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WO2020241453A1 - Puce d'évaluation de canal à membrane bicouche lipidique, son procédé de production et appareil d'évaluation - Google Patents

Puce d'évaluation de canal à membrane bicouche lipidique, son procédé de production et appareil d'évaluation Download PDF

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Publication number
WO2020241453A1
WO2020241453A1 PCT/JP2020/020148 JP2020020148W WO2020241453A1 WO 2020241453 A1 WO2020241453 A1 WO 2020241453A1 JP 2020020148 W JP2020020148 W JP 2020020148W WO 2020241453 A1 WO2020241453 A1 WO 2020241453A1
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WIPO (PCT)
Prior art keywords
lipid bilayer
bilayer membrane
evaluation chip
channel evaluation
film
Prior art date
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Ceased
Application number
PCT/JP2020/020148
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English (en)
Japanese (ja)
Inventor
文彦 廣瀬
健作 鹿又
愛弓 平野
大介 但木
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tohoku University NUC
Yamagata University NUC
Original Assignee
Tohoku University NUC
Yamagata University NUC
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Priority to JP2021522290A priority Critical patent/JP7162283B2/ja
Publication of WO2020241453A1 publication Critical patent/WO2020241453A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B81—MICROSTRUCTURAL TECHNOLOGY
    • B81B—MICROSTRUCTURAL DEVICES OR SYSTEMS, e.g. MICROMECHANICAL DEVICES
    • B81B1/00—Devices without movable or flexible elements, e.g. microcapillary devices
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means

