JP2009103624A - Microchannel substrate, and liquid controller arranged therewith - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a microchannel substrate capable of quickly and precisely controlling liquid, and to provide a liquid controller arranged therewith. <P>SOLUTION: The substrate 3 includes an area 33 capable of introducing the liquid, and a heat accumulation part 34 heat-accumulated by irradiation of a laser beam L<SB>1</SB>as a heat source and capable of heating the liquid is formed pattern-likely based on an intensity distribution of the laser beam L<SB>1</SB>in the heat accumulation part 34, on a face faced to the liquid in the area 33, in the substrate 3. A constitutive unit 341 constituting the pattern of the heat accumulation part may be formed to make an area or a volume thereof inverse-proportional to the intensity distribution of the laser beam. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a microchannel substrate and a liquid control apparatus provided with the same. More specifically, the present invention relates to a microchannel substrate or the like in which a heat storage section that can be heated by laser light irradiation is formed in a pattern.

  In recent years, microchips having reaction regions and flow paths for performing chemical and biological analysis on a silicon or glass substrate have been developed by applying microfabrication technology in the semiconductor industry. These microchips are beginning to be used in, for example, electrochemical detectors for liquid chromatography and small electrochemical sensors in the medical field.

  Such an analysis system using a microchip is called a micro-total analysis system (μ-TAS), a lab-on-chip, a biochip, etc., and has high speed and high efficiency in chemical and biological analysis. As a technology that enables downsizing, integration, or downsizing of analyzers, it is attracting attention.

  Since μ-TAS can be analyzed with a small amount of sample, it is particularly useful when dealing with precious trace samples. On the other hand, because of the small amount of sample, temperature control and flow in the reaction region can be performed. There is a basic problem of how to control the liquid flow in the channel with high accuracy.

  As a technique related to this problem, Patent Document 1 discloses a method for adjusting a temperature by heating a liquid component held in an analysis tool (microchip) using light energy from a light source. (Refer to claim 1 of the document). In this case, a method is described in which light energy is supplied to a temperature rising region (heat storage section) provided close to the liquid component, and the liquid component is heated by the thermal energy moving from the temperature rising region. (Refer to claim 3 of the document).

  Further, in Patent Document 2, various conditions relating to a target chemical reaction in a microchannel of a microchannel chip, for example, a temperature condition of a reaction region, a concentration and a flow rate of a reagent solution, and the like can be suitably adjusted. A chip reaction control system is disclosed. In this microchip reaction control system, the temperature of the reaction region can be adjusted by irradiating a laser beam to the minute reaction channel (see claim 16 of the document). Moreover, it is also possible to adjust the temperature of each reaction area | region independently by irradiating a laser beam to a several area | region (refer the said Claims 16 and 20).

  Further, Patent Document 3 discloses an apparatus and method for treating a liquid in a microchannel system with bubbles generated by a movable light beam. This apparatus or the like irradiates the surface portion of the microchannel with a light beam to form a vapor bubble that acts on the liquid in the microchannel (see claim 1 of the document), and the vapor bubble causes a pump function, a valve function, and The mixer function is obtained. Further, it is described that a light absorbing material (heat storage part) may be provided on the surface portion of the microchannel (see claim 9 of the document).

International Publication No. 2003-093835 JP 2006-145516 A JP-T-2005-538287

  According to the techniques disclosed in Patent Documents 1 to 3 described above, by using a laser beam, control of liquid heating, mixing, pumping, and the like is performed in a reaction region or a channel disposed on a microchip. be able to. Further, it is possible to obtain a valve function by generating bubbles in the flow path by laser light.

  Furthermore, a heat storage part is provided in the reaction region and the flow path (see Patent Document 1 and Patent Document 3), and laser light is irradiated to the heat storage part to efficiently convert light energy into heat, thereby heating and mixing. Liquid control such as pumping can be performed at high speed.

  The main object of the present invention is to provide a substrate that enables higher-speed and higher-precision control in liquid control using such laser light and a heat storage unit, and a liquid control device provided with the substrate. .

In order to solve the above problems, the present invention provides a substrate provided with a region into which a liquid can be introduced, the surface of the region facing the liquid being stored by irradiation with laser light as a heat source, and heating the liquid The heat storage part which can be formed is formed in pattern shape based on the intensity distribution of the laser beam in this heat storage part, The board | substrate characterized by the above-mentioned is provided.
The structural unit constituting the pattern of the heat storage unit can be formed such that its area or volume and the intensity distribution of the laser beam are inversely proportional.
In the substrate according to the present invention, the heat storage section may generate bubbles in the liquid by heating the liquid.
In addition, the region may be configured by an introduction flow channel capable of introducing a liquid and a plurality of branch flow channels communicating with the introduction flow channel, and the heat storage section may be formed in the branch flow channel.
In this case, the liquid flow direction in the branch portion between the introduction channel and the branch channel can be controlled by the bubbles generated in the liquid in the introduction channel by the heat storage unit. The

  In addition, the present invention is also a substrate provided with a region into which a liquid can be introduced, wherein the surface of the region facing the liquid is stored by irradiation with laser light as a heat source to heat the liquid. A liquid control device is also provided, in which the heat storage unit to be obtained includes a substrate formed in a pattern based on the intensity distribution of laser light in the heat storage unit, and a laser irradiation unit that irradiates the heat storage unit with the laser light To do.

  In the present invention, the term “liquid” should be interpreted in a broad sense: a homogeneous liquid, a suspension, ie a liquid containing particulate matter such as microparticles or microcells, a liquid containing small bubbles, an aqueous liquid, Organic liquids, two-phase systems and hydrophobic liquids and hydrophilic liquids may be included.

  According to the present invention, a substrate capable of high-speed and high-precision liquid control and a liquid control apparatus provided with the substrate are provided.

  DESCRIPTION OF EXEMPLARY EMBODIMENTS Hereinafter, preferred embodiments for carrying out the invention will be described with reference to the drawings. In addition, embodiment described below shows an example of typical embodiment of this invention, and, thereby, the range of this invention is not interpreted narrowly.

