KR20220028552A - Fabrication of apparatus for detecting nucleic acid through roll-to-roll Langmuir-Blodgett technology - Google Patents

Fabrication of apparatus for detecting nucleic acid through roll-to-roll Langmuir-Blodgett technology Download PDF

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KR20220028552A
KR20220028552A KR1020200109679A KR20200109679A KR20220028552A KR 20220028552 A KR20220028552 A KR 20220028552A KR 1020200109679 A KR1020200109679 A KR 1020200109679A KR 20200109679 A KR20200109679 A KR 20200109679A KR 20220028552 A KR20220028552 A KR 20220028552A
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nucleic acid
nanoparticles
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KR102418519B1 (en
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리 루크
조규진
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성균관대학교산학협력단
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L7/00—Heating or cooling apparatus; Heat insulating devices
    • B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L7/00—Heating or cooling apparatus; Heat insulating devices
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6844—Nucleic acid amplification reactions
    • C12Q1/686—Polymerase chain reaction [PCR]
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
    • B01L2200/0663—Stretching or orienting elongated molecules or particles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0848—Specific forms of parts of containers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/12—Specific details about materials
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/16—Surface properties and coatings
    • B01L2300/161—Control and use of surface tension forces, e.g. hydrophobic, hydrophilic
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2563/00—Nucleic acid detection characterized by the use of physical, structural and functional properties
    • C12Q2563/107—Nucleic acid detection characterized by the use of physical, structural and functional properties fluorescence

Abstract

The present invention relates to a manufacturing method of a molecular diagnostic device which can detect a target nucleic acid (DNA, RNA) present in a sample. According to the present invention, a nucleic acid detection device, in which a fluorescence signal having a photonic PCR well based on a surface plasmonic for a nucleic acid amplification reaction is amplified, can be mass-produced more efficiently in a short time and at a low cost.

Description

R2R 랭뮤어-블로젯 공정을 이용한 핵산 검출장치 제조{Fabrication of apparatus for detecting nucleic acid through roll-to-roll Langmuir-Blodgett technology}Fabrication of apparatus for detecting nucleic acid through roll-to-roll Langmuir-Blodgett technology using R2R Langmuir-Blodgett process

본 발명은 R2R 랭뮤어-블로젯(roll-to-roll Langmuir-Blodgett) 공정을 이용하여 나노플라즈모닉 PCR 웰(nanoplasmonic PCR well)을 구비하는 핵산 검출장치를 제조하는 방법에 관한 것이다.The present invention relates to a method for manufacturing a nucleic acid detection device having a nanoplasmonic PCR well using the R2R Langmuir-Blodgett process.

유기 분자를 수면 상에 배열하여 1분자 두께의 층(단분자층)을 형성하고 그것을 차례로 고체 표면에 전사하여 만든 초박막을 LB 막(Langmuir-Blodgett film)이라고 한다. 수면 상에 형성된 단분자막을 고체 표면에 1개씩 포개어 초박막을 만드는 방법은 GE사의 I. Langmuir의 연구팀이 개발한 것으로서, 계면화학 분야에 있어서 2차원 모델로 사용되어 왔다. 또한, 분자 일렉트로닉스, 바이오칩 분야에서 유기 고분자의 이용이나 생체 세포를 이용하여 유기 집적칩(IC)을 만들려는 연구가 진행되면서 LB 막에 대한 관심이 증대되었다.An ultra-thin film made by arranging organic molecules on a water surface to form a 1-molecular-thick layer (monolayer) and transferring them one after another on a solid surface is called LB film (Langmuir-Blodgett film). The method of making ultra-thin films by superimposing monomolecular films formed on the water surface one by one on a solid surface was developed by I. Langmuir's research team at GE and has been used as a two-dimensional model in the field of interfacial chemistry. In addition, interest in LB membranes has increased as research to make organic integrated chips (ICs) using organic polymers or living cells is progressing in the fields of molecular electronics and biochips.

LB 막의 특징은 그 두께를 수 십에서 수 백 나노미터 범위로 조절하면서 균질한 대면적의 막을 쉽게 만들 수 있고, 성분 및 구조의 설계와 분자 배향 조절이 가능하며, 순수 단분자층이나 다성분의 혼합분자층, 착체분자층 등을 만들 수 있다는 것이다. 또한, 유기 박막을 보호막, 절연막, 분리막이라고 하는 수동적인 재료로서가 아니라, 능동적 기능을 발휘하는 박막으로 이용하고자 할 때에는 화학 구조가 명확하고 고차 구조가 잘 제어된 고분자 박막을 필요로 한다. 이러한 이유로 다양한 기능을 갖는 박막을 분자 레벨에서 설계하는 것이 가능하다고 할 때, LB 기법은 스핀코팅, 솔벤트 캐스팅 등 다른 유기 박막 제조 기술보다 유리하다고 할 수 있다. 이러한 박막은 최근 전자·바이오 소자 등 다양한 디바이스에 응용하는 연구가 활발하게 이루어지고 있다.The characteristics of the LB membrane are that it can easily make a homogeneous large-area membrane while controlling its thickness in the range of tens to hundreds of nanometers, it is possible to design components and structures and control the molecular orientation, and it is possible to control the molecular orientation of pure monolayers or multicomponent mixed molecules. Layers, complex molecular layers, etc. can be created. In addition, when an organic thin film is to be used as a thin film that exhibits an active function, not as a passive material such as a protective film, an insulating film, or a separator, a polymer thin film with a clear chemical structure and well-controlled high-order structure is required. For this reason, when it is possible to design thin films with various functions at the molecular level, the LB technique can be said to be more advantageous than other organic thin film manufacturing technologies such as spin coating and solvent casting. These thin films are being actively studied to be applied to various devices such as electronic and bio devices in recent years.