Definitions

  • the present invention relates to a lipid bilayer membrane channel evaluation chip for evaluating the functionality of an ion channel (protein channel) embedded in the lipid bilayer membrane, a method for producing the same, and an evaluation device including the lipid bilayer membrane channel evaluation chip. It is a thing.
  • the lipid bilayer membrane has a structure in which phospholipid molecules are arranged in two layers in opposite directions, and is also the basic structure of the cell membrane of living organisms. This plays the role of a septum between the inside of the cell and the outside world as a function of the cell.
  • proteins that control ion and molecular transport that is, protein channels
  • proteins called ion channels have the function of allowing ions to permeate inside and outside cells in response to stimuli.
  • Ion channels that have a receptor function are called ligand-gated channels, and receive signals from outside the cell, causing the influx of ions into the cell.
  • ion channels that control ion inflow and outflow in response to changes in membrane potential are called voltage-gated channels. Both channels play important roles in cell activity and function as signal transmission media, especially in signal propagation in nerves and muscles.
  • the patch clamp method shown in FIG. 9 is used as a method for evaluating the channel function.
  • a glass tube containing an electrode is brought into close contact with the cell membrane, and the ion flow passing through the ion channel in the cell membrane is measured as a current waveform.
  • This method is a method that requires skill by making full use of precision operations, and not only takes time for measurement, but also has many problems such as being easily dependent on the state of cells.
  • Hirano et al. Of Tohoku University made a through hole in a silicon substrate as shown in Patent Document 1, made the end a tapered structure, installed the Si substrate so as to sandwich it with a lipid bilayer membrane, and made a lipid in the through hole.
  • a through hole is formed in the silicon substrate, so as to cover the through-hole to form a SiO 2 film and the Si 3 N 4 film, provided with a SiO 2 film and the Si 3 N 4 film on the microporous, tapered structures
  • a chip characterized by forming the above is used.
  • the lipid bilayer membrane can be easily formed and held in the micropores, and by embedding ion channels in the micropores and placing the chip in physiological saline, the lipid bilayer membrane can be penetrated.
  • an electric field and evaluating the conductivity it becomes possible to evaluate the presence or absence of film formation, the presence or absence of ion channels, and their operation.
  • This method is easier to evaluate than the patch clamp method, and since the ion channels can be arbitrarily embedded and evaluated, it is possible to evaluate only the target ion channels, and the reliability of measurement can be improved. ..
  • the present invention provides a structure and a method for producing the lipid bimolecular membrane channel evaluation chip which can be formed by attaching a lipid bilayer membrane to the pores at low cost, and further embeds the lipid bilayer membrane. It is an object of the present invention to provide an evaluation device capable of easily and inexpensively evaluating the operation of an ion channel.
  • the first aspect of the present invention that achieves the above object is composed of a resin film in which holes are formed and a metal thin film, so that the holes face the surface of the resin film and face each other with the holes in between.
  • the lipid bimolecular film channel evaluation chip is characterized by comprising a pair of provided electrodes and a metal oxide film covering the pair of electrodes.
  • a second aspect of the present invention is the lipid bilayer membrane channel of the first aspect, wherein a silanized film whose surface is silanized is provided on the metal oxide film. It is on the evaluation chip.
  • a third aspect of the present invention is the lipid bilayer membrane channel of the first or second aspect, wherein the resin film has a thickness of 10 to 20 ⁇ m and the pore diameter is 100 to 300 ⁇ m. It is on the evaluation chip.
  • a fourth aspect of the present invention is the lipid bilayer membrane channel evaluation chip according to any one of the first to third aspects, wherein the resin film is made of polytetrafluoroethylene.
  • a fifth aspect of the present invention is a step of forming holes in a resin film, and a pair of electrodes made of a metal thin film are opposed to each other on the surface of the resin film so as to face the holes and sandwich the holes.
  • a method for producing a lipid bilayer film channel evaluation chip which comprises a step of forming the metal oxide film as described above and a step of forming a metal oxide film covering the pair of electrodes.
  • a sixth aspect of the present invention further comprises a step of forming a silanized film whose surface is silanized on the metal oxide film, the two lipid molecules of the fifth aspect. It is in the method of manufacturing a membrane channel evaluation chip.
  • a seventh aspect of the present invention is the lipid bilayer membrane channel of the fifth or sixth aspect, wherein the resin film has a thickness of 10 to 20 ⁇ m and the pores are formed with a diameter of 100 to 200 ⁇ m. It is in the manufacturing method of the evaluation chip.
  • An eighth aspect of the present invention is the method for producing a lipid bilayer membrane channel evaluation chip according to a seventh aspect, wherein the pores are formed by electric field discharge.
  • a ninth aspect of the present invention is the lipid of any one of the fifth to eighth aspects, wherein the metal oxide film is formed to a thickness of 50 to 300 nm by electron beam deposition. It is in the method of manufacturing a molecular membrane channel evaluation chip.
