KR20150048541A - Encoded microcapsules and microarray fabricated therefrom - Google Patents

Abstract

The present invention relates to microcapsules encoded with respect to species of a target substance contained, comprising: a hydrophilic liquid core containing the target substance; and a hydrophobic shell surrounding the liquid core. Provided is the encoded microcapsules comprising a graphic code induced on the surface of the shell.

Description

[0001] The present invention relates to a coded microcapsule and a microarray prepared by using the microcapsule and microarray fabricated therefrom,

The techniques disclosed herein relate to coded microcapsules and microarrays made using them.

Drug screening refers to a task of screening substances that can become drugs by observing changes in cells by substances by reacting with various kinds of substances or drug candidates that are naturally present or artificially synthesized. Many studies are currently being conducted worldwide to find an anticancer agent capable of selectively removing cancer cells. Recent advances in genomics, proteomics, and combinatorial chemistry have greatly increased the number of candidate drug candidates in various classes, and drug screening has been performed on existing well plates Is difficult to handle with all of the increasing drug candidates. In this context, microfluidic technology is gaining popularity in that it can greatly reduce the amount of sample used at a time.

In the case of the microcapsule-related technology, in the field of drug delivery where the capsule is broken or swelled while being exposed to a certain environment (temperature, pH, etc.) Research. These microcapsule-related techniques are rarely applied in the field of drug screening because the number of codes that can be embedded in the microcapsules is limited, and thus it is impossible to handle a large number of candidate drug candidates.

Currently, drug screening using a microarray uses spotting of the drug on the surface of the array chip using equipment such as an ink jet printer. The coordinates of the drug array sprayed on the chip are recognized as codes, And a matching method is used. The above technique has the advantage of using a small amount of sample, but the cost of equipment is high and it is troublesome to change the drug each time to the toner of the printer in order to increase the number of drugs.

According to an aspect of the present invention, there is provided a microcapsule coded according to the type of a target material, comprising: a hydrophilic liquid core including the target material; And a coded microcapsule having a hydrophobic shell surrounding the liquid core, the coded microcapsule including a graphic code introduced into the shell surface.

According to another aspect of the present invention, there is provided a method of preparing a double emulsion, comprising: preparing a double emulsion having a hydrophilic liquid core containing a target material and a hydrophobic shell surrounding the liquid core and containing a photocurable polymer; Curing the photocurable polymer to form microcapsules in the form of a core-shell; And irradiating patterned energy to the hardened shell of the microcapsule to form a graphic code.

According to another aspect of the present invention, there is provided a method of manufacturing a micro-well, comprising: introducing microcapsules coded to be distinguished from each other according to the type of target material contained therein into a substrate having microwells; Reading codes of the coded microcapsules disposed within the microwells; Introducing an analyte into the microwells; And reacting the microcapsules introduced into the microwells with the target material and the analyte, wherein the microcapsule comprises a hydrophilic liquid core including the target material, There is provided an assay method using a coded microcapsule having a hydrophobic shell surrounding a liquid core and including a graphic code introduced into the shell surface.

According to another aspect of the present invention, microcapsules coded so as to be distinguished from each other according to the type of a target material are introduced into a substrate having microwells, and the microcapsules assembled in the microwells are broken, Wherein the microcapsule comprises a hydrophilic liquid core including the target material, and a hydrophobic shell surrounding the liquid core, wherein the microcapsule comprises: There is provided a microarray comprising graphic code introduced into the shell surface.

1 is a view showing the structure of a coded microcapsule according to an embodiment of the present invention.
FIG. 2 is a process flow diagram illustrating a method of producing a coded microcapsule according to an embodiment of the present invention.
3 is a view illustrating a process of manufacturing a microcapsule using a microfluid chip.
4 is a view showing a process of encoding a microcapsule using a patterned mask and ultraviolet rays.
5 shows fluorescence characteristics of DMPA used as a photoinitiator according to ultraviolet irradiation.
6 is a diagram illustrating a coding process using a digital micromirror device (DMD).
FIG. 7 is a view illustrating a large-area encoding process using a film-combined glass mask (FCG mask).
8 is a diagram illustrating a method of bi-directionally encoding microcapsules in two ways.
9 shows the result of the persistence test of the code.
10 shows a method of assembling microcapsules coded on a substrate with microwells.
11 shows a manufacturing method using (a) PDMS and (b) a manufacturing method using PUA as the microwell manufacturing method, respectively.
Figure 12 shows examples of microwells in which the depth of the microwell is appropriately adjusted according to the microcapsule size.
13 is a diagram showing microwells of various shapes.
14 is a view showing a process of releasing internal liquid of microcapsules assembled in a microwell.
15 is a diagram showing the results of cell death test using an anticancer agent.

