KR101810941B1 - Multiple discrimination device and method for fabricating the device - Google Patents

Abstract

The present invention provides a multiple separation apparatus and a method of manufacturing the same. According to this multiple separation apparatus, the three-dimensional fine ferromagnetic pattern can be optimally designed and arranged, so that the magnetic force applied to the separated target particle to be separated can be well controlled so as to be easily separated. The manufacturing method of the multiple separation device according to another example of the present invention can be precisely manufactured and advantageous for mass production by using the semiconductor process technology.

Description

TECHNICAL FIELD [0001] The present invention relates to a multiple separation apparatus and a method for fabricating the same,

The present invention relates to an apparatus for multiple separation of material species including biomaterials and a method for manufacturing the same.

Separation of cell types or intracellular constituents is required as a preliminary tool for final purposes or other analyzes in the field of diagnosis, treatment and research in the medical field. For example, it is necessary to analyze cancer cells. Blood cancer cells are cancer cells that are present in the peripheral blood of cancer patients and are cancer cells that have disappeared from the primary lesion or metastatic lesion. Such blood cancer cells are expected to be a promising biomarker in cancer diagnosis, therapeutic prognosis analysis, and micro metastasis analysis. In addition, blood cancer cell analysis is more promising as a non-invasive method than the conventional cancer diagnosis method. However, blood cancer cells are very difficult to analyze accurately and require very sophisticated analysis methods because the distribution ratio of blood cells is very low in the blood distribution level of one cancer cell per one billion cells or one cancer cell per 10 ⁶ to 10 ⁷ white blood cells.

Various methods have been studied as methods for separating cancer cells from blood. However, it takes a long time to examine the cancer cells, and only the information on the presence or absence of cancer cells and the quantity of cancer cells is analyzed. In addition, interference by non-specific binding hemocytes is a problem.

Accordingly, it is an object of the present invention to provide an apparatus for multiple separation of material species including biomaterials and a method for manufacturing the same.

According to an aspect of the present invention, there is provided a multiple separation apparatus comprising: a channel through which a mixed solution flows in a first direction; And at least one ferromagnetic pattern disposed beneath the bottom of the channel, wherein the slope of the tangent of the ferromagnetic pattern continuously varies with the position of the channel, and the mixed solution includes a separation target particle and other particles.

An angle formed by the tangent line and the first direction in one portion of the ferromagnetic pattern may be about 80 to 90 degrees.

The ferromagnetic pattern may have at least one of 'J', 'U' and 'ω'.

The linewidth of the ferromagnetic pattern can vary depending on the position.

The width of the ferromagnetic pattern may preferably be 10 to 1000 mu m.

The thickness of the ferromagnetic pattern may preferably be 0.1 to 1000 mu m.

The height of the channel may preferably be 10 to 1000 mu m.

And at least one permanent magnet disposed adjacent to the channel.

Wherein the multi-separation device comprises: at least one mixing solution inlet connected to the channel and into which the mixed solution is introduced; A buffer solution inlet connected to the channel; A target particle outlet connected to the channel, through which the separation target particle is discharged; And at least one other particle outlet connected to the channel for discharging the other particles, wherein the mixed solution inlet and the other particle outlet are connected to one side of the channel, and the buffer solution inlet and the target The particle outlet may be connected to the other side of the channel from the one side.

The number of the ferromagnetic patterns may be plural, and the interval between the ferromagnetic patterns may become narrower toward the other particle discharge ports.

The angle formed by the tangent at the point where the other side meets the ferromagnetic pattern and the other side may be 80 to 90 degrees.

The magnetization amount of the separation target particle may be larger than the magnetization amount of the other particles.

The separation target particle may be at least one of a gene, a DNA, an RNA, a protein, a peptide, and a cancer cell to which the magnetic nanoparticle is bound.

The multi-separation device may further include: a lower plate on which the ferromagnetic pattern is disposed; And an upper plate disposed on the lower plate and including an inner space for providing the channel. At least one of the lower plate and the upper plate may include polydimethylsiloxane (PDMS).

The multiple separation device may further include a photoresist pattern interposed between the lower plate and the upper plate and in contact with the sidewalls of the ferromagnetic pattern.

