KR20170107723A - Microparticle separator having weir - Google Patents

Microparticle separator having weir Download PDF

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Publication number
KR20170107723A
KR20170107723A KR1020160031417A KR20160031417A KR20170107723A KR 20170107723 A KR20170107723 A KR 20170107723A KR 1020160031417 A KR1020160031417 A KR 1020160031417A KR 20160031417 A KR20160031417 A KR 20160031417A KR 20170107723 A KR20170107723 A KR 20170107723A
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KR
South Korea
Prior art keywords
flow path
passage
dam
injection
recovery
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KR1020160031417A
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Korean (ko)
Inventor
이승백
윤유상
최재웅
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한양대학교 산학협력단
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Priority to KR1020160031417A priority Critical patent/KR20170107723A/en
Publication of KR20170107723A publication Critical patent/KR20170107723A/en

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502761—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502769—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/026—Fluid interfacing between devices or objects, e.g. connectors, inlet details
    • B01L2200/027—Fluid interfacing between devices or objects, e.g. connectors, inlet details for microfluidic devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
    • B01L2200/0652—Sorting or classification of particles or molecules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/088—Channel loops

Abstract

A fine particle separation element comprising a weir is provided. The fine particle separation element comprises: a main flow path located between opposing upper and lower walls; a first injection flow path and a second injection flow path connected to one longitudinal end portion of the main flow path; a first recovery flow path and a second recovery flow path connected to the other longitudinal end portion of the main flow path; a flow path forming layer including a weir connecting a wall between the first recovery flow path and the second recovery flow path and the upper wall of the main flow path; and a cover layer disposed on the flow path forming layer and forming a gap between the banks. According to the present invention, by arranging a weir structure forming a gap in the fine particle separation element, purity and throughput can be increased in sorting the particles from a dispersion by size. Further, by arranging multiple weir structures having different gaps in the fine particle separation element, it is possible to carry out classification by the particle size in a wider range. In addition, classification of a suspension liquid by size, at the same time, chemical treatment such as attachment of markers and dyeing can be performed to effectively control the fine particles.

Description

[0001] Microparticle separator having weir [

The present invention relates to a fluid device, and more particularly to a fine particle separation element.

The microfluidic device refers to a device for sorting or capturing a dispersion containing fine particles of various sizes by size. Such a microfluidic device is expected to be used for classification of fine organic and inorganic particles, separation of contaminants in microfluid, classification of blood cells, separation of rare cells such as blood cancer cells, or liquid biopsy.

Techniques for capturing or separating fine particles of a specific size or larger in a suspension have already been commercialized using a membrane filter or a filter made by a fine process.

However, the conventional techniques have the problem that the holes or gaps of the filter become smaller due to the particles larger than the target size, and thus particles smaller than the target size are also caught. Further, there is a problem that the oil pressure increases in proportion to the filtration of the particles, so that the target particles are lost, and finally, the element is damaged.

Further, in the case of fine particle separation through a filter, particles are trapped in the filter during filtration. In the case of a cell, it is difficult to collect it on a filter. In the case of a cross flow filtration technique, However, there is a problem that it is difficult to remove the target particles and other particles except for the cells.

Disclosure of Invention Technical Problem [8] The present invention provides a fine particle separating element capable of increasing the purity and the throughput in sorting particles from a suspension by arranging a weir structure having a gap between the covering layer and the cover layer.

According to an aspect of the present invention, there is provided a fine particle separator. The fine particle separator includes a main flow path located between facing upper and lower walls, a first injection path and a second injection path connected to one longitudinal end of the main flow path, and a second injection path connected to the other longitudinal end of the main flow path A flow path forming layer including a first return flow passage and a second return flow passage, and a dam connecting a wall between the first return flow passage and the second return flow passage and an upper wall of the main flow passage, And a cover layer that forms a gap between the banks.

The first injection path and the first recovery path may be disposed closer to the lower side wall than the upper side wall and the second injection path and the second recovery path may be disposed closer to the upper side wall than the lower side wall.

Wherein the second infusion passage is a suspension infusion passage containing a first particle and a second particle smaller in size than the first particle, the first particle is recovered in a first recovery passage, and the second particle is recovered in a second And can be recovered from the recovery flow path.

The suspension is blood, the first particle is blood cancer cells, and the second particle may be blood cells.

The first injection path may be a buffer solution injection path.

In the first recovery flow path, the buffer solution may be recovered together with the first particles.

In the main flow path, the suspension flowing through the first injection path and the buffer solution flowing through the second injection path may form a laminar flow.

Wherein the dam has a first sidewall facing the injection channels and a second sidewall facing the second recovery channel, the first sidewall having a first sidewall and a second sidewall, the first sidewall and the second sidewall, And may have a shape tilted so as to be narrowed in width.