한편, 일반적으로 롤투롤(Roll-to-Roll, R2R) 공정 장치는 롤(roll) 형태의 필름(film) 또는 웹(web)에 다양한 종류의 공정을 수행하는 장치를 의미한다. 이러한 롤투롤 공정 장치는 롤 형태로 권취된 필름을 풀어주는 언와인더(unwinder), 필름에 인쇄 공정 등 다양한 공정을 수행하는 공정 유닛들, 필름을 다시 롤 형태로 감아주는 리와인더(rewinder)를 포함하며, 이들 사이에서 필름을 이송하기 위한 다양한 이송 유닛들을 구비할 수 있다.Meanwhile, in general, a roll-to-roll (R2R) process apparatus refers to an apparatus for performing various types of processes on a roll-type film or web. Such a roll-to-roll process device includes an unwinder that unwinds a film wound in a roll form, process units that perform various processes such as a printing process on a film, and a rewinder that winds the film back into a roll form. And, it may be provided with various transport units for transporting the film between them.

롤투롤 공정 장치의 일 예로, 피공정물인 필름의 표면에 다양한 패턴을 형성하는 롤투롤 인쇄 장치를 들 수 있다. 최근의 롤투롤 인쇄 장치는 전자 회로, 센서, 플렉서블 디스플레이(flexible display) 등의 다양한 전자 부품의 제조에 다양하게 활용되고 있다.As an example of the roll-to-roll process apparatus, a roll-to-roll printing apparatus for forming various patterns on the surface of a film, which is an object to be processed, may be mentioned. A recent roll-to-roll printing apparatus is used in various ways to manufacture various electronic components such as electronic circuits, sensors, and flexible displays.

대한민국 공개특허 제10-2017-0114200호Republic of Korea Patent Publication No. 10-2017-0114200 대한민국 공개특허 제10-2018-0046507호Republic of Korea Patent Publication No. 10-2018-0046507

본 발명자들은 핵산 증폭반응을 위한 나노플라즈모닉 PCR 웰(nanoplasmonic PCR well)을 구비하는 핵산 검출장치를 보다 효율적으로 생산할 수 있는 기술 개발을 위하여 연구한 결과, 기판 표면의 특성(소수성 또는 친수성)과 정반대의 특성을 갖는 물질을 R2R 프린팅으로 미세 패턴을 형성하여 핵산 증폭반응을 위한 반응 공간(PCR well)을 형성시킨 후, 롤투롤 랭뮤어-블로젯(Langmuir-Blodgett) 공정을 실시하는 경우 상기 반응 공간에 플라즈모닉 나노입자 박막을 선택적으로 증착시킬 수 있음을 확인하여, 본 발명을 완성하였다.As a result of research for the development of a technology capable of more efficiently producing a nucleic acid detection device having a nanoplasmonic PCR well for a nucleic acid amplification reaction, the present inventors have conducted research on the characteristics of the substrate surface (hydrophobicity or hydrophilicity) and the opposite. After forming a reaction space (PCR well) for a nucleic acid amplification reaction by forming a micropattern by R2R printing of a material having the characteristics of By confirming that a plasmonic nanoparticle thin film can be selectively deposited on the plasmonic nanoparticle thin film, the present invention was completed.

따라서, 본 발명의 목적은 롤투롤 LB 공정을 이용한 핵산 검출장치의 제조방법을 제공하는 것이다.Accordingly, an object of the present invention is to provide a method for manufacturing a nucleic acid detection device using a roll-to-roll LB process.

본 발명의 다른 목적은 상기 제조방법에 의하여 제조된 핵산 검출장치를 제공하는 것이다.Another object of the present invention is to provide a nucleic acid detection device prepared by the above production method.

그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.However, the technical task to be achieved by the present invention is not limited to the tasks mentioned above, and other tasks not mentioned can be clearly understood by those of ordinary skill in the art to which the present invention belongs from the following description. will be.

본 발명의 목적을 달성하기 위하여, 본 발명은 (a) 롤투롤(roll-to-roll) 공정으로 친수성 표면의 기판 상에 소수성 물질을 일정 거리만큼 이격되도록 인쇄하는 단계, 상기 인쇄된 소수성 물질과 소수성 물질 사이의 공간에는 핵산 증폭반응이 일어나는 미세 우물(microwell) 형태의 반응 공간이 마련되며; (b) 공기/액체 계면에 나노입자를 전개하여 나노입자 단일층을 형성시키는 단계; 및 (c) 롤투롤 LB(Langmuir-Blodgett) 공정을 실시하여, 상기 기판 상의 반응 공간에 단계 (b)의 나노입자 단일층을 단층 또는 다층으로 적층하는 단계를 포함하는, 핵산 검출장치의 제조방법을 제공한다.In order to achieve the object of the present invention, the present invention (a) the step of printing a hydrophobic material to be spaced apart by a predetermined distance on a substrate having a hydrophilic surface in a roll-to-roll process, the printed hydrophobic material and A reaction space in the form of a microwell in which a nucleic acid amplification reaction occurs is provided in the space between the hydrophobic materials; (b) deploying the nanoparticles at the air/liquid interface to form a nanoparticle monolayer; and (c) performing a roll-to-roll LB (Langmuir-Blodgett) process to stack the nanoparticle single layer of step (b) in a single layer or multiple layers in the reaction space on the substrate. Method of manufacturing a nucleic acid detection device provides

