JP4861353B2 - Flow cell - Google Patents

Description

  The present invention relates to a flow cell including a predetermined flow path in which measurement is performed by a measuring device and a pump for flowing a sample solution through the flow path.

  Measurements using advanced biomolecular identification functions, such as antigen-antibody reactions and DNA fragments (DNA probes) and DNA binding, are important technologies for clinical tests, biochemical measurements, and environmental pollutant measurements. It has become. Examples of this measurement include micro TAS (Total Analysis Systems), micro combinatorial chemistry, chemical IC, chemical sensor, biosensor, trace analysis, electrochemical analysis, QCM measurement, SPR measurement, ATR measurement, etc. In the field of simple measurement, the sample solution to be measured is often very small.

  For this reason, in the above-described measurement, a very small amount of sample solution is transferred to the detection unit as it is, so that the measurement is performed with higher sensitivity and higher efficiency without reducing the concentration of the specimen. As a technology for transferring a small amount of sample solution, a flow path with a width of several hundred μm is made on a substrate, and the solution is transferred by external pressure using a syringe pump, etc., or the solution is transferred by electrostatic force. And a method of transferring a solution by volume change by heating and generation of bubbles, a method of using electroosmotic flow, and the like.

  However, in order to transfer a small amount of sample solution by these methods, for example, a fine groove is formed on the substrate (chip) as a flow path or a detection unit, and an electrode, a heater, or the like is formed on the same substrate. It is necessary to provide these components, and the production is not easy. In addition, when transferring the sample solution with external pressure, parts such as a pump and piping are required in addition to the chip constituting the detection unit, and in addition, the sample solution is wasted due to the transfer path of the piping. As a result, the amount of sample solution was limited. Therefore, in recent years, in the field of measurement described above, it has been proposed to form a transfer unit having (alternatively) a pump function together with a detection unit in a fine chip.

  Further, a paper chromatography analysis method using a filter paper has been known as a method for analyzing a trace amount of sample solution. For example, improved immunochromatography and immunoconcentration methods have been proposed as simple and inexpensive means for measuring biologically relevant substances (see Patent Documents 1 and 2). There is also a measuring chip in which a filter paper is arranged in a channel formed in a plastic structure (see Non-Patent Document 1). However, such paper chromatography methods have a problem in that the shape of the flow path is limited and complicated chemical analysis cannot be performed.

  Therefore, in recent years, it has been proposed to form a channel or a region serving as a pump for transferring a sample solution by a capillary phenomenon on a substrate or between a substrate and a substrate by a microfabrication technique (see Non-Patent Document 2). . A measurement chip created by this technique includes an introduction port into which a sample solution is introduced, a capillary pump that sucks the sample solution, and a measurement flow path provided between the introduction port and the capillary pump. . In such a measurement chip, when the sample solution is introduced into the introduction port, the sample solution sequentially flows out from the introduction port to the measurement flow path and the pump, and when the sample solution reaches the capillary pump, a capillary phenomenon occurs in the capillary pump. The sample solution is aspirated. As a result, the sample solution stored in the introduction port flows to the pump through the measurement channel by the suction force of the capillary pump.

Japanese Patent Publication No. 7-036017 JP 2000-329766 A JP 2001-194298 A JP 2002-214131 A Amal. Chem. 2005, 77, 7901-7907. Martin Zimmermann, Heinz Schmid, Patrick Hunziker and Emmanuel Delamarche, “Capillary pumps for autonomous capillary systems”, The Royal Society of Chemistry 2007, Lab Chip, 2007, 7, 119-125, First published as an Advance Article on the web 17th October 2006

  In general, the flow rate and flow rate profile of a desired sample solution vary depending on the type of sample solution and measurement device, such as detection of an antigen-antibody reaction. However, it is difficult to control the flow rate of the sample solution and the profile of the flow rate with the technique using the conventional capillary pump.

  Accordingly, the present invention has been made to solve the above-described problems, and an object thereof is to provide a flow cell capable of flowing a sample solution at a desired flow rate.

In order to solve the above-described problems, a flow cell according to the present invention includes a first substrate through which light is transmitted, a second substrate disposed on the first substrate, and a second substrate. Formed between the first substrate and the second substrate, the channel formed between the first substrate and the second substrate, one end of which is connected to the opening, and the first substrate and the second substrate. The other end of the flow path is connected, and includes a pump unit that sucks the liquid reached through the flow path from the opening by surface tension, and the flow path includes a measurement unit that measures the liquid, the measuring unit respectively provided in the opening portion side and the pump portion than, have a resistor portion that acts as a resistance to the fluid flowing in the flow path, the flow path width is different from the measuring unit and the resistor unit It is what I did.

  In the flow cell, the resistance portion may be configured by a meandering flow path. Here, the meandering flow path may have a bent portion bent in a substantially right angle or arc shape.