The second sidewall may be inclined so that a width between the first sidewall and the second sidewall becomes narrower toward the lid layer.

The cross section of the dam may be rectangular.

The dam may have a rounded edge.

The angle between the upper wall and the dam may be between 0.1 [deg.] And 10 [deg.].

The angle between the upper wall and the dam may be between 0.8 ° and 1.5 °.

Wherein the bank is the first bank and the flow path forming layer is connected to the other end portion in the longitudinal direction of the main flow path and has a third recovery flow passage which is disposed closer to the upper side wall than the second recovery flow passage, Further comprising a second dam connecting a wall between the third return flow paths and an upper wall of the main flow path and spaced apart from the first dam, wherein a gap between the second dam and the cover layer can be formed have.

The height of the gap between the second dam and the cover layer may be smaller than the height of the gap between the first cover and the cover layer.

The first injection path may further include a suspension injection path, a buffer solution injection path, a first processing solution injection path, and a second processing solution injection path which are separated from each other and arranged in sequence.

The suspension injection path is disposed closest to the upper side wall of the main flow path,

The buffer solution injection path may be disposed between the suspension injection path, the first processing solution injection path, and the second processing solution injection path.

The treatment liquid in the first treatment liquid injection path and the second treatment liquid injection path may include a fixer or a staining solution.

According to another aspect of the present invention, there is provided a method for separating fine particles. The particle separation method includes a main flow path located between facing upper and lower walls, a first injection flow path and a second injection flow path connected to one longitudinal end portion of the main flow path, A flow path forming layer disposed on the flow path forming layer and including a first return flow path and a second return flow path, and a dam connecting a wall between the first return flow path and the second return flow path and an upper wall of the main flow path, And a cover layer forming a gap between the first particle and the second particle, and injecting a suspension containing the first particle and the second particle smaller in size than the first particle into the first injection path, The first particles may be recovered in the first recovery flow passage, and the second particles may be recovered in the second recovery flow passage.

The suspension flows through the first infusion passage and the buffer solution flows through the second infusion passage so that the suspension and the buffer solution form a laminar flow in the main passage.

A detector may be attached to the first return passage or the cover layer.

According to the present invention, by arranging a weir structure that forms a gap in the fine particle separation element, purity and throughput can be increased when sorting the particles from the suspension.

Further, by arranging multiple weft structures having different heights of gaps in the fine particle separating element, it is possible to carry out the classification by particle size in a wider range.

Further, the microparticles can be effectively controlled by classifying the suspension by size and simultaneously performing chemical treatment such as attachment of markers and dyeing.

The technical effects of the present invention are not limited to those mentioned above, and other technical effects not mentioned can be clearly understood by those skilled in the art from the following description.

1 is an exploded perspective view illustrating a fine particle separation device according to a first embodiment of the present invention.
2A and 2B are a perspective view and a cross-sectional view illustrating the operation of the fine particle separation device according to the first embodiment of the present invention.
3 is a schematic view showing the shape of banks according to embodiments of the present invention.
4 is a schematic view showing the shape of dams according to other embodiments of the present invention.
5 is an exploded perspective view illustrating a fine particle separation device according to a second embodiment of the present invention.
6 is a cross-sectional view taken along the line X-X 'in FIG.
FIG. 7 is an exploded perspective view illustrating a fine particle separation device according to a third embodiment of the present invention. FIG.
8A and 8B are an exploded perspective view and a cross-sectional view of a fine particle separator according to a fourth embodiment of the present invention.
9A and 9B are a schematic diagram and a graph showing a pressure difference to a dam according to Experimental Example 1 of the present invention.
FIG. 10 is a photograph of an experiment using blood in the device of the first embodiment of the present invention. FIG.
11 is a graph showing the separation efficiency of the device according to Experimental Example 2 of the present invention.
12 is a graph showing a separation efficiency of a device according to Experimental Example 3 of the present invention.

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings.

While the invention is susceptible to various modifications and alternative forms, specific embodiments thereof are shown by way of example in the drawings and will herein be described in detail. Rather, the intention is not to limit the invention to the particular forms disclosed, but rather, the invention includes all modifications, equivalents and substitutions that are consistent with the spirit of the invention as defined by the claims.

It will be appreciated that when an element such as a layer, region or substrate is referred to as being present on another element "on," it may be directly on the other element or there may be an intermediate element in between .

Although the terms first, second, etc. may be used to describe various elements, components, regions, layers and / or regions, such elements, components, regions, layers and / And should not be limited by these terms.

1 is an exploded perspective view illustrating a fine particle separation device according to a first embodiment of the present invention.

Referring to FIG. 1, a flow path forming layer 200 may be formed on a base layer 100 in a plate shape. The base layer 100 may be an insulating layer formed on a silicon substrate or a silicon substrate. The insulating layer may be a silicon oxide film.

