JP2006075680A - Multistage extraction chip - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To perform multistage extraction in the flow channel in a microchip by a simple flow channel shape. <P>SOLUTION: Grooves different in cross-sectional area are respectively formed to the surfaces of two substrates and the groove forming surfaces of both substrates are laminated to form a flow channel having a protruded cross section, which comprises flow channel parts different in cross-sectional area, in the chip. A flow channel 14a is meandered in a continuous state while a flow channel 14b is branched into a plurality of flow channels and an extractable flow channel is formed at the place where the flow channel 14a and the flow channel 14b come into contact with each other. When two kinds of solvents different in properties are allowed to flow from an introducing port, multistage extraction can be performed at the place where the flow channel 14a and the flow channel 14b come into contact with each other. A two-phase flow becomes more stable by chemically treating the inner surfaces of the flow channels to make them hydrophilic or hydrophobic and an extraction effect is increased. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  In the present invention, in order to perform a chemical reaction or analysis, a substance in a micro solution, for example, a microorganism, a protein, a nucleic acid, a sugar, an antigen, an antibody, or a mixture in which these are bound is extracted in a microchannel (microchannel). This relates to a multistage extraction chip.

  In recent years, in the field of analytical chemistry, research on μTAS (Micro Total Systems) has been actively performed, and it is expected to use a microchip to speed up analysis, save samples, and save solvents. It has been shown that the reaction in the microspace of the microchip can improve the reaction efficiency over the reaction using the conventional chemical operation.

  When chemical processes and equipment are used in micro size, the interface area per unit volume (referred to as specific interface area) where chemical reaction occurs is larger than in macro size, so it occurs at the liquid-liquid interface. The efficiency of the phenomenon is increased. Further, the liquid flowing through the microchannel due to fluid dynamics has a small Reynolds number because the flow path is fine, and two layers parallel to the same direction as the flow are easily formed.

  For example, when performing extraction between two liquids such as water and phenol that are not mixed, when the flow path is a normal size, the liquid has a two-layered liquid and the reaction area is small and disadvantageous. When the space size of the path is small, the diffusion distance is shortened and the specific interface area of the reaction is also large. Therefore, it is not necessary to perform mechanical mixing, and mixing and extraction can be performed only by molecular diffusion.

Until now, in order to stabilize the two-phase flow in the microchannel, a method of providing a groove-shaped guide on the bottom surface (see Non-Patent Document 1) and a method of providing a broken-line guideline on the bottom surface (see Non-Patent Document 2). ), A method of treating hydrophobicity by chemical modification with a toluene solution of octadecyltrichlorosilane (see Non-Patent Document 3). However, there is a demand for a method that can stably flow a two-phase flow by a simpler method and thereby perform solvent extraction.
JP2000-298079 Anal. Chem., 74, 1565-1571 (2001) Proceedings of the 7th Chemistry and Micro-Nano System Research Meeting P52 2P08 Proceedings of the 7th Chemistry and Micro-Nano System Research Meeting P59 2P15

When performing extraction in a microchannel, a method of forming a flow path on a single substrate and joining a substrate serving as a cover to the substrate has been generally taken, but when forming a flow path capable of multistage extraction, The formation of the flow path on the substrate was difficult to be complicated. Therefore, it is desired to form a flow path that allows solvent extraction by multi-stage interphase molecular transport more simply.
In general, in a microchannel, a two-phase flow is likely to be formed because the Reynolds number is small, but depending on the type of the solvent, a two-phase flow may be difficult to form due to the viscosity of the solvent or the surface tension with the channel surface. Examples include dichloromethane / water, chloroform / water, n-hexane / water, and the like. That is, it is difficult to carry out solvent extraction by carrying out interphase molecular transport in a microchannel using these solvents because the interface becomes unstable and becomes a plug flow.
An object of the present invention is to perform multistage extraction with a microchip with a simple flow channel shape.

  In general, a microchip is manufactured by attaching a cover to a substrate in which a channel or the like is formed on one joint surface. Therefore, if the multistage extraction function is incorporated in the flow channel shape, the arrangement of the flow channels becomes complicated. Since it is possible to form flow paths in the upper and lower substrates, the present invention forms flow paths of different shapes on the bonding surfaces of the upper substrate and the lower substrate, and joins and adheres them so that only one substrate is present. A complicated flow path arrangement as in the case where the flow paths are formed in a single microchip is eliminated, and a multi-stage extraction flow path is integrated on one microchip.