  The flow cell further includes a third substrate interposed between the first substrate and the second substrate, and the resistance unit and the pump unit are formed on at least one of the first substrate and the second substrate. In addition, the measurement unit may be formed on the third substrate.

  In the flow cell, the pump unit includes a recess formed in at least one of the first substrate and the second substrate, and a plurality of columnar members suspended in the recess. It may not be in contact with the first substrate or the second substrate.

  According to the present invention, the flow rate of the liquid passing through the resistance unit can be controlled by providing the resistance unit on the opening side of the measurement unit. As a result, the liquid can flow at a desired flow rate. it can.

[First Reference Example ]
Hereinafter, a first reference example of the present invention will be described in detail with reference to the drawings.

<Configuration of flow cell>
As shown in FIGS. 1 to 3, the flow cell 1 according to the present reference example includes a first substrate 11 having a substantially rectangular shape in plan view, a sheet-like member 12 disposed on the first substrate 11, and The second substrate 13 is disposed on the sheet-like member 12. In the flow cell 1 in which these are laminated, an inlet 14 through which the sample solution is introduced through the second substrate 13, a suction pump 18 formed between the sheet-like member 12 and the second substrate 13, A flow path connecting the suction pump 18 and the inlet 14 is provided. This flow path has one end connected to the inlet 14 and a resistance flow path 15 formed between the sheet-like member 12 and the second substrate 13, and the other end of the resistance flow path 15 connected to the first flow path. A space 16 formed in the sheet-like member 12 between the substrate 11 and the second substrate 13, one end connected to the space 16, and the other end connected to the suction pump 18, like the space 16. The measurement channel 17 is formed in the member 12 and irradiated with measurement light or the like by an external device.

≪First board≫
The first substrate 11 is made of, for example, optical glass such as BK7, and has a plate-like shape having a substantially rectangular shape in plan view with a plate thickness of about 1 mm and a side of about 16 mm. An Au layer 11a is selectively provided on the upper surface of the first substrate 11, that is, the surface of the first substrate 11 on the side where the sheet-like member 12 is placed by vapor deposition, sputtering, plating, or the like. Yes. The Au layer 11a may be formed only on the portion corresponding to the measurement flow path 17, but it goes without saying that it may be formed on the entire surface.

≪Sheet-like material≫
The sheet-like member 12 is made of, for example, a known adhesive tape having a thickness of about 10 μm to 150 μm, and has a planar shape corresponding to the first substrate 11. The sheet-like member 12 is formed with a slit 121 having a substantially rectangular shape in plan view provided at a substantially central portion, and an opening 122 having a substantially circular shape in plan view connected to one end of the slit 121. Here, the slit 121 is formed so that the longitudinal direction is substantially parallel to any side portion of the sheet-like member 12.

  The slit 121 described above, together with the upper surface of the first substrate 11 and the lower surface of the second substrate 13, forms the measurement channel 17 composed of a substantially rectangular parallelepiped space. The cross section perpendicular to the longitudinal direction of the measurement channel 17 has a dimension within a range in which capillary action occurs with respect to the aqueous solution.

  In addition, the opening 122 described above forms a space 16 formed of a substantially cylindrical space together with the upper surface of the first substrate 11 and the lower surface of the second substrate 13. The space portion 16 has a cross-sectional dimension in a range in which capillary action occurs with respect to the aqueous solution.

  Such a sheet-like member 12 can be produced, for example, by processing an adhesive tape into a desired shape with a cutter or a laser.

≪Second board≫
The second substrate 13 is made of, for example, acrylic having a thickness of about 0.5 to 5 mm, and has a planar shape corresponding to the first substrate 11 and the sheet-like member 12. A through hole 131 for forming the introduction port 14 is formed in a substantially central portion near one side of the second substrate 13. Also, on the lower surface of the second substrate 13, one end is connected to the through hole 131 to form a meandering groove 132 that forms the resistance flow path 15, and the suction pump 18 on the other side opposite to the one side. And a cavity 133 is formed.

  The meandering groove 132 has a plurality of bent portions, and has a crank-like planar shape that is repeatedly bent in a direction perpendicular to the direction connecting both ends. The bent portion is bent at a substantially right angle. The direction connecting the both ends is substantially parallel to the distance direction between the one side of the second substrate 13 and the other side.

  The cavity 133 is provided from the lower surface to the upper surface of the second substrate 13, and a plurality of substantially columnar protrusions 133 b that protrude downward from the ceiling are provided in the cavity. By setting the interval between the plurality of protrusions 133b within a range in which capillary action occurs, the cavity 133 functions as a suction pump. The hollow portion 133 is formed in a substantially “U” shape in plan view so as to surround the periphery of the center portion of the second substrate 13, and both the end portions near the one side of the second substrate 13 and the above-described one side. Air holes 133c to 133f penetrating the second substrate 13 are formed at both corners on the other side.

