KR102507834B1 - Surface modified noncontaminating cell test microfluidic chip and microfluidic device containing the same - Google Patents

Abstract

The present invention relates to a microfluidic device having a long-term antibacterial, antifouling, and cell-adhesive film. Even in a miniaturized microfluidic chip, a functional polymer composite material that satisfies essential conditions for culturing cells or microorganisms and monitoring drug efficacy while being different for each local area. is implemented, and the microfluidic device made of the material can effectively perform cell culture and drug effect monitoring.

Description

Surface modified noncontaminating cell test microfluidic chip and microfluidic device containing the same}

The present invention relates to a surface-modified non-staining cell assay microfluidic chip and a microfluidic device including the same.

Medical diagnostic chips and sensor chips are generally made by introducing a liquid biological sample into a microfluidic chip on which diagnostic reagents are fixed and confirmed. Today, the diagnostic chip has expanded its function as a medical diagnostic chip to drug screening and cell culture chip manufacturing, moving away from being operated in a simple O, X method like a pregnancy test kit. came into being However, among the existing methods of testing drug effects, in vitro clinical trials, that is, toxicity tests at the cell level, prior to animal clinical trials, are applied directly to the cell layer in which the drug has been cultured in advance, unlike the biological environment. As it was tested in contact with cells, it was not possible to distinguish the effects caused by high concentrations and physical contact. In addition, existing microfluidic system development technologies are focused on implementing physically and geometrically complex structures, but in biomedical engineering, it is important to control the chemical and biochemical functions of materials. Therefore, it is necessary to develop a drug delivery system that can be used in microfluidic devices and a functional material capable of maintaining it without contamination for a long time.

An object of the present invention is to provide a microfluidic device with excellent cell culture by preventing contamination of a microfluidic device including a surface-modified microfluidic chip and inducing cell adsorption during cell culture.

In order to achieve the above object, a surface-modified microfluidic chip according to one aspect of the present invention includes a non-adhesive portion formed by alternately repeating the lamination of a hydrophilic single polymer and the lamination of polyacrylamide; and a cell-adhesive formed by alternately repeating the lamination of the hydrophilic homopolymer and the lamination of the supramolecular structure compound.

In addition, it may be a microfluidic chip pre-treated with polyallylamine hydrochloride.

In addition, it may be a microfluidic chip post-processed with silver nanoparticles.

In addition, it may be a microfluidic chip including a channel connected to a drug introducing unit, a drug particle fixing unit, a drug efficacy monitoring unit, and a cell culture unit.

In addition, it may be a microfluidic chip post-processed with at least one selected from the group consisting of poly-L-lysine and tannic acid.

In addition, the stacking may be a microfluidic chip formed by alternately repeating 2 to 100 times.

In addition, the hydrophilic homopolymer may be at least one microfluidic chip selected from the group consisting of polyethylene oxide, polyethylene glycol, polyacrylic acid, and polyvinyl alcohol.

In addition, the supramolecular structure compound may be at least one microfluidic chip selected from the group consisting of crown ether, cyclodextrin, rotaxan, zeolite, porphyrin, and cucurbituril there is.

In addition, the microfluidic chip may be one or more microfluidic chips selected from the group consisting of polydimethyl siloxane, polymethyl methacrylate, and cyclo-olefin copolymer.

In another embodiment, a non-adhesive portion formed by alternately repeating the lamination of a hydrophilic homopolymer and the lamination of polyacrylamide; and cell adhesion portions formed by alternately repeating the lamination of the hydrophilic homopolymer and the lamination of the supramolecular structure compound. Provided is a microfluidic device including a microfluidic chip whose surface is modified with

In addition, the lower surface of the microfluidic chip includes at least one lower plate selected from the group consisting of glass, polydimethyl siloxane, polymethyl methacrylate, and cyclo-olefin copolymer. It may be a microfluidic device.