In the present invention, in a chip formed by bonding two substrates having grooves having a cross-sectional shape with a width and depth of 1 mm or less, the surfaces where the grooves are formed are bonded to the interface where the substrates are bonded. In this way, an internal flow path is formed, the flow path of the one substrate has one continuous shape, the flow path of the other substrate includes a plurality of parallel flow paths, and the other parallel flow path Is a multistage extraction chip characterized by merging at a position different from one of the flow paths and performing extraction by interphase molecular transport at each merged portion.
The other channel may be one channel that branches into a plurality of channels to form the parallel channel.

The cross-sectional shape of the flow path at the confluence portion of both flow paths is convex, and the cross-sectional shape of the flow path of one substrate is larger than the cross-sectional shape of the flow path of the other substrate. be able to.
The cross-sectional shape of the flow path at the confluence portion of both flow paths is convex, the inner surface of the flow path of one substrate is hydrophilic, and the inner surface of the flow path of the other substrate is the flow path of the one substrate. It can be made more hydrophobic than the inner surface. Specifically, one or both of the flow path of one substrate and the flow path of the other substrate are chemically modified to be hydrophilic or hydrophobic, or one substrate is hydrophilic and the other substrate is hydrophobic. ing.

  In the case of extraction in a single flow path, the extraction efficiency approaches an equilibrium state and decreases with time, but in the case of the present invention in which separate flow paths are formed on the upper and lower substrates, the flow path on the side to be extracted is reduced. The continuous flow channel shape of the book, the flow channel on the extraction side is merged at multiple locations as a parallel flow channel with multiple flow channels according to the number of extractions, and at the initial concentration due to correlated molecular transport at each merged part Can be extracted and the extraction efficiency can be increased.

By making the cross-sectional shape of the merging portion of the flow path into a convex shape, the cross-sectional shape of the flow path of one substrate is a chip having a larger cross-sectional area and width than the cross-sectional shape of the flow path of the other substrate. A stable two-phase flow is formed in the flow path, and solvent extraction is performed efficiently.
In addition to or in addition to the flow path shapes having different cross-sectional shapes, the inner surface of the flow path of one substrate is hydrophilic, and the inner surface of the flow path of the other substrate is more hydrophobic than the inner surface of the flow path of the one substrate Or a chip configuration in which one or both of the flow path of one substrate and the flow path of the other substrate are chemically modified to be hydrophilic or hydrophobic. Two-phase flow is stabilized.
The two-phase flow is also stabilized by treating the inner surface of the flow path with hydrophilicity or hydrophobicity, and the extraction efficiency can be further increased.

In the stabilization of the gas-liquid interface, it can be applied to a synthesis reaction such as a gas-liquid reaction using a microchannel, and extraction operation can also be performed at the interface of two-phase flow.
Since the structure of the present invention is a simple structure and can be introduced into various chip manufacturing processes, it can be applied to complicated microchips incorporating valves and the like. High integration of microchips and multilayer liquids in microchips are possible. New technical means for forming are provided.

An embodiment of the present invention will be described in detail.
An embodiment of the multistage extraction chip will be described with reference to FIGS.
In FIG. 1, (A) is an upper substrate 10 serving as a cover, (B) is a lower substrate 12, and (C) is a state in which both substrates 10 and 12 are joined. These substrates 10 and 12 are, for example, quartz glass substrates. The upper substrates 10 and 12 are viewed from above. Both substrates 10 and 12 may be made of any material that can form a flow path.

  In FIG. 2, (A) is the XX position of the flow path 14 formed by overlapping the flow path 14a and the flow path 14b, and (B) is a flow path formed by overlapping the flow path 14a and the substrate 12. 14C is a cross-sectional view at the ZZ position of the flow path 14b formed by overlapping the flow path 14b and the substrate 10 at the YY position of 14a.