The grooves are formed in the flow path forming layer 200 to form grooves in the flow path forming layer 200 so as to form grooves in the flow path forming layer 200. The main flow path 220, the first injection path 211, the second injection path 212, the first recovery path 213, Flow paths can be formed. The main flow channel 220 may be positioned between the upper and lower walls 220a and 220b facing each other.

The first infusion passage 211 and the second infusion passage 212 may be connected to one end portion of the main passage 220 in the longitudinal direction and the other end portion in the longitudinal direction of the main passage 220 The first recovery flow path 213 and the second recovery flow path 214 may be connected to each other. The first inflow passage 211 and the first return passage 213 may be disposed closer to the lower wall 220b than the upper wall 220a of the main passage 220. [ The second injection flow passage 212 and the second recovery flow passage 214 may be disposed closer to the upper side wall 220a than the lower side wall 220b of the main flow passage 220. [

For example, the thickness (H) of the flow path forming layer 200 may be 10 탆 to 50 탆. The height of the grooves in the flow path forming layer 200 forming the flow paths 220, 211, 212, 213 and 214, that is, the height of the walls forming the flow paths 220, 211, 212, 213 and 214, And may be 10 [mu] m to 50 [mu] m. The width W m of the main flow channel 220 may be 0.6 mm to 2 mm and the length of the main flow channel may be 6 mm to 60 cm. The widths W f of the flow passages 211, 212, 213, and 214 excluding the main flow channel 220 may be equal to or different from each other within a range of 0.3 mm to 1 mm.

A dam 221 connecting the wall between the first recovery passage 213 and the second recovery passage 214 and the upper wall 220a of the main passage 220 is formed in the passage forming layer 200, Can be installed. For example, the dam 221 may be formed obliquely at an angle with respect to the longitudinal direction of the main channel 220. For example, the angle θ formed between the dam 221 and the upper wall 220a of the main flow path 220 may be 0.1 ° to 10 °. For example, the angle [theta] may be between 0.8 [deg.] And 10 [deg.]. Specifically, the angle [theta] may be 0.8 [deg.] To 7 [deg.]. The angle [theta] may be between 0.8 [deg.] And 3 [deg.]. The angle &thetas; may be 0.8 DEG to 1.5 DEG.

When the angle θ formed between the dam 221 and the upper wall 220a of the main passage 220 exceeds 10 °, a suspension to be flown in the main passage 220 flows into the dam 221, The pressure applied to the suspension in the direction perpendicular to the dam 221 increases, so that the separation efficiency of the fine particles of the suspension may be lowered. The separation process of the fine particles of the suspension will be described later in detail with reference to FIGS. 2A and 2B. The angle θ of the dam 221 will be described in detail later with reference to FIGS. 8A and 8B.

At the distal end of each of the flow paths 211, 212, 213, and 214, reservoirs for storing suspensions, buffer solutions, or particles may be formed. For example, the first storage part 201 and the second storage part 210 are formed at the ends of the first injection path 211, the second injection path 212, the first recovery path 213 and the second recovery path 214, respectively. 2 storage unit 202, a first particle storage unit 203, and a second particle storage unit 204 may be formed.

The formation of the channels 200, 211, 212, 213, 214, the banks 221 and the reservoirs 201, 202, 203, 204 in the channel forming layer 200 can be performed by photolithography or Stamp method can be used. The channel forming layer 200 may be made of a polymer material. The polymer may be polymethylmethacrylate (PMMA), acryl, SU-8 or polydimethylsiloxane. Thereafter, the surface of the patterned flow path forming layer 200 may be modified using APTES (3-Aminopropyl) triethoxysilane. As a result, the surfaces exposed in the surface and the flow paths 220, 211, 212, 213, 214 and the storage portions 201, 202, 203, 204 of the flow path forming layer 200 can be modified.

On the other hand, a cover layer 300 may be formed on the channel forming layer 200. The cover layer 300 may include a first injection hole 301, a second injection hole 302, a first particle recovery hole 303, and a second particle recovery hole 304. The first filling hole 301, the second filling hole 302, the first particle collecting hole 303 and the second particle collecting hole 304 of the cover layer 300 are respectively formed of the material of the flow path forming layer 200 1 storage unit 201, the second storage unit 202, the first particle storage unit 203, and the second particle storage unit 204, as shown in FIG. The first injection hole 301 may be connected to a passage through which a suspension may be injected from the outside.

A gap may be formed between the cover layer 300 and the bank 221 of the flow path forming layer 200. Therefore, the height of the dam 221 should be smaller than the height of the groove of the channel forming layer 200.

The detector 400 'of FIG. 1 will be described in detail with reference to FIG. 7B to be described later.

FIG. 2A is a perspective view showing a part of FIG. 1, FIG. 2B is a sectional view taken along the line X-X 'in FIG. 1, and FIG. Sectional view.