Embodiments of the present invention will now be described in more detail with reference to the drawings. The following implementations are provided by way of example so that the teachings of the persons skilled in the art are fully conveyed. Therefore, the present invention is not limited to the embodiments described below, but may be embodied in other forms. In the drawings, the width, length, thickness, etc. of components may be exaggerated for convenience. Like reference numerals designate like elements throughout the specification. When an element is described as being "on" another element, it is intended that the element be "on top of" another, as well as where there are other elements in between, .

1 is a view showing the structure of a coded microcapsule according to an embodiment of the present invention. Fig. 1 (a) shows the structure of core-shell type microcapsules, and Fig. 1 (b) shows the structure of coded microcapsules.

The coded microcapsules 100 are coded so as to be distinguished from each other according to the type of the target material contained therein, and have a core-shell shape as a whole. That is, the coded microcapsule 100 has a hydrophilic liquid core 110 containing a target material and a hydrophobic shell 120 surrounding the liquid core 110. Also, a graphical code 130 is introduced into the surface of the shell 120.

The liquid core 110 of the coded microcapsule 100 contains a target material which reacts with a substance to be analyzed later, and the target material includes a chemical substance or a biological substance. For example, the chemical substance may be a drug, and the biological material may be at least one selected from the group consisting of cells, molecules, proteins, bacteria, DNA, and RNA.

The coded microcapsules 100 of the core-shell structure can be made through a double emulsion. The doule emulsion has a structure including a small droplet inside the emulsion droplet. For example, when there is an oil droplet inside the droplet (o / w / o) and when there is a water droplet inside the oil droplet w / o / w). The double emulsion may be prepared through two emulsification steps using a conventional emulsification apparatus or may be prepared using a microfluidic chip. The inner droplet of the double emulsion becomes the liquid core 110 and the outer droplet is formed into the shell 120.

The liquid core 110 may be made of any hydrophilic medium capable of dissolving or dispersing the target material, but may be a biocompatible material and may be water or an alcohol. The preferred form of liquid core 110 is a water droplet.

The diameter of the liquid core 110 is not particularly limited, but may be about 50 to 500 占 퐉 m.

The shell 120 surrounds the liquid core 100 and maintains the shape of the liquid core 110. The shell 120 may be made from a hardening of the photo-curable polymer. The photo-curable polymer may include a silicon-containing polymer or an acrylate-based polymer. In order to enhance hydrophobicity, the hydrogen atoms in the polymer chain may be replaced with a fluorine group or may be copolymerized with a fluorine-containing polymer. For example, the photocurable polymer may be a liquid Teflon material. As a specific example, the photo-curable polymer may be perfluoropolyether-urethane dimethacrylate. The shell 120 is formed by curing the photo-curable polymer contained in the external droplet in the double emulsion state, and the external liquid further includes a photoinitiator, and the curing reaction of the photo-curable polymer by an external energy source, Thereby forming the shell 120. The thickness of the shell 120 is not particularly limited, but may be about 5 to 50 占 퐉.

The graphic code 130 may be composed of characters or graphics. Conventionally, a method of engraving a cord into a microcapsule includes mixing a fluorescent material such as a fluorescent dye or a quantum dot with a substance forming a capsule or a substance intended to be contained in a capsule, A spectral coding method using a ratio as a code has mainly been performed. In this case, the spectrum coding method using the ratio of the fluorescence intensity as a code has a very limited number of codes that can be expressed, and thus there are great limitations in using various drug candidates required for drug screening and the like. In addition, when the fluorescent material is mixed with the target material inside the capsule, the state of the substance inside the capsule to be used may be influenced.

The graphic code 130 may contain a fluorescent material. The fluorescent substance may be derived from a photoinitiator having a chromophore. For example, irradiating the patterned energy source to engrave the graphic code 130 in the shell 120 results in an increase in the fluorescence intensity of the photoinitiator contained in the irradiated region.

According to another embodiment of the present invention, a method of producing a coded microcapsule is provided. FIG. 2 is a process flow diagram illustrating a method of producing a coded microcapsule according to an embodiment of the present invention.