  The through hole 131 described above forms the introduction port 14 formed of a substantially cylindrical space with the upper surface of the sheet-like member 12 as the bottom.

  Further, the meandering groove 132 described above forms the meandering resistance flow path 15 when the second substrate 13 and the sheet-like member 12 are in contact with each other. The resistance flow path 15 has a cross-sectional dimension in a range in which capillary action occurs with respect to the aqueous solution.

  In addition, each dimension inside the suction pump 18 such as the interval, width, and height of the protrusion 133b in the cavity 133 described above is set to a value within a range where the capillary phenomenon occurs.

  The second substrate 13 as described above can be manufactured by, for example, injection molding using a mold on which a predetermined pattern is formed, laser processing, cutting using an end mill, or the like.

<Manufacturing method of flow cell>
Next, an example of the manufacturing method of the flow cell 1 according to this reference example will be described. First, the sheet-like member 12 is placed on the first substrate 11. Here, when the Au layer 11a is provided only on a part of the first substrate 11, a sheet is formed on the first substrate 11 so that the slit 121 forming the measurement channel 17 is located on the Au layer 11a. The member 12 is placed.

  Next, on the sheet-like member 2, the other end of the meandering groove 132 is located inside the opening 122 of the sheet-like member 12 and the other end of the slit 121 of the sheet-like member 12 is located inside the cavity 133. The second substrate 13 is placed on the substrate.

Since the slit 121 and the meandering groove 132 are formed narrow as shown in FIG. 1 and the like, it is difficult to directly connect the slit 121 and the meandering groove 132. Therefore, in this reference example , an opening 122 is provided at one end of the slit 121. Since the opening 122 has a substantially circular shape in plan view that is wider than the slit 121, the other end of the meandering groove 132 can be easily disposed therein. Thereby, the slit 121 and the meandering groove 132 can be easily connected via the opening 122.

  In this way, the first substrate 11, the sheet-like member 12, and the second substrate 13 are stacked, and these are pressed from the upper surface side of the first substrate 11 and the lower surface side of the second substrate 13. Thereby, the first substrate 11 and the second substrate 13 are fixed to each other via the sheet-like member 12 made of double-sided tape or the like, and the introduction port 14, the resistance channel 15, the space portion 16, the measurement channel 17, and the suction channel. The flow cell 1 provided with the pump 18 is completed.

<Operation of the flow cell>
Next, the operation of the flow cell 1 according to this reference example will be described.

  First, when a sample solution is injected into the introduction port 14, the sample solution proceeds in the order of the resistance channel 15, the space portion 16, and the measurement channel 17 by capillary action, and flows into the suction pump 18. Since the inside of the suction pump 18 is formed with a plurality of protrusions 133b, the surface area per unit volume is larger than when the protrusions 133b are not formed, and the dimensions are such that capillary action appears. It has become. Accordingly, the sample solution that has flowed into the suction pump 18 proceeds through the inside thereof. The traveling speed varies depending on the shape of the cavity 133 such as the outer shape and interval of the protrusion 133b, the resistance applied to the sample solution, and the like.

  Therefore, the sample solution injected into the introduction port 14 flows into the suction pump 18 through the resistance flow path 15, the space portion 16, and the measurement flow path 17, and proceeds inside the suction pump 18.

Here, in this reference example , the resistance flow path 15 is provided between the introduction port 14 and the measurement flow path 17. As a result, the sample solution passing through the resistance channel 15 is subjected to resistance according to its shape and the flow rate is changed. For example, if the number of bendings is increased, that is, if a large number of bent portions are provided or the width of the flow path is reduced, the pressure loss due to these portions increases, and the flow velocity decreases. Further, if the inner surface is subjected to a hydrophobic treatment or the resistance flow path 15 is lengthened, the frictional force from the wall surface increases, so the flow velocity decreases. Conversely, if the number of bendings is reduced, the width of the flow path is widened, the flow path is shortened, or the inner surface is subjected to a hydrophilic treatment, the flow velocity can be increased as compared with the case described above. Accordingly, the flow rate of the sample solution passing through the resistance flow channel 15 can be controlled by forming the resistance flow channel 15 according to the flow rate of the desired sample solution and the flow rate profile. The flow rate of the sample solution flowing through each component inside the flow cell 1 can also be controlled. As a result, the sample solution can be flowed into the measurement flow path 17 with a flow rate or flow rate profile of the sample solution desired according to the type of the sample solution or the measuring device.

  In addition, since the resistance channel 15 is provided in front of the measurement channel 17, the sample solution flows directly from the measurement channel 17 to the suction pump 18, so that the sample solution flows into the measurement channel 17 and the suction pump 18. There is no significant time difference between the sample solution flowing in. Thereby, it is possible to prevent the sample solution having a low flow rate from flowing into the measurement channel 17 as much as possible.