Referring to FIGS. 2A and 2B, the microparticle-containing suspension may be injected through the first injection hole (301 in FIG. 1). For example, the suspension may be blood, but is not limited thereto. At this time, the suspension may contain fine particles 230, 231 of different sizes. For example, the relatively large particle may be the first particle 231, and the particle smaller than the first particle 231 may be the second particle 230. For example, the first particles 231 may be blood cancer cells. The second particles 230 may be blood cells.

The injected suspension may flow through the second storage part 202 and through the second injection flow path 212 in the F direction. At this time, if the buffer solution is flowed in the first storage part 201 in the same direction (F ') as the flow of the suspension through the first injection flow path 211, the suspension and the buffer solution may be laminar flow (F, F '). At this time, the laminar flows (F, F ') formed by the suspension and the buffer solution can reach the dam (221) formed in the main flow path (220) while maintaining the suspension at a constant flow rate.

When the suspension reaches the dam 221 in the main flow path 220, the second particle 230 of the fine particles 230 and 231 in the suspension flows through the dam 221 and the cover layer 330, (F a ) of the gap 224 is smaller than the height h g of the gap 224 formed between the first particle storage portion 204 and the second particle storage portion 204, . The first particles 231 of the fine particles 230 and 231 are larger than the height h g of the gap 224 and can not pass over the dam 221, As shown in FIG. Then, the first particles 231 meet the buffer solution flowing in the direction F 'and are collected together in the direction of F b , and recovered together with the buffer solution in the first recovery channel 213.

Thus, the microparticles 230 and 231 of the microparticle-containing dispersion can be classified by size using the gap 224 formed by the dam 221. Further, in the fine particle separation device according to an embodiment of the present invention, when the filter is used in the conventional fine particle separation element by using the dam 221, fine particles are trapped or broken between the filters The effect of maximizing purity and throughput during particle classification can be achieved.

3 is a schematic view showing the shape of banks according to embodiments of the present invention.

Referring to FIG. 3A, the height h g of the gap 224 can be adjusted by adjusting the height h w of the dams 221. For example, the height h w of the dam 221 may be between 18 μm and 45 μm. For example, the height (h g) of the weir 221, the height (h w) and the gap 224 of the 3: may have a ratio of 1: 1 to 5. For example, the height h g of the gap 224 may be between 6 μm and 9 μm.

The height h g of the gap 224 may be set in consideration of the size of the particles to be separated and the fluid resistance.

The weir 221 may have a width (w) of 20 μm to 100 μm. If the width w of the dam 221 is less than 20 占 퐉, the flow rate of the flowing fluid is increased and the resistance of the fluid becomes too low, so that the separation efficiency may be lowered. If the width w of the weir 221 is 60 탆 or more, the flow resistance of the flowing fluid may become too high to lower the separation efficiency.

The dam 221 has a first sidewall 226 facing the injection flow paths 211 and 212 and a second sidewall 227 facing the second recovery flow path 213, . ≪ / RTI > The cross section of the dam 221 may be a square. The corners of the dam 221 may be rounded. Thereby, when the suspension passes over the dam (221), damage of the fine particles in the suspension can be prevented.

3A and 3B, the first sidewall 226 is inclined so that the width between the first sidewall 226 and the second sidewall 227 decreases toward the lid layer 300, Lt; / RTI > For example, the shape of the dam 221 may be trapezoidal, but is not limited thereto. The shape of the weir 221 is made to be a trapezoid so that turbulence is prevented from being formed when the suspension passes over the weir 221 so that the shape of the weir of FIGS. 3C and 3D, that is, the shape of the first side wall 226 ) Can form a more natural flow of fluid.

4 is a schematic view showing the shape of dams according to other embodiments of the present invention.

4A and 4D, a bottom bank 221 is disposed in the flow path forming layer 200, and an upper bank 221 'is disposed in the cover layer 300. At this time, a gap 224 may be formed in a space between the lower dam 221 and the upper dam 221 '. Referring to FIG. 3, the upper dam 221 'may have a shape symmetrical with the lower dam 221. Referring to FIG.

5 is an exploded perspective view illustrating a fine particle separation device according to a second embodiment of the present invention.

Referring to FIG. 5, the fine particle separation device according to the second embodiment of the present invention may be the same as that described in FIG. 1 except for the following features.

A plurality of banks 221a and 221b may be provided in the flow path forming layer 200. E.g,

A first injection channel 211 and a second injection channel 212 may be connected to one end of the main channel 220 in the longitudinal direction of the main channel 220. In the other end of the main channel 220 in the longitudinal direction, The recovery flow path 213 and the second recovery flow path 214 may be connected to each other. The first injection passage 211 and the first recovery passage 213 may be disposed closer to the lower wall 220b than the upper wall 220a of the main passage 220. [ The second injection flow passage 212 and the second recovery flow passage 214 may be disposed closer to the upper side wall 220a than the lower side wall 220b of the main flow passage 220. [

The flow path forming layer 200 is connected to the other longitudinal end portion of the main flow path 220 and includes a third recovery flow path 215 disposed closer to the upper side wall 220a than the second recovery flow path 214 .