또한, 본 발명은 (a) 롤투롤 공정으로 소수성 표면의 기판 상에 친수성 물질을 일정 거리만큼 이격되도록 인쇄하는 단계, 상기 인쇄된 친수성 물질과 친수성 물질 사이의 공간에는 핵산 증폭반응이 일어나는 미세 우물 형태의 반응 공간이 마련되며; (b) 공기/액체 계면에 나노입자를 전개하여 나노입자 단일층을 형성시키는 단계; 및 (c) 롤투롤 LB 공정을 실시하여, 상기 기판 상의 반응 공간에 단계 (b)의 나노입자 단일층을 단층 또는 다층으로 적층하는 단계를 포함하는, 핵산 검출장치의 제조방법을 제공한다.In addition, the present invention provides (a) a step of printing a hydrophilic material to be spaced apart by a predetermined distance on a substrate having a hydrophobic surface in a roll-to-roll process, and in the space between the printed hydrophilic material and the hydrophilic material, a nucleic acid amplification reaction takes place in the form of a fine well a reaction space is provided; (b) deploying the nanoparticles at the air/liquid interface to form a nanoparticle monolayer; And (c) performing a roll-to-roll LB process, it provides a method for manufacturing a nucleic acid detection device, comprising the step of laminating the nanoparticle monolayer of step (b) in a single layer or a multilayer in the reaction space on the substrate.

또한, 본 발명은 상기 제조방법으로 제조된 핵산 검출장치를 제공한다.In addition, the present invention provides a nucleic acid detection device manufactured by the above manufacturing method.

본 발명의 일 구현예에 있어서, 상기 기판은 PVDF(Polyvinylidene fluoride), PET(Polyethylene terephthalate), PEN(Polyethylene naphthalate), PMMA(Poly(methyl methacrylate)), PE(Polyethylene), PP(Polypropylene), PC(Polycarbonate), PI(Polyimide), PES(Polyethersulfone), 폴리에스테르(Polyester), PS(Polystyrene), PDMS(Polydimethylsiloxane) 및 이들의 조합으로 이루어진 군으로부터 선택될 수 있다.In one embodiment of the present invention, the substrate is PVDF (Polyvinylidene fluoride), PET (Polyethylene terephthalate), PEN (Polyethylene naphthalate), PMMA (Poly (methyl methacrylate)), PE (Polyethylene), PP (Polypropylene), PC (Polycarbonate), PI (Polyimide), PES (Polyethersulfone), polyester (Polyester), PS (Polystyrene), PDMS (Polydimethylsiloxane), and may be selected from the group consisting of a combination thereof.

본 발명의 다른 구현예에 있어서, 상기 기판은 반투명 또는 투명일 수 있다.In another embodiment of the present invention, the substrate may be translucent or transparent.

본 발명의 또 다른 구현예에 있어서, 상기 소수성 물질은 PP(Polypropylene), PE(Polyethylene), PMMA(Polymethylmethacrylate), PET(Polyethylene terephthalate), PEN(Polyethylene nitrile), PI(Polyimide), PDMS(Polydimethyl siloxane) 및 이들의 조합으로 이루어진 군으로부터 선택될 수 있다.In another embodiment of the present invention, the hydrophobic material is PP (Polypropylene), PE (Polyethylene), PMMA (Polymethylmethacrylate), PET (Polyethylene terephthalate), PEN (Polyethylene nitrile), PI (Polyimide), PDMS (Polydimethyl siloxane) ) and combinations thereof.

본 발명의 또 다른 구현예에 있어서, 상기 친수성 물질은 소수성 물질을 오존 플라즈마 처리하여 사용하거나, 또는 PU(Polyurethane), PEO(Polyethylene oxide), PVA(Polyvinyl alcohol), PVP(Polyvinyl pyridine) 및 이들의 조합으로 이루어진 군으로부터 선택된 물질을 사용할 수 있다.In another embodiment of the present invention, the hydrophilic material is used by ozone plasma treatment of a hydrophobic material, or PU (Polyurethane), PEO (Polyethylene oxide), PVA (Polyvinyl alcohol), PVP (Polyvinyl pyridine) and their Substances selected from the group consisting of combinations may be used.

본 발명의 또 다른 구현예에 있어서, 상기 나노입자는 QD(quantum dot), QP(quantum particle), CQ(carbon quantum dot), GQ(graphene quantum dot), GNP(gold nanoparticle), SNP(silica nanoparticle), MNP(magnetic nanoparticle), ANP(silver nanoparticle), SiO2 및 이들의 조합으로 이루어진 군으로부터 선택될 수 있다.In another embodiment of the present invention, the nanoparticles are QD (quantum dot), QP (quantum particle), CQ (carbon quantum dot), GQ (graphene quantum dot), GNP (gold nanoparticle), SNP (silica nanoparticle) ), magnetic nanoparticles (MNPs), silver nanoparticles (ANPs), SiO 2 and combinations thereof may be selected from the group consisting of.

본 발명의 또 다른 구현예에 있어서, 상기 나노입자는 금속 나노입자 또는 그래핀 나노입자 일 수 있다.In another embodiment of the present invention, the nanoparticles may be metal nanoparticles or graphene nanoparticles.