Referring to Fig. 2, in step S1, a double emulsion having a hydrophilic liquid core containing a target material and a hydrophobic shell surrounding the liquid core and containing a photocurable polymer is prepared. As the material corresponding to the shell part of the microcapsule, a material having hydrophobicity such as a liquid Teflon-based compound may be used. On the other hand, the capsule inner material can be made of various materials having hydrophilic properties.

In step S2, the photocurable polymer is cured to form core-shell type microcapsules. The curing of the photocurable polymer may be performed by ultraviolet light. So that the solidified shell encapsulates the internal liquid.

In step S3, patterned energy is irradiated to the hardened shell of the microcapsule to form a graphic code.

The hydrophobic shell may contain a photoinitiator whose fluorescence property is enhanced by irradiation of the patterned energy source. The photoinitiator used in the present invention is photolyzed when exposed to ultraviolet rays, and some photodecomposition products cure the photocurable polymer through a radical reaction, and some photodegradation products have fluorescence properties. The more the ultraviolet rays are irradiated, the greater the degree of photodecomposition becomes, so that the amount of photodecomposition products having fluorescence properties is increased and the fluorescence intensity is increased. The photoinitiator is for photocuring and curing. For example, 1 to 5% by weight of the photoinitiator is mixed with the photo-curable polymer in terms of the weight of the entire shell, so that the capsule can be solidified by ultraviolet rays and have a code.

Examples of the material used as the photoinitiator are not particularly limited as long as they have a moiety that can be decomposed by an external energy source such as ultraviolet rays and can have a chromophore capable of emitting fluorescence after decomposition. Preferably, the photoinitiator may be 2,2-dimethoxy-2-phenylacetophenone.

The step of preparing the double emulsion may be performed using a microfluidic chip having a channel region having a hydrophobic surface and a channel region having a hydrophilic surface. The microfluidic chip can be made of, for example, polydimethylsiloxane (PDMS). Specifically, when a microfluidic chip pattern is formed on a silicon wafer by photolithography using a photolithography technique, and PDMS is poured on the wafer, the PDMS is cured and then the PDMS hardened on the wafer is removed . When two PDMS microfluidic chips are subjected to oxygen plasma treatment and then aligned, the microfluidic chip can be completed.

The patterned energy used for forming the graphic code may include ultraviolet rays, visible rays, infrared rays, and electron beams without limitation. The formation of the graphic code may also be performed in a lithographic manner. For example, the irradiation of the patterned energy may be performed by a physical mask or a digital micromirror device (DMD) using ultraviolet light.

3 is a view illustrating a process of manufacturing a microcapsule using a microfluid chip. Referring to FIG. 3, a microfluidic chip 300 having a fluid channel 310 for forming an inner droplet, a fluid channel 320 for forming an outer droplet, and an outermost fluid channel 330 is provided.

A hydrophilic coating may be applied to the outermost fluid channel 330 of the microfluidic chip 300 to form microcapsules of a double emulsion of water, oil, and water. For example, the hydrophilic coating material can be prepared by reacting 2- [methoxy (polyethyleneoxy) propyl] trimethoxysilane, which is a silane coupling agent, with toluene in volume ratio The coating material is adhered to the channel 330 of the microfluidic chip 300 and the surface of the channel 330 is made hydrophilic by flowing the material into the outermost fluid channel 330.

A hydrophilic coating is applied to the outermost fluid channel 330 and a core flow of the fluid channel 310 for forming an inner droplet is flowed while water is flowing. Thus, the center fluid is cut by the liquid Teflon (for example, PFPE-based photo-curable polymer), which is the fluid of the fluid channel 320 for forming the external droplet, to form the internal droplet. The fluid for forming an external droplet further includes a photoinitiator necessary for curing the liquid Teflon. The central fluid may be water containing the target material. This inner droplet is again cut by the water of the outermost fluid channel 330 to form a droplet in the form of a double emulsion in which the inner droplet is contained in the outer droplet. The size of the droplet in the form of a double emulsion can be controlled by varying the size of the microfluidic chip channels 310, 320, 330. Then, the liquid Teflon material is photo-cured by irradiating ultraviolet rays from the external light source 340 to form a polymerized Teflon micro-shell, thereby forming a solidified microcapsule 350 including a liquid core therein. The microcapsules 350 may contain a target material such as a drug and may be stably stored in the capsule 350 for at least 30 days without exiting the capsule 350.