  In addition, since the resistance flow path 15 is provided in the front stage of the measurement flow path, when the energized sample solution immediately after being injected into the introduction port 14 passes through the resistance flow path 15, the momentum is reduced, so that an injection shock occurs. Can be prevented. As a result, even when a plurality of sample solutions are sequentially injected into the flow cell 1, no injection shock occurs, so that the sample solution can be accurately measured.

In this reference example , the case where the slit 121 has a substantially rectangular shape in plan view and is provided in the substantially central portion of the sheet-like member 12 has been described as an example. However, the slit 121 passes over the Au layer 11a. In this case, the shape and position of the slit 121 are not limited to those described above, and can be freely set as appropriate. Therefore, the shape and position of the measurement flow path 17 constituted by the slits 121 can be set freely as appropriate.

Further, in this reference example , the case where the opening 122 has a substantially circular shape in plan view has been described as an example. However, if the opening 122 exists at a position continuous with the through hole 131 of the second substrate 13. The shape of the opening 122 is not limited to a substantially circular shape in plan view, and can be set as appropriate.

Further, in this reference example , the case where the cavity portion 133 has a substantially “U” shape in plan view has been described as an example, but the planar shape of the cavity portion 133 is not limited to a substantially “U” shape. It can be set freely as appropriate. Similarly, the shape of the protrusion 133b formed inside the cavity 133 is not limited to a substantially cylindrical shape as long as the surface area inside the cavity 133 is increased, and can be set as appropriate.

[Second Reference Example ]
Next, a second reference example of the present invention will be described. In this reference example , a resistance channel is provided between the measurement channel and the suction pump. Therefore, in this reference example , the same name is attached | subjected about the component equivalent to 1st Embodiment mentioned above, and description is abbreviate | omitted suitably.

<Configuration of flow cell>
As shown in FIGS. 4 to 8, the flow cell 2 according to the present reference example includes a first substrate 21 having a substantially rectangular shape in plan view, a sheet-like member 22 disposed on the first substrate 21, The second substrate 23 is disposed on the sheet-like member 22. In the flow cell 2 in which these layers are laminated, the inlet 24 through which the sample solution is introduced through the second substrate 23 and the two suction pumps 27 formed between the sheet-like member 22 and the second substrate 23. And a flow path connecting the suction pump 27 and the inlet 24 is provided. This flow path has one end connected to the inlet 24 and a measurement flow path 25 formed in the sheet-like member 22 between the first substrate 21 and the second substrate 23, and one end connected to the measurement flow path. The resistor 25 is connected to the other end of the sheet 25 and is formed between the sheet-like member 22 and the second substrate 23. Thus, in this reference example , the resistance channel 26 is provided between the measurement channel 25 and the suction pump 27.

≪First board≫
The first substrate 21 has the same shape and configuration as the first substrate 11 of the first reference example described above, and an Au layer 21a is selectively provided on the upper surface.

≪Sheet-like material≫
The sheet-like member 22 has the same shape and configuration as the sheet-like member 12 of the first reference example described above, and has a substantially rectangular slit 221 provided in a substantially central portion, and one end of the slit 221. And an opening 222 having a substantially circular shape in plan view. Here, the slit 221 is formed so that the longitudinal direction is substantially parallel to any side portion of the sheet-like member 22.

  The above-described slit 221 forms a measurement channel 25 composed of a substantially rectangular parallelepiped space together with the upper surface of the first substrate 21 and the lower surface of the second substrate 23. The cross section perpendicular to the longitudinal direction of the measurement flow path 25 has a dimension within a range in which capillary action occurs with respect to the aqueous solution.

<< Configuration of second substrate >>
The second substrate 23 has the same shape and configuration as the second substrate 13 of the first reference example described above, and a through hole 231 is formed in a substantially central portion closer to one side. In addition, on the lower surface of the second substrate 23, meandering grooves 232 formed from approximately the center to the vicinity of the other side opposite to the one side, and two hollow portions 233 formed on both sides of the meandering grooves 232. And are provided.

  The through hole 231 is formed in a planar shape equivalent to the opening 222.

  The meandering groove 232 has a plurality of bent portions, and has a crank-like planar shape that is repeatedly bent in a direction perpendicular to the distance direction between the one side and the other side. The bent portion is gently bent in a substantially arc shape, that is, in a curved shape. The other end of the meandering groove 232 branches near the other side of the second substrate 23 and extends to the opposite side along the vertical direction and is connected to the adjacent cavity 233. .

  The cavity 233 is provided from the lower surface to the upper surface of the second substrate 23, and a plurality of substantially columnar protrusions 233b projecting downward from the ceiling are provided in the cavity. The hollow portion 233 is formed in a substantially rectangular shape in plan view, and is formed on the second substrate at a corner portion on the opposite side to the end portion on the one side and the other end of the meandering groove 132 on the other side. Air holes 233c to 233f penetrating through 23 are formed.