본 발명의 또 다른 구현예에 있어서, 상기 핵산 증폭반응은 상기 반응 공간에 적층된 나노입자에 조사된 빛에 의한 표면 플라즈몬 현상에 의한 광-열 변환을 이용한 광 PCR(Photonic Polymerase Chain Reaction) 일 수 있다.In another embodiment of the present invention, the nucleic acid amplification reaction may be a photonic polymerase chain reaction (PCR) using light-to-thermal conversion by a surface plasmon phenomenon by light irradiated to the nanoparticles stacked in the reaction space. there is.

본 발명의 또 다른 구현예에 있어서, 상기 핵산 검출장치는 증착된 나노입자에 의하여 형광신호가 증폭될 수 있다.In another embodiment of the present invention, the nucleic acid detection device may amplify a fluorescence signal by the deposited nanoparticles.

본 발명은 시료에 존재하는 타겟 핵산(DNA, RNA)을 검출할 수 있는 분자진단 장치의 제조방법에 관한 것으로, 본 발명을 이용하면 핵산 증폭반응을 위한 표면 플라즈모닉 기반 포토닉 PCR 웰(photonic PCR well)을 구비하는, 형광신호가 증폭된 핵산 검출장치를 보다 효율적으로 단시간 내에 저렴한 비용(low-cost)으로 대량 생산할 수 있다.The present invention relates to a method for manufacturing a molecular diagnostic device capable of detecting a target nucleic acid (DNA, RNA) present in a sample. well), it is possible to mass-produce a nucleic acid detection device in which the fluorescence signal is amplified more efficiently in a short time and at low cost.

도 1은 본 발명의 일 실시예에 따른 롤투롤 LB(Langmuir-Blodgett) 공정을 이용하여 핵산 검출장치를 제조하는 공정을 개략적으로 도시한 도이다.
도 2는 나노입자 단일층이 기판의 반응 공간에 선택적으로 적층되는 과정을 개략적으로 도시한 도이다.
도 3은 본 발명의 일 실시예에 따른 롤투롤 LB 공정을 이용한 핵산 검출장치의 제조 공정을 개략적으로 도시한 것으로서, 나노입자 단일층을 반응 공간에 다층(multilayer)으로 적층하는 과정을 보여준다.1 is a diagram schematically illustrating a process for manufacturing a nucleic acid detection device using a roll-to-roll LB (Langmuir-Blodgett) process according to an embodiment of the present invention.
2 is a diagram schematically illustrating a process in which a nanoparticle single layer is selectively stacked in a reaction space of a substrate.
3 schematically shows a manufacturing process of a nucleic acid detection device using a roll-to-roll LB process according to an embodiment of the present invention, and shows a process of stacking a single layer of nanoparticles in a reaction space as a multilayer.

이하, 본 발명의 실시예를 첨부된 도면들을 참조하여 더욱 상세하게 설명한다. 본 발명의 실시예는 여러 가지 형태로 변형할 수 있으며, 본 발명의 범위가 아래의 실시예들로 한정되는 것으로 해석되어서는 안 된다. 본 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 더욱 완전하게 설명하기 위해 제공되는 것이다. 따라서 도면에서의 요소의 형상은 보다 명확한 설명을 강조하기 위해 과장되게 도시된 부분도 있다. 또한, 본 명세서 및 청구범위에 사용된 용어나 단어는 통상적이거나 사전적인 의미로 한정해서 해석되어서는 안 되며, 발명자는 그 자신의 발명을 가장 최선의 방법으로 설명하기 위해 용어의 개념을 적절하게 정의할 수 있다는 원칙에 입각하여 본 발명의 기술적 사상에 부합하는 의미와 개념으로 해석되어야만 한다.Hereinafter, embodiments of the present invention will be described in more detail with reference to the accompanying drawings. Embodiments of the present invention may be modified in various forms, and the scope of the present invention should not be construed as being limited to the following embodiments. This example is provided to more completely explain the present invention to those of ordinary skill in the art. Therefore, the shape of the element in the drawings is exaggerated to emphasize a clearer description. In addition, the terms or words used in the present specification and claims should not be construed as being limited to their ordinary or dictionary meanings, and the inventor appropriately defines the concept of the term in order to best describe his invention. It should be interpreted as meaning and concept consistent with the technical idea of the present invention based on the principle that it can be done.

도면을 참조하여 설명할 때 동일 하거나 대응하는 구성 요소는 동일한 도면부호를 부여하고 이에 대한 중복되는 설명은 생략하기로 한다.When describing with reference to the drawings, the same or corresponding components are given the same reference numerals, and the overlapping description thereof will be omitted.

도 1은 본 발명의 일 실시예에 따른 롤투롤 LB(Langmuir-Blodgett) 공정을 이용하여 핵산 검출장치를 제조하는 공정을 개략적으로 도시한 도이다.1 is a diagram schematically illustrating a process for manufacturing a nucleic acid detection apparatus using a roll-to-roll LB (Langmuir-Blodgett) process according to an embodiment of the present invention.

도 1을 참조하면, 본 발명의 일 실시예에 따른 핵산 검출장치의 제조방법은, 롤투롤 장치를 이용하여 기판(S) 상에 기판(S) 표면의 친수성 또는 소수성 특성과 정반대의 특성을 갖는 물질을 일정 간격만큼 이격되도록 프린팅 하여 미세 우물(microwell)을 형성시키는 단계(S100), 공기/액체 계면에 나노입자를 전개하여 나노입자 단일층(10)을 형성시키는 단계(S200), 및 롤투롤 LB 공정을 실시하여, 상기 나노입자 단일층(10)을 기판(S) 상에 마련된 반응 공간(미세 우물)에 단층 또는 다층으로 적층하는 단계(S300)를 포함한다.Referring to FIG. 1 , in the method for manufacturing a nucleic acid detection device according to an embodiment of the present invention, the hydrophilic or hydrophobic property of the surface of the substrate S on the substrate S by using a roll-to-roll device has a characteristic opposite to that of the surface. Forming a microwell by printing the material to be spaced apart by a predetermined interval (S100), forming a nanoparticle single layer 10 by developing nanoparticles at the air/liquid interface (S200), and roll-to-roll By performing the LB process, the step (S300) of laminating the nanoparticle single layer 10 as a single layer or multiple layers in a reaction space (fine well) provided on the substrate S (S300).