4 is a view showing a process of encoding a microcapsule using a patterned mask and ultraviolet rays. 4, when solidified microcapsules 400 are sprayed on a transparent substrate 410 as a single layer (200) and patterned ultraviolet rays are irradiated through the mask 420, a code 405 ) Is embedded in the shell of the microcapsule. The code 405 can be locally squeezed using the condensation of the lens and the code 405 can be squeezed in a large area by irradiating the parallel light using the mask 420. [ For example, 2,2-dimethoxy-2-phenylacetophenone (DMPA), which is a photoinitiator that mixes with liquid Teflon polymer for photocuring, is coded. The fluorescence intensity of DMPA is increased according to the irradiation of ultraviolet rays of DMPA. The fluorescence intensity of the cord is changed according to the concentration of the photoinitiator mixed with the polymer and the ultraviolet intensity, and the pattern of the mask can be changed by changing the mask pattern.

5 shows fluorescence characteristics of DMPA used as a photoinitiator according to ultraviolet irradiation. The left image of FIG. 5 shows the fluorescence image when the solid photoinitiator is irradiated with ultraviolet light directly. The fluorescence intensity of the solid photoinitiator increases as the time for irradiating ultraviolet rays increases, when the ultraviolet light is not irradiated. The graph on the right side of FIG. 5 is an analysis of the emission spectrum of the solid photoinitiator irradiated with ultraviolet rays. It can be seen that the fluorescence intensity is about 550um in the vicinity of the wavelength band, which is similar to the maximum fluorescence intensities in the fluorescence spectrum of the substance extracted by using column chromatography.

6 is a diagram illustrating a coding process using a digital micromirror device (DMD). Referring to FIG. 6, a digital micromirror device (DMD) is a device capable of electrically controlling the angle of a mirror by electrically driving a micro-mirror array. Each mirror in the DMD can be adjusted so that only the light of the desired pattern can be reflected to the desired position. This makes it easy to embed various shapes and character codes. DMD and objective lens can be used to focus ultraviolet light from ultraviolet light sources to locally pattern at desired positions and to move an automated moving stage to encode a large area It is also possible. The lower right inset picture of FIG. 6 is a fluorescence photograph taken with an optical microscope of the actual coded microcapsules. From the optical microscope picture, a code array of the final coded microcapsules can be identified.

FIG. 7 is a view illustrating a large-area encoding process using a film-combined glass mask (FCG mask). Referring to FIG. 7, a process of coding a large area using an FCG mask can be seen. The FCG mask is a combination of a patterned film and a transparent glass. The size of the mask can be adjusted in various ways. When the microcapsules are sprayed on the FCG mask and then the ultraviolet rays are irradiated from below, the ultraviolet rays are irradiated through the transparent patterned part of the mask And the code of the same pattern as the mask can be embedded in the microcapsule. The larger the size of the mask, the greater the number of microcapsules that can engage the code at once, thereby enabling large area coding.

On the other hand, when the microcapsule is sprayed and irradiated with ultraviolet rays only in one direction, the code is well engraved on the capsule shell near the mask, but not on the opposite shell. This is because ultraviolet light must pass through the microcapsules in order to engrave the cords in the opposite shell, since the light spreads before reaching the opposite side. There are two ways to solve this problem. 8 is a diagram illustrating a method of bi-directionally encoding microcapsules in two ways.

According to one embodiment, the irradiation of the patterned energy can be performed in a manner of bidirectional encoding using the two masks with the microcapsule interposed therebetween (Fig. 8 (a)). This is a method of placing ultraviolet rays on both the upper and lower surfaces by placing a mask on the upper and lower sides. This can be done by irradiating ultraviolet light from both the top and bottom, or by irradiating ultraviolet light once on both sides of the substrate with the capsules scattered.

According to another embodiment, the irradiation of the patterned energy may be performed by disposing a flat substrate separate from the mask with the microcapsule interposed therebetween, compressing the mask and the substrate, and then performing bidirectional encoding 8 (b)). This is a method of placing a microcapsule between a mask and a flat substrate, pressing the microcapsules under pressure up and down to make them flat and reaching the opposite skin before the ultraviolet light emitted through one shell spreads.