In another embodiment, stacking the non-adhesive portion formed by alternately repeating the stacking of the hydrophilic homopolymer and the stacking of polyacrylamide; and stacking the cell adhesive portion formed by alternately repeating the stacking of the hydrophilic homopolymer and the stacking of the supramolecular structure compound; It provides a method for manufacturing a microfluidic chip whose surface is modified by

As described above, the microfluidic device including the surface-modified microfluidic chip according to the present invention is coated with long-term antibacterial, non-fouling, and cell adsorption properties, so that the drug introduction part and the cell culture part are well separated, thereby culturing cells without contamination of other microorganisms. And drug release can be achieved, so toxicity test and drug release effect can be effectively monitored in real time. In addition, the non-staining coating material according to the present invention can be applied to the pharmaceutical and medical engineering industries by implementing a functional polymer composite material that meets the essential conditions for cell or microbial culture and drug efficacy monitoring, while being different for each local area. It can be used as a delivery system and medical diagnostic chip, or it can be applied to various fields where microbial contamination must be prevented.

Figure 1 shows (a) an assembly configuration diagram of a microfluidic device and (b) a configuration diagram for each part of a microfluidic chip according to an embodiment of the present invention. The top plate represents a microfluidic chip.
2 shows (a) a photograph of drug-loaded gel particles and (b) a result of drug release behavior in a microfluidic device according to an embodiment of the present invention.
3 shows a structure of a polymer compound used for surface modification of a microfluidic chip according to an embodiment of the present invention. (a): High molecular compound used for non-adhesive coating, (b): High molecular compound used for cell adhesive coating.
4 shows the result of measuring the contact angle of a microfluidic device according to an embodiment of the present invention.
5 shows a cell adhesive surface image of a microfluidic device according to an embodiment of the present invention.
6 is an image showing the results of cell culture in a microfluidic device according to an embodiment of the present invention. (a): general PDMS microfluidic chip, (b) microfluidic chip selectively coated with non-staining film (PAA/PAAm), (c) non-staining film (PAA/PAAm) and cell-adhesive film (PAA/Cat- CyD) microfluidic chip selectively coated for each site.
7 is an image showing the shape of drug-containing sodium alginate (SA) gel particles introduced into the drug particle fixing part of the microfluidic device according to an embodiment of the present invention. (a): Normal PDMS fluid chip, (b): PDMS fluid chip with non-contamination surface treatment.
8 is an image showing the result of long-term cell culture of a non-staining coated microfluidic device according to the presence or absence of silver nanoparticles according to an embodiment of the present invention.
9 is an image showing the results of anticancer drug release from gel particles in a microfluidic device treated with a functional coating film according to an embodiment of the present invention.

Hereinafter, the present invention will be described in more detail. In describing the present invention, if it is determined that a detailed description of a related known configuration or function may obscure the gist of the present invention, the detailed description will be omitted. All documents cited herein are incorporated as part of this invention.

As used in this specification and appended claims, unless otherwise indicated, the following terms have the following meanings:

The term "poly(dimethylsiloxane)" used herein should be understood as the same as "PDMS" below.

As used herein, the term "sodium alginate" should be understood as the same as "SA" below.

As used herein, the term "polyallylamine hydrochloride" should be understood as the same as "PAH" below.

The term "polyacrylic acid" used herein should be understood as the same as "PAA" below.

As used herein, the term "polyacrylamide" should be understood as the same as "PAAm" below.

The term "cyclodextrin" or "cyclodextrin" as used herein is to be understood as synonymous with "CyD" hereinafter.

The term "betacyclodextrin" or "β-cyclodextrin" as used herein should be understood as synonymous with "β-CyD" below.

As used herein, the term "Cationic cyclodextrin oligomer" should be understood as the same as "Cat-CyD" below.

As used herein, the term "poly-L-Lysine" should be understood as synonymous with "PLL" below.

As used herein, the term "tannic acid" should be understood as the same as "TA" below.

As used herein, the term "non-adhesive coating" means a coating having hydrophilicity and antifouling properties (prevention of microbial adhesion).

As used herein, the term "cell-adhesive coating" means a coating having cell-adhesive properties.

The surface-modified microfluidic chip of the present invention includes a non-adhesive portion formed by alternately repeating the lamination of a hydrophilic single polymer and the lamination of polyacrylamide; and a cell adhesion portion formed by alternately repeating the lamination of the hydrophilic homopolymer and the lamination of the supramolecular structure compound.