단계 S100을 설명하면, 롤투롤 장치의 제1롤(R1)에 감겨진 형태로 준비된 기판(S)은 제1롤(R1)에서 풀어지면서 제2롤(R2)로 이송되며, 제2롤(R2)은 기판(S)의 표면 특성에 따라 기판(S)에 친수성 또는 소수성 물질을 인쇄할 수 있도록 준비되어 있어, 기판(S)이 제2롤(R2)을 지나는 과정에서 친수성 또는 소수성 물질이 기판(S) 상에 인쇄된다.When explaining step S100, the substrate S prepared in the form wound on the first roll R1 of the roll-to-roll device is transferred to the second roll R2 while being unwound from the first roll R1, and the second roll ( R2) is prepared to print a hydrophilic or hydrophobic material on the substrate S according to the surface characteristics of the substrate S, so that in the process of the substrate S passing the second roll R2, the hydrophilic or hydrophobic material It is printed on the substrate (S).

상기 기판(S)은 바이오센서, 바이오칩, 미세유체칩 등 생체분자의 검출을 위한 장치 제조에 통상적으로 사용되는 소재(예컨대, 플라스틱, 유리 등)를 제한 없이 사용할 수 있으며, 예를 들어 본 발명에서는 PVDF(Polyvinylidene fluoride), PET(Polyethylene terephthalate), PEN(Polyethylene naphthalate), PMMA(Poly(methyl methacrylate)), PE(Polyethylene), PP(Polypropylene), PC(Polycarbonate), PI(Polyimide), PES(Polyethersulfone), 폴리에스테르(Polyester), PS(Polystyrene), PDMS(Polydimethylsiloxane) 및 이들의 조합으로 이루어진 군으로부터 선택된 고분자 소재를 사용할 수 있다.As the substrate S, materials (eg, plastics, glass, etc.) commonly used in manufacturing devices for detection of biomolecules such as biosensors, biochips, and microfluidic chips may be used without limitation, for example, in the present invention PVDF(Polyvinylidene fluoride), PET(Polyethylene terephthalate), PEN(Polyethylene naphthalate), PMMA(Poly(methyl methacrylate)), PE(Polyethylene), PP(Polypropylene), PC(Polycarbonate), PI(Polyimide), PES(Polyethersulfone) ), polyester, polystyrene (PS), polydimethylsiloxane (PDMS), and a polymer material selected from the group consisting of combinations thereof may be used.

상기 기판(S)은 그 자체로서 표면에 친수성 또는 소수성을 띨 수 있으며, 목적에 맞도록 친수성 또는 소수성을 띠도록 표면이 개질될 수도 있다. 예를 들어, 본 발명은 단계 S100 실시 전에 기판(S)의 친수성(또는 소수성) 표면을 더 강화시키거나, 기판(S) 표면에 친수성(또는 소수성)을 부여하도록 개질하는 단계를 실시할 수 있다.The substrate S may have hydrophilicity or hydrophobicity on the surface itself, and the surface may be modified to have hydrophilicity or hydrophobicity to suit the purpose. For example, in the present invention, the hydrophilic (or hydrophobic) surface of the substrate (S) is further strengthened or modified to impart hydrophilicity (or hydrophobicity) to the surface of the substrate (S) before step S100 is carried out. .

다음으로, 단계 S200에서는 공기/액체 계면에 나노입자 단일층(10)을 형성시킨다. 상기 나노입자 단일층(10)은 다음 단계(S300)에서 기판(S)에 마련된 반응 공간에 증착된다. 단계 S200은, 예를 들어 나노입자를 포함하는 용액(예컨대, 유기 용매 중에 분산된 나노입자)을 공기/물 계면에 적하시켜 전개함으로써 공기/물 계면에 나노입자 단일층(LB 박막)을 형성시킬 수 있다. 나노입자 단일층(10)은 이동식 배리어(movable barrier, 20)의 정밀한 제어에 의해 액체 표면 상에 고밀도로 압축될 수 있다.Next, in step S200, the nanoparticle monolayer 10 is formed at the air/liquid interface. The nanoparticle single layer 10 is deposited in the reaction space provided on the substrate S in the next step (S300). Step S200 is, for example, to form a nanoparticle monolayer (LB thin film) at the air/water interface by dripping and developing a solution containing nanoparticles (eg, nanoparticles dispersed in an organic solvent) on the air/water interface. can The nanoparticle monolayer 10 can be compressed to a high density on the liquid surface by precise control of the movable barrier 20 .

