid flow path, and a dilution flow path device using the same is also provided. [Solution] The two-liquid confluence dilution device comprises a target fluid supply channel 1, a diluent fluid supply channel 2, and a mixing channel 3. The diluent fluid supply channel has a first narrowed section 21 at its downstream end, the target fluid supply channel has a second narrowed section 11 at its downstream end, and the mixing channel 3 has an expanded section 31 at its base end. The diluent fluid supply channel and the mixing channel are continuously provided, forming a boundary via the first narrowed section and the expanded section, and the target fluid supply channel is continuously provided via the second narrowed section to a confluence section set downstream of the boundary between the first narrowed section and the expanded section of the mixing channel. The dilution channel device is installed at the confluence point of channels connected in cascade or in parallel.

Description

[Technical Field]

[0001] The present invention relates to a two-liquid mixing dilution apparatus that dilutes a target fluid with a dilution fluid by mixing two types of fluid in a microchannel, and a dilution channel device that uses this dilution apparatus. [Background technology]

[0002] When testing specimen samples or reagents, it is often necessary to adjust the concentration to an appropriate level, and concentration adjustment is a common practice in fields such as medicine, new drug development, environmental monitoring, etc. In such cases, high-concentration samples are diluted to an appropriate concentration, but as this generally involves human intervention, there is an inherent risk of human error.

[0003] Therefore, we developed a method to measure the concentration of 10 ... n A microfluidic device that enables multi-fold serial dilution has been proposed (see Non-Patent Document 1). A method for designing a flow channel that can achieve various dilution ratios (linear, binary logarithm, common logarithm, etc.) has also been proposed (see Non-Patent Document 2). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] A serial dilution microfluidic device using a ladder network generating logarithmic or linear concentrations, Lab on a Chip, 2008, 8(3), 473-479. [Non-patent document 2] Generalized serial dilution module for monotonic and arbitrary microfluidic gradient generators, Lab on a Chip. 2009, 9(5), 709-717. Summary of the Invention [Problem to be solved by the invention]

[0005] According to the above-mentioned technology, when two liquids join together, the timing of their inflow differs, and the liquid flowing down one flow path is supplied to the mixing flow path first, and it takes several tens of minutes for the mixing ratio (dilution ratio) to reach the expected state. Furthermore, because the two liquids to be mixed are joined at a predetermined flow rate ratio, the flow rate ratios of the two liquids differ greatly, and the liquid with a higher flow rate may enter the other flow path with a lower flow rate, causing a backflow within this flow path.

[0006] However, the samples and reagents used for dilution are valuable, and continuing the flow until the mixing ratio (dilution ratio) stabilizes or the backflow normalizes results in the waste of reagents, preventing the effective use of valuable reagents.

[0007] The present invention has been made in consideration of the above points, and its purpose is to provide a two-liquid confluence type dilution device in which two liquids can start flowing in simultaneously during mixing, without one liquid entering the other's flow path, and to provide a dilution flow path device that uses this. [Means for solving the problem]

[0008] Therefore, the first invention relating to a two-liquid confluence type dilution device is configured by a micro-channel, and includes a target fluid supply channel for supplying a target fluid to be diluted, a diluent fluid supply channel for supplying a diluent fluid for diluting the target fluid, and a mixing channel for sending a mixed fluid of the target fluid and the diluent fluid, the target fluid supply channel and the diluent fluid supply channel being continuous to a base end of the mixing channel, and the target fluid and the diluent fluid being confluenced to mix and dilute two liquids, The flow path has a first constriction section where the flow path is narrowed at the downstream end, the target fluid supply flow path has a second constriction section where the flow path is narrowed at the downstream end, the mixing flow path has an expansion section where the flow path is expanded at the base end, the dilution fluid supply flow path and the mixing flow path are provided continuously, forming a boundary section via the first constriction section and the expansion section, and the target fluid supply flow path is provided continuously via the second constriction section to a confluence section that is set downstream of the boundary section between the first constriction section and the expansion section of the mixing flow path.

[0009] According to the above configuration, the dilution fluid supply channel is continuous with the mixing channel, but has a first narrowed section just before the boundary with the mixing channel, so that the flow rate of the dilution fluid flowing down the dilution fluid supply section can be changed to maintain the flow rate. Similarly, the target fluid supply channel has a second narrowed section just before the junction to which it is to be connected, so that the flow rate can be adjusted. In this case, by adjusting the flow rate of the dilution fluid flowing down the boundary section and the flow rate of the target fluid flowing down the junction so that they are equal (1:1 ratio), it is possible to prevent the intrusion (backflow) of one fluid into the other channel.

[0010] Furthermore, both the dilution fluid supply flow path and the target fluid supply flow path are connected to the mixing flow path via a narrowed section, and the cross-sectional area of ​​the flow path at their ends (boundary or confluence) is expanded at the expansion section of the mixing flow path. As a result, the dilution fluid and target fluid that reach the end (boundary or confluence) are temporarily stopped from flowing downward due to surface tension, and mixing begins when both fluids remain at the boundary or confluence and then break.

[0011] The term "fluid" generally refers to a liquid fluid, but it may be a single liquid or a mixture of multiple liquids, or a suspension containing fine particles. The present invention is based on a flow channel structure in a microchannel, and this "microchannel" generally refers to a channel having a size of 0.005 to 2.0 mm. 2 The microfluidic flow path has a cross-sectional area of ​​about 100 microliters, and is a flow path for transporting microfluids (very small liquid fluids of about 1 to 500 microliters), and the surface tension of the microfluid, viscous resistance with the inner wall surface of the flow path, and other factors cause the microfluid to behave differently from the transport of general liquids. Furthermore, the "temporary halt" of flow at the tip of the constriction (boundary or confluence) refers to a state in which the surface tension acts on the liquid surface at the opening when flowing from the small cross-sectional flow path to the large cross-sectional flow path, and the liquid cannot flow down when the surface tension is greater than the pressure within the fluid, and the liquid can flow down when the surface tension is reduced under certain conditions.

[0012] The second invention of the present invention, which relates to a two-liquid confluence type dilution device, is the first invention described above, wherein the flow path cross-sectional area of ​​the dilution fluid supply flow path and the flow path cross-sectional area of ​​the target fluid supply section are different in size, and the ratio of the flow path cross-sectional areas is adjusted to match the ratio of the flow rate at which the dilution fluid is to be supplied to the flow rate at which the target fluid is to be supplied.