Some of the configurations included in the present invention include the contents of Korean Registered Patent No. 1928048, and some of the contents described in the registered patent may be included as part of the present invention even if not specifically described in the present invention.

The surface of the microfluidic chip of the present invention may be pre-treated by a known method such as plasma treatment and/or primer treatment in order to improve adhesion to a polymer multilayer film described later. However, when the material of the microfluidic chip is hydrophobic, it is necessary to modify the surface to be hydrophilic so that an aqueous solution such as a cell culture medium can be easily introduced. Preferably, surface modification to be hydrophilic may be induced by pre-treatment with polyallylamine hydrochloride prior to forming the polymer multilayer film, but is not limited thereto.

The microfluidic chip of the present invention may include a channel connected to a drug introduction unit, a drug particle fixing unit, a drug efficacy monitoring unit, and a cell culture unit.

The cell culture part may be substantially the same as the cell adhesion part, and cell adhesion may use any material that improves cell adhesion efficiency used in the field to which the present invention belongs, and preferably has a positive charge depending on the charge property of the cell A material may be used, more preferably one post-processed with one or more selected from the group consisting of poly-L-lysine and tannic acid, but is not limited thereto.

Since the microfluidic chip of the present invention is manufactured for cell assay, various contaminants can be excluded only when the entire process is performed in an aseptic state. In order to achieve the non-fouling effect, the present invention used a non-adhesive portion formed by alternately repeating the lamination of hydrophilic homopolymer and the lamination of polyacrylamide, but all of the non-adhesive parts used in the field to which the present invention belongs to additional contamination prevention An antifouling material may be included, and post-treatment may be preferably performed with silver nanoparticles, but is not limited thereto.

The silver nanoparticles can be used in all parts of the microfluidic chip, preferably in the cell culture part, but are not limited thereto.

In the present invention, the lamination includes the number of laminations showing hydrophilicity and antifouling properties (prevention of microbial adhesion) of the microfluidic chip, preferably 2 to 100 times, 2 to 50 times, 2 to 10 times, and 2 to 5 times. It is formed by repeating, more preferably by alternating 3 to 4 times, but is not limited thereto.

In the present invention, the hydrophilic polymer refers to a polymer having a polar or charged functional group on the main chain or side chain of the polymer chain and thus soluble in a polar solvent such as water. The hydrophilic polymer may be a crystalline or amorphous polymer. Meanwhile, a homo-polymer refers to a polymer obtained by polymerizing one monomer.

In the present invention, the hydrophilic homopolymer may be at least one selected from the group consisting of polyethyleneoxide (PEO), polyethyleneglycol (PEG), polyacrylic acid (PAA), and polyvinyl alcohol (PVA), , preferably PAA, but is not limited thereto.

In the present invention, the supramolecular compound can be easily prepared as a coating film compared to the conventional organic low molecular based supramolecular formation, and the combination of various molecules with guest molecules on the solid surface can be utilized. It can be a new functional material that can be. Molecules that bind to guest molecules are compounds with cavities, and their binding phenomena have been studied in supramolecular chemistry. Supramolecules refer to molecular complexes formed by gathering molecules or ions through non-covalent bonds such as hydrogen bonds, electrostatic interactions, or van der Waals forces. Representative non-covalent bonds that form the structure of supramolecules are very weak compared to covalent bonds, so the structure of supramolecular materials can easily change depending on the surrounding environment. Using these characteristics, the shape of the material can be arbitrarily controlled. A representative principle of forming a supramolecular structure is molecular recognition.

n) and self-assembly. Molecular recognition can be seen as a lock and key relationship as a result of molecules structurally matching, such as an antigen-antibody reaction. On the other hand, self-assembly is a phenomenon in which molecules are assembled through spontaneous interactions, and the supramolecular sieve formed in this way is due to the characteristics of the molecules. If the supramolecules in the ecosystem are more based on molecular recognition, it can be seen that the synthesis-based supramolecular chemistry is more diverse in cases where it is controlled by self-assembly. Since the range of supramolecular sieves can be quite broad, starting with the simplest and smallest units, we can refer to monomer-based molecules.

