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WO2018131731A1 - Dispositif de fractionnement d'un échantillon liquide sur une nano-unité - Google Patents

Dispositif de fractionnement d'un échantillon liquide sur une nano-unité Download PDF

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Publication number
WO2018131731A1
WO2018131731A1 PCT/KR2017/000423 KR2017000423W WO2018131731A1 WO 2018131731 A1 WO2018131731 A1 WO 2018131731A1 KR 2017000423 W KR2017000423 W KR 2017000423W WO 2018131731 A1 WO2018131731 A1 WO 2018131731A1
Authority
WO
WIPO (PCT)
Prior art keywords
substrate
micro
hydrophilic
container
dispensing mechanism
Prior art date
Application number
PCT/KR2017/000423
Other languages
English (en)
Korean (ko)
Inventor
신상모
김동민
Original Assignee
한밭대학교 산학협력단
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 한밭대학교 산학협력단 filed Critical 한밭대학교 산학협력단
Priority to PCT/KR2017/000423 priority Critical patent/WO2018131731A1/fr
Publication of WO2018131731A1 publication Critical patent/WO2018131731A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices

Definitions

  • the present invention relates to a mechanism for dispensing a liquid sample in nano units, and more particularly, to a technique for evenly dispersing an aqueous solution of biomolecules having a small volume or diameter at a desired position on a substrate.
  • Microphysical or chemical sensor technology has been applied to the biotechnology field with the development of ultra-high density semiconductor technology.
  • MEMS microelectromechanical systems
  • semiconductor manufacturing technology for the analysis of gene sequencing, proteomics, biometabolism detection and trace amount of reactants in life science, genetic engineering, medical diagnosis, new drug development, etc. Actively researched.
  • unlike classical methods it is possible to analyze single cells, very small amounts of genetic material, proteins, and complex and unpurified complex samples without using many samples for bioanalysis.
  • PCR polymerase chain reaction
  • Korean Patent No. 10-0723427 (apparatus and method for printing biomolecule droplets on a substrate)
  • Korean Patent Publication No. 2005-0072540 (apparatus for printing biomolecules on a substrate using electrohydraulic phenomena and a printing method thereof)
  • an object of the present invention is to provide a sample dispensing mechanism capable of dispersing and containing as many biomolecules as desired.
  • the present invention which is derived to achieve the object as described above, is a mechanism for distributing a liquid sample in nano units, and includes a substrate, and a micro container formed on the substrate with opposite characteristics of the hydrophilicity and hydrophobicity of the substrate. It features.
  • the microcontainers are stacked at a height of 500-800 nm or etched to a depth of 500-800 nm relative to the substrate.
  • the plurality of micro-containers are provided on the substrate, the plurality of micro-containers gradually increase or decrease in size in a specific direction.
  • the apparatus further includes a temperature adjusting unit configured to adjust the temperature of the substrate by heating or cooling the substrate.
  • the apparatus further includes a nozzle unit for providing a liquid sample, and an XY drive unit for adjusting the position of the nozzle unit to a position of a specific microcontainer on the substrate.
  • the substrate is hydrophobic and the microvessel is hydrophilic.
  • the substrate is a silicon wafer or mica.
  • the micro container is formed of a hydrophilic oxide.
  • the micro container is formed by laminating a hydrophilic material on the substrate.
  • the bottom surface of the microcontainer has a hydrophilic slope so as to become more hydrophilic toward the edge.
  • the micro container is formed by etching the substrate and laminating a hydrophilic material at the etched position.
  • the bottom surface of the microchamber has a hydrophilic slope so that the hydrophilicity is weaker toward the edge.
  • micro-containers can be manufactured and mounted on micro analysis equipment or mounted on molecular analysis equipment, thereby enabling efficient molecular analysis.
  • use of a mask allows for the mass production of sample dispensing devices, thereby reducing the cost of biotechnology research and medical analysis.
  • the present invention to overcome the phenomenon that the droplets on the micro-container and the droplets of the neighboring micro-container to maintain the droplets of the nano-volume on the micro-vessel can do.
  • the temperature of the micro-container through the present invention it is possible to freeze or dry the droplets, and to induce the droplets to cause a chemical reaction at a specific temperature.