[0013] According to the above configuration, by configuring the cross-sectional areas of the dilution fluid supply channel and the target fluid supply channel to a predetermined ratio, a flow rate corresponding to a desired dilution ratio (mixing ratio) can be supplied to the mixing channel. For example, if the ratio of the cross-sectional area of ​​the dilution fluid supply channel to the cross-sectional area of ​​the target fluid supply channel is set to 9:1, the flow rate ratio of the two fluids supplied will also be 9:1. Furthermore, if the contraction rates toward the ends of both constrictions (first and second constrictions) are set to be approximately the same, the ratio of the opening sizes of both channels (both constrictions) at the boundary and junction will also be 9:1. If the flow velocities are the same (1:1 ratio) as described above, the flow rate ratio of the dilution fluid to the target fluid will also be 9:1, resulting in a dilution ratio of 10.

[0014] The third aspect of the present invention, which relates to a two-liquid confluence type dilution device, is the second aspect of the present invention, wherein the cross-sectional area of ​​the target fluid supply flow path is smaller than the cross-sectional area of ​​the dilution fluid supply flow path, and the target fluid supply flow path has approximately the same flow path width as the dilution fluid supply flow path, but is configured to have a flow path height lower than that of the dilution fluid supply flow path.

[0015] According to the above configuration, the target fluid supply channel and the diluent fluid supply channel have the same channel width, so the ratio of the channel cross-sectional areas of the two channels is the same as the ratio of their channel heights. Therefore, when fluids are introduced into both channels at the same pressure, the flow rates are equal (1:1 ratio), and the flow rate ratio of the supplied fluids can be determined by the channel cross-sectional area ratio (channel height ratio). Therefore, if the channel ratio between the two channels is 9:1 (dilution ratio: 10), the channel height of the target fluid supply channel should be 1 / 9 of the channel height of the diluent fluid supply channel, and can be designed appropriately depending on the dilution ratio.

[0016] The fourth aspect of the present invention, which relates to a two-liquid confluence type dilution device, is the third aspect of the present invention, wherein the first narrowing section and the second narrowing section are both configured by narrowing the flow path width while keeping the flow path height constant.

[0017] According to the above configuration, the state of narrowing in both narrowed sections can be adjusted simply by changing the flow path width, and by keeping the width dimensions of both narrowed sections the same, the ratio of the flow path cross-sectional area at the tip can also be adjusted simply by the ratio of the flow path heights.

[0018] The fifth aspect of the present invention, which relates to a two-liquid confluence type dilution device, is the fourth aspect of the present invention, wherein the channel height of the target fluid supply channel is 1 / 9 of the channel height of the dilution fluid supply channel. In this configuration, the flow rate ratio of the dilution fluid to the target fluid is 9:1, and the target fluid contained in the mixed solution after mixing is 1 / 10. Therefore, when multi-stage dilution is performed using the same type of dilution device, the logarithmic dilution ratio (10 n In other words, it is possible to obtain a dilution device that can achieve a standard logarithmic dilution ratio.

[0019] On the other hand, the first invention relating to a dilution flow path device uses the above-mentioned first to fourth inventions relating to a two-liquid confluence type dilution apparatus, and is characterized in that the target fluid supply flow path has a target fluid inlet, the dilution fluid supply flow path has a dilution fluid inlet, the flow path structure of the target fluid supply flow path from the target fluid inlet to the confluence is adjusted to a shape that generates a desired flow path resistance in the target fluid supply flow path, and the flow path structure of the dilution flow path side flow path from the dilution fluid inlet to the boundary is adjusted to a shape that generates a desired flow path resistance in the dilution fluid supply flow path, and the flow rate ratio of the target fluid and dilution fluid supplied to the mixing flow path is adjusted by the flow path provided by the respective flow path structures of the target fluid supply flow path and the dilution fluid supply flow path.

[0020] According to the above configuration, each fluid experiences flow resistance as it flows down each flow path until the two fluids merge at the junction or boundary. Therefore, adjusting the shape of the flow path structure to adjust the magnitude of the flow path resistance allows the desired flow rate to be supplied to the mixing flow path. Therefore, in addition to adjusting the mixing ratio (dilution ratio) by adjusting the ratio of the flow path cross-sectional area of ​​the target fluid supply flow path to the flow path cross-sectional area of ​​the dilution fluid supply flow path, the mixing ratio (dilution ratio) can also be adjusted by adjusting the ratio of the supply amounts (flow rates at the time of merging) due to the flow path resistance. The flow path structure for adjusting the flow path resistance is specified by the cross-sectional shape and longitudinal shape (flow path length) of the flow path, and is adjusted by either the flow path cross-sectional area or the flow path length, or both. Therefore, by appropriately configuring the flow path structure according to the introduction pressure when introducing the fluids into each flow path, mixing (dilution) at a suitable flow rate ratio can be achieved. For example, when the target fluid and diluent fluid are introduced from the target fluid inlet and diluent fluid inlet, respectively, at the same pressure, if the flow path structure is such that the target fluid supply flow path and the diluent fluid supply flow path have the same flow path length, the flow rate ratio corresponds to the ratio of the flow path cross-sectional areas of the two flow paths, and the mixing ratio (dilution ratio) coincides with this flow rate ratio.On the other hand, if the flow path structure is such that both fluids are introduced at the same pressure but the flow path length as well as the flow path cross-sectional area are different by a predetermined ratio, the flow path resistance acts according to the ratio of the flow path lengths, and the mixing ratio (dilution ratio) can be further changed.

[0021] A second aspect of the present invention, relating to a dilution flow path device, is the first aspect of the present invention, wherein the mixing flow path is a cascade of multiple branched dilution fluid supply flow paths, and the branched flow paths branched from the upstream mixing flow path serve as target fluid supply flow paths, supplying the dilution fluid supply flow path with the diluted fluid of the preceding order, thereby enabling multi-stage dilution in which the degree of dilution increases sequentially. When configuring this type of flow path system, the introduction pressure to each flow path can be considered as "voltage," the magnitude of flow path resistance as "resistance value," and the flow rate as "current," and the system can be designed equivalently to an electrical circuit. When the dilution fluid supply flow paths are connected in a cascade, stable mixing (dilution) can be achieved by adjusting the flow rate of the flowing fluid, as in a constant current circuit.

[0022] According to the above configuration, the target fluid and the diluent fluid are mixed at a predetermined ratio in the most upstream portion, and the diluted fluid is treated as the next-order target fluid and further mixed with the diluent fluid. By repeating this process several times, multiple mixed fluids with graded dilution ratios can be obtained. In this case, to maintain a constant dilution ratio (dilution factor), the diluted mixed fluid is branched from the upstream side, with one branch used as the diluted treatment fluid and the other branch used as the next-order target fluid. To use the mixed fluid as the next-order target fluid, the configurations of the next-order target fluid supply flow path and the diluent fluid supply flow path are configured in the same way as for the first-order target fluid.