The supramolecular structure compound may be one or more selected from the group consisting of crown ether, cyclodextrin (CyD), rotaxan, zeolite, porphyrin, and cucurbituril, preferably Preferably, it may be alpha, beta, or gamma CyD, and more preferably, it is developed by the inventor in prior research (S. Y. Yang et al., Bull. Korean Chem. Soc. 2013, Vol. 34, No. 7. 2016-2022) It may be a cationic cyclodextrin oligomer (Cat-CyD), but is not limited thereto.

In the present invention, the microfluidic chip is made of a material selected from the group consisting of polymers with high optical transparency, such as polydimethyl siloxane, polymethyl methacrylate, and cyclo-olefin copolymer. It can be used, but is not limited thereto.

In addition, the present invention provides a first laminate formed by alternately repeating the lamination of hydrophilic homopolymer and the lamination of polyacrylamide; and a second layered portion formed by alternately repeating the layering of the hydrophilic homopolymer and the layering of the supramolecular structure compound. Provided is a microfluidic device including a microfluidic chip whose surface is modified with

In the present invention, the lower surface (lower plate) of the microfluidic chip is made of polymers with high optical transparency such as glass, polydimethyl siloxane, polymethyl methacrylate, and cyclo-olefin copolymer. It may be one or more selected from the group consisting of, but is not limited thereto.

In another embodiment, laminating a first laminate formed by alternately repeating a hydrophilic homopolymer laminate and a polyacrylamide laminate; and laminating a second layered portion formed by alternately repeating the layering of the hydrophilic homopolymer and the layering of the supramolecular structure compound on the surface of the first coating layer. Provided is a method for manufacturing a substrate having a modified surface thereof.

Hereinafter, examples of the present invention will be specifically described, but the present invention is not limited to the following examples.

Example 1. Contains drugs hydrogel particle manufacturing

6-mercaptopurine (hereinafter abbreviated as 6-MP), a cancer treatment, is a poorly soluble drug that is difficult to dissolve in aqueous solutions such as body fluids. Hydrogel particles capable of effectively loading and releasing 6-MP were synthesized. First, 6-MP was dissolved in distilled water at a concentration of 0.05% (w/v) at 70°C. Sodium alginate (hereinafter abbreviated as SA) was dissolved in double distilled water at a concentration of 4% (w/v) at room temperature. After 6-MP was completely dissolved, it was mixed with SA solution and stirred for 4 hours while maintaining at 40°C. Prepare a 1 M calcium chloride solution dissolved in secondary distilled water at room temperature, put the mixed solution of 6-MP and SA in a syringe, drop it drop by drop into the calcium chloride solution, and stir at 300 rpm for about 20 minutes to crosslink. made it The resulting particles (SA beads containing 6-MP) were filtered through a filter, washed three or more times with distilled water, and then dried at 70° C. for 24 hours.

Example 2. Microfluidic chip and microfluidic device manufacturing

Poly(dimethylsiloxane) (hereinafter abbreviated as PDMS) was prepared by uniformly mixing sylgard 184A as a precursor and sylgard 184B as a crosslinking agent at a weight ratio of 9:1 using a vortex mixer for 5 minutes. After pouring the blended PDMS onto a silicon master mold in which multiple microfluidic chips were embedded using lithography, air bubbles present in the PDMS were removed in a vacuum oven at a pressure of 60 mmHg for more than 1 hour. . Then, the PDMS was cured at 60° C. for 3 hours. The cured PDMS was separated from the master mold and cut into individual microfluidic chip units.

A microfluidic device is manufactured by adhering a PDMS microfluidic chip (top plate) with channels and glass (slide glass) or PDMS as a bottom plate to each other. Before fabricating the microfluidic device, the PDMS microfluidic chip and slide glass were washed using a sonicator for 15 minutes in an aqueous solution in which distilled water and micro detergent were diluted. After that, after rinsing several times with secondary distilled water to sufficiently remove the detergent, it was put into secondary distilled water again and washed 2 to 3 times for 15 minutes each. The substrate was put in a solution of isopropanol and NaOH diluted in double distilled water, washed for 15 minutes, and finally washed with double distilled water for 15 minutes.