According to another aspect of the present invention, there is provided a method of fabricating a multiple separation apparatus, comprising: forming a lower plate including a photoresist pattern on a top surface and a ferromagnetic pattern between the photoresist patterns; Forming an upper plate including a depression therein and a plurality of holes connected to the depression; And bonding the top plate onto the bottom plate.

The step of bonding the upper plate on the lower plate may include bonding the upper plate to the lower plate using an adhesive.

The step of forming the lower plate may include: forming a seed film on the lower plate; Forming photoresist patterns on the seed film; And forming the ferromagnetic pattern between the photoresist patterns by performing a plating process.

The forming of the upper plate may include: preparing a sacrificial substrate; Forming a sacrificial photoresist pattern on the sacrificial substrate; Forming a mold film covering the sacrificial photoresist pattern on the sacrificial substrate; Removing the sacrificial substrate and the sacrificial photoresist pattern to form a depression in the mold film; And punching the mold film to be connected to the depression.

The mold film may comprise polydimethylsiloxane (PDMS).

According to an embodiment of the present invention, a three-dimensional fine ferromagnetic pattern can be optimally designed and arranged, so that the magnetic force applied to the separated target particles to be separated can be well controlled so as to be easily separated. The ferromagnetic pattern is disposed at the bottom of the channel to easily control the movement of the bio-particles so that only the separated target particles can be selectively separated.

In addition, the slope of the tangent line of the ferromagnetic pattern changes continuously according to the position of the channel. This allows the target particles to be well separated without loss due to trapping of the target particles at undesired locations.

The manufacturing method of the multiple separation device according to another example of the present invention can be precisely manufactured and advantageous for mass production by using the semiconductor process technology.

1A is a perspective view of a multi-separation apparatus according to an embodiment of the present invention.
1B is a sectional view taken along line I-I 'of FIG. 1A.
1C is an exploded perspective view of FIG. 1A.
FIG. 2 shows species included in a mixed solution according to an example of the present invention.
FIG. 3A illustrates the movement of particles within a multiple separation apparatus according to an example of the present invention.
3B is an enlarged plan view of a ferromagnetic pattern according to an example of the present invention.
Figures 4A through 4E show schematic plan views according to examples of the present invention.
Figs. 5A to 5E show the manufacturing process of the bottom plate of Fig. 1B.
Figs. 6A to 6D show the manufacturing process of the top plate of Fig. 1B.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings. The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. It is to be understood that the disclosure of the present invention is only illustrative and not restrictive, and that the scope of the invention is to be informed to those skilled in the art. In the accompanying drawings, the constituent elements are shown enlarged for the sake of convenience of explanation, and the proportions of the constituent elements may be exaggerated or reduced.

It is to be understood that when an element is described as being "on" or "connected to" another element, it may be directly in contact with or coupled to another element, but there may be another element in between . On the other hand, when an element is described as being "directly on" or "directly connected" to another element, it can be understood that there is no other element in between. Other expressions that describe the relationship between components, for example, "between" and "directly between"

The terms first, second, etc. may be used to describe various components, but the components should not be limited by the terms. The terms are used only for the purpose of distinguishing one component from another. For example, without departing from the scope of the present invention, the first component may be referred to as a second component, and similarly, the second component may also be referred to as a first component.

The singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. The word "comprising" or "having ", when used in this specification, is intended to specify the presence of stated features, integers, steps, operations, elements, A step, an operation, an element, a part, or a combination thereof.

The terms used in the embodiments of the present invention may be construed as commonly known to those skilled in the art unless otherwise defined. Also, "at least one" is used in the same sense as at least one and may optionally refer to one or more.

1A is a perspective view of a multi-separation apparatus according to an embodiment of the present invention. 1B is a sectional view taken along line I-I 'of FIG. 1A. 1C is an exploded perspective view of FIG. 1A. FIG. 2 shows species included in a mixed solution according to an example of the present invention. FIG. 3A illustrates the movement of particles within a multiple separation apparatus according to an example of the present invention. 3B is an enlarged plan view of a ferromagnetic pattern according to an example of the present invention.