  • a tenth aspect of the present invention is connected to the lipid bilayer membrane channel evaluation chip of any one of the first to fourth aspects and the pair of electrodes provided on the lipid bilayer membrane channel evaluation chip. It is an evaluation device characterized in that it is configured to include a power source that applies a voltage to an electrode.
  • the present invention it is possible to provide a structure and a method for producing the lipid bimolecular membrane channel evaluation chip which can be formed by sticking the lipid bimolecular membrane to the pores at low cost. Further, it is possible to provide an evaluation device provided with this lipid bilayer membrane channel evaluation chip, which can easily and inexpensively evaluate the operation of an ion channel embedded in the lipid bilayer membrane.
  • FIG. 1 is a conceptual perspective view of a lipid bilayer membrane channel evaluation chip according to an embodiment of the present invention.
  • FIG. 2 is a view showing a cross-sectional structure of a lipid bilayer membrane channel evaluation chip according to an embodiment of the present invention, and is a cross-sectional view corresponding to the line AA'of FIG.
  • FIG. 3 is a plan view showing a modified example of the lipid bilayer membrane channel evaluation chip.
  • FIG. 4 is a plan view showing a modified example of the lipid bilayer membrane channel evaluation chip
  • FIG. 5 is a cross-sectional view corresponding to the line BB'of FIG.
  • the lipid bilayer membrane channel evaluation chip (hereinafter, also referred to as ion channel evaluation chip) 10 is made of a resin film 11 having pores 11a formed therein and a metal thin film.
  • a pair of electrodes 12 provided on the surface of the film 11 so as to face the holes 11a and facing each other with the holes 11a interposed therebetween, and a metal oxide film 13 covering the pair of electrodes 12 are provided.
  • the material and thickness of the resin film 11 are not particularly limited, but a fluororesin film (fluorocarbon resin film) having a thickness of 10 to 20 ⁇ m is preferably used, and more preferably, polytetrafluoroethylene having a thickness of 12 to 15 ⁇ m.
  • the size and shape of the hole 11a, which is a through hole formed in the resin film 11, is not particularly limited as long as the lipid bimolecular film can be provided, but the diameter is, for example, about 100 to 200 ⁇ m. Has.
  • the pair of electrodes 12 are provided so as to face each other with the hole 11a interposed therebetween.
  • Each of the pair of electrodes 12 is formed in an L shape, one end of each electrode 12 faces each other with the hole 11a interposed therebetween, and the entire pair of electrodes 12 are line-symmetrical with the hole 11a interposed therebetween. It is arranged so as to be. Further, one end of each electrode 12 is provided so as to face the hole 11a.
  • the electrode 12 is provided so as to face the hole 11a" means that the electrode 12 is provided up to the edge of the peripheral edge of the hole 11a or at least a part of the inner peripheral surface of the hole 11a. Further, the other end of each electrode 12 is a connection terminal 12a connected to the power supply of the evaluation device described later.
  • Such an electrode 12 may be a patterned metal thin film formed on the entire surface of the resin film 11 or a patterned metal thin film.
  • the pair of electrodes 12 may be any as long as a voltage can be applied in a direction parallel to the diameter direction of the pore 11a provided with the lipid bimolecular membrane, and the pattern shape and the like thereof are not particularly limited.
  • Examples of the material of the metal thin film forming the electrode 12 include aluminum (Al), gold (Au), silver (Ag), titanium (Ti), and titanium (Ti) is particularly preferable.
  • the thickness of the metal thin film is, for example, 50 to 300 nm.
  • the metal oxide film 13 is provided so as to cover the electrode 12. Specifically, the metal oxide film 13 is provided so as to cover a portion other than the connection terminal 12a provided at one end of each electrode 12.
  • the material of the metal oxide film 13 is not particularly limited as long as it can secure electrical insulation with the surroundings. Examples of the material of the metal oxide film 13 include oxides such as silicon (Si), zirconium (Zr), hafnium (Hf), and aluminum (Al), and silicon oxide (SiO 2 ) is particularly preferable. preferable.
  • the thickness of the metal oxide film 13 is, for example, about 50 to 200 nm, preferably 70 to 120 nm.
  • a metal oxide film 13 which is a thin film of silicon oxide (SiO 2 ) is formed with a thickness of 100 nm on a pair of electrodes 12 provided on both sides of the hole 11a.
  • a silaneized film 14 obtained by silicating the surface is provided on the surface of the metal oxide film 13.
  • the silanized film 14 is hydrophobized, and the formation of a lipid film on the surface of the metal oxide film 13 is promoted.
  • the silanized film 14 is not an indispensable configuration, and may be provided as needed.
  • connection terminal 12a of the electrode 12 is formed of a single layer of metal thin film like the other parts of the electrode 12, but may be formed of a plurality of layers of metal thin film.
  • the connection terminal 12a has a first layer 121 made of titanium (Ti) provided on the resin film 11 and platinum (Pt) or gold (Au) provided on the first layer 121. It may be formed by the second layer 122 made of.
  • connection terminal 12a when the connection terminal 12a is formed of a plurality of layers, the portion of the electrode 12 other than the connection terminal 12a may also be formed of a plurality of layers. For example, as shown in FIGS. 4 and 5, when the connection terminal 12a is formed of the first layer 121 made of titanium (Ti) and the second layer 122 made of gold (Au), the connection terminal of the electrode 12 is formed. The portion other than 12a may be formed by the first layer 121 and the second layer 122, and the third layer 123 made of titanium (Ti).