상기 나노입자는 QD(quantum dot), QP(quantum particle), CQ(carbon quantum dot), GQ(graphene quantum dot), GNP(gold nanoparticle), SNP(silica nanoparticle), MNP(magnetic nanoparticle), ANP(silver nanoparticle), SiO2 및 이들의 조합으로 이루어진 군으로부터 선택될 수 있다. 또한, 상기 나노입자는 금속 나노입자 또는 그래핀 나노입자 일 수 있다.The nanoparticles are QD (quantum dot), QP (quantum particle), CQ (carbon quantum dot), GQ (graphene quantum dot), GNP (gold nanoparticle), SNP (silica nanoparticle), MNP (magnetic nanoparticle), ANP ( silver nanoparticles), SiO 2 and combinations thereof. In addition, the nanoparticles may be metal nanoparticles or graphene nanoparticles.

다음으로, 단계 S300은 롤투롤 LB 공정을 실시하여, 단계 S200에서 형성시킨 나노입자 단일층(10)을 단계 S100에서 기판(S) 표면과 반대되는 특성을 갖는 물질을 프린팅 하여 마련한 반응 공간에 단층으로 적층하는 공정이다. 반응 공간이 마련된 기판(S)은 제2롤(R2)을 통하여 다음 가이드 롤(guiding roll)인 제3롤(R3)로 이송되며, 이 과정에서 롤투롤 LB 장치에 마련된 이동식 배리어(20)가 제2롤(R2) 방향으로 이동함에 따라 S200에서 형성된 나노입자 단일층(10)이 기판(S)의 반응 공간에 선택적으로 적층된다. 이와 같이 나노입자 단일층(10)이 적층된 반응 공간은 나노플라즈모닉 PCR 웰로서 기능하며, 상기 나노플라즈모닉 PCR 웰에 빛을 조사하여 광 PCR(Photonic Polymerase Chain Reaction)을 통하여 핵산을 증폭시키는 동시에 형광 신호를 증가시킬 수 있다.Next, in step S300, a roll-to-roll LB process is performed to form a single layer of nanoparticles 10 formed in step S200 in a reaction space prepared by printing a material having a characteristic opposite to that of the surface of the substrate (S) in step S100. It is a process of laminating with The substrate S provided with the reaction space is transferred to the third roll R3, which is the next guiding roll, through the second roll R2, and in this process, the movable barrier 20 provided in the roll-to-roll LB device is As the second roll (R2) moves in the direction, the nanoparticle single layer 10 formed in S200 is selectively laminated in the reaction space of the substrate (S). As such, the reaction space in which the nanoparticle single layer 10 is stacked functions as a nanoplasmonic PCR well, and at the same time amplifies the nucleic acid through photonic polymerase chain reaction (PCR) by irradiating light to the nanoplasmonic PCR well. It can increase the fluorescence signal.

단계 S300이 실시됨에 따라 나노입자 단일층(10)이 친수성 표면의 기판(S)에 마련된 반응 공간에 선택적으로 적층되는 과정을 도 2에 도시하였다.As the step S300 is carried out, the process in which the nanoparticle single layer 10 is selectively laminated in the reaction space provided on the substrate S of the hydrophilic surface is shown in FIG. 2 .

도 2를 참조하면, 친수성 표면의 기판(S)에 소수성 층이 롤투롤 공정으로 인쇄되며, 이에 따라 기판(S)에는 각 소수성 층 사이에 반응 공간(30)이 마련되고(S100), 단계 S200에서 제조된 나노입자 단일층(10)은 이동식 배리어에 의하여 기판(S) 쪽으로 이동하게 되면서 기판(S)의 각 반응 공간(30)에 선택적으로 적층된다.Referring to Figure 2, the hydrophobic layer is printed on the substrate (S) of the hydrophilic surface by a roll-to-roll process, and accordingly, the substrate (S) is provided with a reaction space 30 between each hydrophobic layer (S100), step S200 The nanoparticle single layer 10 prepared in is selectively stacked in each reaction space 30 of the substrate S while moving toward the substrate S by the movable barrier.

상기 반응 공간(30)은 미세 우물 형태의 나노플라즈모닉 PCR 웰(nanoplasmonic PCR well)로서, 시료 내에 존재하는 목적하는 핵산을 검출하기 위한 중합효소 연쇄반응(핵산 증폭반응)이 일어나는 공간이다. 상기 핵산 증폭반응을 위하여, 반응 공간(30)에는 타겟 핵산 분자에 상보적인 염기서열을 갖는 프라이머, 4종의 dNTP 분자 및 중합효소 등의 PCR을 위한 시료 용액이 놓여질 수 있다.The reaction space 30 is a nanoplasmonic PCR well in the form of a fine well, and is a space in which a polymerase chain reaction (nucleic acid amplification reaction) for detecting a target nucleic acid present in a sample occurs. For the nucleic acid amplification reaction, a sample solution for PCR such as a primer having a base sequence complementary to a target nucleic acid molecule, four dNTP molecules, and a polymerase may be placed in the reaction space 30 .

상기 반응 공간(30)에 놓인 핵산 시료는 반응 공간(30)에 적층된 나노입자로 조사된 빛에 의한 광 PCR(Photonic Polymerase Chain Reaction)을 통하여 핵산 증폭이 이루어질 수 있다. 빛이 조사되면 광열 변환(light-to-heat conversion)에 의하여 열이 발생하여 반응 공간(30)에 위치하는 핵산 및 PCR 시료 용액의 히팅과 쿨링이 빠른 사이클로 일어나게 되어 핵산 증폭반응이 신속하게 일어나게 된다. 이때 핵산 증폭을 위한 온도 조절은 빛의 조사를 조절하여 이루어질 수 있다. 상기 광 PCR에 대한 내용은, 예를 들어 대한민국 공개특허 제10-2017-0106995호에 개시되어 있다.The nucleic acid sample placed in the reaction space 30 may be amplified through photonic polymerase chain reaction (PCR) by light irradiated with nanoparticles stacked in the reaction space 30 . When light is irradiated, heat is generated by light-to-heat conversion, and heating and cooling of the nucleic acid and PCR sample solution located in the reaction space 30 occur in a fast cycle, so that the nucleic acid amplification reaction occurs quickly. . In this case, temperature control for nucleic acid amplification may be performed by controlling light irradiation. The content of the photo-PCR is disclosed, for example, in Korean Patent Laid-Open No. 10-2017-0106995.