Referring to FIGS. 1A to 1C, in the multi-separation apparatus 300 according to the present example, the upper plate 250 may be glued or bonded to the lower plate 200 with an adhesive. A seed film 202 is disposed on the surface of the lower plate 200. The seed film 202 may be formed of at least one selected from the group consisting of titanium, nickel, copper, and chromium, or a compound thereof. A lower photoresist film 204 is disposed on the seed film 202. Grooves 206 are formed in the lower photoresist film 204 to expose the seed film 202. In the grooves 206, ferromagnetic patterns 208 are disposed. The ferromagnetic patterns 208 may be formed of a ferromagnetic material such as nickel, nickel-cobalt, nickel-iron, magnesium-aluminum, nickel-iron-copper- Magnesium, and the like. The thickness of the ferromagnetic pattern 208 may be, for example, 0.1 to 1000 mu m. The slope of the tangent line of the ferromagnetic patterns 208 can be continuously changed according to the position of the channel CH1. The linewidth of the ferromagnetic pattern can vary depending on the position. The width of the ferromagnetic pattern 208 may preferably be 10 to 1000 mu m. The thickness of the ferromagnetic pattern 208 may preferably be 0.1 to 1000 mu m.

Subsequently, the upper plate 250 includes a recessed depression 252 and a plurality of holes 254a to 254d therein. The holes 254a to 254d are formed by a mixed solution inlet 254a through which a mixed solution is injected, a buffer solution inlet 254b through which a buffer solution such as saline is injected, a target particle outlet 254c through which the separated target particles 104 are discharged, And other particle outlets 254d through which other particles 105 are discharged. The upper plate 250 meets the lower plate 200 and provides a channel CH1 and passages 253a to 253d between the depressed portion 252 and the upper surface of the lower plate 200. [ The passages 253a to 253d include a mixed solution passage 253a for connecting the mixed solution inlet 254a and the channel CH1 and a buffer solution 253b for connecting the buffer solution inlet 254b and the channel CH1, A target particle passage 253c connecting the target particle outlet 254c and the channel CH1 and another particle passage 253d connecting the other particle outlet 254d and the channel CH1, . The height of the channel CH1 may be preferably 10 to 1000 mu m.

At least one of the upper plate 250 and the lower plate 200 may be a cycloolefin copolymer, a polymethylmethacrylate (PMMA), a polycarbonate (PC), a cycloolefin polymer (COP), a liquid crystalline polymer (LCP), a polydimethylsiloxane , Polyamide (PA), polyethylene (PE), polyimide (PI), polypropylene (PP), polyphenylene ether (PPE), polystyrene (PS), polyoxymethylene (POM), polyetheretherketone a polymer substrate made of at least one polymer material selected from polytetrafluoroethylene (PTFE), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutyleneterephthalate (PBT), fluorinated ethylenepropylene (FEP) and perfluoralkoxyalkane (PFA). At least one of the upper plate 250 and the lower plate 200 may be a glass substrate, a silicon substrate, or a metal. Preferably, at least one of the upper plate 250 and the lower plate 200 may be formed of PDMS that is optically transparent and has excellent chemical resistance, or may be formed of a thermoplastic polymer.

Although not shown, permanent magnets may be disposed adjacent to at least one of the lower plate 200 and the upper plate 250 to continuously magnetize the ferromagnetic pattern 208.

The mixed solution flows in the first direction D1 in the channel CH1. The injection, transfer and discharge of the solution may preferably be a flow due to the pressure generated by the operation of the syringe pump.

The mixed solution passage 253a and the other particle passage 253d are connected to the first side S1 of the channel CH1 (or between the first side S1 and the first side S1). The buffer solution passage 253b and the target particle passage 253c may be connected to the second side surface S2 spaced apart from the first side surface S1 of the channel CH1.

In one example, the top plate 250 and the bottom plate 200 may be made of materials having different hydrophobic and / or hydrophilic properties. Further, the upper plate 250 and the lower plate 200 may further be provided with films having hydrophobic and / or hydrophilic portions which are partially different from each other on surfaces facing each other. This is to make it possible to adjust the moving speed of the fluid sample through manipulation of the fine shape of the channel or surface modification of the channel.