[0023] A third invention relating to a dilution flow path device is the first invention described above, wherein the target fluid supply flow path is branched into multiple flow paths near the target fluid inlet, and the dilution fluid supply flow path is branched into multiple flow paths near the dilution fluid inlet, and the branched target fluid supply flow path and dilution fluid supply flow path each have a different flow path structure, which generates different flow path resistances, thereby adjusting the flow rate, and the flow rates of the target fluid supply flow path and the dilution fluid supply flow path are mixed individually while gradually adjusting the ratio of the flow rate on the target fluid supply flow path side to the flow rate on the dilution fluid supply flow path side, thereby enabling multi-stage dilution.

[0024] According to the above configuration, the basic dilution ratio (dilution factor) is determined by the ratio of the cross-sectional areas of the target fluid supply flow path and the dilution fluid supply flow path, but by adjusting the flow rate of the liquid supplied to the base end (boundary with the dilution fluid supply section) of the mixing flow path where the two fluids are mixed by the effect of flow path resistance caused by changes in the flow path structure, and by arbitrarily adjusting the flow rate ratio of the two fluids to be mixed, it is possible to set the desired mixing ratio (dilution ratio).

[0025] A fourth invention relating to a dilution flow path device is the third invention described above, in which the branched target fluid supply flow path and the dilution fluid supply flow path are arranged in parallel for each stage, and the flow rate of the target fluid supply flow path and the dilution fluid supply flow path at each stage arranged in parallel is adjusted in stages by the flow path structure, provided that the introduction pressure of the target fluid introduced from the target fluid inlet portion is maintained constant and the introduction pressure of the dilution fluid introduced from the dilution fluid inlet portion is maintained constant.

[0026] According to the above configuration, since the flow path system is arranged in parallel for each stage, when the configured flow path system is designed equivalent to an electric circuit, it can be regarded as a parallel circuit, and therefore, like a constant voltage circuit, the flow rate can be adjusted by appropriately adjusting the magnitude of the flow path resistance (resistance value) while keeping the inlet pressure (voltage) constant. Since the flow rate can be adjusted by changing the flow path resistance while keeping the inlet pressure constant, the flow path design can be made extremely easy. [Effects of the Invention]

[0027] According to the present invention relating to the two-liquid confluence dilution device, the dilution fluid supply flow path and the target fluid supply flow path are both connected to the mixing flow path via a constriction, so that the flow downwards are temporarily stopped at their ends (tips), and the fluids can be supplied from both paths simultaneously. In particular, when the cross-sectional areas of the two paths are different, the tip of the constriction on the side with the flow path with the larger cross-sectional area will break relatively more easily than the tip of the constriction on the side with the smaller cross-sectional area. Therefore, when the fluid supplied from the flow path with the larger cross-sectional area starts to flow downwards, contact with the liquid at the tip of the other constriction area will cancel out the surface tension of the other fluid, simultaneously inducing the other fluid to flow downwards, allowing them to start flowing simultaneously.

[0028] Furthermore, by providing these narrowed sections, it is possible to adjust the flow rates of the two fluids as they flow downward. Therefore, by setting the flow rates when supplying the mixed fluid to the same rate (1:1 ratio), it is possible to prevent one fluid from entering the other flow path (backflow).

[0029] On the other hand, according to the present invention relating to the dilution flow path device, a dilution device capable of mixing two liquids at a desired mixing ratio (dilution rate) is used, which makes it easy to design a dilution flow path device. In this case, mixed fluids with multiple dilution rates can be obtained by either connecting dilution fluid supply flow paths in a cascade configuration to the mixing flow path, or by adjusting the flow rate using flow path resistance (connecting them in parallel). [Brief explanation of the drawings]

[0030] [Figure 1] FIG. 2 is an explanatory diagram showing an example (first embodiment) of a dilution flow path device. [Figure 2] FIG. 1 is an explanatory diagram showing an embodiment of a two-liquid confluence type dilution device. [Figure 3] FIG. 10 is an explanatory diagram showing the structure of the periphery of a boundary portion centered on a buffer supply channel and a mixing channel. [Figure 4] FIG. 10 is an explanatory diagram showing a confluence state of a sample and a buffer. [Figure 5] FIG. 10 is an explanatory diagram showing the state of the connection position of the sample supply flow channel. [Figure 6] FIG. 10 is an explanatory diagram showing an experimental dilution flow path device. [Figure 7] FIG. 10 is an explanatory diagram showing a second embodiment of the dilution flow path device. DETAILED DESCRIPTION OF THE INVENTION

[0031] Hereinafter, an embodiment of the present invention will be described with reference to the drawings. For convenience of explanation, first, an outline of the dilution flow path device will be described, then a two-liquid confluent dilution apparatus used for dilution will be described, and then the dilution flow path device will be described in detail.

[0032] <Outline of the dilution flow path device> An example of a dilution flow path device is shown in Figure 1. The dilution flow path device shown in Figure 1 is a multi-stage dilution flow path device connected in a cascade. This dilution flow path device mixes a fluid to be diluted (for example, a specimen sample or a solution in which a reagent or the like is dissolved in a solvent; hereinafter, this may be abbreviated as "sample") with a dilution fluid (for example, pure water or a solvent; hereinafter, this may be abbreviated as "buffer"), and dilutes the sample with the buffer at a predetermined ratio.

[0033] The dilution channel device is basically configured with a sample supply channel (target fluid supply channel) 1 for supplying a sample, a buffer supply channel (dilution fluid supply channel) 2 for supplying a buffer, and a mixing channel 3 through which these mixed fluids flow. A sample introduction section (target fluid introduction section) 10 is provided in the sample supply channel 1, and a buffer introduction section (dilution fluid introduction section) 20 is provided in the buffer supply channel 2, at the base end of each channel 1, 2, and can be introduced into each channel 1, 2 at the same predetermined introduction pressure (for example, 3.5 kPa, 7.0 kPa, or 10.0 kPa for both). Each channel 1, 2 is branched as needed, and is configured to supply the sample or buffer to a predetermined channel.

[0034] The buffer supply channel 2 is cascade-connected to the mixing channel 3, allowing the sample to be diluted in multiple stages. That is, the fluid diluted at each level is sent to the reaction vessel 4 via the individual mixing channels 3a, 3b, 3c, and 3d, allowing the reaction at each dilution ratio to be confirmed, and the branch channels branching from each of the mixing channels 3a to 3d can be used for the next level of dilution. The branch channels in this case are considered to be sample supply channels (target fluid supply channels) in the first level, and by mixing (diluting) the sample with a buffer, a mixed fluid with a high dilution ratio can be obtained.