Before bonding the upper and lower plates of the microfluidic device, SA particles were placed and bonded to the drug introduction part of the PDMS microfluidic chip. The upper and lower plates were treated with a plasma processor for 30-90 seconds and then bonded. In order to fix the junction well, the microfluidic device combining the upper and lower plates was used after placing it under a constant pressure for about 48 hours.

Example 3. Inducing cell adhesion cyclodextrin ( CyD ) polymer synthesis

Cyclodextrin (hereinafter abbreviated as CyD)-based polymer has the characteristics of a sugar analog and a cavity, so it can impregnate biochemical signal substances or active substances, so it has the effect of helping cells adsorb or grow. there is. Cationic cyclodextrin oligomer (hereinafter abbreviated as Cat-CyD) was synthesized because an oligomer type material having an ionic functional group is required to use the CyD polymer as a material for a functional coating film. For CyD, beta cyclodextrin (β-cyclodextrin; hereinafter abbreviated as β-CyD), which showed the highest yield and good introduction of ionizing groups in previous studies, was used (S. Y. Yang et al., Bull. Korean Chem. Soc. 2013, Vol. 34, No. 7. 2016-2022).

Example 4. Inside the microfluidic device surface modification

Since the microfluidic device has a hydrophobic surface, it is necessary to modify the surface to be hydrophilic to facilitate the introduction of an aqueous solution such as a cell culture medium, and also to prevent contamination by bacteria or the like. For this surface modification, a polyelectrolyte multilayer membrane was used. The polymer electrolyte for surface modification is polyallylamine hydrochloride (hereinafter abbreviated as PAH), polyacrylic acid (hereinafter abbreviated as PAA), and polyacrylamide (hereinafter abbreviated as PAAm). ), Cat-CyD, and natural polymer poly-L-Lysine (hereinafter abbreviated as PLL) and tannic acid (hereinafter abbreviated as TA) were used. Each polymer electrolyte was adjusted to a concentration of 0.01 M using double distilled water, and the pH was maintained at 3.0.

First, PAH was injected into the pre-adhered microfluidic device using a syringe pump, and adsorption was induced by filling the channel for 15 minutes, and residual PAH was removed by washing twice with distilled water. At this time, PAH is well adsorbed on PDMS so that the PAA/PAAm coating introduced later can be well formed. In the same way as for PAH, PAA and PAAm were alternately injected into the fluidic channels and stacked. Here, the PAA/PAAm coating exhibits non-staining properties that prevent adsorption of cells or other microorganisms. The thickness of the coating film was laminated to PAH(3.0)/[PAA(3.0)/PAAm(3.0)] ₃ , which is the minimum thickness representing hydrophilicity and antifouling property (prevention of microbial adhesion) of the microfluidic channel. Here, a layer in which a pair of different polymers such as PAA and PAAm are bonded and laminated is referred to as 1 bilayer, and _the number of stackings is indicated. For the stability of the PAA/PAAm coating, thermal crosslinking was performed at 80° C. for 10 hours using an oven after lamination. In addition, the cell culture part, which is a cell growth observation part, was additionally laminated with [Cat-CyD/PAA] _3.5 coating film in which Cat-CyD, a polymer showing cell adsorption, was laminated together with PAA. As a cell-adhesive coating film, natural polymers such as PLL and TA were used, and good results were obtained.

Example 5. Synthesis of silver nanoparticles

Silver nanoparticles were synthesized through ion exchange and reduction reactions in a polymer multilayer thin film using the Layer-by-Layer (LbL) technology. First, the polymer multilayer film is immersed in 5 mM silver acetate (CH ₃ COOAg) aqueous solution for 15 minutes to cause an ion exchange reaction between the -COOH functional group and silver cations inside the multilayer film, and then washed twice for 2 minutes in double distilled water to remove residual substances. did Then, silver cations dispersed inside the multilayer film were reduced to silver nanoparticles by soaking in a reducing solution, 2 Mm Borane-dimethylamine complex ((CH ₃ ) ₂ NH·BH ₃ ; DMAB) aqueous solution for 5 minutes. Finally, it was washed twice for 2 minutes with deionized distilled water to remove the residual reducing solution.