Referring to FIGS. 1A and 2, a mixed solution is introduced into the mixed solution inlet 254a and a buffer solution such as saline is injected into the buffer solution inlet 254b. The mixed solution includes separate target particles 104 and other particles 105 to be separated. The mixed solution may be mixed with the magnetic nanoparticles 101 coupled with the antibody 102 to bind the magnetic nanoparticles 101 to the separation target particles 104. An antigen 103 is present on the surface of the separation target particle 104 so that the antigen 102 binds to the antibody 102. Thus, the antigen 103, the antibody 102 and the magnetic nanoparticles 101 can be sequentially bonded to the surface of the separation target particle 104. The other particles 105 do not have an antigen 103 capable of reacting with the antibody 103, so that the magnetic nanoparticles 101 can not be specifically bound. For example, the mixed solution may be blood, and the separation target particles 104 may be cancer cells contained in the blood. The cancer cells may be circulating tumor cells (CTC) or disseminated tumor cells (DTC). The antigen 103 may be, for example, an epithelial cellular adhesion molecule (EpCAM) marker. The other particles 101 may be normal cells such as leukocytes contained in the blood. Alternatively, the separation target particle 104 may be one of a gene, a DNA, an RNA, a protein, and a peptide. Since the magnetic nanoparticles 101 are specifically bound to the separation target particles 104 and the magnetic nanoparticles 101 can not be specifically bound to the other particles 105, There is a big difference. The greater the number of magnetic nanoparticles, the greater the magnetization.

Referring to FIGS. 1A and 3A, when solutions are injected into the inlet ports 254a and 254b, they flow into the channel CH1 through the passages 253a and 253b and join together. At this time, a magnetic force F _m may be applied to the particles 104 and 105 included in the mixed solutions, as shown in the following Equation 1.

&Quot; (1) "

In the equation (1), F _m is the magnetic force applied to the particles 104 and 105 by the magnetic field gradient, and Ms is the saturation magnetizing force possessed by the particles 104 and 105 by the ferromagnetic pattern 203 , And B indicates a magnetic field gradient generated by the shape of the ferromagnetic pattern 203. [ Since the separation target particle 104 contains a relatively large amount of magnetic nanoparticles than the other particles 105, the saturation magnetization force also becomes relatively large. As a result, the magnetic force received by the separation target particles 104 becomes much larger than that received by the other particles 105. Therefore, the separation target particles 104 are more likely to be trapped in the ferromagnetic pattern 208.

The particles (104, 105) are also subjected to a force (F _d ) in accordance with the flow of the mixed solution. Therefore, the resultant force F _s of the magnetic force F _m and the force F _d by the flow of the mixed solution acts on the particles 104 and 105.

The magnetic force F _m may have a negative sign with the sign of the force F _d due to the flow of the mixed solution. The condition that the particles 104 and 105 are trapped in the ferromagnetic pattern 203 is expressed by the following equation (2).

&Quot; (2) "

F _m + F _d cos? < 0

In Equation (2),? Is the angle formed by the direction of the force received by the magnetic particles by the magnetic field gradient and the flow direction of the mixed solution. As the angle? Increases, the possibility that the particles 104 and 105 pass through the ferromagnetic pattern 203 without being captured is increased.

1A and 3A, the separation target particle 104 may move along the channel CH1 and may be captured on the ferromagnetic pattern 208 to move along the surface of the ferromagnetic pattern 208. [ The separation target particle 104 is separated from the surface of the ferromagnetic pattern 208 on a first point P1 where an angle between the tangent line and the first direction is about 80 to 90 degrees at one portion of the ferromagnetic pattern And flows along the channel CH1. As a result, the ferromagnetic pattern 208 flows along the first arrow A1 and is discharged through the target particle outlet 254c. However, since the magnetic force applied to the other particles 105 is insignificant, it is not captured on the surface of the ferromagnetic pattern 208, but is transported as it is in the initial direction D1 due to laminar flow flow characteristics and is transmitted through the other particle outlet 254d . In this way, the separation target particles 104 can be effectively separated from the other particles 105.

Since the ferromagnetic pattern 208 is arranged to be wider than the width of the entire channel CH1, there is an advantage that magnetic particle traps or the like, which may have a high magnetic field gradient locally and affect the separation, can be eliminated. In addition, the ferromagnetic pattern 208 has a curved shape without an angled portion as shown in FIG. 3B. That is, the tilt angles? 1,? 2,? 3,? 4 of the tangential lines L1, L2, L3, and L4 of the ferromagnetic pattern 208 continuously change according to the position of the channel CH1. As a result, the trapping phenomenon does not occur at the undesired position of the separation target particle 104. Also, the gradient of the magnetic field is gradually increased by the curved shape, thereby improving the separation efficiency. Further, the angle formed by the tangent of the ferromagnetic pattern 208 and the first direction D1 at the first point P1 is about 80 to 90 degrees, and more preferably about 90 degrees, Thereby preventing trapping of the exhaust gas 104. The first point P1 may preferably be disposed adjacent to the side of the channel CH1 between the buffer solution passage 253b and the target particle passage 253c.