The bidirectional encoding allows the microcapsule to be observed even if the microcapsule rotates in an undesired direction when observing the code of the microcapsule. For example, if a code is engraved only in one direction of the microcapsule, it is difficult to observe the code when the microcapsule is rotated 180 degrees and the opposite side of the code is located on the microscope side. At this time, if the microcapsule is coded in both directions, the microcapsule has a code on all sides of the microcapsule, so that the code can be observed regardless of the direction of rotation.

In order to library a coded microcapsule, the code must be retained for a long time after inserting the code into the microcapsule. 9 shows the result of the persistence test of the code. Referring to FIG. 9, the microcapsules having the coded microcapsules with different ultraviolet irradiation times were stored for a long time to confirm that the codes were maintained. As a result, it was confirmed that the fluorescence intensity of the cord was kept constant even after more than 20 days.

According to one embodiment of the present invention, there is provided a microarray using the above-described coded microcapsules. The microarrays are prepared by introducing microcapsules coded so as to be distinguished from each other according to the type of target material contained therein into a substrate having microwells and breaking the microcapsules to release liquid inside the microcapsules containing the target material . Further, the microcapsule has a hydrophilic liquid core including the target material, and a hydrophobic shell surrounding the liquid core. Graphic codes are also introduced on the surface of the shell.

According to an embodiment of the present invention, there is provided an analysis method using the above coded microcapsules. The analysis method includes the steps of introducing microcapsules coded so as to be distinguished from each other according to the type of the target material, into a substrate having microwells, reading codes of the microcapsules encapsulated in the microwells, , Introducing the analyte into the microwells, and breaking the microcapsules introduced into the microwells to react with the target material and the analyte. A variety of said target materials, including drugs, are sealed to the microcapsules and assembled to the substrate with the microwells. At this time, by inserting the graphic code engraved in the shell part of the microcapsule, it is possible to grasp which target material is contained in the capsule. The reading of the graphic code can be performed, for example, through image processing. Analysis of fluorescence images taken through a microscope through an image processing algorithm automatically recognizes text or graphic patterns to enable reading of graphic codes. On the other hand, if microcapsules coded on the microwells are sprinkled for assembly, the microcapsules are assembled into the respective microwells simply by sweeping them down with a flat plate-like tool such as glass. Different designs of microwells may be used to assemble a number of microcapsules in a single, independent reaction space.

Preferably, after introducing the microcapsules into the microwells, a layer of liquid not mixed with the liquid inside the microcapsules is formed on the microwells so that each of the microwells is separated into independent reaction spaces After micro-capsules are assembled, sprinkling liquids that do not mix with water on the micro-wells and making each microwell into an isolated environment will cause each microwell to become an independent reaction space without contamination of each other. . Thereafter, the microcapsule assembled through the micropillar corresponding to the microwell is broken, so that the liquid inside the capsule is allowed to escape to the outside and react with the external material. The disruption of the microcapsules may be performed by bonding a separate substrate having micro-pillars corresponding to the micro-wells to the substrate having the micro-wells, followed by pressing.

10 shows a method of assembling microcapsules coded on a substrate with microwells. Referring to FIG. 10, a plurality of microwells 1010, which contain microcapsules 1016, are aligned on a substrate 1000. The microwells 1010 each have a size capable of accommodating one microcapsule 1016. Each microcapsule 1016 sparged from the library of microcapsules 1030 is introduced into the microwell 1010. The microwell 1010 includes a microcapsule well 1012 for assembling the microcapsule 1016 and a reaction well 1014 for observing the reaction when the liquid in the capsule is released to the outside. After the microcapsules 1016 are sprayed on the substrate 1000 and then simply sweeping the microcapsules 1016 using a flat plate 1020 such as a cover glass, each capsule is assembled into each microwell .

A substrate with microwells can be fabricated, for example, in the following two ways. One method is to pour PDMS onto a wafer having a microwell pattern engraved with a photoresist (SU-8 photoresist) by using polydimethylsiloxane (PDMS), thermally cure the wafer, and then remove the hardened PDMS. Another method is a method using polyurethane acrylate (PUA). Unlike the PDMS having elasticity, PUA-based microwell has a hard surface. The PUA microwell was prepared by spraying a liquid PUA monomer onto a PDMS structure, covering a transparent substrate such as a glass coated with an adhesion primer, and irradiating ultraviolet rays to attach the PUA monomer to the substrate while being photo- By removing the structure, a microwell deposited on a transparent substrate can be made. In the case of the PUA microwell, the pattern of the photoresist deposited on the wafer has a reverse phase of the pattern in the PDMS microwell since the PDMS mold is once passed. 11 shows a manufacturing method using (a) PDMS and (b) a manufacturing method using PUA as the microwell manufacturing method, respectively.