  FIG. 1 is a diagram showing a first embodiment of a substrate according to the present invention provided with a region into which a liquid can be introduced.

  FIG. 1A is a cross-sectional side view of a substrate including one of regions into which liquid can be introduced (hereinafter also referred to as “reaction region”). (B) is a simplified top view of the substrate including the same reaction region.

  In FIG. 1, the substrate denoted by reference numeral 1 includes a substrate body 11 in which a reaction region 13 is formed and a substrate lid 12 that closes the reaction region 13. In the figure, the center of the reaction region 13 is indicated by symbol P.

  In the reaction area 13, a liquid sample for chemical and biological analysis is introduced. Liquid samples (hereinafter simply referred to as “liquids”) include homogeneous liquids, suspensions, ie liquids containing microparticles, liquids containing small bubbles, aqueous liquids, organic liquids, two-phase systems and hydrophobic liquids. In addition, hydrophilic liquids and the like are not particularly limited and are used. In addition, the microparticles include a wide range of microparticles such as bio-related microparticles such as cells, microorganisms, and liposomes, or synthetic particles such as latex particles, gel particles, and industrial particles.

Surface facing the liquid in the reaction region 13, the bottom surface is more specifically this figure (in the figure, the hatched portion) thermal storage unit 14 to the laser beam indicated by reference numeral L ₁ is irradiated are provided. Thus, in the substrate 1, to convert the light energy of the laser light L ₁ to the heat in the heat storage unit 14, by utilizing this heat, it is possible to perform liquid control of the reaction area 13.

Therefore, direct conversion elements such as semiconductor lasers (LD) and light-emitting diodes (LEDs) with high-precision output control and high responsiveness are available for the laser light L ₁ to enable high-precision and high-speed temperature control. Is preferably employed. Furthermore, by using a semiconductor laser (LD) that is excellent in single wavelength (coherence) and can focus on a minute region, each structural unit constituting the heat storage layer 14 (described later) can be accurately used. Laser irradiation can be performed. Also, by using a semiconductor laser (LD) with a resonator in the diode chip, it is possible to obtain a higher output than a light-emitting diode (LED), and the laser light irradiation time is shortened and high-speed temperature control is possible. Can be realized.

In addition, it is desirable that the heat storage unit 14 is formed of a material that is excellent in light absorption with respect to the laser light L ₁ and has a high melting point. Examples of the material of the heat storage unit 14 include metals such as iron, nickel, cobalt, chromium, aluminum, copper, zinc, and tin, and alloys based on these metals, such as stainless steel, carbon steel, brass, white copper, and aluminum alloys. Furthermore, ceramics including alumina, zirconia, titania, silicon nitride, silicon carbide can be used. And the thermal storage part 14 is formed by apply | coating, spraying, welding, or spotting these raw materials. Moreover, the heat storage part 14 can also be formed integrally with the substrate 1 as a fine structure on the surface of the reaction region 13. In this case, the light-absorbing material is added to glass or various plastics (PP, PC, COP, PDMS) as the material of the substrate 1, and the heat storage unit 14 is formed by nanoimprinting or molding.

In order to transmit the laser beam L ₁ to the heat storage unit 14, the substrate lid 12 of the substrate A is formed of a material that can transmit the laser beam L ₁ . The material of the substrate cover 12, for example, glass or plastic is employed having optical transparency to the wavelength of the laser beam L _1. In the drawing, the laser light L ₁ is irradiated from above the substrate, but it is naturally possible to irradiate the laser light L ₁ from below the substrate. In this case, it is necessary to provide the substrate body 11 with the same light transmittance.

Specifically, the substrate 1 (substrate body 11 and the substrate lid 12) is glass and various plastics (PP, PC, COP, PDMS) a is permeable to laser light _{L 1,} the measuring laser light _{L 1} On the other hand, it is formed using a material with little chromatic dispersion and little optical error.

  When the material of the substrate 1 is glass, the reaction region 13 is transferred by wet etching or dry etching. In the case of plastic, the reaction region 13 is formed on the substrate by nanoimprinting or molding. The substrate lid 12 can be a cover seal using the same material as the substrate body 11.

The surface on which the heat storage unit 14 is provided is not limited to the bottom surface of the reaction region 1 shown in the drawing, and may be the side surface or the bottom surface side as long as it faces the liquid in the reaction region 13. Further, when the substrate 1 (substrate body 11 and the substrate lid 12) is permeable to laser light L ₁ is not limited to the surface of these surfaces, the laser beam L ₁ is reachable, the heat storage unit 14 As long as the heat from the heat can be transferred to the liquid, it is possible to configure the heat storage section 14 in the inner layer on the upper surface side, side surface side, or bottom surface side of the reaction region 13.

FIG. 1C shows the distribution of the beam intensity of the laser light L _{1 on} the irradiation surface of the heat storage unit 14. Normally, the beam intensity of laser light is the highest at the center of the optical axis and gradually decreases from the center to the outside. Therefore, the beam intensity of the laser light L _{1 on} the surface of the heat storage section 14 is maximized at the center P of the reaction region 13 and gradually decreases in the peripheral portion of the reaction region 13 as shown in FIG.

Substrate 1, based on the intensity distribution of the laser light L _1, is characterized in that the formation of the heat accumulating portion 14 in a pattern.

  That is, as shown in FIG. 1 (A), the heat storage unit 14 is formed by a plurality of structural units 141 having different sizes, and the size of the structural unit 141 extends from the center P of the reaction region 13 to the peripheral direction. It is configured to gradually increase.

  The simplified top view of FIG. 1B shows that the size (area) of the structural unit 141 gradually increases from the center P of the reaction region 13 toward the peripheral direction. The figure is a schematic diagram and shows each structural unit 141 relatively larger than the reaction region 13. Further, the substrate lid 12 is omitted.