Figures 4A through 4E show schematic plan views according to examples of the present invention.

Referring to FIG. 4A, the number of the ferromagnetic patterns 208 may be plural, and the interval between the ferromagnetic patterns 208 may be wider as the discharge ports 253c and 253d are closer to the discharge ports 253c and 253d. Referring to FIG. 4B, the spacing between the ferromagnetic patterns 208 may become narrower toward the discharge ports 253c and 253d. The planar shapes of the ferromagnetic patterns 208 in FIGS. 1A, 1C, 3, 4A and 4B may be similar to the 'J' character. At this time, the first point P1 may be disposed adjacent to the side of the channel CH1, preferably between the buffer solution passage 253b and the target particle passage 253c.

Or 4C and 4D, the planar shape of the ferromagnetic patterns 208 may be similar to the 'U' shape. And may include two mixing solution passages 253a and two other particle passages 253d. Or 4E, the planar shape of the ferromagnetic patterns 208 may be similar to the '?' Shape.

4C, 4D and 4E, particle separation takes place at the center of the channel CH1. When particle separation occurs at the first point P1 adjacent to the side of the channel CH1 as shown in Figs. 1A, 1C, 3, 4A and 4B, there is a bad influence on the particle separation due to vortex that may occur in the channel wall portion There is a possibility of madness. However, if the separation occurs at the center of the channel CH1 as shown in Figs. 4C, 4D and 4E, the adverse influence due to the eddy current can be excluded.

When the mixed solution is blood containing cancer cells, for example, it contains 1 billion cells per 1 ml, most of them are normal cells, and cancer cells can be from several to dozens. The type and number of the cancer cells captured are used to determine the type of cancer and progress of cancer. Therefore, it is very important that most of the separated target particles 104 escape through the target particle passage 253c without loss, that is, to capture the separated target particles 104 well.

The first factor affecting the capture of the separation target particles 104 is the planar pattern shape of the ferromagnetic pattern 208. If the shape of the ferromagnetic pattern 208 has a bent line shape having a discontinuously varying slope, rather than a curve shape in which the slope continuously changes, the separation target particle 104 may be trapped at the bent portion. When the trap is formed at such an undesired position, the separation efficiency is lowered. Therefore, in FIGS. 4A to 4E, the planar shape of the ferromagnetic patterns 208 has a curved shape in which the inclination continuously varies, thereby improving the separation efficiency.

The second factor affecting the capture of the separation target particles 104 is the sidewall (or interface) of the channel CHl. The flow rate of the mixed solution is the fastest at the center of the channel CH1 and slowest at the side wall (boundary) of the channel CH1 (theoretically the zero velocity point). Further, when the ferromagnetic pattern 208 is disposed on the sidewall (boundary surface) of the channel CH1, the separation target particles 104 may be trapped and may not flow. Further, vortices of fluid (mixed solution) may be generated on the side wall (boundary surface) of the channel CH1, or may be adversely affected by bubbles generated on the side wall (boundary surface). As shown in FIGS. 4C, 4D and 4E, when the ferromagnetic pattern 208 has a 'U' or '?' Shape, separation at the center of the channel CH1 can be achieved to solve these problems.

A third factor affecting the capture of the separation target particles 104 should be minimization of the separation target particles 104 at the exit side into the other unwanted particle passage 253c. When the mixture solution (ex, blood) and the buffer solution of different densities are introduced from the injection ports 254a and 254b, the fluid moves to the lower density at the same flow rate. That is, the mixed solution is pushed into the buffer solution. So that the flow velocity must be controlled to capture only the separated target particles 104 in the mixed solution and the remaining other particles 105 to the other particle outlet 254d. Although the laminar flow is mostly laminar in the microchannel, the width of the channel CH1 in the passages 253c and 253d may change, and a vortex may occur. There is a need for a structure that prevents a part of the separation target particles 104 from entering the other particle passage 253c by this vortex. 4E, the magnetic force received by the separation target particle 104 at the center portion is minimized by Equations 1 and 2, so that the separated target particles (i.e., 104), only the force due to the laminar flow of the solution is almost reached. As a result, the separated target particles 104 can be maintained in a state of being separated according to the laminar flow, and the separated target particles 104 can be captured as much as possible without loss.