  • connection terminal 12a By forming the connection terminal 12a with a plurality of layers of metal thin films in this way, it is possible to suppress an increase in the contact resistance at the connection terminal 12a when the voltage is repeatedly applied to the electrode 12.
  • FIG. 6 is a schematic diagram showing a schematic configuration of an evaluation device using a lipid bilayer membrane channel evaluation chip (ion channel evaluation chip).
  • the ion channel evaluation chip 10 is used as a part of the evaluation device 100 as shown in FIG. 6, for example.
  • a lipid bimolecular membrane 20 is formed from both the front and back surfaces of the ion channel evaluation chip 10 so as to cover the pores 11a, and an ion channel protein is embedded therein.
  • the ion channel evaluation chip 10 including the lipid bimolecular membrane 20 is immersed in a buffer 30 made of physiological saline. At that time, the buffer 30 is separated into separate chambers on the left and right in the figure by the ion channel evaluation chip 10. Further, the electrodes 40 are inserted into the buffers 30 in the left and right separate chambers in the drawing, and an electric potential is applied to these electrodes 40. As a result, an electric field in the vertical direction is applied to the lipid bilayer membrane 20 formed on both the front and back surfaces of the ion channel evaluation chip 10, and the ions passing through the ion channel 50 can be measured as current pulses.
  • the evaluation device 100 includes a power supply 110 for applying a voltage between the pair of electrodes 12 provided on the ion channel evaluation chip 10. That is, the evaluation device 100 includes an ion channel evaluation chip 10 and a power supply 110 connected to a pair of electrodes 12 provided on the ion channel evaluation chip 10 and applying a voltage between the pair of electrodes 12. ing.
  • a voltage is applied between the pair of electrodes 12 by the power supply 110 in a direction parallel to the lipid bimolecular membrane 20, that is, a direction parallel to the diameter direction of the hole 11a.
  • the ion channel evaluation chip 10 used in the evaluation device 100 may be an array of a plurality of chips. As a result, the throughput of the evaluation device 100 can be improved.
  • the ion channel evaluation chip 10 can be sold not only as a single chip or as an evaluation device 100, but also as a set of the ion channel evaluation chip 10 and a dedicated power supply box.
  • FIG. 7 shows a method for manufacturing an ion channel evaluation chip.
  • a Teflon (registered trademark) film is prepared as the resin film 11, and as shown in FIG. 7B, the diameter is formed by electric field discharge. Form a hole 11a of about 100 ⁇ m.
  • a metal mask made of nickel (Ni) is used to spatially selectively form a pair of electrodes 12 made of a metal thin film such as titanium (Ti) as shown in FIG. 7 (c).
  • the electron beam vapor deposition method it is preferable to use the electron beam vapor deposition method as the vapor deposition method for the metal thin film.
  • a metal oxide film 13 made of silicon oxide (SiO 2 ) is uniformly deposited on the electrodes 12 except for the connection terminals 12a of each electrode 12. As a result, the electrical contact between the electrode 12 and the outside world is suppressed. Further, if necessary, as shown in FIG. 7E, the surface of the metal oxide film 13 made of silicon oxide (SiO 2 ) is subjected to a silanization treatment to form the silanized film 14. Through the above steps, the ion channel evaluation chip 10 embedded in the lipid bilayer membrane 20 is completed (see FIG. 7 (f)).
  • the ion channel evaluation chip 10 was prepared as follows. As the resin film 11, a Teflon (registered trademark) film (YSI Inc. High Sensitivity Membrane Kit) having a thickness of 12 to 15 ⁇ m and a width of 32 ⁇ 40 mm 2 was prepared, and a hole 11a having a thickness of about 100 ⁇ m was formed by electric field discharge. At that time, the resin film 11 is placed on a flat copper plate, the tungsten needle is brought into contact with the resin film 11, and an alternating current having an amplitude of 3 kV at 1.7 kHz is used as a burst wave for 340 cycles between the copper plate and the tungsten needle. It was discharged by putting it on.
  • a Teflon (registered trademark) film YSI Inc. High Sensitivity Membrane Kit
  • a pair of electrodes 12 made of a titanium (Ti) metal thin film is spatially selectively formed by using a nickel (Ni) metal mask.
  • the thickness of the electrode 12 is 200 nm.
  • an electron beam vapor deposition method was used as a vapor deposition method for the titanium thin film to be the electrode 12, and the temperature of the resin film 11 at this time was 25 ° C.
  • the shape of the pair of electrodes 12 is L-shaped, and they are arranged so as to face each other with the hole 11a interposed therebetween.
  • a metal oxide film 13 which is a thin film of silicon oxide (SiO 2 ) is uniformly vapor-deposited except for a part of the upper part of the L-shape of the electrode 12, that is, the connection terminal 12a. As a result, the electrical contact between the electrode 12 and the outside world is suppressed.
  • the thickness of the metal oxide film 13 is 100 nm.
  • the vapor deposition method of the metal oxide film 13 is also electron beam deposition, and the temperature of the resin film 11 at that time is room temperature.
  • the surface of the metal oxide film 13 is silanized to form the silaneized film 14.
  • PFDS tridecafluoro-1,1,2,2-tetrahydrooctyl demethylchlorosilane
  • Nav1.5 channel was embedded in the lipid bimolecular membrane 20, and a test was conducted in which the current through the membrane was evaluated by the evaluation device 100. The result is shown in FIG.
  • the Nav1.5 channel is a sodium channel responsible for depolarizing the myocardial action potential, which is normally closed.
  • a flat current waveform as shown in FIG. 8B is obtained.