As described above, in the substrate 1, the size (area) of the structural unit 141 of the heat storage unit 13 is small in the vicinity of the center P of the reaction region 13 where the beam intensity of the laser beam L ₁ to be irradiated is large. in the peripheral portion of the laser light L ₁ of the beam intensity is low reaction zone 13, the size of the constituent unit 141 (area) is larger. This is the size of the constituent unit of the heat storage layer 14 (area), it can be seen to be inversely proportional to the beam intensity distribution of the laser light L _1.

2 and 3 show other specific examples regarding the formation pattern of the heat storage section 14 based on the intensity distribution of the laser light L ₁ . FIG. 2 is a simplified top view of the substrate A including the reaction region 13, and FIG. 3 is a cross-sectional side view.

  In FIG. 2, the structural unit 141 of the heat storage unit 14 is circular when viewed from above, and the size (area) of the circular structural unit is configured to gradually increase from the center P of the reaction region 13 to the peripheral direction.

In FIG. 3, the size (volume) is configured to gradually increase from the center P of the reaction region 13 to the peripheral direction by changing the volume of the structural unit 141. That is, in the vicinity of the center P of the reaction region 13 where the beam intensity of the irradiated laser beam L ₁ is large, the height h is low, and conversely, in the periphery of the reaction region 13 where the beam intensity of the irradiated laser beam L ₁ is small. The height h was formed high. Thereby, it is possible to obtain the same effect as when the area of the structural unit 141 is increased.

  The height h of the structural unit 141 can be adjusted by changing the film thickness at the time of film formation by sputtering, or the mold (master) at the time of nanoimprinting or molding, whereby the heat storage amount of the structural unit 141 can be adjusted. It can be set arbitrarily.

  FIG. 4 is a diagram for explaining the heating control of the liquid using the substrate 1.

As described above, in the substrate 1, the heat storage layer 14 is formed of a plurality of structural units 141 whose size (area or volume) is inversely proportional to the beam intensity distribution of the laser light L ₁ . Then, by the irradiation of the laser light L _1, light energy absorbed in each of the structural units 141, dependent on the area or volume.

  Accordingly, in the substrate 1, the light energy absorbed by each structural unit 141 can be made equal, and an equal amount of heat can be generated from each structural unit 141 (see arrow H in FIG. 4).

  As a result, the substrate 1 can uniformly heat the liquid in the reaction flow region 13 without causing local temperature unevenness, and can stabilize predetermined chemical and biochemical reactions performed in the reaction region 13. It is possible to proceed with high reproducibility.

  Moreover, the convection of the liquid in the reaction region 13 can be suppressed by heating the liquid uniformly. Suppression of convection is considered to be effective for chemical reaction control that requires a stable (stable) process such as a chemical reaction between substances having different specific gravities and protein crystallization.

  FIG. 5 is a diagram for explaining another specific example of liquid control using the substrate 1.

FIG. 5 shows a case where the liquid in the reaction region 13 is heated and vaporized by heat generated from the heat storage unit 14 by the irradiation of the laser light L ₁ to generate bubbles in the liquid.

In the substrate 1, the heat storage layer 14 is formed by a plurality of structural units 141, and when the heat storage layer 14 is irradiated with the laser light L ₁ , the liquid in contact with each structural unit 141 is heated and vaporized to generate bubbles B. appear.

At this time, the size (area or volume) of each structural unit 141 is formed so as to be inversely proportional to the beam intensity distribution of the laser light L ₁ , so that the same amount of heat is generated from each structural unit 141 as described above. Thereby, in the substrate 1, it is possible to generate bubbles B having a uniform size in each constituent unit 141.

When pattern formation is performed by changing the size of the structural unit 141 according to the area, in order to avoid the bubbles B generated in each structural unit 141 from contacting and fusing, the distance between the centers of the adjacent structural units 141 is reduced. It is desirable to keep the distance constant. That is, as shown in FIGS. 1B and 2, a small structural unit 141 is located near the center P of the reaction region 13 where the beam intensity of the laser light L ₁ is large, and a large unit is formed around the reaction region 13 where the beam intensity is small. The structural units 141 are arranged so that the distance between the centers is constant. As a result, the heat storage unit 14 is in a state in which the structural units 141 are sparsely arranged (wide gaps) in the vicinity of the center P and the structural units 141 are densely arranged (narrow gaps) in the peripheral portion in the top view.

  Further, in the case of pattern formation by changing the size of the structural unit 141 and changing the height thereof, the generated heat is concentrated on the tip (upper surface) of each structural unit 141 as shown in FIG. As described above, the bubble B can be generated at the tip of each constituent unit 141.

  Such bubble generation in the liquid is performed for the mixing (mixing) of the liquid in the reaction region 13 and the flow control of the liquid in the flow path, which will be described later. It can be suitably used for flow control for separating fine particles in a flow path.

Up to now, the case where the size (area or volume) of the structural unit of the heat storage unit 14 is formed in inverse proportion to the beam intensity distribution of the laser beam L ₁ has been described, but conversely, the beam intensity distribution of the laser beam L _1. It is naturally possible to form the structural unit 141 with a size that is in direct proportion to.

  FIG. 6 is a diagram showing a second embodiment of the substrate according to the present invention in which a region into which a liquid can be introduced is provided.

In the substrate indicated by reference numeral 2 in FIG. 6, the size (area) of the structural unit 241 of the heat storage section 24 is large in the vicinity of the center P of the reaction region 23 where the beam intensity of the irradiated laser light L ₁ is large. the peripheral portion of the laser light L ₁ of the beam intensity is low reaction area 23 to be irradiated is formed smaller. That is, the size (area) of the structural unit 241 is formed to be directly proportional to the beam intensity distribution of the laser light L ₁ .

  6 illustrates the case where the area of the structural unit 241 is configured to gradually decrease from the center P of the reaction region 23 toward the peripheral direction, but as described in FIG. 3, the volume of the structural unit 241 is illustrated. You may change the magnitude | size by changing.

  FIG. 7 is a diagram for explaining the heating control of the liquid using the substrate 2.