[0035] The mixing sections j1, j2, j3, and j4 for mixing the two liquids, sample and buffer, use a two-liquid confluence dilution device described below, and are configured to mix the sample and buffer in a predetermined ratio (for example, sample:buffer = 1:9).

[0036] A discharge unit 5 is connected downstream of the reaction vessel (chamber) 4, and fluid is supplied to each flow path. Air within the flow path is discharged during the fluid transfer, and excess fluid is discharged after the fluid has passed through the reaction vessel (chamber) 4. The serpentine flow paths 6 formed in the middle of each flow path are intended to synchronize the timing at which fluid transfer is completed throughout the entire flow path (reaching the discharge unit 5). The upstream serpentine flow path 6a, formed upstream of the aforementioned mixing units j1-j4, is provided to adjust the flow path resistance to the mixing units j1-j4. The flow path resistance, which acts according to the flow path length, adjusts the flow rates of the sample and buffer supplied to (mixed with) the mixing units j1-j4. The downstream serpentine flow path 6b, formed downstream of the mixing units j1-j4, is provided to adjust the timing at which the fluid reaches the discharge unit 5.

[0037] <Embodiment of Two-liquid Converging Dilution Device> Next, an embodiment of the invention relating to a two-liquid confluence type dilution device will be described. This embodiment corresponds to the portions shown as mixing sections j1 to j4 of the above-mentioned flow path device, and illustrates a partially enlarged view of mixing sections j1 and j2 in FIG. 1. Note that FIG. 1 illustrates an enlarged view of only mixing sections j1 and j2, but the remaining mixing sections j3 and j4 have the same configuration as the illustrated mixing section j2. The only difference between one mixing section j1 ​​and the other mixing section j2 is whether the buffer supply channel (dilution fluid supply channel) 2 merges from a direction facing the sample supply channel (target fluid supply channel) 1 (j1) or from an angled direction (j2), and the basic configurations are the same.

[0038] In this embodiment, as shown in the figure, the buffer supply channel 2 is connected to the mixing channel 3 via a narrowed section 21, and the sample supply channel 1 is connected to the boundary between the two via a narrowed section 11. Since the boundary is narrowed on the mixing channel 3 side, a widened section (expansion section) 31 is provided on the upstream side to widen the channel width and gradually increase the cross-sectional area of ​​the channel. The narrowed sections 11 and 21 and each widened section 31 are configured by widening or reducing only the channel width.

[0039] Fig. 2 shows the details of the two types of embodiments (hereinafter, for convenience, they may be referred to as "mixing sections") j1 and j2. Fig. 2(a) shows the mixing section j1 ​​of one embodiment, and Fig. 2(b) shows the mixing section j2 of the other embodiment, but because they have the same basic configuration, the same reference numerals will be used and both will be described together.

[0040] As shown in these figures, the sample supply channel 1, buffer supply channel 2, and mixing channel 3 have the same channel widths W1, W2, and W3, but the channel heights D1, D2, and D3 are the same for the buffer supply channel 2 and mixing channel 3, with only the channel height D1 of the sample supply channel 1 being lower. Therefore, the basic channel cross-sectional area (without considering the narrowed section) is the same for the buffer supply channel 2 and the mixing channel 3, so that in terms of the channel configuration, the buffer supplied to the buffer supply channel 2 flows down into the mixing channel 3 via the narrowed section 21 and the widened section 31.

[0041] A boundary portion P is formed at the point where the two flow paths 2, 3 are connected. The narrowed portion 21 is formed in the buffer supply flow path 2, and the wide portions 31 are provided in the mixing flow path 3. Therefore, the flow path width Wp at the boundary portion P is the portion where the flow path cross-sectional area is smallest along the path through which the buffer flows. The buffer supply flow path 2 thus forms the narrowed portion 21 with the boundary portion P as its leading end (most downstream end), making it possible to set the flow rate of the buffer as it passes through the boundary portion P. The narrowed portion 21 is provided to gradually narrow the flow path width in order to guide the buffer toward the boundary portion P. However, when buffer is flowed at the same flow rate, the flow rate varies depending on the size of the flow path cross-sectional area at the leading end (boundary portion P). Therefore, the flow rate can be adjusted to a desired value by adjusting the flow path cross-sectional area at the leading end (boundary portion P) (which ultimately becomes the flow path width Wp).

[0042] On the other hand, the width of the sample supply flow channel 1 is also reduced to form a narrowed section 11. The tip (most downstream end) of this narrowed section 11 is connected while opening at the boundary P, so that the sample can be mixed with the buffer. When the flow rate of the sample supplied to the sample supply flow channel 1 is kept constant, the narrowed section 11 in the sample supply flow channel 1 also makes it possible to adjust the flow rate when the sample flows from the tip (most downstream end) of the narrowed section 11 into the mixing flow channel 3.

[0043] Therefore, when the cross-sectional areas of the non-narrowed flow channels 1 and 2 are set to a predetermined ratio (e.g., a ratio of 1:9) and the same pressure is applied to supply the fluids, the expected ratio (e.g., a ratio of 1:9 in the above case) is supplied to both flow channels 1 and 2, and when attempting to mix them at that ratio (e.g., a ratio of 1:9 in the above case), the flow channel widths at the tips of the narrowed portions 11 and 21 are made the same, so that the sample and buffer can flow into the mixing flow channel 3 at the same flow rate. In this way, by having the two types of liquids flow into the mixing flow channel 3 at the same flow rate, it is possible to prevent one fluid from entering the other flow channel (backflow). Furthermore, as will be described later, the two liquids can be simultaneously flowed down the mixing channel 3, which makes it possible to eliminate the intrusion of air remaining in the flow channels.

[0044] Here, we will further explain the structure around the boundary P. Figure 3 is a diagram showing the structure around the boundary P, centered on the buffer supply channel 2 and the mixing channel 3 connected to it. Note that Figure 3(b) shows the cross section taken along line IIIB-IIIB in Figure 3(a).

[0045] 3(a), the buffer supply channel 2 is connected to the widened section 31 of the mixing channel 3 via a narrowed section 21 formed by narrowing the channel width near the downstream end, and the flow region at the boundary line Pa between the two channels is the boundary section P, where the channel cross-sectional area (channel width Wp) is the smallest. Basically, the supply amount (flow rate) of the buffer is set to be larger than the supply amount (flow rate) of the sample, so as described above, the buffer supply channel 2 and the mixing channel 3 can be considered to form the main channel.