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  • Chemical & Material Sciences (AREA)
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Abstract

Selon la présente invention, une puce d'évaluation de canal à membrane bicouche lipidique (10) est conçue pour comprendre : un film de résine (11) qui est doté d'un trou (11a) ; d'une paire d'électrodes (12) qui sont constituées de films minces métalliques et qui sont disposées sur la surface du film de résine de façon à se faire face l'une à l'autre, le trou (11a) étant positionné entre elles, tout en faisant face au trou (11a) ; et un film d'oxyde métallique (13) qui recouvre la paire d'électrodes (12).
PCT/JP2020/020148 2019-05-27 2020-05-21 Puce d'évaluation de canal à membrane bicouche lipidique, son procédé de production et appareil d'évaluation Ceased WO2020241453A1 (fr)

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JP2021522290A JP7162283B2 (ja) 2019-05-27 2020-05-21 脂質二分子膜チャネル評価チップ及びその製造方法並びに評価装置

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005337734A (ja) * 2004-05-24 2005-12-08 Shigetoshi Oiki シス−トランス液流方式によるイオンチャネル解析方法と、その方法に使用するイオンチャネル解析装置
JP2011160718A (ja) * 2010-02-09 2011-08-25 Nippon Telegr & Teleph Corp <Ntt> 脂質二分子膜基板
JP2011167609A (ja) * 2010-02-17 2011-09-01 Japan Science & Technology Agency 平面脂質二重膜の形成方法
JP2013036865A (ja) * 2011-08-09 2013-02-21 Hitachi High-Technologies Corp ナノポア式分析装置
JP2015024936A (ja) * 2013-07-26 2015-02-05 国立大学法人福井大学 脂質平面膜を形成するための貫通孔を有するガラス基板、およびその製造方法と用途
WO2018195222A1 (fr) * 2017-04-19 2018-10-25 Electronic Biosciences, Inc. Séquençage d'exonucléase activé par des électrodes à nanopores/nanopuits

Family Cites Families (5)

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Publication number Priority date Publication date Assignee Title
US6863833B1 (en) 2001-06-29 2005-03-08 The Board Of Trustees Of The Leland Stanford Junior University Microfabricated apertures for supporting bilayer lipid membranes
EP2474829A1 (fr) 2011-01-07 2012-07-11 Axetris AG Procédé permettant de déterminer les structures moléculaires et les fonctions
EP2814983B1 (fr) 2012-02-16 2019-04-24 Genia Technologies, Inc. Procédés de création de bicouches destinées à être utilisées avec des capteurs de nanopore
JP2017187443A (ja) 2016-04-08 2017-10-12 Ｔｏｗａ株式会社 分析装置用ポリマー膜、分析装置、分析装置用基板、分析装置用ポリマー膜の製造方法、および分析装置用基板の製造方法
JP2018140478A (ja) 2017-02-28 2018-09-13 国立大学法人東北大学 シリコンチップ及びその製造方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005337734A (ja) * 2004-05-24 2005-12-08 Shigetoshi Oiki シス−トランス液流方式によるイオンチャネル解析方法と、その方法に使用するイオンチャネル解析装置
JP2011160718A (ja) * 2010-02-09 2011-08-25 Nippon Telegr & Teleph Corp <Ntt> 脂質二分子膜基板
JP2011167609A (ja) * 2010-02-17 2011-09-01 Japan Science & Technology Agency 平面脂質二重膜の形成方法
JP2013036865A (ja) * 2011-08-09 2013-02-21 Hitachi High-Technologies Corp ナノポア式分析装置
JP2015024936A (ja) * 2013-07-26 2015-02-05 国立大学法人福井大学 脂質平面膜を形成するための貫通孔を有するガラス基板、およびその製造方法と用途
WO2018195222A1 (fr) * 2017-04-19 2018-10-25 Electronic Biosciences, Inc. Séquençage d'exonucléase activé par des électrodes à nanopores/nanopuits

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