The microwell may be composed of one layer or two layers. Figure 12 shows examples of microwells in which the depth of the microwell is appropriately adjusted according to the microcapsule size. Figure 12 (a) shows a microwell composed of one layer and (b) shows a microwell composed of two layers. Referring to FIG. 12, for example, when the microwell is composed of one layer, the microwell depth h1 is configured to be one size smaller than the size (d) of one microcapsule, Mechanisms allow extra microcapsules to be easily removed. For example, if the microwell is composed of two layers, the lower layer (h1) should be at least one microcapsule but less than one half size, and the upper layer (h2) should be at a depth of less than half the microcapsules, Allow the microcapsules to be easily removed.

According to some embodiments, microwells of various shapes can be made through a photolithography process. In addition to assembling one microcapsule in one reaction space, multiple microcapsules can be assembled in one reaction space, and reactions depending on the combination of various drugs can also be observed. 13 is a diagram showing microwells of various shapes. Referring to FIG. 13, microcapsules are assembled in a microwell array. The upper picture is the microwell array and its enlarged view, and the inset in the upper picture is the image of the entire microwell array compared with the size of the coin. The bottom images represent various types of microwells. For each image, the scale bar is 200 μm.

By crushing the assembled microcapsules, the liquid inside can be released. 14 is a view showing a process of releasing internal liquid of microcapsules assembled in a microwell. 14, the microwell array 1400 includes a microwell 1430 in which a microcapsule 1410 is assembled, and an analyte material 1450 is disposed in each microwell 1430. An immiscible liquid 1420, such as oil, can be sprayed on the microwell 1430 to make each microwell 1430 an independent reaction space. The micropillar 1445 is aligned with the microwell 1430 so that the substrate 1440 on which the micropillar 1445 aligned with the microwell 1430 is aligned. And presses the substrate 1440 using a tool 1460 such as a roller to physically break the microcapsule 1410 to release the internal liquid to react with the analyte 1450. For example, in the case of drug screening using cells, the cells are first incubated in a microwell, then the microcapsules are assembled, and when the liquid inside the capsule is released, the drug reacts with the cells, can do. In the case of enzymatic assay, a substrate and an inhibitor are put into a microcapsule without a cell, and a microwell outside the capsule is filled with an enzyme to release a liquid inside the capsule, The degree of inhibition of the reaction can be grasped.

Micro-column arrays can be fabricated by irradiating PUA columns with ultraviolet light onto flexible substrates such as PET films. The manufacturing method is similar to PUA microwell, but it is manufactured using a flexible substrate instead of a rigid substrate such as glass. When the liquid PUA is poured into the PDMS frame, the flexible film is put on the PDU frame, and the photo-curing is performed by irradiating ultraviolet rays, the PUA and the film are adhered and the micropillar pattern corresponding to the PDMS frame is formed as the PUA material.

A variety of analyzes are possible using the above-described coded microcapsules and substrates with microwells. For example, an apoptosis experiment using an anticancer agent can be performed using the substrate having the microwells. First, the cells are first grown in a microwell, and then the encoded microcapsules containing each drug are assembled in a microwell. Which drug is contained in each microwell can be determined by reading the code of the microcapsule. After each microwell is isolated with oil, the micropores array is used to release the liquid inside the capsule. The result is a liquid microarray. After incubation in an incubator for 12 hours to 24 hours, an apoptosis kit capable of observing the cell death was sprayed on a microwell to react with the cells, Under the type and concentration, we observe how dead and live.

15 is a diagram showing the results of cell death test using an anticancer agent. 15 (a) to 15 (d) are graphs showing (a) microcapsules and cells assembled into microwells, (b) cell death fluorescence images by apoptosis after drug reaction, (c) image processing And (d) graphs of cell viability according to the type and concentration of each drug, respectively. The drugs used were camptothecin (CPT), toxoflavin (PKF), and paclitaxel (PTX). Referring to FIG. 15, the degree of apoptosis of various drug types and concentration differences can be determined through one liquid microarray.