Example 6. Cells using microfluidic devices monitoring

Cell culture and cytotoxicity to drugs were observed by injecting cells into microfluidic channels to which various functional coatings were applied. HEK293 cells and HeLA cells were used as cells. First, before cell injection, the fabricated microfluidic channel was exposed to UV-light for 30 minutes, and then the specimen was disinfected using 70% ethanol. In addition, using a 1 ml syringe, the DPBS solution was flowed into the channel several times to wash it, and the cell culture medium was injected into the channel in the same way. Thereafter, the prepared cells were injected into the channel using a 1 ml syringe and cultured in an incubator at 37° C., 5% CO ₂ , and cell changes according to drug release were observed from 4 hours to 96 hours after introduction of the cells.

Figure 2 is a photograph of hydrogel particles loaded with drugs such as anticancer drugs in the present invention (Fig. 2a) and the results of drug release from the gel particles at pH 5.5 of deionized water and plasma pH 7.4, the pH environment of the living body. indicates

Figure 3 shows the structure of the polymer compound used for surface modification of the microfluidic device, (a) is PAA, PAAm polymer of non-adhesive coating film, (b) is Cat-CyD, PAH, PLL of cell-adhesive coating film , representing the TA polymer. Among these, the multilayer film of PAA/PAAm exhibits hydrophilicity and antifouling property (prevention of microbial adhesion) of the microfluidic channel, so they are hereinafter referred to as “Non-adhesive” coatings. The Cat-CyD/PAH multilayer film and the PLL/TA multilayer film seem to have cell adhesion by promoting cell surface adsorption and culture. Accordingly, these coatings are hereinafter referred to as “cell-adhesive” coatings.

Both PLL/TA polymers are natural polymers and were developed as biocompatible and friendly coatings. In the case of the [PLL(7.0)/TA(5.0)] coating film, the hydrophobic surface of PDMS was changed to hydrophilic and cell growth was facilitated.

4 shows the results of improving the surface wettability of a microfluidic chip by using PLL/TA as a coating film, (a) water contact angle change according to the number of layers of the coating film, (b) PDMS before and after applying the PLL/TA coating film. It is a photograph of water contact angle measurement. As shown in FIG. 4, the contact angle of about 110° was lowered to around 50° after the PLL/TA coating, and as shown in FIG. 5, PC12 cells grew well on the coating. It seems that it can be applied when culturing neurons in microfluidic devices, such as PC12 cells.

Figure 5 shows the cell adhesive surface using PLL / TA as a coating film, (a) TA outermost layer, (b) shows the culture results of PC12 neurons on the PLL outermost layer coating film up to the 4th day.

Figure 6 shows the results of cell culture in a microfluidic device. (a) In the case of an existing general microfluidic chip that is not surface-treated, cancer cells and normal cells (control group) are not selectively cultured in the cell culture unit. It can be seen that it is not possible and irregularly formed in the first half of the channel. On the other hand, in the case of microfluidic chips (b) and (c) with a non-staining coating, it can be confirmed that cell growth is selectively concentrated in the cell culture part, thereby preventing contamination when the released drug reaches the cells. can be analyzed without In particular, in the case of (c) using non-adhesive coating and cell-adhesive coating, even with the stacking of only one layer of Cat-CyD, cell culture was well performed in the cell culture section, and highly reliable analysis results were obtained. Cat-CyD is a compound synthesized in the form of a polymer by adding an ionizing functional group to the CyD molecule and is a patented compound owned by the present inventors (Republic of Korea Patent Nos. 1190267 and 1195533, etc.).

7 is a microscopic image of SA gel particles including drugs introduced into a drug particle fixing part of a microfluidic device. Referring to this, (a) in the case of a general microfluidic device, the surface of the microfluidic device is not treated. While cells adsorbed to the drug particles are in direct contact, (b) in the case of the microfluidic device of the present invention with a non-fouling surface treatment, no cells in direct contact around the drug particles are found due to the non-fouling coating. You can check.