  • FIG. 1 is a view showing a sample dispensing mechanism in which nano-sized micro containers are integrated on a substrate by an embodiment of the present invention.
  • FIG. 2 is a plan view of a sample dispensing mechanism in which the size of the microcontainers is gradually changed according to another embodiment of the present invention.
  • FIG 3 is a view for explaining a method for producing a nano-sized micro-container according to an embodiment of the present invention.
  • FIG. 4 is a view for explaining that biomolecules are dispersed in a microcontainer according to the present invention.
  • FIG. 5 is a view for explaining a sample dispensing mechanism according to still another embodiment of the present invention.
  • FIG. 1 is a diagram illustrating a sample dispensing mechanism 100 in which a nano-sized microcontainer 104 is integrated on a substrate 102 according to an embodiment of the present invention.
  • the micro-container 104 is formed by laminating or etching a nano-sized pattern on the substrate 104, and may contain a very small amount of biomolecule aqueous solution.
  • Biomolecules include probe DNA, RNA, peptide nucleic acid (PNA), nucleic acid such as LNA, proteins such as antigens and antibodies, oligopeptides, human cells, animal cells, plants Cells such as cells, microorganisms such as viruses, bacteria, and the like, but other biomolecules may also be included.
  • PNA peptide nucleic acid
  • LNA peptide nucleic acid
  • proteins such as antigens and antibodies
  • oligopeptides human cells, animal cells, plants
  • Cells such as cells, microorganisms such as viruses, bacteria, and the like, but other biomolecules may also be included.
  • the substrate 102 is composed of a silicon wafer, mica, or the like having a hydrophobic component.
  • Substrate 102 may also be composed of other hydrophobic solids.
  • Substrate 102 may be hydrophobic to prevent biomolecules from contacting.
  • a plasma treatment using a gas, a deposition treatment, a wet treatment, or the like can be used.
  • plasma treatment using a gas such as NH 3 , NF 3 , F 2 , or the like, Si 3 N 4 , SiF 4 , or the like is deposited on the substrate 102, electrolytic plating, electroless plating, or the like. Wet treatment can be performed.
  • a microcontainer 104 capable of containing an extremely small amount of aqueous solution is manufactured.
  • the pattern may be SiO 2 , polyvinylidene fluoride, alkoxy oxide, or the like.
  • the trace amount refers to the size of the micro-container 104, that is, the stack height or the trench depth of 500-800 nm, the bottom surface of a 50 nm diameter circle, the length of one side 50 nm square, etc. Corresponds to the volume in the form.
  • the size of the micro container 104 may be determined by designing a pattern of a mask used for etching, and may be variously determined according to the size of the biomolecule.
  • the stack height or trench depth of the microcontainer 104 is preferably 500-800 nm in which the contrast between the microcontainer 104 which is a hydrophilic oxide and the hydrophobic silicon substrate 102 can be maximized.
  • the object of the present invention can be achieved even outside the stack height or trench depth.
  • the bottom surface of the micro container 104 may be formed in various forms such as a circular shape having a diameter of 50 nm and a square having a length of 50 nm on one side thereof.
  • the area of the bottom surface of the micro-container 104 may be varied according to the type within a large classification such as the size of the molecule, the average size of the protein, and the average size of the cells, which are most used for gene sequencing.
  • the microcontainer 104 may contain and distribute as many biomolecules as desired according to the following description so as to enable efficient molecular analysis.
  • FIG. 2 is a plan view of a sample dispensing mechanism 200 in which the size of the microcontainer 204 is gradually changed in a particular direction of the substrate 202 according to another embodiment of the present invention.
  • the microcontainer 204 gradually increases or decreases in size in the horizontal direction on the substrate 202.
  • the microcontainer 204 is formed of a stacked hydrophilic pattern or an etched hydrophilic pattern on the substrate 202.
  • the hydrophilic pattern introduces a discontinuous hydrophilic slope to prevent the dispersion of biomolecules in the process of preparing a microvolume of the sample.
  • Discontinuous hydrophilic gradients can be created by patterning hydrophilic materials using a series of masks in which the size of the hydrophilic pattern is adjusted sequentially.