As described above, the light energy absorbed in each structural unit 241 of the heat storage unit 24 by irradiation with the laser light L ₁ depends on its area or volume. In the substrate 2, the size of the respective structural units 241 (area or volume), since the formed by direct proportion to the beam intensity distribution of the laser light L _1, larger size of the constituent units 141, and is irradiated A larger amount of heat can be generated in the vicinity of the center P of the reaction region 23 where the beam intensity of the laser beam L ₁ is strong. On the contrary, a smaller amount of heat is generated in the periphery of the reaction region 23 where the size of the structural unit 241 is small and the beam intensity is weak (see arrow H in the figure).

  Thereby, compared with the periphery of the reaction flow area 23, the liquid in the center can be heated at a higher temperature to cause intense convection (see arrow C in the figure) in the liquid. Then, the liquid is effectively stirred by this convection, so that the reaction efficiency of a predetermined chemical and biochemical reaction performed in the reaction region 23 can be increased and advanced rapidly.

  FIG. 8 is a diagram showing a third embodiment of a substrate according to the present invention in which a region into which a liquid can be introduced is provided.

  In FIG. 8, a plurality of reaction regions 33 are arranged on a substrate denoted by reference numeral 3 so as to communicate with an introduction flow path 35 through which a liquid can be introduced. The liquid is introduced from the sample inlet 36 into the introduction flow path 35 and further fed into each reaction region 33. The liquid fed beyond the capacity of the reaction region 33 and the liquid after a predetermined reaction is performed in the reaction region 33 are led to the discharge channels 37 and 37, and the sample discharge ports 38 and 38 are further discharged. To the outside of the substrate A. In the figure, a case is shown in which two flow paths comprising the sample injection port 36, the introduction flow channel 35, the plurality of reaction regions 33, the discharge flow channels 37, 37, and the sample discharge ports 38, 38 are disposed on the substrate. However, the number of flow paths arranged can be two or more.

In this substrate 3, the liquid introduced into each reaction region 33 is independently controlled by the laser light L ₁ scanned by the scanning means D on the scanning line S (see the dotted arrow in the figure) on the substrate 3. be able to. The scanning line 3 is designed so that the reaction region 33 can be sequentially irradiated with the laser light L ₁ for each column.

FIG. 9 (A) comprises a reaction zone 33 where the laser beam L ₁ is irradiated 8 is a sectional side view showing the RR cross-section of the substrate 3. (B) is a simplified top view of the substrate 3 including the same reaction region 33. Reference symbol S in FIG. 9A indicates a scanning line of the laser light L ₁ (see FIG. 8). In FIG. 9B, the substrate lid 32 is omitted.

  As described in FIG. 1, the substrate 3 includes a substrate body 31 in which the reaction region 33 and the like are formed, and a substrate lid 32 that closes the reaction region 33. The material, formation method, and the like of the substrate 3 (substrate body 31 and substrate lid 32) are as described above.

A heat storage section 34 irradiated with the laser light L ₁ is formed in a pattern on the surface (here, the bottom surface) facing each liquid in each reaction region 33. The formation surface and material of the heat storage section 34 are the same as described above.

FIG. 9C shows a distribution of the beam intensity of the laser light L _{1 on} the irradiation surface of the heat storage section 34 in a cross section perpendicular to the scanning line S (an RR cross section in FIG. 8, corresponding to FIG. 9A). As shown, the beam intensity of the laser beam L ₁ is the largest on the scanning line S center of the laser beam L ₁ is positioned gradually becomes smaller as departing from the scan line S.

As shown in FIG. 9B, when the heat storage layer 34 provided on the bottom surface of the reaction region 33 is irradiated with the laser light L ₁ , the light energy applied to the heat storage layer 34 is changed to the scanning line S of the heat storage unit 34. The closer to the position, the larger, and the farther the position, the smaller.

Therefore, in the substrate 3, the size of the constituent units 341 to form the heat storage section 34, formed in accordance with the scanning direction S of the laser beam L _1.

That is, as shown in FIGS. 9A and 9B, the size of the structural unit 341 of the heat storage section 34 is configured to gradually increase from the vicinity of the scanning line S of the laser light L _{1 in} the peripheral direction. This is because the size (area) is small in the structural unit 341 in the vicinity of the scanning line S where the beam intensity of the irradiated laser beam L ₁ is large, and conversely, the beam intensity of the irradiated laser beam L ₁ is small. In the structural unit far from the scanning line S, the size (area) is increased, and the size (area) of the structural unit 341 is formed in inverse proportion to the beam intensity distribution in the scanning direction of the laser light L _1. is there.

  In addition, each structural unit 341 is arranged so that the distance between the centers is constant, and in the heat storage section 34, the structural unit 341 is sparse in the vicinity of the scanning line S in the top view (the gap is wide), and the structural unit is disposed in the peripheral portion. 341 is densely arranged (the gap is narrow) (see also FIG. 10).

10 and 11, based on the intensity distribution in the scanning direction of the laser beam L _1, relates to the formation pattern of the heat storage unit 34, showing the other ingredients regular. 10 is a simplified top view of the substrate 3 including the reaction region 33, and FIG. 11 is a cross-sectional side view.

In FIG. 10, the structural unit 341 of the heat storage section 34 is circular when viewed from above, and the size (area) of the circular structural unit 341 is gradually increased from the scanning line S of the laser light L _{1 in} the peripheral direction. A configured example is shown.

In FIG. 11, the volume (volume) is gradually increased from the scanning line S of the laser light L ₁ to the peripheral direction by changing the volume of the structural unit 341 of the heat storage section 34. In other words, the structural unit 341 in the vicinity of the scanning line S of the laser beam L ₁ having a high beam intensity of the irradiated laser beam L ₁ has a low height, and conversely, the scanning line having a low beam intensity of the irradiated laser beam L _1. In the structural unit 341 far from S, the height is high.

By configuring the heat storage unit 34 in this manner, each of the components can be similarly configured as described with reference to FIG. 4 even when the laser light L ₁ is scanned and the liquid control in the plurality of reaction regions 33 is performed individually. The light energy absorbed by the unit 341 can be made equal to generate the same amount of heat from each structural unit 341.