As described above, according to various embodiments of the present invention, each drug can be physically independent by putting various kinds of drug candidates into the microcapsule. Compared to a serial liquid handling method using a conventional pipette, the present invention can employ a particle-based handling method, which allows a small amount of liquid to be varied in parallel and effectively. In addition, since a graphic code can be easily produced without the need for a special coding material, fabrication cost can be reduced because fluorescent dyes and quantum dots used in conventional spectrum code production are not required. Because it can be coded as a character or a graphic, the number of codes can be increased in comparison with the existing limited spectrum code method, so that a microcapsule library can be created. Therefore, it is possible to deal effectively with rapidly increasing drug candidates according to the technology development.

When the microcapsules thus prepared are assembled into a microwell and the liquid inside the capsule is released to form a liquid microarray, parallel drug screening becomes possible. Since each reaction takes place in micrometer space, the number of data that can be obtained from one image is increased, and the amount of consumed drug can be drastically reduced compared to conventional plate-based screening technology, Is also economical. In addition, it is possible to assemble multiple microcapsules in a separate reaction space by changing the shape of the microwell, so that the reaction according to the combination of various drugs can be easily seen.

Claims (18)

A microcapsule coded according to the type of target material contained,
A hydrophilic liquid core comprising the target material; And
A hydrophobic shell surrounding the liquid core,
Coded microcapsules comprising graphic code introduced on said shell surface. The method according to claim 1,
Wherein the target material comprises a chemical substance or a biological substance. 3. The method of claim 2,
Wherein the chemical substance is a drug and the biological substance is at least one selected from the group consisting of cells, molecules, proteins, bacteria, DNA, and RNA. The method according to claim 1,
The liquid core is water droplet coded microcapsules. The method according to claim 1,
The shell is made of a microcapsule made by curing a photocurable polymer. The method according to claim 1,
Wherein the graphic code is a microcapsule containing a fluorescent substance. Preparing a double emulsion having a hydrophilic liquid core containing a target material and a hydrophobic shell surrounding the liquid core and containing a photocurable polymer;
Curing the photocurable polymer to form microcapsules in the form of a core-shell; And
And irradiating patterned energy to the hardened shell of the microcapsule to form a graphic code. 8. The method of claim 7,
Wherein the hydrophobic shell contains a photoinitiator whose fluorescence property is enhanced upon irradiation of the patterned energy. 8. The method of claim 7,
Wherein said photoinitiator is 2,2-dimethoxy-2-phenylacetophenone. 8. The method of claim 7,
Wherein the step of preparing the double emulsion is performed using a microfluidic chip having a channel region having a hydrophobic surface and a channel region having a hydrophilic surface. 8. The method of claim 7,
Wherein the irradiation of the patterned energy is performed using a digital micromirror device (DMD). 8. The method of claim 7,
Wherein the irradiation of the patterned energy is performed by a lithography method using a mask. 13. The method of claim 12,
Wherein the irradiation of the patterned energy is carried out in such a manner that bidirectional encoding is performed using the two masks with the microcapsule interposed therebetween. 13. The method of claim 12,
Wherein the irradiation of the patterned energy is performed in such a manner that a flat substrate separate from the mask is interposed between the microcapsules, and the mask and the substrate are compressed and then bidirectionally coded. Introducing coded microcapsules into the substrate with microwells so that they are differentiated according to the type of target material contained;
Reading codes of the coded microcapsules disposed within the microwells;
Introducing an analyte into the microwells; And
And disrupting the microcapsules introduced into the microwells to react with the target substance and the analyte,
Wherein the microcapsule comprises a hydrophilic liquid core comprising the target material and a coded microcapsule having a hydrophobic shell surrounding the liquid core and including a graphic code introduced into the shell surface Analysis method. 16. The method of claim 15,
Introducing the microcapsules into the microwells and forming a layer of liquid not mixed with the liquid inside the microcapsules on the microwells to separate the microwells into independent reaction spaces Containing microcapsules. 16. The method of claim 15,
Wherein the disruption of the microcapsules is performed by bonding a separate substrate having micro-pillars corresponding to the micro-wells to the substrate having the micro-wells, followed by pressing. The microcapsules coded so as to be distinguished from each other according to the type of the target material are introduced into a substrate having microwells, the microcapsules assembled in the microwells are broken, As a microarray,
Wherein the microcapsule comprises a hydrophilic liquid core comprising the target material and a graphic cord introduced into the shell surface having a hydrophobic shell surrounding the liquid core.

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