  The above-described through-hole 231 forms an introduction port 24 composed of a substantially cylindrical space with the upper surface of the first substrate 21 as a bottom, together with the opening 222 and the upper surface of the first substrate 21.

  Further, the meandering groove 232 described above forms the meandering resistance channel 26 when the second substrate 23 and the sheet-like member 22 are in contact with each other. The resistance flow path 26 has a cross-sectional dimension in a range where capillary action occurs with respect to the aqueous solution.

  In addition, each dimension inside the suction pump 27, such as the interval, width, and height of the protruding portion 233b in the cavity portion 233 described above, is set to a value within a range where the capillary phenomenon appears.

<Manufacturing method of flow cell>
Next, an example of the manufacturing method of the flow cell 2 according to this reference example will be described. First, the sheet-like member 22 is placed on the first substrate 21. Here, when the Au layer 21a is provided only on a part of the first substrate 21, a sheet is formed on the first substrate 21 so that the slit 221 forming the measurement channel 25 is located on the Au layer 21a. The member 22 is placed.

  Next, the second substrate 23 is placed on the sheet-like member 22 so that the through hole 231 and the opening 222 are continuous and one end of the meandering groove 232 is located inside the other end of the slit 221.

  In this way, the first substrate 21, the sheet-like member 22, and the second substrate 23 are stacked, and these are pressed from the upper surface side of the first substrate 21 and the lower surface side of the second substrate 13. Thus, the first substrate 21 and the second substrate 23 are fixed to each other via the sheet-like member 22 made of double-sided tape or the like, and the introduction port 24, the measurement channel 25, the resistance channel 26, and the suction pump 27 are provided. The flow cell 2 is completed.

<Operation of the flow cell>
Next, the operation of the flow cell 2 according to this reference example will be described.

Also in this reference example , as in the first reference example described above, a plurality of projecting portions 233b are formed inside the suction pump 27, so that the sample solution injected into the inlet port 24 is sucked into the suction pump 27. Then, it passes through the measurement channel 25 and the resistance channel 26 and reaches the suction pump 27.

Here, in this reference example , a resistance channel 26 is provided between the measurement channel 25 and the suction pump 27. As a result, the sample solution passing through the resistance channel 26 is subjected to resistance according to its shape and the flow rate is changed. Therefore, as in the case of the first reference example , the flow rate of the sample solution passing through the resistance flow channel 26 is controlled by forming the resistance flow channel 26 according to the desired flow rate and flow rate profile of the sample solution. Therefore, it is possible to control the flow rate of the sample solution flowing through each of the components in the front stage and the rear stage and thus the flow cell 1. Thereby, the sample solution can be flowed into the measurement channel 25 with a flow rate of the desired sample solution or a flow rate profile according to the type of the sample solution or the measuring device.

  Further, since the bent portion of the meandering groove 232 is formed in a gentle curved line that draws an arc, it is possible to prevent a rapid change in the contact angle of the sample solution inside the resistance channel 26, and the sample solution is trapped in the channel. Can be prevented.

Conventionally, after first injecting a buffer solution or the like and measuring a baseline of a signal output from the measuring apparatus, an antigen-antibody reaction or the like is measured by injecting a sample solution to be actually measured. However, if the measurement can be performed by injecting only the sample solution from the beginning as in immunochromatography, it is not necessary to use a buffer solution, so that the measurement can be performed easily. In this case, the baseline measurement must be performed before the start of the full-scale antigen-antibody reaction, but the measurement is performed by providing the resistance channel 26 at the rear stage of the measurement channel 25 as in this reference example. Can be realized. That is, in the flow cell 2 according to the present reference example , the flow rate of the sample solution is set by, for example, setting the shape of the cavity 233 so that the flow rate of the sample solution is higher in the suction pump 27 than in the resistance flow channel 26. It is possible to realize a flow velocity profile that is fast until the measurement flow channel 25, slow in the resistance flow channel 26, and fast again when reaching the suction pump 27. Thereby, measurement using only the sample solution can be performed by measuring the baseline while the sample solution is slowly flowing through the resistance flow path 26.

As a specific example, in the flow cell 2 according to the present reference example , a resistance channel 26 having a width of about 200 μm, a depth of about 150 μm, and a total length of about 14.6 mm was created. In this case, the time required to reach the suction pump 27 from the resistance flow path 26 is longer than the time required to reach the measurement flow path 25 after the sample is injected into the introduction port 24. I was able to confirm. At this time, by introducing a resistance member into the inner surface of the resistance channel 26 or changing the wettability of the material, a sample of several tens of μl can be fed in about several minutes, or can be fed over one hour or more. I was able to confirm that I could do it.