  • FIG 3 is a view for explaining a method for producing a nano-sized micro-container according to an embodiment of the present invention.
  • FIG. 3A illustrates a method of manufacturing the microcontainer 306 formed by stacking the hydrophilic pattern 304 on the substrate 302.
  • the degree of evaporation and sublimation can be maintained by giving a hydrophilic gradient to the bottom surface of the stacked microcontainer 306 toward the edge thereof so as to maintain hydrophilicity.
  • FIG. 3B illustrates a method of manufacturing the micro container 316 prepared by etching the hydrophilic pattern 314 on the substrate 312.
  • the etched microcontainer 316 is made less hydrophilic toward the edge of the bottom surface and the wall so that the surface tension with water molecules is weak.
  • the micro containers of the same area may be integrated on one substrate, or the micro containers may be integrated such that various areas are sequentially mixed.
  • 3A and 3B illustrate a case where the micro containers are integrated such that various areas are sequentially mixed.
  • FIG. 4 is a view for explaining that the biomolecules 48 are dispersed in the microchamber 404 formed on the substrate 402 according to the present invention.
  • the area of the microcontainer 404 to be used is determined according to the size of the biomolecule 408 to be analyzed, and the liquid 406 containing the biomolecule 408 prepared by diluting the concentration of the sample is prepared in a micro liquid transport apparatus or atmosphere. Sprinkle with a atomizer to contain as many biomolecules 408 as desired in each microcontainer 404.
  • aqueous solution 406 in which the biomolecule 408 is dissolved can be uniformly contained in each microcontainer 404 by using hydrophilicity and hydrophobic selectivity, the same number of molecules are confined by confining any number of molecules in a drop of any size. Cheap samples can be made cheaply and simply.
  • the ID and location information of the microvessel 404 may be etched using a mask near the edge of the microvessel 404 to store the information of the microvessel 404.
  • the sample dispensing mechanism 600 includes a substrate 602, microcontainers 604a and 604b, a nozzle unit 606, an XY drive unit 610, solution transfer tubes 612 and 616, and a pump 614. And a solution reservoir 618, a control unit 620, and a temperature adjusting unit 624.
  • the description of the substrate 602 and the microcontainers 604a and 604b is as described above.
  • the nozzle unit 606 drops droplets 608a and 608b containing biomolecules into the microcontainers 604a and 604b.
  • the nozzle unit 606 is mounted to the XY drive unit 610, the XY drive unit 610 adjusts the position of the nozzle unit 606 so that the nozzle unit 606 can drop the droplets in a specific micro-container.
  • the shift of the XY driver 610 is controlled by the controller 620.
  • the control line 628 transmits the shift-related control signal generated by the controller 620 to the XY driver 610.
  • the pump 614 provides the sample solution stored in the solution reservoir 618 to the nozzle unit 606 via the solution transfer pipes 616 and 614.
  • the control unit 620 drives the pump 614 after the position of the nozzle unit 606 is moved to a specific micro container by the XY drive unit 610.
  • the control line 626 transmits a pump related control signal generated by the controller 620 to the pump 614.
  • the edges of the hydrophilic microcontainers 604a and 604b have high hydrophilicity so that the droplets 608a and 608b are retained on the microcontainers 604a and 604b.
  • the droplets 608a and 608b may be frozen or dried by adjusting the temperature of the substrate 602 supporting the microcontainers 604a and 604b through the temperature adjusting unit 624, and the droplets 608a at a specific temperature. 608 may be mounted on an analytical instrument to induce a chemical reaction.
  • the control line 630 transmits a temperature related control signal generated by the controller 620 to the temperature adjuster 624.
  • nano-sized micro-container When manufacturing a device for printing a solution containing a biomolecule on the substrate by such a method, highly efficient molecular analysis is possible when the nano-sized micro-container is manufactured and mounted on a micro analysis device or on a molecular analysis device.
  • nano-sized containers can be mounted on analytical instruments, and mass production can be made using the manufactured masks, thereby reducing the cost of biotechnology research and medical analysis and increasing the efficiency of analysis.
  • sample dispensing mechanism 100, 200, 300, 310, 400, 600: sample dispensing mechanism
  • control unit 620 control unit