  As a result, the liquid in the reaction flow region 33 can be heated uniformly without causing local temperature unevenness, and predetermined chemistry and biochemical reactions performed in the reaction region 33 can proceed stably and with high reproducibility. It becomes possible to make it. Moreover, the liquid convection in the reaction region 33 can be suppressed by heating the liquid uniformly.

Furthermore, as described in FIG. 5, in the case where the liquid in the reaction region 33 is heated and vaporized by the heat generated from the heat storage unit 34 by the irradiation of the laser light L ₁ to generate bubbles, It becomes possible to generate bubbles of uniform size.

Further, as described with reference to FIG. 6, the size (area or volume) of the structural unit of the heat storage unit 34 can be formed in direct proportion to the beam intensity distribution in the scanning direction of the laser light L _1. . As a result, as shown in FIG. 7, the liquid in the vicinity of the scanning line S can be heated at a higher temperature than that of the portion far from the scanning line S of the laser light L ₁ , thereby causing intense convection in the liquid. By this convection, the liquid can be effectively stirred to increase the reaction efficiency of predetermined chemical and biochemical reactions performed in the reaction region 33 and to proceed quickly.

  Here, the substrate 3 described here is a liquid flow control device for performing flow control in the flow path by the generation of bubbles in the liquid described below and for sorting the fine particles dispersed in the liquid. It is preferably used for the above.

  FIG. 12 is a schematic diagram illustrating the configuration of the liquid flow control device 4 according to the present invention. Here, as the liquid flow control device 4, a device configured especially for the above-described fine particle sorting is shown.

The liquid flow control device 4 includes a flow path A capable of introducing a fine particle dispersion solvent disposed on a substrate a, and a laser light source 41 that emits laser light L ₁ (see white arrow in the figure) as a heat source. And a laser light source 42 that emits laser light L ₂ (see the black arrow in the figure) for optical measurement of microparticles, and a scanning unit that scans the laser light L ₁ and laser light L ₂ with respect to the channel A 43, an objective lens 44 for condensing the laser beam L ₁ and the laser light L ₂ at a predetermined position of the flow path a. In the figure, reference numerals 411 and 421 denote collimator lenses for making the laser light L ₁ and the laser light L 2 from the laser light source 1 and the laser light source ₂ into parallel rays, respectively.

Further, the liquid flow control device 4 detects the detection target light R (refer to the hatched arrow in the figure) generated from the fine particles in the flow path A by irradiation with the laser light L ₂ (hereinafter referred to as “measurement laser light L ₂ ”). ) Is detected. The detection target light R generated from the fine particles in the flow path A is collected by the objective lens 44, passes through the scanning unit 43, and is guided to the light detection unit 45.

Further, the liquid flow control device 4 receives the analysis unit 46 that analyzes the data output from the light detection unit 45 and the output of the analysis result from the analysis unit 46, and the laser light L ₁ emitted from the laser light source 41. An optical modulator 47 for controlling the laser power is provided.

    The material, the formation method, and the like of the substrate a are as described above.

The laser beam L ₁ is scanned at a predetermined position on the substrate a by the scanning unit 43 and is introduced into the flow path A at a position corresponding to the scanning line of the flow path A (see the dotted arrow S _{2 in the} figure). Air bubbles are generated in the dispersed solvent. Hereinafter, the laser light L ₁ is referred to as “bubble generating laser light L ₁ ”.

Similarly, the measurement laser light L ₂ is scanned at a predetermined position on the substrate a by the scanning unit 43, and the flow path A is at a position corresponding to the scanning line of the flow path A (see the dotted arrow S _{2 in the} figure). The fine particles introduced into the inside are irradiated.

In order to enable high-precision and high-speed temperature control, the bubble-generating laser beam L ₁ has direct conversion elements such as semiconductor lasers (LD) and light-emitting diodes (LEDs) with high-precision output control and high responsiveness. Preferably employed. Furthermore, in order to generate bubbles accurately at a predetermined position in the flow path A, a semiconductor laser (LD) that has excellent single wavelength characteristics (coherence) and can focus on a minute area should be used. desirable. By using a semiconductor laser (LD) with a resonator in the diode chip, it is possible to obtain a higher output than a light emitting diode (LED), and the laser light irradiation time is shortened and high-speed temperature control is realized. can do.

The measurement laser beam L ₂ includes a laser light source 41, a gas laser such as argon or helium, a semiconductor laser (LD), or a light emitting diode (LED) according to the minute particles to be sorted and the purpose of sorting. By appropriately selecting from known light sources such as), laser beams of various wavelengths can be selected and used.

The scanning unit 43 is arranged as a polygon mirror, a galvanometer mirror, an acoustooptic device, an electrooptic device, or the like on the optical path of the bubble generation laser beam L ₁ and the measurement laser beam L ₂ emitted from the laser light source 41 and the laser light source 42. In Figure 12, it constitutes a scanning unit 43 as a dichroic mirror, the bubble generating laser light L ₁ and the measurement laser beam L ₂ is configured to be scanned together.

Scanning of the bubble generating laser light L ₁ and the measurement laser beam L ₂ by the scanning unit 43 is performed in a constant cycle. For example, scanning at about 30,000 rpm is possible by rotating the dichroic mirror at a high speed.

The bubble generation laser beam L ₁ and the measurement laser beam L ₂ are irradiated with each laser beam perpendicularly to each channel, and the positions corresponding to the scanning lines S ₁ and S ₂ in the channel A (laser) It is desirable to use a telecentric optical system in which the spot width of the laser beam is constant on the light imaging plane.

By irradiation of the measurement laser beam L _2, the detection target light R generated from fine particles which has been introduced at a position corresponding to the scanning line S ₂ of the flow path A is detected by the photodetector 45. In FIG. 12, a multi-channel photomultiplier tube (PMT) is used as the photodetector 45, and the detection target light R is grating by the spectroscope 48 and can be detected for each wavelength.

  The detection target light R may be forward scattered light for measuring the size of the measurement target microparticles, side scattered light for measuring the structure, scattered light such as fluorescence, Rayleigh scattering, and Mie scattering. The fluorescence may be coherent fluorescence or incoherent fluorescence.