도 3은 본 발명의 일 실시예에 따른 롤투롤 LB 공정을 이용한 핵산 검출장치의 제조 공정에 있어서, 나노입자 또는 QD 단일층을 반응 공간에 다층(multilayer)으로 적층하는 과정을 보여준다.3 shows a process of stacking nanoparticles or QD monolayers as a multilayer in the reaction space in the manufacturing process of the nucleic acid detection device using the roll-to-roll LB process according to an embodiment of the present invention.

도 3을 참조하면, 기판(S)에 반응 공간(30)을 형성시키는 단계 S100 및 공기/액체 계면에 나노입자 단일층(10)을 형성시키는 단계 S200은 도 1에서 설명한 바와 같으며, 도 3에서는 나노입자 단일층(10)을 반응 공간(30)에 다층으로 적층하기 위하여 제2롤(R2)에서 다음 가이드 롤인 제3롤(R3) 방향으로 반응 공간(30)이 형성되어 있는 기판(S)을 이송하여 나노입자 단일층(10)을 반응 공간(30)에 한 차례 적층시키고, 다시 제3롤(R3)에서 제2롤(R2) 방향으로 기판(S)을 이송하여 기적층된 나노입자 단일층 위에 다시 나노입자 단일층을 적층시킨다. 이와 같은 과정의 반복 수행을 통하여 나노입자 단일층을 다층으로 적층시킬 수 있다.Referring to FIG. 3 , the step S100 of forming the reaction space 30 on the substrate S and the step S200 of forming the nanoparticle single layer 10 at the air/liquid interface are the same as those described in FIG. 1 , and FIG. 3 In the substrate (S) on which the reaction space 30 is formed in the direction of the third roll (R3), which is the next guide roll from the second roll (R2), in order to stack the nanoparticle single layer (10) in a multilayered manner in the reaction space (30) ) to stack the nanoparticle single layer 10 in the reaction space 30 once, and then transfer the substrate S from the third roll (R3) to the second roll (R2) in the direction of the previously layered nanoparticle. A single layer of nanoparticles is again stacked on the single layer of particles. By repeating this process, a single layer of nanoparticles can be stacked as a multilayer.

전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.The description of the present invention described above is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

S: 기판
R1: 제1롤
R2: 제2롤
R3: 제3롤
10: 나노입자 단일층
20: 이동식 배리어
30: 반응 공간S: substrate
R1: first roll
R2: 2nd roll
R3: 3rd roll
10: Nanoparticle monolayer
20: removable barrier
30: reaction space

Claims (12)