A first dam 221a connecting a wall between the first recovery passage 213 and the second recovery passage 214 to the upper wall 220a of the main passage 220 may be installed. The wall between the second recovery flow passage 214 and the third recovery flow passage 215 is connected to the upper wall 220a of the main flow passage 220, The second dam 221b may be further installed.

The angle formed between the first dam 221a and the upper wall 220a of the main passage 220 and the angle between the second dam 221b and the upper wall 220a of the main passage 220 The angle? 'May be formed to be the same.

6 is a cross-sectional view taken along line X-X 'in FIG.

Referring to FIG. 6, the dam according to the second embodiment of the present invention is the same as that described in FIG. 2 except for the following features.

A first gap 224a and a second gap 224b may be formed between the first dam 221a and the second dam 221b and the cover layer 300, respectively. At this time, the first the first dam (221a) and the cover layer 300 is the height (h g) and the second weir (221b) and the cover layer 300 of the first gap (224a) constituting the forming And the height h g 'of the two gaps 224b may be different from each other.

For example, the height h g 'of the second gap 224b may be less than the height h g of the first gap 224a. Here, when the heights of the gaps 224a and 224b are different from each other, the height h w of the first dam 221a and the height h w 'of the second dam 221b It must be different.

Referring again to FIGS. 5 and 6, when a suspension containing microparticles of different sizes is flowed in the direction F in accordance with the same principle as described in FIGS. 2A and 2B, the first duck The particles which can not pass through the first recovery passage 221 can be collected in the first recovery passage 213. [ Particles that have not passed through the second gap 224b among the particles passing through the first gap 224a are discharged to the second recovery passage 214 while particles passing through the second gap 224b are discharged to the third recovery And the flow path 215, respectively.

That is, the fine particle separation device according to the second embodiment of the present invention can classify fine particles into finer sizes by providing two or more kinds of weaves having different sizes.

FIG. 7 is an exploded perspective view illustrating a fine particle separation device according to a third embodiment of the present invention. FIG.

Referring to FIG. 7, the fine particle separation device according to the third embodiment of the present invention is the same as that described in FIG. 1 except for the following features.

A plurality of injection ports for injecting fluid may be provided in the flow path forming layer 200. For example, the second infusion passage 212 may include a suspension infusion passage, a buffer solution infusion passage, and a processing solution infusion passage that are separated from each other and disposed in sequence. The first buffer solution infusion passage 216, the first processing solution infusion passage 217, and the second buffer solution infusion passage 218 (hereinafter, referred to as " ), And a second treatment liquid injection flow path 219.

The suspension injection path 212 'may be disposed closest to the upper side wall 220a of the main flow path 220. The treatment liquid in the first treatment liquid injection path 217 and the second treatment liquid injection path 219 can perform the chemical treatment on the fine particles while simultaneously flowing when the suspension flows. The chemical treatment may be, but is not limited to, fixation, adsorption, dyeing or detection (sensing, detection, classification). For example, the chemical treatment may be an antigen-antibody reaction or a fluorescent label, but is not limited thereto.

The buffer solution and the processing solution can form a laminar flow due to the buffer solution injection flow paths 216 and 218 disposed between the suspension injection path 212 'and the processing solution injection paths 217 and 219 have. That is, when the treatment liquids flow, a buffer is allowed to flow between the treatment liquids to avoid interference between the treatment liquids.

For example, blood containing cancer cells may flow through the suspension injection channel 212 '. The cell fixation solution can flow through the first treatment solution injection channel 217. Further, the dyeing solution may flow through the second processing solution injection path 219. As the blood flows in the direction F, blood cells that are the target particles are sorted through the dam 221. At this time, the cancer cells are fixed by the cell fixation liquid, and the cancer cells are stained by the staining liquid, And can be collected in the single recovery flow path 213.

At this time, the detector 400 may be installed in the device to detect the sorted particles. The detector 400 may be an electrical detector or an optical detector. For example, the detector 400 may be attached to one surface of the first recovery channel 213 in which the stained cancer cells are sorted and recovered. If the detector 400 is an optical detector, detection using a fluorescent label may be performed. Specifically, the fluorescent-labeled cancer cells recovered in the first recovery channel 213 are detected and counted by an optical method using an immunofluorescence cytometer provided on one surface of the first recovery channel 213 .

FIG. 8A is an exploded perspective view of a microparticle separation device according to a fourth embodiment of the present invention, and FIG. 8B is a cross-sectional view showing a cross section cut in a direction parallel to a dam in a circle portion of FIG. 8A. The fine particle separation element according to the fourth embodiment of the present invention is the same as that described in Fig. 1 except for the following features.