[0046] The sample supply channel 1 is connected to the main channel as described above at a tip (junction) Q having a small cross-sectional opening, and this tip Q is connected so as to open downstream (toward the mixing channel) of the boundary line Pa between the buffer supply channel 2 and the mixing channel 3. To open downstream of the boundary line Pa, at least the side wall 11A on the sample supply channel 1 side of the side walls 11A and 11B constituting the narrowed section 11 is not positioned beyond the boundary line Pa toward the buffer supply channel 2, and the other wall surface 11B is sufficiently spaced from the boundary line Pa toward the mixing channel 3 so that the opening of the tip (junction) Q is maintained. The reason for this connection position will be described later; by connecting the tip Q of the sample supply channel 1 while opening toward the mixing channel 3, the sample can be mixed with the buffer at a predetermined ratio while flowing down the mixing channel 3.

[0047] Furthermore, as shown in FIG. 3(b), the tip (junction) Q of the sample supply channel 1 (narrowed section 11), which serves as a small-cross-section opening, has a channel width Wq equivalent to the channel width Wp of the buffer supply section 2 (narrowed section 21), and a channel height D1 lower than the buffer-side channel height D2, resulting in a small overall channel cross-sectional area. The illustrated state shows a state in which the ratio of the sample-side channel height D1 to the buffer-side channel height D2 is 1:9. Therefore, the channel cross-sectional area ratio is also 1:9. In this case, since the two liquids are supplied at the same flow rate, the flow rate ratio is 1:9. Since the sample accounts for 10% of the 100% liquid after mixing, a mixed fluid with a 10x dilution ratio can be obtained.

[0048] Furthermore, the narrowed portions 11 and 21 of the sample supply channel 1 and the buffer supply channel 2 reduce the cross-sectional area of ​​their tip portions (boundary portion P, confluence portion Q), and so resistance (resistance due to surface tension) is encountered when they are opened at the widened portion 31 of the mixing channel 3, causing the initial outflow to stop (temporarily stop) at each tip portion (boundary portion P, confluence portion Q). In the state where the flow is temporarily stopped, the two fluids come into contact with each other, which eliminates the effect of surface tension, and the fluids simultaneously flow out from the tip portions (boundary portion P, confluence portion Q) into the mixing channel 3.

[0049] 4(a), the sample Sm supplied from the sample supply channel 1 is temporarily stopped from flowing downward at its tip (junction) Q. At this time, the internal pressure (introduction pressure) acts on the sample Sm in the outflow direction, and surface tension also acts on the sample Sm, causing the liquid surface of the sample Sm to bulge slightly at the tip Q. At this time, if the buffer Bf supplied from the buffer supply channel 2 has not yet reached the tip (boundary) P, the sample Sm will maintain its stopped state of flowing downward at the tip Q.

[0050] When the leading edge of the buffer Bf reaches the tip (boundary) P, as shown in Figure 4(b), the buffer Gf also temporarily stops flowing at tip P due to the action of surface tension, causing the liquid surface to bulge slightly. As the two fluids Sm and Bf bulge at their respective tips P and Q, they come into contact with each other. This contact eliminates the action of surface tension, and the temporary flow stop is released (the dammed state changes to a state of breaching), causing the two fluids to start flowing simultaneously. Therefore, even if the timing of the flow of the two fluids Sm and Bf differs (the sample Sm arrives first as shown in Figure 4(a)), the difference in arrival time between the fluids Sm and Bf can be adjusted because they are temporarily stopped at the tip of the flow channel (boundary P, confluence Q). Naturally, when both fluids Sm and Bf reach the tips P and Q at the same time, they come into contact almost simultaneously after the liquid surface bulges due to surface tension, so the temporary cessation of flow is extremely short.

[0051] The temporary halt of flow due to surface tension is more pronounced at the tip (junction) Q of the sample supply flow channel 1 due to the small cross-sectional area of ​​the flow channel (where surface tension acts strongly), and therefore the halt of flow is more reliable than at the tip (boundary) P of the buffer supply flow channel 2. Therefore, adjustment may be made so that the sample Sm reaches the tip (junction) Q before the buffer Bf.

[0052] In this way, the sample supply channel 1 is filled with the sample Sm all the way up to the tip Q, and the buffer supply channel 2 is filled with the buffer Bf, so when the flow into the mixing channel 3 begins, it is possible to prevent internal air from entering the channels 1 and 2. Furthermore, by making the flow rates of the channels 1 and 2 flowing from the tips P and Q into the mixing channel 3 the same, it is possible to prevent one liquid from entering the other channel (backflow).

[0053] Since the configuration of this embodiment is as described above, the two-fluid confluence dilution device configured as described above allows the two fluids to be mixed in a diluted state according to a preset dilution ratio by adjusting the flow rate ratio based on the ratio of the cross-sectional areas of the flow paths. At this time, the flow of one fluid is temporarily stopped at the downstream end, and when the other fluid reaches the downstream end (tip), both fluids are allowed to flow, so the timing of mixing can be synchronized.

[0054] Unlike the above configuration, for example, as shown in Figure 5(a), if the tip (junction) Q of the sample supply flow path 1 is connected upstream (beyond the boundary line Pa to the buffer side) of the tip (boundary) P of the buffer supply flow path 2, even if the sample Sm is supplied to the sample supply flow path 1 first and the flow can be temporarily stopped at the tip Q, the buffer Bf will come into contact with the sample Sm at the simple flow-down stage, and the sample Sm will start to flow down before the internal pressure (introduction pressure) fully acts on the head part of the buffer Bf, and the pressure difference between the two may cause the sample Sm to enter the buffer supply flow path 2 (the buffer Bf will flow back).

[0055] Furthermore, as shown in Figure 5(b), if the cross-sectional area of ​​the confluence Q at the downstream end of the sample supply flow path 1 is made the same size as that of the buffer supply flow path 2, the flow rate must be changed to adjust the flow rate ratio, and if the flow rate of the sample Sm is extremely slower than that of the buffer Bf, the buffer Bf may enter the sample supply flow path 1 (sample Sm may flow backward).

[0056] Therefore, in order to stably mix two liquids in the mixing flow channel 3 at a predetermined mixing ratio (dilution ratio), it is necessary to mix them at the same timing and at approximately the same flow rate.To achieve this, it is necessary to adjust the cross-sectional areas of both flow channels and then connect them at the downstream ends of both channels in a state where surface tension can act on both channels.