The light detection unit 45 amplifies the detected light of each wavelength, converts it into an electrical signal, and outputs it to the analysis means 46. The analysis unit 46 analyzes the optical characteristics of the microparticles based on the electrical signal input from the light detection unit 45 and outputs an analysis result as to whether or not to sort the microparticles to the light modulation unit 47. Then, the light modulator 47 receives the output of the analysis result from the analysis means 46, controls the laser power of the bubble generation laser light L ₁ emitted from the laser light source 41, and applies it to the scanning line S ₁ of the flow path A. At the corresponding position, bubbles are generated in the dispersion solvent introduced into the flow path A.

Hereinafter, a method for separating the fine particles by controlling the liquid flow using the bubbles generated in the dispersion solvent by the bubble generation laser light L ₁ will be described.

  FIG. 13 is a diagram for explaining a liquid flow control method and a fine particle sorting method in the liquid flow control device 4.

  FIG. 13 schematically shows one of the flow paths A disposed on the substrate a in FIG. FIG. 12 shows the case where five channels A are provided on the substrate a, but the number of channels A provided on the substrate a is not particularly limited, and one or more channels are provided. A can be appropriately disposed.

As shown in FIG. 13, the flow path A includes an introduction flow path A ₁ into which a fine particle dispersion solvent is introduced, and a branch flow path A ₂ and a branch flow path A ₃ communicating with the introduction flow path A _1. Contains. Hereinafter, the communication part of the introduction flow path A ₁ , the branch flow path A _2, and the branch flow path A ₃ is referred to as a “flow path branch part”.

At one end of the branch channel A ₂ and the branch channel A _3, it is provided a sample reservoir Ap ₂ and the sample reservoir Ap ₃ for pooling microparticles.

Furthermore, the flow path A includes a sample flow path As ₁ for introducing a fine particle dispersion solvent into the introduction flow path A ₁ and a sheath flow for introducing a solvent laminar flow (sheath flow) into the introduction flow path A _1. Roads As ₂ and As ₂ are provided. The dispersion solvent of the microparticles introduced from the sample channel As ₁ is introduced into the introduction channel A ₁ as a laminar flow positioned in the center of the channel by the solvent laminar flow introduced from the _two sheath channels As _2. be introduced. At this time, as shown in the figure, the fine particles are arranged at a constant distance in the laminar flow.

As shown in FIG. 13, the fine particles arranged in the introduction flow path A ₁ at a constant distance interval are measured laser light at a position corresponding to the scanning line of the measurement laser light L ₂ indicated by reference numeral S ₂ in FIG. the L ₂ is irradiated. In the figure, the fine particles irradiated with the measurement laser light L ₂ are indicated by the symbol T.

As described above, the measurement target light R generated from the fine particles T by the irradiation of the measurement laser light L ₂ is detected by the photodetector 45 (see FIG. 12) and converted into an electrical signal, and then the analysis means. 46 is output. The light modulation unit 47 receives the determination result as to whether or not the fine particles T output from the analyzing means 46 are to be sorted, and is emitted from the laser light source 41 when the fine particles T are to be sorted. In the position corresponding to the scanning line S ₁ of the branch channel A ₂ or the branch channel A ₃ (see symbol b in the figure), the bubble power is generated in the dispersion solvent by controlling the laser power of the bubble generating laser beam L ₁ . Is generated. In the figure, showing a case where bubbles are generated branch channel A _2.

The liquid flow control device 4 controls the flow direction of the dispersion solvent in the flow path branching portion based on the increase in flow resistance generated in the branch flow path A ₂ or the branch flow path A _{3 due} to the generation of the bubbles, The flow direction of the particles T is controlled, and the microparticles T are selectively introduced into either the branch channel A ₂ or the branch channel A ₃ , and either the sample reservoir Ap ₂ or the sample reservoir Ap ₃ Store.

Hereinafter, a method for controlling the flow direction of the dispersed solvent in the flow path branching section by using the bubbles generated by the bubble generation laser light L ₁ will be specifically described with reference to FIGS.

  FIG. 14 is a diagram (top view) showing the flow direction in the flow path branching portion when it is determined by the analyzing means 46 that the fine particles T should not be sorted.

In the passage A, the dispersion solvent has been introduced into the introduction channel A ₁ is normally (no fractionation) in the state, flows sent to introduction channel A ₁ into the branch flow path A ₂ which communicates on a straight line (in the figure, an arrow F ₂ reference) are being configured.

Therefore, when it is determined by the analyzing means 46 that the fine particles T should not be sorted, the bubble generation laser light L ₁ corresponds to the scanning line S ₁ of the branch channel A ₂ and the branch channel A _3. By not generating bubbles in any of the positions, the dispersion solvent is sent to the branch flow path A ₂ and the fine particles T are stored in the sample storage part Ap ₂ .

  FIG. 15 shows the flow direction in the flow path branching portion when the analyzing means 46 determines that the fine particles T should be sorted.

When it is determined by the analyzing means 46 that the fine particles T should be sorted, the position corresponding to the scanning line S ₁ of the branch flow path A ₂ (shown by the symbol b in the figure) is generated by the bubble generation laser light L ₁ . Bubbles are generated in the dispersion solvent in the range, hereinafter referred to as “bubble generation range b”. The generation of the bubble, the pressure loss occurs in the branch channel A _2, that the flow resistance branch channel A ₂ is increased, it becomes possible to flow the branch channel A ₂ stagnates temporarily introduced The dispersion solvent sent from the channel A ₁ flows to the branch channel A ₃ (see arrow F _{3 in the} figure). Thus, by introducing a dispersion solvent containing fine particles T in the branch channel A _3, it is possible to retrieve the fine particles T in the sample reservoir Ap ₃ min.

16 and 17 are a cross-sectional view (A) and a simplified top view (B) of the substrate a including the branch flow path A ₂ in the scanning line S ₁ in FIG. 15, and the vicinity of the bubble generation range b in the UU cross section. An enlarged sectional view (C) is shown. Reference sign S _{1 in the} figure indicates a scanning line of the bubble generation laser light L ₁ .

