WO2018025876A1 - Measurement apparatus and measurement method - Google Patents
Measurement apparatus and measurement method Download PDFInfo
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- WO2018025876A1 WO2018025876A1 PCT/JP2017/027935 JP2017027935W WO2018025876A1 WO 2018025876 A1 WO2018025876 A1 WO 2018025876A1 JP 2017027935 W JP2017027935 W JP 2017027935W WO 2018025876 A1 WO2018025876 A1 WO 2018025876A1
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- sample
- measuring
- gate insulating
- insulating film
- measurement
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Images
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
-
- 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
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/403—Cells and electrode assemblies
- G01N27/414—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS
-
- 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
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/416—Systems
Definitions
- the present invention relates to a measuring apparatus and a measuring method, and more particularly to a measuring apparatus for measuring a sample flowing in a flow path.
- a sample such as a cell or microorganism flowing in a flow path is irradiated with a laser beam, and the properties of the sample are quantified by detecting the intensity of fluorescence or scattered light emitted from the sample.
- a flow cytometer is known (for example, Patent Document 1). With this flow cytometer, the sample can be individually measured or separated. The flow cytometer requires a laser irradiation unit that irradiates a sample with laser light and an optical detector that detects the intensity of fluorescence or scattered light emitted from the sample for each sample.
- the above-mentioned flow cytometer requires a laser irradiation part and an optical detector for each flow path, and there is a concern that the apparatus will be enlarged.
- an object of the present invention is to provide a measuring apparatus and a measuring method that can be further simplified.
- the measurement apparatus is a measurement apparatus including a measurement unit that measures charges, wherein the measurement unit includes at least two electrodes that draw the sample near the gate insulating film by a dielectrophoretic force, and charges discharged from the sample. And a field-effect transistor that measures through the gate insulating film.
- the measurement method according to the present invention includes a step of drawing a sample in a liquid near a gate insulating film by a dielectrophoretic force, and a step of measuring charges discharged from the sample through the gate insulating film. To do.
- the laser irradiation unit and the optical detector can be omitted as in the conventional optical measurement device. Therefore, it can be simplified.
- FIG. 2 is a partially enlarged view of the AA cross section in FIG. 1, schematically showing a circuit configuration. It is a partial expanded sectional view which shows typically the use condition of the measuring apparatus which concerns on this embodiment. It is a top view which shows typically the structure of the modification of the measuring apparatus which concerns on this embodiment. It is a perspective view showing typically the composition of another modification of the measuring device concerning this embodiment. It is a graph which shows the result of having measured the sample with the measuring device concerning this embodiment, and Drawing 6A shows the result of having measured a cancer cell and Drawing 6B with a normal cell.
- a measurement apparatus 10A shown in FIG. 1 includes a measurement unit 12 and a flow path 18 that supplies a liquid containing a sample 20 onto the measurement unit 12.
- the sample 20 is a living body microparticle such as a cell or a microorganism, a microbead, or the like.
- the measurement unit 12 includes a gate insulating film 28, and a field effect transistor (FET) 14 that measures the charge discharged from the sample 20, and the sample 20 near the gate insulating film 28 by a dielectrophoretic force. And two electrodes 16 for attracting each other.
- the size of the inner space of the flow path 18 can be selected as appropriate. For example, both the width and the height are preferably about 20 ⁇ m to 100 ⁇ m.
- the inner space of the flow path 18 may have a circular cross section in the width direction as well as a quadrangle.
- the electrode 16 is provided so as to face the short direction of the flow path 18, has a substantially trapezoidal shape in plan view, and is formed so as to taper from the side of the flow path toward the center.
- a DEP (Dielectrophoresis) solution As the liquid, a DEP (Dielectrophoresis) solution, a cell culture solution, or a buffer solution having a pH of about 7 can be used.
- Examples of the electric charges discharged from the sample 20 include ions and ionic molecules discharged from cell membranes and cells, ions discharged from particles other than cells, and the like.
- Examples of ionic / ionic molecules discharged from the cell membrane include sugar chains present in the cell membrane, specifically, sugar chains containing sialic acid that is highly expressed in cancer cells.
- Examples of ion / ionic molecules excreted from cells include hydrogen ions brought about by changes in CO 2 concentration excreted by cell respiration, lactic acid excreted by cell metabolism, and histamine excreted from leukemia stem cells.
- Examples of ions ejected from particles other than cells include ions ejected by antigen / antibody reaction on the microbead surface, DNA molecule recognition reaction, various biomolecule recognition reactions, and the like.
- the FET 14 is formed substantially at the center in the width direction of the flow path 18, and a source 24 is disposed on the upstream side of the flow path 18, and a drain 26 is disposed on the downstream side.
- An electrode 16 is formed on the FET 14 via a gate insulating film 28.
- the electrodes 16 are provided on both sides in the width direction of the flow path 18 across the channel of the FET 14.
- the electrode 16 is preferably formed of a material having high conductivity.
- the electrode 16 can be formed of gold, silver, copper, or the like.
- the electrode 16 is electrically connected to a power source that applies an alternating voltage having a specific frequency. When an AC voltage having a specific frequency is applied to the electrode 16 from the power source, a non-uniform electric field, that is, an electric field having a gradient in electric field strength is generated between the electrodes 16.