Hereinafter, the process of manufacturing the multiple separation apparatus of the present invention will be described.

The upper plate 250 and the lower plate 200 of the multi-separation apparatus are respectively formed by injection molding, hot embossing, casting, stereolithography, laser ablation, May be formed in one manner selected from conventional mechanical processing methods such as rapid prototyping, silk screen, numerical control machining (NC machining), or semiconductor processing using photolithography, It is preferable to use a photolithography process.

After the microstructures described above are formed on the upper plate 250 and the lower plate 200, the upper plate 250 and the lower plate 200 are coupled to each other. At this time, it is preferable to form a functional material for bonding on the surface through surface modification such as surface plasma treatment and self-assembled film formation, and then, after bonding, bonding through heat treatment while applying pressure. Or the upper plate and the lower plate engagement can be combined by the adhesive member. When the upper plate 250 and the lower plate 200 are made of the same kind of material, the adhesive member may be heat, chemicals, ultrasonic waves or the like. In the case of different materials, a thin plate- Adhesive material. When room temperature or low temperature bonding is required to prevent denaturation of a biochemical substance (antibody or the like) in the process of bonding the upper plate 250 and the lower plate 200, a pressure sensitive adhesive can be used.

As a concrete example, a process of forming the lower plate will be described first with reference to FIGS. 5A to 5E.

Referring to FIG. 5A, a lower plate 200 is prepared. The lower plate 200 may be, for example, a silicon wafer and may be prepared by cleaning.

Referring to FIG. 5B, a seed film 202 is formed on the lower plate 200. The seed layer 202 may be formed by a deposition process using at least one metal selected from the group consisting of titanium, nickel, copper, and chromium or a compound thereof.

Referring to FIG. 5C, a lower photoresist film 204 is formed on the seed film 202.

Referring to FIG. 5D, a plurality of grooves 206 are formed in the lower photoresist film 204 to expose the seed film 202 through an exposure and development process.

Referring to FIG. 5E, ferromagnetic patterns 208 filling the grooves 206 are formed through an electroplating process or a deposition process using an electron beam. The ferromagnetic patterns 208 may be formed of at least one material selected from the group consisting of nickel, nickel-cobalt, nickel-iron, magnesium-aluminum, nickel-iron-copper-chromium and iron-nickel-molybdenum-magnesium. At this time, the thickness of the ferromagnetic pattern 208 may be, for example, 0.1 to 1000 mu m. Subsequently, a planarizing process such as chemical mechanical polishing (CMP) may be performed to planarize the surface. Thus, the lower plate 200 can be formed.

Next, a process of forming the upper plate 250 will be described with reference to FIGS. 6A to 6D.

Referring to FIG. 6A, a mold substrate 240 is first formed. The mold substrate 240 may be, for example, a silicon wafer.

Referring to FIG. 6B, an upper photoresist pattern 242 is formed on the mold substrate 240. To form the upper photoresist pattern 242, an epoxy-based photosensitive photoresist is preferably applied first. The thickness of the photoresist can be controlled in various ways (for example, 1 to 1000 μm) in accordance with the viscosity of the photoresist or the number of revolutions per minute (eg, 500 to 5000 rpm) in the spin coating equipment. Epoxy-based photosensitive photoresists can be precisely patterned without further exposure after thermal curing and can easily and quickly reach desired pattern and depth by exposure process. Exemplary epoxy-based photoresists may be SU-8 series negative photoresists. A precise pattern shape (resolution of 1 탆 or more) can be controlled by the pattern of the exposure mask. By this process, a top mold mold including the upper photoresist pattern 242 corresponding to a fluid channel shape having an ultra-precise channel depth and pattern shape can be completed.

Referring to FIG. 6C, a PDMS material is coated on the mold substrate 240 and cured to form an upper plate 250.

Referring to FIG. 6D, the upper plate 250 is separated from the mold substrate 240. A depression 252 may be formed in the upper plate 250 where the upper photoresist pattern 242 is located. The holes 254a to 254d may be formed by a method such as punching.