As shown in FIG. 16, in the bubble generation range b of the branch channel A ₂ , a heat storage part a ₄ that is irradiated with the bubble generation laser light L _{1 on the} surface facing the dispersion liquid (here, the bottom surface) It is formed in a pattern in accordance with the scan lines S _1. Incidentally, the same as described above for forming surface and the material, etc. of the heat storage section a _4.

That is, the size of the structural units a ₄₁ of the heat storage unit a _4, the bubble-generating laser beam L scanning lines S ₁ constituent unit a ₄₁ near the beam intensity is large ₁ to be irradiated, the size (area) On the contrary, in the structural unit a ₄₁ that is far from the scanning line S ₁ where the beam intensity is small, the size (area) is increased, and the size (area) of the structural unit a ₄₁ is set to the bubble generation laser light L ₁ . It is formed in inverse proportion to the beam intensity distribution in the scanning line S ₁ .

By thus configuring the heat storage unit a _4, in the same manner as described in FIG. 9, when irradiated in the thermal storage unit a ₄ scans the bubble-generating laser light L _1, which constitutes the heat storage unit a ₄ It is possible to apply equal light energy to each structural unit a ₄₁ and generate an equal amount of heat.

As a result, as shown in FIG. 17, it is possible to uniformly heat and vaporize the dispersion solvent in contact with each structural unit a ₄₁ to generate a large number of bubbles B of uniform size. This bubble, the pressure loss in the branch flow path A within ₂ occurs, by increasing the flow resistance branch channel A _2, it is possible to control the flow sending direction of the above.

Here, based on FIG. 15 again, the timing at which the bubble B is generated by the bubble generation laser light L ₁ will be described.

The generation of the bubble B by the bubble generation laser beam L ₁ is appropriate when the microparticle T irradiated with the measurement laser beam L ₂ scanned on the scanning line S ₂ is sent to the flow path branching portion. It is done at the timing. The control of the irradiation timing of the bubble generating laser light L ₁ is realized by controlling the laser power of the bubble generating laser light L ₁ by the light modulating section 47 (see FIG. 12).

As previously described, the fluid control apparatus 4, the scanning of the bubble generating laser light L ₁ and the measurement laser beam L ₂ is intended to be performed together by the scanning unit 43 (see FIG. 12). Since this scanning is performed at an extremely short period (for example, 30,000 rpm), the bubble generation laser light L ₁ and the measurement laser light L ₂ are minutely irradiated with the measurement laser light L ₂ on the scanning line S _2. The scanning line S ₁ and the scanning line S ₂ are each scanned a plurality of times before the particle T reaches the flow path branching portion. The light modulation unit 47 increases or switches the laser power of the bubble generation laser light L ₁ from off to on at an appropriate timing while the bubble generation laser light L ₁ is scanned a plurality of times. bubbles are generated B in the dispersion solvent in the _2, introducing the fine particles T in the branch channel a _3.

After the disappearance of the bubble, the flow resistance branch channel A ₂ is reduced, because the retention of the flow branch channel A ₂ is eliminated, dispersion solvent for the microparticles, as described in FIG. 14, the introducing flow It is sent from the path A ₁ to the branch flow path A ₂ (see arrow F _{2 in} FIG. 14). As a result, the next microparticles arranged at regular intervals in the introduction flow path A ₁ are sent onto the scanning line S ₁ of the measurement laser light L ₁ and fractionation is performed by the same procedure. Become.

At this time, if the bubbles B generated in the dispersion solvent in the branch flow path A ₂ are maintained for an excessively long time, even the microparticles that should not be introduced into the branch flow path A ₃ are likely to be introduced into the sample reservoir Ap. There is a possibility that it will be sorted into ₃ .

This is because, when vaporizing the dispersion solvent by irradiation of the bubble generating laser light L _1, by heating unduly dispersion solvent, tends to occur when a bubble large occurs. This is because the heat transfer coefficient of the solvent and air is lower in air, and the internal heat is difficult to disperse and disappear in a large bubble.

Therefore, in order to sort out the fine particles arranged and sent at regular intervals in the introduction flow path A ₁ with high accuracy, the bubble B is appropriately sized and one fine particle is divided into the branch flow path A _3. necessary and sufficient time for introduction into, it is necessary to stay the flow branch channel a _2.

Therefore, the liquid flow control device 4, as described above, the heat storage unit a ₄ to form a bubble generation range b of the branch flow path, the size based on the beam intensity distribution in the scan lines S ₁ of the bubble generating laser L ₁ is It is composed of a plurality of structural units a ₄₁ that are changed. Thereby, it is possible to generate a large number of bubbles having a uniform size in the bubble generation range b.

Further, the center distance between the structural units a ₄₁ adjacent constant, bubbles B generated by each of the structural units a ₄₁ contact, are configured so as not to fuse. Each structural unit a ₄₁ generates an equal amount of heat and generates bubbles B of uniform size, but in this case as well, if the bubbles B generated between adjacent structural units a ₄₁ merge, the bubbles B become larger. There is a possibility that. The center-to-center distance between the structural units a ₄₁ is constant, and the bubbles B generated from the structural units a ₄₁ are arranged at regular intervals, thereby preventing the bubbles B from contacting and increasing the size. It becomes possible to do.

  As described above, in the liquid flow control device 4, since the contact area with the solvent is large with respect to the bubble volume, the waste heat property is good, and a large number of small bubbles that can disappear in a short time are formed. By increasing the flow resistance, it is possible to control the flow direction in the flow path branching section more flexibly, with high accuracy and at high speed, compared to the conventional method of generating large bubbles alone.

For comparison, FIG. 18 illustrates a bubble B generated when the heat storage unit a ₄ is configured as a single continuous region in accordance with the prior art.

  In addition, in FIG. 13 to FIG. 15, the case where two branch channels are provided and the fine particles are separated into two populations according to the optical characteristics has been described as an example. However, when two or more branch channels are provided Is of course possible.