(a) 롤투롤(roll-to-roll) 공정으로 친수성 표면의 기판 상에 소수성 물질을 일정 거리만큼 이격되도록 인쇄하는 단계, 상기 인쇄된 소수성 물질과 소수성 물질 사이의 공간에는 핵산 증폭반응이 일어나는 미세 우물(microwell) 형태의 반응 공간이 마련되며;
(b) 공기/액체 계면에 나노입자를 전개하여 나노입자 단일층을 형성시키는 단계; 및
(c) 롤투롤 LB(Langmuir-Blodgett) 공정을 실시하여, 상기 기판 상의 반응 공간에 단계 (b)의 나노입자 단일층을 단층 또는 다층으로 적층하는 단계를 포함하는, 핵산 검출장치의 제조방법.(a) a step of printing a hydrophobic material to be spaced apart by a predetermined distance on a substrate having a hydrophilic surface in a roll-to-roll process, in the space between the printed hydrophobic material and the hydrophobic material, a microscopic nucleic acid amplification reaction occurs A reaction space in the form of a microwell is provided;
(b) deploying the nanoparticles at the air/liquid interface to form a nanoparticle monolayer; and
(c) performing a roll-to-roll LB (Langmuir-Blodgett) process, and laminating the nanoparticle monolayer of step (b) as a single layer or multiple layers in the reaction space on the substrate. Method of manufacturing a nucleic acid detection device. (a) 롤투롤(roll-to-roll) 공정으로 소수성 표면의 기판 상에 친수성 물질을 일정 거리만큼 이격되도록 인쇄하는 단계, 상기 인쇄된 친수성 물질과 친수성 물질 사이의 공간에는 핵산 증폭반응이 일어나는 미세 우물(microwell) 형태의 반응 공간이 마련되며;
(b) 공기/액체 계면에 나노입자를 전개하여 나노입자 단일층을 형성시키는 단계; 및
(c) 롤투롤 LB(Langmuir-Blodgett) 공정을 실시하여, 상기 기판 상의 반응 공간에 단계 (b)의 나노입자 단일층을 단층 또는 다층으로 적층하는 단계를 포함하는, 핵산 검출장치의 제조방법.(a) a step of printing a hydrophilic material to be spaced apart by a predetermined distance on a substrate having a hydrophobic surface in a roll-to-roll process, the space between the printed hydrophilic material and the hydrophilic material is a microscopic nucleic acid amplification reaction A reaction space in the form of a microwell is provided;
(b) deploying the nanoparticles at the air/liquid interface to form a nanoparticle monolayer; and
(c) performing a roll-to-roll LB (Langmuir-Blodgett) process, and laminating the nanoparticle monolayer of step (b) as a single layer or multiple layers in the reaction space on the substrate. Method of manufacturing a nucleic acid detection device. 제1항 또는 제2항에 있어서,
상기 기판은 PVDF(Polyvinylidene fluoride), PET(Polyethylene terephthalate), PEN(Polyethylene naphthalate), PMMA(Poly(methyl methacrylate)), PE(Polyethylene), PP(Polypropylene), PC(Polycarbonate), PI(Polyimide), PES(Polyethersulfone), 폴리에스테르(Polyester), PS(Polystyrene), PDMS(Polydimethylsiloxane) 및 이들의 조합으로 이루어진 군으로부터 선택된 것을 특징으로 하는, 제조방법.3. The method of claim 1 or 2,
The substrate is PVDF (Polyvinylidene fluoride), PET (Polyethylene terephthalate), PEN (Polyethylene naphthalate), PMMA (Poly (methyl methacrylate)), PE (Polyethylene), PP (Polypropylene), PC (Polycarbonate), PI (Polyimide), PES (Polyethersulfone), polyester (Polyester), PS (Polystyrene), PDMS (Polydimethylsiloxane), characterized in that selected from the group consisting of a combination thereof, a manufacturing method. 제1항 또는 제2항에 있어서,
상기 기판은 반투명 또는 투명인 것을 특징으로 하는, 제조방법.3. The method of claim 1 or 2,
The substrate is characterized in that translucent or transparent, the manufacturing method. 제1항에 있어서,
상기 소수성 물질은 PP(Polypropylene), PE(Polyethylene), PMMA(Polymethylmethacrylate), PET(Polyethylene terephthalate), PEN(Polyethylene nitrile), PI(Polyimide), PDMS(Polydimethyl siloxane) 및 이들의 조합으로 이루어진 군으로부터 선택된 것을 특징으로 하는, 제조방법.The method of claim 1,
The hydrophobic material is selected from the group consisting of polypropylene (PP), polyethylene (PE), polymethylmethacrylate (PMMA), polyethylene terephthalate (PET), polyethylene nitrile (PEN), polyimide (PI), polydimethyl siloxane (PDMS), and combinations thereof. Characterized in that, the manufacturing method. 제2항에 있어서,
상기 친수성 물질은 소수성 물질을 오존 플라즈마 처리한 것을 특징으로 하는, 제조방법.3. The method of claim 2,
The hydrophilic material is characterized in that the ozone plasma treatment of the hydrophobic material, the manufacturing method. 제2항에 있어서,
상기 친수성 물질은 PU(Polyurethane), PEO(Polyethylene oxide), PVA(Polyvinyl alcohol), PVP(Polyvinyl pyridine) 및 이들의 조합으로 이루어진 군으로부터 선택된 것을 특징으로 하는, 제조방법.3. The method of claim 2,
The hydrophilic material is characterized in that it is selected from the group consisting of PU (Polyurethane), PEO (Polyethylene oxide), PVA (Polyvinyl alcohol), PVP (Polyvinyl pyridine) and combinations thereof, the manufacturing method. 제1항 또는 제2항에 있어서,
상기 나노입자는 QD(quantum dot), QP(quantum particle), CQ(carbon quantum dot), GQ(graphene quantum dot), GNP(gold nanoparticle), SNP(silica nanoparticle), MNP(magnetic nanoparticle), ANP(silver nanoparticle), SiO2 및 이들의 조합으로 이루어진 군으로부터 선택된 것을 특징으로 하는, 제조방법.3. The method of claim 1 or 2,
The nanoparticles are QD (quantum dot), QP (quantum particle), CQ (carbon quantum dot), GQ (graphene quantum dot), GNP (gold nanoparticle), SNP (silica nanoparticle), MNP (magnetic nanoparticle), ANP ( silver nanoparticles), SiO 2 and a combination thereof, characterized in that selected from the group consisting of, the manufacturing method. 제1항 또는 제2항에 있어서,
상기 나노입자는 금속 나노입자 또는 그래핀 나노입자인 것을 특징으로 하는, 제조방법.3. The method of claim 1 or 2,
The nanoparticles are metal nanoparticles or graphene nanoparticles, characterized in that, the manufacturing method. 제1항 또는 제2항에 있어서,
상기 핵산 증폭반응은 상기 반응 공간에 적층된 나노입자로 조사된 빛에 의한 표면 플라즈몬 현상에 의한 광-열 변환을 이용한 광 PCR(Photonic Polymerase Chain Reaction)인 것을 특징으로 하는, 제조방법.3. The method of claim 1 or 2,
The nucleic acid amplification reaction is a photonic polymerase chain reaction (PCR) using light-to-thermal conversion by a surface plasmon phenomenon by light irradiated with nanoparticles stacked in the reaction space, characterized in that it is a manufacturing method. 제1항 또는 제2항의 제조방법으로 제조된, 핵산 검출장치.A nucleic acid detection device manufactured by the method of claim 1 or 2. 제11항에 있어서,
상기 핵산 검출장치는 증착된 나노입자에 의하여 형광신호가 증폭되는 것을 특징으로 하는, 핵산 검출장치.12. The method of claim 11,
The nucleic acid detection device is a nucleic acid detection device, characterized in that the fluorescence signal is amplified by the deposited nanoparticles.
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