[0057] <Experimental Example> An experiment was conducted to confirm that the above configuration prevents one fluid from entering the other (backflow). A simple flow path was constructed for the experiment, as shown in Figure 6(a). The sample supply flow path 1 and the buffer supply flow path 2 were each branched, and a two-liquid mixing dilution device (mixing section) j1 was constructed at one location. A serpentine flow path was provided downstream of the branched flow path to adjust the flow rate from the outlet, and an outlet section 5 was provided at the end of the flow path. Each flow path was configured with a width of 200 μm, a flow height of 10 μm for the sample supply flow path 1, and a flow height of 90 μm for the buffer supply flow path 2, resulting in a flow path cross-sectional area ratio of 1:9. Furthermore, the flow path widths Wp and Wq at the ends of the narrowed sections 11 and 21 (boundary section P, confluence section Q) were both 32 μm. As shown in Figure 6(b), the two-liquid mixing dilution device (mixing section) j1 was configured such that the tip (junction) Q of the sample supply flow path 1 was located downstream of the tip (boundary) P of the buffer supply flow path 2. For comparison, a similar experiment was also conducted on a configuration in which the tip (junction) Q of the sample supply flow path 1 was located upstream of the tip (boundary) P of the buffer supply flow path 2, as shown in Figure 6(c).

[0058] With the above-described flow path configuration, a blue colored solution (0.5 w / v%) was introduced into the sample supply flow path 1 from the sample introduction section 10, and pure water was introduced into the buffer supply flow path 2 from the buffer introduction section 20 using a syringe pump, and the state of the blue colored solution was observed. The timing of the flow was adjusted so that the sample reached the tip Q first. The state of the confluence was observed by taking a video and playing it back to check the details. The results are shown in the table below.

[0059] [Table 1]

[0060] As is clear from the above experimental results, it was found that when the connection position of the tip (junction Q) of the sample supply channel 1 is upstream of the tip (boundary P) of the buffer supply channel 2, the sample flows back into the buffer for more than 3 seconds. Therefore, the mixed fluid mixed during this time does not have a constant dilution ratio and cannot be used as a dilution fluid and must be discarded, requiring a channel structure for discarding. On the other hand, when the connection position of the tip (junction Q) of the sample supply channel 1 is downstream of the tip (boundary P) of the buffer supply channel 2, as in this embodiment, the mixed fluid flows down simultaneously, and it was found that the mixed fluid from the beginning of mixing can be used as a dilution fluid.

[0061] <First embodiment of dilution flow path device> The embodiment of the two-liquid mixing dilution apparatus has been described above, and a flow path device for dilution can be configured by using this dilution apparatus. The outline of the dilution flow path device has been described above, but here, a first embodiment will be described with reference to FIG.

[0062] As shown in FIG. 1, this embodiment is a flow channel device that enables multistage dilution. A sample introduction section 10 is provided at the base end (top right corner of the figure) of sample supply flow channel 1, and a buffer introduction section 20 is provided at the base end (top left corner of the figure) of buffer supply flow channel 2, allowing the sample and buffer to be introduced into flow channels 1 and 2 at predetermined flow rates. Buffer supply flow channel 2 branches into multiple channels near buffer introduction section 20, allowing the supply of buffer for dilution at each stage. Both sample supply flow channel 1 and buffer supply flow channel 2 also constitute flow channels that allow the sample to flow 100% without mixing with other fluids, allowing them to be used for comparison with other dilution fluids (comparison of reaction states, etc.).

[0063] First, the first-order mixing section j1 ​​is configured to merge a sample supply channel 1 branched off near the sample introduction section 10 with a buffer supply channel 2 branched off near the buffer introduction section 20. In the first-order mixing section j1, the mixing ratio of the sample flow rate and the buffer flow rate is adjusted to a predetermined ratio (e.g., 1:9) and the two channels are merged, and a channel is configured to allow the mixed fluid at a predetermined dilution ratio (e.g., 10 times (diluted to a concentration of 1 / 10)) to flow into the reaction vessel 4. As mentioned above, the flow rate ratio is adjusted by the channel cross-sectional area, but since there is channel resistance depending on the channel length, the fluid introduction conditions are determined taking into account the overall shape of the channel structure. The channel structure to be considered here is specified by the cross-sectional shape and longitudinal shape (channel length) of the channel, and is adjusted by either the channel cross-sectional area or the channel length, or both.

[0064] The mixing channel 3 is provided with a branch channel, which is considered a sample supply channel and sends the fluid to the next-order (second-order) mixing section j2. Because the conditions for introducing fluids from both inlet sections 10 and 20 are constant, the channel length reaching the second-order mixing section j2 is adjusted by passing the fluid through the serpentine channel 6a. By passing both the sample and buffer sections through the serpentine channel 6a, the fluids are mixed in the mixing section j2 with the flow rate adjusted due to the channel resistance caused by their respective channel lengths. By adjusting the mixing ratio (flow rate ratio) to a predetermined ratio (e.g., 1:9), the fluid diluted in the previous order (first order) can be further diluted. For example, if the first order is diluted 10 times (to a 1 / 10 concentration) and the second order is also diluted 10 times (to a 1 / 10 concentration), the overall dilution rate achieved by the second order mixing section j2 will be 100 times (to a 1 / 100 concentration).

[0065] Furthermore, part of the mixed fluid diluted in the second-order mixing section j2 is sent to the reaction vessel 4, and part is branched off and sent to the next-order (third-order) mixing section j3 for further dilution. Thereafter, the mixed fluid diluted in the third order is similarly supplied to the next-order (fourth-order) mixing section j4, allowing the degree of dilution to progress. The diluted mixed liquid at each stage is sent to the reaction vessel 4, making it possible to observe multi-stage reaction states according to the degree of dilution at each stage. By configuring this in multiple stages (four stages are shown as an example, but more stages may be added), multi-stage dilution is possible.

[0066] In this case, for example, when the dilution ratio in all the mixing sections j1 to j4 is set to 10 times (diluted to a concentration of 1 / 10), the dilution ratio in each stage is a logarithmic dilution ratio (10 n 10000 (10 fold dilution) is possible. 4 ) times dilution ratio, and if it is further increased, a mixed fluid with a dilution ratio of ×10 times can be obtained in each step.

[0067] The flow rate adjustment in each mixing unit j1 to j4 can be designed as equivalent to an electric circuit. That is, by regarding the fluid introduction pressure as "voltage" and the flow path resistance due to the flow path structure (mainly the flow path length) as "resistance," the flow rate can be designed as "current." By maintaining the introduced flow rate (current) constant, the flow rates of the sample and buffer to be mixed in the mixing units j1 to j4 can be adjusted by adjusting the flow path length, for example by inserting a serpentine flow path 6, thereby adjusting the magnitude of the flow path resistance (resistance value), and thereby adjusting the flow rate to be merged.