  On the contact surface side of the glass substrate 10 with the glass substrate 12, a flow path 14 a for flowing a sample having a width 40 of 100 μm and a depth 42 of 40 μm, a hole 16 for introducing a sample, and a hole 18 for discharging A hole 20 for introducing a solvent and a hole 22 for discharging are formed. The flow path 14 a is meandering, and one end is connected to the sample introduction hole 16 and the other end is connected to the discharge hole 18.

  On the contact surface side of the glass substrate 12 with the glass substrate 10, a flow path 14b having a width 46 of 300 μm and a depth 48 of 40 μm is formed. The groove 14b branches into three parallel flow paths 15a, 15b, and 15c in the substrate, and one end of the flow path 14b is connected to the solvent introduction hole 20 that is a through hole formed in the substrate 10, and the like. The end is connected to a solvent discharge hole 22 which is a through hole formed in the substrate 10. A chip 24 shown in (C) is obtained by bonding the substrate 10 on the substrate 12 by bonding with, for example, a hydrofluoric acid solution so that the flow path forming surface overlaps.

Since the flow paths 14 a and 14 b have different flow path shapes, five parallel flow paths, a sample and solvent introduction hole, and a discharge hole are formed in the chip 24.
The widths 40 and 46 and the depths 42 and 48 of the flow path are examples, and both the width and the depth can be changed.

In the XX sectional view shown in FIG. 2 (A), the grooves of the substrates 10 and 12 face each other and are in close contact, but the YY sectional view shown in (B) and ZZ shown in (C). In the cross-sectional view, the grooves 14a and 14b are formed by joining the groove and the substrate facing each other.
In FIG. 1C, a sample to be extracted from the introduction hole 16 is introduced into the flow path 14a, and a solvent to be extracted from the introduction hole 20 is introduced into the flow path 14b. The solvent branches into flow paths 15a, 15b, and 15c and flows in parallel, and solvent extraction is performed in the flow path where two flow paths 14a and 14b join as shown in FIG. Since the sample is not in contact with the extraction solvent at the position where only the flow path 14a exists, the solvent extraction is not performed. Further, only the solvent flows through the flow path 14b at the position where only the flow path 14b exists, but the solvent extraction is not performed because it is not in contact with the sample solution.

Since the sample water flowing through the flow path 14a is extracted by the initial concentration solvent through the flow paths 15a, 15b, and 15c, the extraction effect is increased.
The sample water introduced from the introduction hole 16 is collected by flowing out from the discharge hole 18 after flowing through the flow path 14a and being extracted. The solvent guided from the introduction hole 20 flows through the flow path 14b and is extracted, and then recovered by flowing out from the discharge hole 22.

The effect by the difference in cross-sectional shape of this invention is demonstrated.
In the flow path 14, when a gas is flowed from the introduction hole 16 and water is flowed from the introduction hole 20, easy-flow air flows through the flow path 14 a of the glass substrate 10 having a narrow flow path width, and water that is difficult to flow is glass substrate. Therefore, the two-phase flow in the flow channel 14 is stabilized, and air selectively flows in the flow channel portion 14a of the glass substrate 10 and water selectively flows in the flow channel portion 14b of the glass substrate 12.

The flow path of the embodiment is characterized in that the cross-sectional shape differs between the upper and lower substrates, but by chemically modifying the flow path inner surface, the two-phase flow in the flow path can be further stabilized. it can. For example, it can be treated hydrophobic by chemical modification with a toluene solution of octadecyltrichlorosilane, and can be treated hydrophilic by a photocatalyst such as TiO ₂ .

  As a means for stabilizing the two-phase flow, a hydrophobic or hydrophilic substrate can be used in addition to the chemical modification method. For example, it can be made hydrophilic by using a glass substrate and can be made hydrophobic by using PTFE (polytetrafluoroethylene) as a substrate.

  The means for stabilizing the two-phase flow described above can be combined. For example, a flow path is formed by etching on a glass substrate, and this is chemically treated as a hydrophilic substrate and etched on a PTFE substrate. What formed the flow path with can be used as a hydrophobic substrate.