  For reference, FIG. 19 shows a channel A provided with three branch channels.

A channel A shown in FIG. 19 includes a branch channel A ₄ as a branch channel communicating with the introduction channel A ₁ in addition to the branch channel A ₂ and the branch channel A ₃ . Then, the one end of the branch channel A _4, the sample storage portion Ap ₄ for pooling the fine particles are provided.

In the flow channel A shown in FIG. 19, the fine particles introduced into the introduction flow channel A ₁ are in a straight line with respect to the introduction flow channel A _{1 in} a normal state (without sorting). (in the figure, an arrow F ₂ references) feeding into ₂ flows are configured.

Accordingly, when it is determined by the analyzing means 46 that the fine particles T should not be sorted, the branch channel A ₂ , the branch channel A _3, and the branch channel A ₄ are scanned by the bubble generation laser light L ₁ . by at any position corresponding to line S ₁ is not generated bubbles, (see arrow F ₂₎ fine particles T is introduced into the branch channel a _2, it is stored into the sample reservoir Ap _2.

On the other hand, when it is determined by the analysis means 46 that the fine particles T should be sorted, the branch flow path A ₂ and the branch flow path A are generated by the bubble generation laser light L ₁ as shown in FIG. If the bubble B is generated at the position corresponding to the scanning line S _{1 of 3} (bubble generation range b), the fine particles T can be introduced into the branch channel A ₄ and sorted into the sample storage part Ap ₄ . It can become (see the arrow in the figure F _4).

In addition, if bubbles B are generated in (the bubble generation range b) of the branch channel A ₂ and the branch channel A ₄ , the microparticles T are introduced into the branch channel A ₃ and separated into the sample reservoir Ap ₃ . It is also possible to take.

  According to the fluid control device 4, by generating a large number of small bubbles that disappear in a short time, even when fine particles are separated into three or more populations in this way, the flow direction can be flexibly and rapidly increased. Control can be performed, and high-precision sorting can be performed.

Furthermore, in FIG. 13 to FIG. 15 and FIG. 19, one of the flow paths A is schematically enlarged and described. However, as described with reference to FIG. generating laser light L ₁ and the measurement laser beam L _2, by being scanned on the scanning line S ₁ and the scanning line S ₂ by the scanning unit 43, an optical measurement of fine particles as described above at the same time in all of the flow paths a And sort.

  The substrate according to the present invention is suitably used as a microchip for performing chemical and biological analyses, and can be used for, for example, an electrochemical detector for liquid chromatography or a small electrochemical sensor in a medical field. .

It is a figure showing a first embodiment of a substrate concerning the present invention. It is a figure which shows the example of a formation pattern of the thermal storage part. It is a figure which shows the example of a formation pattern of the thermal storage part. It is a figure explaining the liquid control using the board | substrate 1. FIG. It is a figure explaining the liquid control using the board | substrate 1. FIG. It is a figure which shows 2nd embodiment of the board | substrate which concerns on this invention. It is a figure explaining the liquid control using the board | substrate 2. FIG. It is a figure which shows 3rd embodiment of the board | substrate which concerns on this invention. FIG. 3 is a diagram illustrating a configuration of a substrate 3. It is a figure which shows the example of a formation pattern of the thermal storage part. It is a figure which shows the example of a formation pattern of the thermal storage part. It is a figure explaining the composition of liquid flow control device 4 concerning the present invention. It is a figure explaining the liquid flow control method and the fine particle fractionation method in the liquid flow control apparatus. It is a figure which shows the flow direction in the flow-path branching part when it determines with the analysis means 46 not to fractionate the microparticle T. FIG. It is a figure which shows the flow direction in a flow-path branch part, when it determines with the analysis means 46 having to fractionate the microparticles T. It is a figure explaining the structure of the board | substrate a. It is a figure explaining the liquid control using the board | substrate a. It is a figure (reference drawing) explaining the liquid control by a prior art. It is a figure explaining the flow control method in the flow path A which provided three branch flow paths.

Explanation of symbols

1, 2, 3, a Substrate 11, 21, 31 Substrate body 12, 22, 32 Substrate lid 13, 23, 33 Reaction region 14, 24, 34 Heat storage unit 141, 241, 341 Structural unit 35, Introducing flow path 36 Sample Injection port 37 Discharge flow path 38 Sample discharge port 4 Fluid control devices 41 and 42 Laser light sources 411 and 412 Collimator lens 43 Scan unit 44 Objective lens 45 Light detection unit 46 Analyzing means 47 Light modulation unit 48 Spectrometer
A flow path
A ₁ Introduction channel
A ₂ , A ₃ , A ₄ branch flow path
Ap ₂ , Ap ₃ , Ap ₄ sample reservoir
B bubbles
L ₁ laser light (bubble generation laser light)
L ₂ laser light (measurement laser light)
R Light to be detected
T fine particles

Claims (6)

A substrate provided with a region into which a liquid can be introduced,
The surface of the region facing the liquid is stored in a pattern based on the intensity distribution of the laser light in the heat storage unit, which stores heat by irradiation with laser light as a heat source and can heat the liquid. A substrate characterized by that.   2. The substrate according to claim 1, wherein the structural unit constituting the pattern of the heat storage part is formed so that an area or volume thereof and an intensity distribution of the laser light are in inverse proportion.   The substrate according to claim 2, wherein the heat storage unit generates bubbles in the liquid by heating the liquid. The region comprises an introduction channel capable of introducing a liquid and a plurality of branch channels communicating with the introduction channel,
The substrate according to claim 3, wherein the heat storage unit is formed in the branch flow path.   The flow direction of the liquid in a branch portion between the introduction channel and the branch channel can be controlled by bubbles generated in the liquid in the branch channel by the heat storage unit. 4. The substrate according to 4. A substrate provided with a region into which a liquid can be introduced, and a heat storage unit that stores heat by irradiating a laser beam as a heat source on a surface facing the liquid in the region and can heat the liquid, A substrate formed in a pattern based on the intensity distribution of the laser beam;
And a laser irradiation unit that irradiates the heat storage unit with the laser light.