In this reference example , the case where the cavity 233 has a substantially rectangular shape in plan view has been described as an example. However, the planar shape of the cavity 233 is not limited to a substantially rectangular shape, and can be freely set as appropriate.

First Embodiment
Next, a first embodiment according to the present invention will be described. In the present embodiment, resistance channels are provided at the front and rear stages of the measurement channel. Therefore, in the present embodiment, the same components as those in the first and second reference examples described above are given the same names, and description thereof will be omitted as appropriate.

<Configuration of flow cell>
As shown in FIGS. 9 to 11, the flow cell 3 according to the present embodiment includes a first substrate 31 having a substantially rectangular shape in plan view, and a sheet-like member 32 disposed on the first substrate 31. The second substrate 33 is disposed on the sheet-like member 32. In the flow cell 3 in which these layers are stacked, an inlet 34 through which the sample solution is introduced through the second substrate 33, and two suction pumps 38 formed between the sheet-like member 32 and the second substrate 33. And a flow path connecting the suction pump 38 and the introduction port 34 is provided. This flow path has one end connected to the inlet 34 and formed between the sheet-like member 32 and the second substrate 33, and one end connected to the first resistance flow path 35. The measurement flow path 36 formed in the sheet-like member 32 connected and between the first substrate 31 and the second substrate 33, and one end connected to the other end of the measurement flow path 36, the sheet-like member 32. And a second resistance channel 37 formed between the second substrate 33 and the second substrate 33. Thus, in the present embodiment, the first resistance channel 35 and the second resistance channel 37 are provided at the front stage or the rear stage of the measurement channel 36.

≪First board≫
The first substrate 31 has the same shape and configuration as the first substrate 11 of the first reference example described above, and an Au layer 31a is selectively provided on the upper surface.

≪Sheet-like material≫
The sheet-like member 32 has the same shape and configuration as the sheet-like member 12 of the first reference example described above, and has a slit 321 having a substantially rectangular shape in plan view provided at a substantially central portion. The slit 321 is formed so that the longitudinal direction is substantially parallel to any side portion of the sheet-like member 32.

  The slit 321 described above forms a measurement flow path 36 composed of a substantially rectangular parallelepiped space together with the upper surface of the first substrate 31 and the lower surface of the second substrate 33. The cross section perpendicular to the longitudinal direction of the measurement flow path 36 has a dimension within a range in which capillary action occurs with respect to the aqueous solution.

<< Configuration of second substrate >>
The second substrate 33 has the same shape and configuration as the second substrate 13 of the first reference example described above, and a through hole 331 is formed at a substantially central portion near one side of the second substrate 33. Is formed. Further, a first meandering groove 332 having one end connected to the through-hole 331 and a second meandering formed on the lower surface of the second substrate 33 from the center to the vicinity of the other side opposite to the one side. A groove 333 and two cavities 334 formed on both sides of the second meandering groove 333 are provided.

  The first meandering groove 332 has a plurality of bent portions, and has a crank-like planar shape that is repeatedly bent in a direction perpendicular to the direction connecting both ends. The bent portion is gently bent in a substantially arc shape, that is, in a curved shape. The direction connecting the both ends is substantially parallel to the distance direction between the one side and the other side of the second substrate 13.

  The second meandering groove 333 has a plurality of bent portions, and has a crank-like planar shape that is repeatedly bent in a direction perpendicular to the distance direction. The bent portion is gently bent in a substantially arc shape, that is, in a curved shape. The other end of the second meandering groove 333 is branched near the other side of the second substrate 33, and extends to the opposite side along the vertical direction to the adjacent cavity 334. Connected.

  The cavity portion 334 is provided from the lower surface to the upper surface of the second substrate 33, and a plurality of substantially cylindrical protrusion portions 334b that protrude downward from the ceiling are provided in the cavity. The hollow portion 334 is formed in a substantially rectangular shape in plan view, and is formed at a corner portion on the opposite side to the end portion on the one side and the other end of the second meandering groove 333 on the other side. Air holes 334c to 334f penetrating the second substrate 33 are formed.

  The through hole 331 described above forms the introduction port 34 formed of a substantially cylindrical space with the upper surface of the sheet-like member 32 as the bottom.

  The first meandering groove 332 described above forms the first resistance flow path 35 meandering when the second substrate 33 and the sheet-like member 32 are in contact with each other. The first resistance flow path 35 has a cross-sectional dimension in a range where capillary action occurs with respect to the aqueous solution.

  Further, the second meandering groove 333 described above forms a meandering second resistance flow path 37 when the second substrate 33 and the sheet-like member 32 are in contact with each other. The second resistance flow path 37 has a cross-sectional dimension in a range where capillary action occurs with respect to the aqueous solution.