Although not shown, before the PDMS material is coated, a metal mold may be manufactured by applying an electroplating process to the circular mold structure of the upper plate. The electroplating may be performed after forming a seed layer made of a metal such as Ti, Cr, Al, or Au. The thickness of the metal mold is sufficient to prevent warping or bending when transferred onto a substrate (for example, a polymer substrate) to be transferred. Thereafter, the mold substrate (for example, the silicon substrate) is removed by wet etching or the like so that only the metal mold remains.

The metal mold may be transferred to a substrate (e.g., a polymer substrate) by a method such as injection molding, hot embossing, casting, or the like. Thereafter, holes 254a through 254d may be formed.

Referring to FIG. 1C, the upper plate 250 is coupled to the lower plate 200. At this time, the ferromagnetic pattern 208 and the channel CH1 are coupled so as to correspond to each other. When the upper plate 250 and the lower plate 200 are made of the same material, they can be adhered by heat, chemicals, ultrasonic waves or the like. In the case of different materials, a liquid adhesive material, a powdery adhesive material, A plate-like adhesive material may be used. In order to prevent denaturation of biochemical substances (antibodies, etc.) in the process of bonding the upper plate 250 and the lower plate 200, a pressure sensitive adhesive may be used in which bonding is performed only by pressure when room temperature or low temperature bonding is required .

The embodiments of the present invention described above are not only implemented by the apparatuses and methods, but can be easily implemented by those skilled in the art from the description of the embodiments described above.

Claims (20)

A channel through which the mixed solution flows in the first direction; And
At least one ferromagnetic pattern disposed beneath the bottom of the channel,
Wherein the at least one ferromagnetic pattern has a curved shape protruding from an edge portion of the channel to a center portion of the channel in a plan view,
Wherein the slope of the tangent of the ferromagnetic pattern varies continuously with the position of the channel,
Wherein the mixed solution includes a separation target particle and other particles,
Wherein the separation target particles are separated along a central portion of the channel. The method according to claim 1,
Wherein the angle formed by the tangent line and the first direction at one portion of the ferromagnetic pattern is 80 to 90 degrees. The method according to claim 1,
Wherein the ferromagnetic pattern has at least one of 'U' and 'ω'. The method of claim 1, wherein
Wherein the line width of the ferromagnetic pattern varies depending on the position. The method according to claim 1,
Wherein the ferromagnetic pattern has a width of 10 to 1000 mu m. The method according to claim 1,
Wherein the thickness of the ferromagnetic pattern is 0.1 to 1000 mu m. The method according to claim 1,
Wherein the channel has a height of 10 to 1000 mu m. The method according to claim 1,
And at least one permanent magnet disposed adjacent to the channel. The method according to claim 1,
At least one mixing solution inlet connected to the channel and into which the mixed solution is introduced;
A buffer solution inlet connected to the channel;
A target particle outlet connected to the channel, through which the separation target particle is discharged; And
And at least one other particle outlet connected to the channel and through which the other particles are discharged,
The mixing solution inlet and the other particle outlet are connected to one side of the channel
Wherein the buffer solution inlet and the target particle outlet are connected to the other side and the other side of the channel. 10. The method of claim 9,
The number of the ferromagnetic patterns is plural,
Wherein the spacing between the ferromagnetic patterns is narrower toward the other particle outlet. 10. The method of claim 9,
Wherein an angle formed by the tangent at the point where the other side meets the ferromagnetic pattern and the other side is 80 to 90 degrees. The method according to claim 1,
Wherein the magnetization amount of the separation target particle is larger than the magnetization amount of the other particles. 13. The method of claim 12,
Wherein the separation target particle is at least one of a gene, a DNA, an RNA, a protein, a peptide, and a cancer cell, to which the magnetic nanoparticles are bound. The method according to claim 1,
A lower plate on which the ferromagnetic pattern is disposed; And
Further comprising an upper plate disposed on the lower plate and including an inner space for providing the channel,
Wherein at least one of the lower plate and the upper plate comprises polydimethylsiloxane (PDMS). 15. The method of claim 14,
And a photoresist pattern interposed between the lower plate and the upper plate and in contact with the sidewalls of the ferromagnetic pattern. delete delete delete delete delete

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