Referring to FIGS. 8A and 8B, the detector 400 'includes a lid layer 300, specifically, the detector 400' in the element is positioned above the dam 221 and the first recovery channel 213 The particles recovered in the first recovery flow path 213 along the dam 221 can be detected. If the detector 400 'is an electric detector, it can perform detection by measuring an increasing impedance when the particles 230 pass through the detector 400'.

For example, a plurality of electrodes may be provided on the lower surface of the cover layer 300. When the particles 230 pass through the intersection of both electrodes, the particles 230 instantaneously increase the impedance while intercepting the electric field between the electrodes. At this time, the impedance peak is determined as the amplitude according to the degree of blocking the electric field. The target impedance can be detected and counted by analyzing the impedance amplitude.

The microfluidic separation element according to the third and fourth embodiments of the present invention can perform various chemical treatments on the target particle as well as the function of classifying the target particles in a single element by arranging multiple injection ports and detectors have. Accordingly, it is possible to provide a microfluidic separation device capable of processing a plurality of equipment and manpower required processes in a single device at a high speed in the field of liquid biopsy and the like.

Hereinafter, the present invention will be described in detail with reference to examples. It is to be understood, however, that the following examples are intended to assist the understanding of the present invention and are not intended to limit the scope of the present invention.

<Production Example>

Separation of blood cancer cells by using a microfluidic separation element

First, a silicon substrate was prepared, and SU-8 having a thickness of 24 占 퐉 was coated on the substrate. Then, exposure processing was performed in the form of a flow path forming layer including a main flow path with a width of 0.5 mm, two injection paths with a width of 0.25 mm, two recovery paths, and a bank having a width of 50 m. At this time, an angle formed between the upper wall of the main flow path and the dam is 1 °, and the dam is arranged obliquely between the injection flow path and the recovery flow path.

Subsequently, the SU-8 layer having a thickness of 24 탆 was coated with a 6 탆 SU-8 layer containing only the remaining channels except for the bank, and then exposed to light to develop a thickness To form a flow path forming layer of 30 μm.

Next, polyimethylsiloxane (PDMS) having a thickness of 5 mm was provided as a cover layer on the channel forming layer to fabricate a microfluidic separation element so that a gap of 6 μm was formed between the dam and the cover layer Respectively. At this time, the cover layer includes injection holes and particle recovery holes corresponding to the injection flow path and the recovery flow path of the flow path forming layer, respectively.

Then, blood containing cancer cells is allowed to flow through one injection channel of the two injection channels, and a buffer is allowed to flow through the remaining injection channels so that the blood flows toward the bank.

Thereafter, as the blood flows, the cancer cells in the blood do not pass because they are larger than the gap, and the cells in the remaining blood have separated through the gap.

<Experimental Example 1>

The main channel The upper side wall  Comparing the pressure difference acting on the dam by the angle formed by the dam

Except that the angle formed between the upper wall of the main flow path and the bank was 0.5 °, 0.8 °, 1 °, 1.5 ° 3 °, 7 ° and 10 °, respectively, Was prepared as an experimental group.

A fluid sample containing polymethyl methacrylate (PMMA) having a diameter of 6 to 25 占 퐉 was then flowed through the test group elements.

FIG. 9A is a graph showing pressures in a vertical direction (b) and a parallel direction (a) acting on a portion indicated by a circle in FIG. 1A, that is, And the pressure ratio according to the angle.

9A and 9B, as the angle θ between the dam 221 and the upper wall 220a of the main flow path 220 is smaller, the pressure in the parallel direction a with respect to the vertical direction b increases .

When the angle θ between the dam 221 and the upper wall 220a of the main passage 220 increases, the pressure in the direction b perpendicular to the dam 221 increases, Larger particles than the gaps (224 in FIG. 2B) to be flowed may be trapped in gaps (224 in FIG. 2B) between the dam and the cover layer (300 in FIG. 1) or even beyond the dam Can cause problems.

Therefore, the angle [theta] may be more than 0.5 DEG and less than 10 DEG. (A) relative to the pressure (P vertical ) in the vertical direction (b) when the angle (?) Between the dam (221) and the upper wall (220a) (P parallel / P vertical ) of the pressure (P parallel ) of the gasket is the largest. However, if the pressure ratio P parallel / P vertical is greater than 1, particles smaller than the gap (224 in Figure 2b) between the dam (221) and the cover layer (300 in Figure 1) 221 to flow into the first recovery flow path 213 to reduce the separation efficiency of the device.