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  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • Physics & Mathematics (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)

Abstract

La présente invention concerne une technique dans le cadre de laquelle une solution aqueuse de biomolécules présentant un petit volume ou un petit diamètre est uniformément dispersée au niveau de sites souhaités d'un substrat. Un dispositif de fractionnement d'échantillon de la présente invention comprend : un substrat; et un micro-récipient formé sur le substrat, le substrat et le micro-récipient présentant des caractéristiques opposées en termes d'hydrophilie-hydrophobie.
PCT/KR2017/000423 2017-01-12 2017-01-12 Dispositif de fractionnement d'un échantillon liquide sur une nano-unité WO2018131731A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/KR2017/000423 WO2018131731A1 (fr) 2017-01-12 2017-01-12 Dispositif de fractionnement d'un échantillon liquide sur une nano-unité

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/KR2017/000423 WO2018131731A1 (fr) 2017-01-12 2017-01-12 Dispositif de fractionnement d'un échantillon liquide sur une nano-unité

Publications (1)

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WO2018131731A1 true WO2018131731A1 (fr) 2018-07-19

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115064618A (zh) * 2022-08-17 2022-09-16 苏州晶台光电有限公司 一种cob模组封装方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH1164213A (ja) * 1997-06-09 1999-03-05 Fuji Photo Film Co Ltd サンプルプレート
US20030080143A1 (en) * 2001-04-04 2003-05-01 Arradial, Inc. System and method for dispensing liquids
KR20030088782A (ko) * 2002-05-15 2003-11-20 삼성전자주식회사 친수성 영역과 소수성 영역으로 구성되는 생물분자용어레이 판의 제조방법
US20100028985A1 (en) * 2005-03-29 2010-02-04 Shimadzu Corporation Reaction Vessel, Reaction Vessel Processing Apparatus and Diagnostic Apparatus
KR20100114238A (ko) * 2009-04-15 2010-10-25 임현우 소수성과 친수성 표면을 이용한 생체분자 분석용 고감도 어레이 칩 및 이의 제조방법

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH1164213A (ja) * 1997-06-09 1999-03-05 Fuji Photo Film Co Ltd サンプルプレート
US20030080143A1 (en) * 2001-04-04 2003-05-01 Arradial, Inc. System and method for dispensing liquids
KR20030088782A (ko) * 2002-05-15 2003-11-20 삼성전자주식회사 친수성 영역과 소수성 영역으로 구성되는 생물분자용어레이 판의 제조방법
US20100028985A1 (en) * 2005-03-29 2010-02-04 Shimadzu Corporation Reaction Vessel, Reaction Vessel Processing Apparatus and Diagnostic Apparatus
KR20100114238A (ko) * 2009-04-15 2010-10-25 임현우 소수성과 친수성 표면을 이용한 생체분자 분석용 고감도 어레이 칩 및 이의 제조방법

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115064618A (zh) * 2022-08-17 2022-09-16 苏州晶台光电有限公司 一种cob模组封装方法
CN115064618B (zh) * 2022-08-17 2022-11-29 苏州晶台光电有限公司 一种cob模组封装方法

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