  In addition, each dimension inside the suction pump 38, such as the interval, width, and height of the protruding portion 334b in the hollow portion 334 described above, is a value within a range where the capillary phenomenon appears.

<Manufacturing method of flow cell>
Next, an example of the manufacturing method of the flow cell 3 according to the present embodiment will be described. First, the sheet-like member 32 is placed on the first substrate 31. Here, when the Au layer 31a is provided only on a part of the first substrate 31, a sheet is formed on the first substrate 31 so that the slit 321 forming the measurement channel 36 is located on the Au layer 31a. The shaped member 32 is placed.

  Next, on the sheet-like member 32, the other end of the first serpentine groove 332 is positioned inside one end of the slit 321 and one end of the second serpentine groove 333 is positioned inside the other end of the slit 321. The second substrate 33 is placed.

  When the first substrate 31, the sheet-like member 32, and the second substrate 33 are stacked in this manner, these are pressed from the upper surface side of the first substrate 31 and the lower surface side of the second substrate 33. Thereby, the first substrate 31 and the second substrate 23 are fixed to each other via the sheet-like member 32 made of double-sided tape or the like, and the introduction port 34, the first resistance channel 35, the measurement channel 36, the second The flow cell 3 including the resistance flow path 37 and the suction pump 38 is completed.

<Operation of the flow cell>
Next, the operation of the flow cell 3 according to the present embodiment will be described.

Also in the present embodiment, as in the first and second reference examples described above, since the plurality of protrusions 334b are formed inside the suction pump 38, the sample solution injected into the inlet 34 is used as the suction pump. The first suction flow path 38 sucks the first resistance flow path 35, the measurement flow path 36, and the second resistance flow path 37, and reaches the suction pump 38.

In the present embodiment, the first resistor flow path 35 is provided, and measurement flow similar to the second reference example between a first reference example as well as inlet 34 and the measuring flow path 36 A second resistance flow path is provided between the path 36 and the suction pump 38. Therefore, an operational effect equivalent to that of the first and second reference examples described above can be obtained.

[Application example of flow cell]
Here, the form and the first of the first embodiment described above will be briefly described application example of the flow cell illustrated in the second reference example. The flow cell described above is used for measurement using the well-known surface plasmon resonance phenomenon (see Patent Documents 3 and 4). The measurement using the surface plasmon resonance phenomenon uses resonance between the evanescent wave and the surface plasmon wave on the surface of the metal in contact with the specimen to be measured.

  In this measurement, as shown in FIG. 13, the measurement unit of the flow cell 1005 in which the light emitted from the light source 1001 is collected by the incident side lens 1002 and is incident on the prism 1003 and is in close contact with the upper surface 1004 of the prism 1003. The Au film functioning as is irradiated. The flow cell 1005 is formed with an Au thin film. The specimen is placed in contact with the surface of the Au thin film, and the back surface of the Au thin film is irradiated with the condensed light transmitted through the flow cell 1005. The condensed light irradiated in this manner is reflected by the back surface of the thin Au film, and the intensity (light intensity) is measured by a light detection unit 1006 made of an imaging device such as a so-called CCD image sensor, and the angle at which the resonance occurs. A valley where the reflectance decreases is observed.

  In such a measurement, the presence or absence of a sample that selectively binds to an antibody or DNA fragment immobilized on the surface of the Au film (on the detection unit side) is detected, but the sample solution is placed in the detection unit. In this case, there is no distinction between a change due to the reaction between the target specimen and the antibody and a change due to a state in which foreign matter has settled and accumulated on the detection unit. On the other hand, by allowing the sample solution to flow in the detection unit, the sedimentation of the foreign matter can be suppressed, and the change due to the reaction described above can be selectively detected.

Note that embodiment and the first first embodiment described above, the flow cell shown in the second reference example, was to provide a sheet-like member, the first substrate and the second substrate without providing this You may make it comprise. In this case, each slit formed in the sheet-like member is formed in the first substrate or the second substrate, and members that are engaged with these side portions are provided to join each other, or to each other by an adhesive or the like. It can be realized by bonding.

Further, in the first reference example , the bent portion of the meandering groove 132 forming the resistance flow path 15 is bent at a substantially right angle. However, as in the first embodiment and the second reference example , It may be bent gently in an arc shape, that is, in a curved shape. Similarly, in the first embodiment and the second reference example , the meandering groove 232 and the first meandering groove 332 constituting the resistance channel 26, the first resistance channel 35, and the second resistance channel 37. The bent portion of the second meandering groove 333 is bent in a substantially arc shape, but may be bent substantially at a right angle as in the first reference example . Furthermore, the shape of the meandering channel, i.e. resistance flow path of the first embodiment and the first, not limited to the shape shown in the second reference example, whether the provided in a region that does not interfere with other components For example, the shapes shown in FIGS. 12A to 12C and the like can be set as appropriate. Here, as shown in FIGS. 12A to 12C, a long resistance channel can be provided by repeatedly providing the same shape. In FIGS. 12B and 12C, the bent portion may be bent in a substantially arc shape.