Thus, for example, the angle [theta] may be between 0.8 [deg.] And 10 [deg.]. At this time, the pressure ratio (P parallel / P vertical ) may be 0.089 to less than 1. Specifically, the angle [theta] may be 0.8 [deg.] To 7 [deg.]. At this time, the pressure ratio (P parallel / P vertical ) may be 0.1 to less than 1. More specifically, the angle [theta] may be between 0.8 [deg.] And 3 [deg.]. At this time, the pressure ratio (P parallel / P vertical ) may be 0.2 to less than 1.

Preferably, the angle [theta] may be between 0.8 [deg.] And 1.5 [deg.]. In this case, the pressure ratio P parallel / P vertical may be 0.4 to less than 1.

FIG. 10 is a photograph of an experiment using actual blood in the device of the first embodiment of the present invention. FIG.

Referring to FIG. 10A, it can be confirmed that the cells in the blood pass through the upper bank and pass through the upper discharge port. The cells in the blood collected at the upper outlet were collected in a hemocytometer and observed under an optical microscope and a fluorescence microscope. As a result, it was confirmed that cancer cells were not detected among the cells in the blood.

Referring to FIG. 10B, it can be seen that the cancerous cells in the blood do not pass over the dam, move along the dam, and are classified as a lower outlet. The cancer cells collected at the lower outlet were collected in a hemocytometer and observed under an optical microscope and a fluorescence microscope. As a result, it was confirmed that no cells were detected in the blood between the cancer cells.

<Experimental Example 2>

Efficiency of separation of device according to width of dam

The microfluidic separation element fabricated in the same manner as described in Production Example 1 was prepared as an experimental group except that the width of the bank was 10 μm, 20 μm, 30 μm, 50 μm, 60 μm and 100 μm, respectively.

A fluid sample containing polymethyl methacrylate (PMMA) having a diameter of 6 to 25 占 퐉 was then flowed through the test group elements.

11 is a graph showing the separation efficiency of the device according to Experimental Example 2 of the present invention.

Referring to FIG. 11, it can be seen that the separation efficiency of the microfluidic separator was the highest when the width of the bank was 30 .mu.m or 50 .mu.m.

For example, when the width of the weir is 20 μm or less, the resistance of the fluid becomes too small when the flow velocity increases, so that the hydraulic pressure acting in the vertical direction with respect to the parallel direction of the weir becomes too large and the separation efficiency can be rather reduced. If the width of the bank is 60 탆 or more, the resistance of the fluid acting on the bank becomes too large when the flow velocity is reduced, so that the separation efficiency can be reduced.

<Experimental Example 3>

The height of the dam Of the gap  Separation efficiency according to height ratio

A microfluidic separator fabricated in the same manner as described in Production Example 1 was prepared as an experimental group, except that the height of the weir and the height of the gap were set to 40 μm and 10 μm, 40 μm and 6 μm, and 24 μm and 6 μm, respectively. For convenience, the height of the dam and the height of the gap were 40 ㎛ and 10 ㎛ in the experimental group A, 40 ㎛ and 6 ㎛ in the experimental group B, and 24 ㎛ and 6 ㎛, respectively.

Then, a blood sample containing cancer cells was flowed into the test group elements.

12 is a graph showing a separation efficiency of a device according to Experimental Example 3 of the present invention.

Referring to FIG. 12, it can be seen that in the case of the experimental group A, the isolation efficiency is lower than that of the experimental group C because the number of cancer cells passing through the gap increases.

However, in the experimental group B, the separation efficiency is lower than that of the experimental group A having a gap height of 6 μm and a gap height of 10 μm. As a result, when the size (height) of the gap is reduced without maintaining the ratio of the height of the weir and the height of the gap, the resistance ratio of the fluid is varied and the separation efficiency is rather low.

It should be noted that the embodiments of the present invention disclosed in the present specification and drawings are only illustrative of specific examples for the purpose of understanding and are not intended to limit the scope of the present invention. It will be apparent to those skilled in the art that other modifications based on the technical idea of the present invention are possible in addition to the embodiments disclosed herein.

100: base layer 200:
201: first storage unit 202: second storage unit
202 ': suspension reservoir
203: first particle storing section 204: second particle storing section
205: third particle storage unit 206: third storage unit
207: fourth storage unit 208: fifth storage unit
209: sixth storage unit 211: first injection channel
212: Second infusion passage 212 ': Suspension infusion passage
213: first flow passage 214: second flow passage
215: third circulation flow passage 216: first buffer solution injection channel
217: First treatment liquid infusion passage 218: Second buffer solution infusion passage
219: second treatment liquid injection channel 220:
220a: Upper side wall 220b: Lower side wall
221, 221 ': dam 221a: first dam
221b: second dam 224: gap
224a: first gap 224b: second gap
226, 226 ': first side wall 227, 227': second side wall
230: second particle 231: first particle
300: cover layer 301: first injection hole
302: second injection hole 303: first particle recovery hole
304: second particle recovery hole 305: third particle recovery hole
306: third injection hole 307: fourth injection hole
308: fifth injection hole 309: sixth injection hole
400, 400 ': probe
H: thickness of flow path forming layer hw , hw ' : height of bank
hg, hg ': height of the gap W, W': width of the bank
W m : main flow path width W f : Width of Euro
θ, θ ': the angle between the upper wall and the dam
F: direction of suspension flow
F ': Flow direction of buffer solution F a : Second particle flow direction
F b : first particle flow direction