  The cross-sectional shape of the flow path according to the present invention is determined by the contact portion of the two substrates, and FIG. 3 shows another shape example of the XX cross-sectional view shown in FIG. Regarding the means for processing each sectional shape, the triangular or trapezoidal portions shown in (B), (C), (D), (F), and (H) are obtained by anisotropic etching of the silicon substrate with alkali, and For the rectangles shown in (A), (B), (C), (E), and (G), (E), (F), (G), and (H) are performed by an anisotropic etching method using dry etching. The portions having the curves shown in (1) can be formed by a wet etching method. The cross-sectional shape of the flow channel is not limited to the above shape, and the widths 40 and 46, the depths 42 and 48, and the shapes of the flow channels 14a and 14b can be changed.

FIG. 4 shows an example of a method for manufacturing a microchip manufactured by bonding two substrates each having a channel serving as a channel on the substrate.
(A) First, after the glass substrate 30 is washed, a film of Si, Cr or the like is formed on the surface, and a photoresist 32 is coated thereon.
(B) Next, the photoresist 32 is exposed to UV (ultraviolet) light using the photomask 34.
(C) Thereafter, the photoresist 32 is developed and patterned.
(D) Si and Cr are etched and patterned using the patterned photoresist 32 as a mask, and the glass substrate 30 is etched using, for example, a 46% aqueous hydrofluoric acid solution using the Si and Cr patterns as a mask. A channel groove 36 is formed.
(E) The photoresist 32 is removed, and Si, Cr, etc. are removed.
(F) Similarly, the flow path grooves having different cross-sectional sizes are formed on the other substrates, the surfaces of the both substrates on which the grooves are formed are faced to each other, and the flow path 38 is bonded by a hydrofluoric acid solution. Form.

  As a substrate material, a glass substrate, a silicon substrate, or a resin substrate can be used. In any case, a groove to be a flow path is formed on the bonding surface of the upper substrate and the lower substrate chemically, mechanically, or by various means such as laser irradiation or ion etching so that the grooves overlap. By sticking together, a convex channel used in the present invention can be created.

  The multistage extraction chip according to the present invention can be used for a very small amount of liquid-liquid extraction and a very small amount of gas-liquid reaction.

The top view of the channel shape of the multistage extraction chip of one example is shown, (A) and (B) are the top views showing the channel shape of each substrate, and (C) superposed both substrates. It is a top view which shows the flow-path shape at the time. (A) to (C) are cross-sectional views each showing a cross-sectional shape on the flow path of FIG. 1 (C). (A) to (H) is a cross-sectional view showing an example of a cross-sectional shape of a merged portion of both flow paths. It is process sectional drawing which shows the flow-path formation method by the etching method.

Explanation of symbols

10, 12, 24 Glass substrates 14a, 14b, 14 Flow path 16, 20 Inlet 18, 22 Outlet

Claims (6)

In a chip formed by joining two substrates having a cross-sectional groove with a width and depth of 1 mm or less,
At the interface where the substrates are bonded, internal flow paths are formed by bonding the surfaces on which the grooves are formed,
The flow path of the one substrate has one continuous shape, and the flow path of the other substrate includes a plurality of parallel flow paths,
A multi-stage extraction chip, wherein parallel flow channels of the other flow channel merge at a position different from one flow channel, and extraction is performed by interphase molecular transport at each merged portion.   2. The multistage extraction chip according to claim 1, wherein one of the other channels is branched into a plurality of channels to form the parallel channel.   The cross-sectional shape of the flow path of the confluence portion of both flow paths is convex, and the cross-sectional shape of the flow path of one substrate is larger than the cross-sectional shape of the flow path of the other substrate. Or the multistage extraction chip | tip of 2.   The cross-sectional shape of the flow path at the confluence portion of both flow paths is convex, the inner surface of the flow path of one substrate is hydrophilic, and the inner surface of the flow path of the other substrate is the flow path of the one substrate. The multistage extraction chip according to claim 1, which is more hydrophobic than the inner surface.   5. The multistage extraction chip according to claim 3, wherein one or both of the flow path of one substrate and the flow path of the other substrate in the flow path of the confluence portion are chemically modified to be hydrophilic or hydrophobic. The multistage extraction chip according to any one of claims 1 to 5, wherein one substrate is hydrophilic and the other substrate is hydrophobic.

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