8 shows the results of testing the cell persistence during long-term cell culture according to the presence or absence of silver nanoparticles introduced into the non-fouling coated microfluidic device using a polymer having a carboxyl group such as PAA of the coating film used in the present invention. Compared to (a) without silver nanoparticles, it can be seen that (b) with silver nanoparticles introduced into the coating film is well cultured without contamination during long-term cell culture due to the antimicrobial activity of silver nanoparticles.

Finally, the results of observing the effect of the drug while culturing the cells by inserting the drug-carrying particles in the microfluidic chip are summarized in FIG. 9 . 9 is a result of monitoring changes occurring in cultured cells as the drug is released from hydrogel particles loaded with anticancer drugs. After 72 hours of anticancer drug release, all HeLa cells, which are cancer cells, are killed, but HEK293 cells, which are normal cells, have problems. It was confirmed that it was cultured without. In this way, the cells were well cultured without contamination for several days, and the efficacy of the drug could be monitored in real time, and it was easy to compare the efficacy against normal cells versus cancer cells under the same conditions.

Taken together, the miniaturized microfluidic chip according to the present invention is a functional polymer composite material that is different for each local area and meets the essential conditions for culturing cells or microorganisms and monitoring drug efficacy, and the microfluidic device is a drug introduction part and cancer cell Since the culture part is well separated, cell culture and drug release can be performed without microbial contamination, so that the effect of the drug on cancer cells can be effectively monitored in real time.

In the above, the present invention has been described as an example, and those skilled in the art will be able to make various modifications without departing from the essential characteristics of the present invention. Accordingly, the embodiments disclosed in this specification are intended to explain, not limit, the present invention, and the spirit and scope of the present invention are not limited by these embodiments. The protection scope of the present invention should be construed by the following claims, and all techniques within the equivalent range should be construed as being included in the scope of the present invention.

(1): introduction part (2): drug particle fixing part
(3): Drug efficacy monitoring unit (4): Cell culture unit

Claims (12)

a non-adhesive portion formed by alternately repeating the lamination of a hydrophilic homopolymer and the lamination of polyacrylamide; and
a cell-adhesive formed by alternately repeating the lamination of hydrophilic homopolymers and the lamination of supramolecular structure compounds; Microfluidic chip surface modified with The microfluidic chip according to claim 1, comprising a channel connected to a drug introduction unit, a drug particle fixing unit, a drug efficacy monitoring unit, and a cell culture unit. The microfluidic chip according to claim 1, which is pre-treated with polyallylamine hydrochloride. The microfluidic chip according to claim 1, post-processed with at least one selected from the group consisting of poly-L-lysine and tannic acid. The microfluidic chip according to claim 1, post-processed with silver nanoparticles. The microfluidic chip according to claim 1, wherein the stacking is alternately repeated 2 to 100 times. The microfluidic chip according to claim 1, wherein the hydrophilic homopolymer is at least one selected from the group consisting of polyethylene oxide, polyethylene glycol, polyacrylic acid, and polyvinyl alcohol. The method of claim 1, wherein the supramolecular structure compound is at least one selected from the group consisting of crown ether, cyclodextrin, rotaxan, zeolite, porphyrin, and cucurbituril. microfluidic chip The microfluidic chip of claim 1, wherein the microfluidic chip is at least one selected from the group consisting of polydimethyl siloxane, polymethyl methacrylate, and cyclo-olefin copolymer. a non-adhesive portion formed by alternately repeating the lamination of hydrophilic homopolymer and the lamination of polyacrylamide; and
Cell adhesion layer formed by alternately repeating the stacking of the hydrophilic homopolymer and the stacking of the supramolecular structure compound; Microfluidic device including a microfluidic chip whose surface is modified with The method of claim 10, wherein at least one selected from the group consisting of glass, polydimethyl siloxane, polymethyl methacrylate, and cyclo-olefin copolymer on the lower surface of the microfluidic chip Microfluidic device including a lower plate laminating a non-adhesive portion formed by alternately repeating lamination of hydrophilic homopolymer and lamination of polyacrylamide; and
stacking the cell adhesive portion formed by alternately repeating the stacking of the hydrophilic homopolymer and the stacking of the supramolecular structure compound; Manufacturing method of microfluidic chip whose surface is modified by

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