Claims (21)

A first injection flow path and a second injection flow path connected to one longitudinal end portion of the main flow path, a first return flow path connected to the other longitudinal end portion of the main flow path, A flow path forming layer including two flow paths and a dam connecting a wall between the first flow path and the second flow path to an upper wall of the main flow path; And
And a cover layer disposed on the channel forming layer and forming a gap between the banks. The method according to claim 1,
Wherein the first infusion passage and the first recovery passage are disposed closer to the lower wall than the upper side wall,
And the second infusion passage and the second recovery passage are disposed closer to the upper wall than the lower wall. 3. The method of claim 2,
Wherein the second infusion passage is a suspension infusion passage containing first particles and second particles smaller in size than the first particles,
The first particles are recovered in the first recovery passage,
And the second particles are recovered in the second recovery passage. The method of claim 3,
The suspension is blood,
Wherein the first particle is a blood cancer cell, and the second particle is a blood cell. The method according to claim 2 or 3,
Wherein the first injection path is a buffer solution injection path. The method of claim 3,
And the buffer solution is recovered together with the first particles in the first recovery flow path. The method according to claim 1,
Wherein the suspension flowing through the first injection path and the buffer solution flowing through the second injection path in the main flow path are capable of forming a laminar flow. The method according to claim 1,
Wherein the dam comprises a first sidewall facing the injection ports and a second sidewall facing the second recovery flow path,
Wherein the first sidewall has a tapered shape such that a width between the first sidewall and the second sidewall becomes narrower toward the lid layer direction. 9. The method of claim 8,
Wherein the second sidewall has a tapered shape such that a width between the first sidewall and the second sidewall becomes narrower toward the lid layer direction. The method according to claim 1,
Wherein the cross section of the dam is rectangular. The method according to claim 1,
Said dam having a rounded edge. The method according to claim 1,
Wherein an angle between the upper wall and the dam is 0.1 DEG to 10 DEG. The method according to claim 1,
Wherein an angle between the upper wall and the dam is 0.8 to 1.5 degrees. 3. The method of claim 2,
The dam is the first dam,
The flow-
A main flow path connected to the other longitudinal end of the main flow path,
A third recovery flow passage disposed closer to the upper side wall than the second recovery flow passage; And
A wall between the second recovery flow passage and the third recovery flow passage and an upper wall of the main flow passage,
Further comprising a second dam spaced apart from the first dam,
And a gap is formed between the second dam and the cover layer. 15. The method of claim 14,
Wherein the height of the gap between the second dam and the cover layer is smaller than the height of the gap between the first cover and the cover layer. The method according to claim 1,
Wherein the first injection path further comprises a suspension injection path, a buffer solution injection path, a first processing solution injection path and a second processing solution injection path which are separated from each other and arranged in sequence. 17. The method of claim 16,
The suspension injection path is disposed closest to the upper side wall of the main flow path,
Wherein the buffer solution injection path is disposed between each of the suspension injection path, the first processing solution injection path and the second processing solution injection path. 18. The method of claim 17,
Wherein the treatment liquid in the first treatment liquid injection path and the second treatment liquid injection path includes a fixer or a dyeing solution. A first injection flow path and a second injection flow path connected to one longitudinal end portion of the main flow path, a first return flow path connected to the other longitudinal end portion of the main flow path, A flow path forming layer including two return passages and a dam connecting the wall between the first return flow passage and the second return flow passage and the upper wall of the main flow passage; And a cover layer disposed on the channel forming layer and forming a gap between the banks; And
Injecting a suspension containing the first particles and the second particles smaller in size than the first particles into the first injection path,
The first particles are recovered in the first recovery passage,
And the second particles are recovered in the second recovery passage. 20. The method of claim 19,
Wherein the suspension flows through the first infusion passage and the buffer solution flows through the second infusion passage so that the suspension and the buffer solution form a laminar flow in the main passage. 20. The method of claim 19,
And a detector is attached to the first recovery passage or the cover layer.

KR1020160031417A 2016-03-16 2016-03-16 Microparticle separator having weir KR20170107723A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102066052B1 (en) 2018-08-16 2020-01-14 한양대학교 산학협력단 Apparatus and method of separating micro fluid cell

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102066052B1 (en) 2018-08-16 2020-01-14 한양대학교 산학협력단 Apparatus and method of separating micro fluid cell

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