[0068] <Second embodiment of dilution flow path device> FIG. 7 illustrates a second embodiment of the dilution flow path device. As shown in FIG. 7, this embodiment is configured like a parallel circuit in an electric circuit, and is configured to supply sample and buffer with adjusted flow rates from both the left and right sides to mixers j1 to j4 installed in parallel. In the case of a cascade structure like the first embodiment, the flow path resistance ratios of the dilution ratios affect each other, which was a concern as it made designing the flow path difficult. This is an improvement on that. The parallel configuration allows the flow path resistance ratios of the sample and buffer to be designed independently for each dilution ratio, which has the advantage of making flow path design easier. An embodiment of such an improved structure will be described in detail below.

[0069] The sample introduction section 10 and the buffer introduction section 20 are located at the upper left and right ends of the figure, respectively. A sample and a buffer are supplied to the parallel flow paths arranged near the introduction sections 10 and 20. The introduction pressure of each fluid to the introduction sections 10 and 20 is constant. In this embodiment, the introduction pressures of the sample and the buffer are also the same. The cross-sectional area of ​​the sample supply flow path 1 is set to the same size but is smaller (e.g., 1 / 9) than the cross-sectional area of ​​the buffer supply flow path 2. Furthermore, as mentioned above, when the same introduction pressure (voltage) is used, the flow rate (current) varies depending on the magnitude of the resistance (resistance value) within the flow path. Therefore, to adjust the flow rate, the flow path length from the introduction sections 10 and 20 to the mixing sections j1 to j4 is calculated so that a predetermined resistance (resistance) is applied within the flow path. It is noteworthy that all the mixing sections j1 to j4 have the same structure (e.g., a flow path cross-sectional area ratio of 1:9). This is because it has been experimentally demonstrated that even when the flow rate ratio flowing down the sample supply channel 1 and the buffer supply channel 2 is increased (for example, 1:10000), it is possible to adjust the timing of confluence and prevent backflow.

[0070] In this embodiment, a mixed fluid is formed in each of the parallel-arranged flow path systems Ja, Jb, Jc, and Jd, and the mixed fluid flows into a reaction vessel (chamber) 4 installed at the downstream end of each of the flow path systems Ja to Jd individually, allowing the reaction of each diluted fluid to be confirmed. Each of the flow path systems Ja to Jd may be connected to one reaction vessel (chamber), or may be dispensed into multiple reaction vessels 4. The figure shows a configuration in which the solution is dispensed into five reaction vessels 4, and the dispensing structure in this case employs the dispensing device disclosed in International Publication No. 2023-120648. The dispensing structure is not limited to the configuration disclosed in the above publication, and other dispensing devices may also be used.

[0071] The first-order (low dilution rate) flow path system Ja in this embodiment is the system Ja (shown at the bottom in the figure) that has the longest flow path length of the buffer supply flow path 2 while interposing the serpentine flow path 6. By setting the flow path length of the buffer supply flow path 2 to be long, flow path resistance acts before reaching the mixing section j1, reducing the supplied flow rate, and therefore increasing the mixing ratio with the sample, making it possible to obtain a mixed fluid with a ratio (1:9) equivalent to that of the first-order flow path system in the first embodiment. In order to lengthen the flow path length of the buffer supply flow path 2, a serpentine flow path 6a is interposed upstream of the mixing section j1.

[0072] As the next order, the flow path system Jb, which has a shorter flow path length of the buffer supply flow path 2 than the first order described above, corresponds to the second order in the first embodiment, the flow path system Jc, which has an even shorter flow path length, corresponds to the third order, and the flow path system Jd, which has the shortest flow path length, corresponds to the fourth order. The second order flow path system Jb is provided with a serpentine flow path 6a that is shorter than the first stage, and the third and fourth order flow path systems Jc and Jd are configured such that the serpentine flow path 6a is interposed on the sample supply flow path 1 side to suppress the flow rate of the sample while increasing the flow rate of the buffer.

[0073] In this embodiment, the lengths of the mixing sections j1 to j4 in the sample supply channel 1 are adjusted as appropriate to adjust the channel resistance ratio, but they may also be configured based on the same channel length. Since it is necessary to adjust the flow rate of the buffer for dilution in the channel design, the channel length of the sample supply channel 1 can be adjusted according to the channel length of the buffer supply channel 2, but this is not a limitation. Furthermore, when the channel cross-sectional area is fixed and only the flow rate is changed, the flow rate of the fluid supplied in each of the channel systems Ja to Jd changes. However, this flow rate can be adjusted by adjusting the constriction conditions of the constriction sections formed at the ends of each of the channels 1 and 2.

[0074] As described above, if the flow rate is adjusted only by changing the length of the flow channel while the flow channel cross-sectional area of ​​the sample supply flow channel 1 and the buffer supply flow channel 2 is fixed, and the flow rate ratio reaching the mixing sections j1 to j4 is set arbitrarily, any number of multi-stage dilutions (four stages in the figure) are possible. In this embodiment, multi-stage logarithmic dilution ratios (10 n To achieve this multi-step dilution (multiple-fold stepwise dilution), the first-stage flow path system Ja is configured to perform a 10-fold dilution, the second-stage flow path system Jb to perform a 100-fold dilution, the third-stage flow path system Jc to perform a 1000-fold dilution, and the fourth-stage flow path system Jd to perform a 10,000-fold dilution. Note that the flow path systems Ja to Jd may be configured to perform multi-step dilution at any dilution ratio depending on the type of object (sample) to be diluted, the purpose of the test, etc.

[0075] <Summary> As described above, according to this embodiment of the two-liquid confluence type dilution device (mixing section) j1 to j4, by providing the narrowed sections 11, 21 at the ends of the sample supply channel (target fluid supply channel) 1 and the buffer supply channel (dilution fluid supply channel) 2, the fluids can be temporarily stopped at the ends of both supply channels 1, 2 and then start flowing down simultaneously. Furthermore, by providing the narrowed sections 11, 12, it is possible to adjust the flow rates of both fluids when flowing down, and by setting the flow rates when supplying the mixed fluid to the same (1:1 ratio), it is possible to prevent one fluid from entering (backflowing) into the other channel.

[0076] Furthermore, according to the present embodiment (two embodiments) of the dilution flow path device, a dilution device capable of mixing two liquids at a desired mixing ratio (dilution rate) is used, thereby enabling multi-stage dilution. Multi-stage dilution can be achieved either by a configuration in which a buffer supply flow path (dilution fluid supply flow path) 2 is connected in a cascade to the mixing flow path (first embodiment), or by a configuration in which multiple flow paths are arranged in parallel like a parallel circuit (second embodiment).