In the first embodiment and the first and second reference examples described above, the end portions of the protruding portions 133b, 233b, and 334b formed inside the hollow portions 133, 233, and 334 are the sheet-like member 12. , 22 and 32 have been described as an example, but the end portions may not be in contact with the sheet-like member. As a result, the volume inside the suction pump is increased by the amount corresponding to the shortening of the protrusion, so that the capacity of the suction pump can be increased. In addition, since the end of the protruding portion and the portion of the sheet-like member that has been in contact with this end are exposed, not only can a large surface area be maintained, but in some cases, the surface area can be further increased. In this case, the suction force can be further increased. In addition, for example, when a sample fluid containing contaminants such as food and drink or body fluid is injected into the flow cell, conventionally, the contaminants may be clogged inside the suction pump. However, as described above, by preventing the end of the projecting portion from coming into contact with the sheet-like member, a gap is formed between them, so that impurities can pass through the gap, and as a result. Thus, the contaminants can be prevented from clogging inside the suction pump 17. Even when the first substrate and the second substrate are used without using a sheet-like member, the end of the protruding portion may not be in contact with the first substrate. Needless to say.

  For example, in the field of handling sample solutions such as micro TAS, Lab on a chip, micro combinatorial chemistry, chemical IC, chemical sensor, biosensor, trace analysis, electrochemical analysis, chromatography, QCM measurement, SPR measurement, ATR measurement, etc. Can be applied.

It is a top view which shows the structural example of the flow cell of the 1st reference example of this invention. It is the II sectional view taken on the line of FIG. It is a disassembled perspective view at the time of seeing the flow cell of FIG. 1 from the lower surface direction. It is a top view which shows the structural example of the flow cell of the 2nd reference example of this invention. It is the II-II sectional view taken on the line of FIG. It is the III-III sectional view taken on the line of FIG. It is the IV-IV sectional view taken on the line of FIG. It is a disassembled perspective view at the time of seeing the flow cell of FIG. 4 from the lower surface direction. It is a top view which shows the structural example of the flow cell of the 1st Embodiment of this invention. FIG. 10 is a cross-sectional view taken along line VV in FIG. 9. It is a disassembled perspective view at the time of seeing the flow cell of FIG. 9 from the lower surface direction. (A)-(c) It is a top view which shows typically the modification of a meandering groove | channel. It is a block diagram which shows the structural example of an SPR measuring apparatus.

Explanation of symbols

  1, 2, 3 ... flow cell, 11, 21, 31 ... first substrate, 11a, 21a, 31a ... Au layer, 12, 22, 32 ... sheet-like member, 13, 23, 33 ... second substrate, 14 , 24, 34 ... introduction port, 15, 26 ... resistance channel, 16 ... space, 17, 25, 36 ... measurement channel, 18, 27, 38 ... suction pump, 35 ... first resistance channel, 37 ... 2nd resistance flow path, 121, 221 ... slit, 122, 222 ... opening, 131, 231, 331 ... through hole, 132, 232 ... serpentine groove, 133, 233, 334 ... cavity, 133b, 233b, 334b ... protrusion, 133c to 133f, 233c to 233f, 334c to 334f ... air hole, 321 ... slit, 332 ... first serpentine groove, 333 ... second serpentine groove.

Claims (6)

A first substrate through which light passes;
A second substrate disposed on the first substrate;
An opening formed in the second substrate;
A flow path formed between the first substrate and the second substrate and having one end connected to the opening;
A pump unit formed between the first substrate and the second substrate, connected to the other end of the flow path, and sucking the liquid that has reached through the flow path from the opening by surface tension; With
The flow path is
A measurement unit for measuring the liquid;
The measuring unit respectively disposed on the opening side and the pump portion than, have a resistor portion that acts as a resistance to the fluid flowing in the flow channel,
The flow cell characterized in that the measurement section and the resistance section have different flow path widths . The resistor unit according to claim 1 Symbol placement of the flow cell is characterized by consisting of serpentine flow paths. The flow cell according to claim 2 , wherein the meandering flow path has a bent portion bent substantially at a right angle. The flow cell according to claim 2 , wherein the meandering flow path has a bent portion bent in an arc shape. A third substrate interposed between the first substrate and the second substrate;
The resistor portion and the pump portion are formed on at least one of the first substrate and the second substrate,
The measurement unit flow cell according to any one of claims 1 to 4, characterized in that formed on the third substrate. The pump unit includes a recess formed in at least one of the first substrate and the second substrate, and a plurality of columnar members suspended in the recess,
The flow cell according to any one of claims 1 to 5 , wherein the columnar member does not contact the first substrate or the second substrate.

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