[0077] As described above, the two-component confluent dilution device described above allows for suitable dilution, and the flow path device using this two-component confluent dilution device enables multistage dilution, facilitating various tests in the medical field, new drug development, and other chemical fields. Multistage dilution in this case allows for on-site operation, simplifying on-site detection in illegal drug investigations by law enforcement authorities. In particular, the flow path device in a multistage diluted state can be placed under conditions based on gene amplification (e.g., loop-mediated isothermal amplification (LAMP)) to amplify genes, allowing individual amplification of genes in a multistage diluted state. Therefore, the device can also be used to perform gene amplification reactions.

[0078] Although the embodiments of the present invention are as described above, the present invention is not intended to be limited to the above-described embodiments, and the elements constituting the above-described embodiments may be appropriately modified or other elements may be added.

[0079] For example, while the cross-sectional shapes of the supply channels 1 and 2 for each fluid and the mixing channel 3 have been described as being basically rectangular, the cross-sectional shapes of the channels do not have to be rectangular and may be polygonal or circular. Furthermore, while the serpentine channels 6, 6a, and 6b have been wavy to adjust the channel length, any serpentine shape may be used as long as the channel length can be adjusted. Furthermore, while the first embodiment and the second embodiment illustrate a state in which one reaction vessel 4 is installed in the channel device, and five reaction vessels are installed in the channel device in the second embodiment, the number and shape of these vessels can be changed as appropriate. [Explanation of symbols]

[0080] 1. Sample supply channel (target fluid supply channel) 2. Buffer supply channel (dilution fluid supply channel) 3 Mixing channel 4. Reaction vessel (chamber) 5 Discharge section 6,6a,6b Serpentine flow path 10 Sample introduction section 11,21 Stenosis 20 Buffer introduction 31 Widening section (expansion section) j1, j2, j3, j4 Mixing section (two-liquid confluence type dilution device) P border Pa boundary line Q Junction Sm Sample Bf buffer

Claims

1. A flow path structure is configured with microflow paths, and includes a target fluid supply flow path that supplies a target fluid to be diluted, a dilution fluid supply flow path that supplies a dilution fluid for diluting the target fluid, and a mixing flow path that sends a mixed fluid of the target fluid and the dilution fluid, the target fluid supply flow path and the dilution fluid supply flow path being continuous with a base end of the mixing flow path, and the target fluid and the dilution fluid being merged to mix and dilute the two liquids, the dilution fluid supply channel includes a first narrowed portion at a downstream end of the channel, the target fluid supply flow path includes a second narrowed portion at a downstream end of the flow path, the mixing channel has an expanded portion at a base end where the channel is expanded; the dilution fluid supply channel and the mixing channel are provided continuously with the first narrowed portion and the expanded portion forming a boundary therebetween, The target fluid supply flow path is provided continuously through the second narrowed portion to a junction portion that is set downstream of the boundary portion between the first narrowed portion and the widened portion of the mixing flow path. A two-liquid confluence type dilution device in a microchannel.

2. 2. The two-liquid confluence type dilution device in a microchannel according to claim 1, wherein the flow path cross-sectional area of ​​the dilution fluid supply flow path and the flow path cross-sectional area of ​​the target fluid supply section are different in size, and the ratio of the flow path cross-sectional areas is adjusted to match the ratio of the flow rate at which the dilution fluid is to be supplied to the flow rate at which the target fluid is to be supplied.

3. 3. The two-liquid confluence type dilution device in a microchannel according to claim 2, wherein a flow path cross-sectional area of ​​the target fluid supply flow path is configured to be smaller than a flow path cross-sectional area of ​​the dilution fluid supply flow path, and the target fluid supply flow path is configured to have a flow path width substantially the same as that of the dilution fluid supply flow path but a flow path height lower than that of the dilution fluid supply flow path.

4. 3. The two-liquid confluence type dilution device in a microchannel according to claim 2, wherein the first narrowed portion and the second narrowed portion are both formed by narrowing the channel width while keeping the channel height constant.

5. 5. The two-liquid confluence type dilution device in a microchannel according to claim 4, wherein the channel height of the target fluid supply channel is 1 / 9 of the channel height of the dilution fluid supply channel.

6. A dilution flow path device using the two-liquid confluence type dilution device according to any one of claims 1 to 5, the target fluid supply flow path has a target fluid inlet, and the dilution fluid supply flow path has a dilution fluid inlet, a flow path structure of the target fluid supply flow path from the target fluid inlet portion to the target junction portion is adjusted to a shape that generates a desired flow path resistance in the target fluid supply flow path; a flow path structure of the dilution flow path side flow path from the dilution fluid inlet portion to the boundary portion is adjusted to a shape that generates a desired flow path resistance in the dilution fluid supply flow path, A dilution flow path device, characterized in that the flow rate ratio of the target fluid and the dilution fluid supplied to the mixing flow path is adjusted by the flow path resistance due to the respective flow path structures of the target fluid supply flow path and the dilution fluid supply flow path.

7. 7. The dilution flow path device according to claim 6, wherein the mixing flow path is a cascade of multiple branched dilution fluid supply flow paths, and the branched flow paths branched from the upstream mixing flow path serve as target fluid supply flow paths, supplying the diluted fluid in the preceding order to the dilution fluid supply flow path, thereby enabling multi-stage dilution in which the degree of dilution is successively increased.

8. the target fluid supply flow path is branched into a plurality of flow paths near the target fluid inlet, and the dilution fluid supply flow path is branched into a plurality of flow paths near the dilution fluid inlet, the branched target fluid supply flow path and the dilution fluid supply flow path have different flow path structures, which cause different flow path resistances, thereby adjusting the flow rates; The dilution flow path device according to claim 6, wherein the ratio of the flow rate of the target fluid supply flow path side to the flow rate of the dilution fluid supply flow path side is adjusted stepwise while the fluids are mixed individually, thereby enabling multi-stage dilution.

9. the branched target fluid supply flow path and the dilution fluid supply flow path are arranged in parallel for each stage, 9. The dilution flow path device according to claim 8, wherein the flow rates of the target fluid supply flow path and the dilution fluid supply flow path at each stage arranged in parallel are adjusted in stages by the flow path structure, provided that the introduction pressure of the target fluid introduced from the target fluid introduction portion is maintained constant and the introduction pressure of the dilution fluid introduced from the dilution fluid introduction portion is maintained constant.

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