- the measurement part 12 is formed in the bottom part of the flow path 18, as shown in FIG.
- the FET 14 includes a semiconductor substrate 22, a source 24 and a drain 26 formed on the surface of the semiconductor substrate 22, and a gate insulating film 28 formed on the source 24 and the drain 26.
- the FET 14 can use either n-MOS or p-MOS.
- the semiconductor substrate 22 may be formed of Si, Ga, As, ITO, IGZO, IZO, or the like, or an organic semiconductor, a carbon semiconductor (for example, a carbon nanotube, a graphene semiconductor, a diamond semiconductor, or the like) may be used.
- the gate insulating film 28 can be formed of an oxide or nitride such as SiO 2 , Si 3 N 4 (SiN x ), Ta 2 O 5 , Al 2 O 3 .
- the source 24 and the drain 26 are electrically connected to a power source 34 and an ammeter 36, and are configured to measure a drain current flowing from the source 24 to the drain 26.
- a drain current flowing from the source 24 to the drain 26 When the charge density on the gate insulating film 28 changes, the magnitude of the drain current changes. That is, in order to keep the drain current constant, it is necessary to change the gate voltage as the charge density on the gate insulating film 28 changes.
- the FET 14 electrically measures the change in the charge density on the gate insulating film 28 by measuring the change in the gate voltage.
- a reference electrode 32 is used as shown in FIG.
- the reference electrode 32 is a reference potential in the FET 14 and is electrically connected to the liquid in the flow path 18.
- a liquid containing an infinite number of samples 20 is flowed from the upstream side of the flow path 18 to the downstream side at a predetermined flow rate.
- the sample 20 reaches the vicinity of the measurement unit 12 through the flow path 18 in a row at a predetermined interval.
- a non-uniform electric field is generated between the electrodes 16 due to the applied AC voltage having a specific frequency.
- the sample 20 that has reached the vicinity of the measurement unit 12 is polarized by the electric field, and is attracted between the electrodes 16 by the dielectrophoretic force generated by the polarization of the surrounding liquid and the gradient of the electric field, and approaches the gate insulating film 28 of the channel (FIG. 3).
- the dielectrophoretic force is determined by the degree of non-uniformity of the electric field, that is, the electric field intensity gradient between the pair of electrodes 16, that is, the amount of change in the density of the electric field lines.
- the measuring apparatus 10A can measure the property of the sample 20.
- the sample 20 Since the liquid is flowing at a predetermined flow velocity, the sample 20 once approaches the gate insulating film 28 of the channel by the dielectrophoretic force, and then flows on the liquid flow again downstream.
- the measuring device 10A continuously measures one sample at a predetermined interval for the countless samples 20 flowing through the flow path 18 at a predetermined interval.
- the measurement apparatus 10 ⁇ / b> A may stop the voltage applied between the electrodes 16 and cause the sample 20 to flow downstream along the liquid flow. As a result, the measuring apparatus 10A can smoothly return the sample 20 once brought close to the gate insulating film 28 of the channel by the dielectrophoretic force by the flow of the liquid.
- the measurement apparatus 10A electrically measures the property of the sample 20 by the measurement unit 12 formed at the bottom of the flow path 18, so that a laser irradiation unit, a conventional optical measurement apparatus, Since the optical detector can be omitted, it can be simplified accordingly.
- the measurement apparatus 10A can measure the sample 20 without damaging the sample 20 in the liquid flowing at a predetermined flow rate by bringing the sample 20 close to the channel gate insulating film 28 so that the charge can be measured by the FET 14 by the dielectrophoretic force. it can. Further, the measurement apparatus 10A measures the electric charge by once bringing the sample 20 close to the channel gate insulating film 28 by the dielectrophoretic force, and then again flows on the liquid flow and flows downstream. Properties can be measured.
- the present invention is not limited to the above-described embodiment, and can be appropriately changed within the scope of the gist of the present invention.
- an identification film (not shown) having an identification substance that combines with a characteristic substance that characterizes the properties of the sample 20 and discharges electric charges may be provided.
- a characteristic substance sialic acid Lewis X sugar chain (the following (Chemical Formula 1)) or sialic acid Lewis A sugar chain (the following (Chemical Formula 2)) existing on the surface of the cancer cell is applied.
- NeuAc is N-acetylneuramic acid (siarylic acid)
- Gal is galactose
- GlcNAc is N-acerylglucosamine
- Fuc is fucose
- the identification film is a so-called molecular template and has a base material and an identification substance.
- the base material is formed of a hydrophilic polymer.
- the hydrophilic polymer is a polymer having a hydrophilic functional group (hydroxyl group, carboxyl group), such as hydrogel, paper, superabsorbent polymer (SAP).
- Hydrogel is a gel-like material in which hydrophilic polymer chains are cross-linked and retains a large amount of water and is excellent in water absorption, for example, polyhydroxyethyl methacrylate (Poly-HEMA, polyhydroxymethacrylate 2-hydroxyethyl). And polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), and the like.
- Poly-HEMA may be a homopolymer of hydroxyethyl methacrylate (HEMA) or a copolymer with other monomers (for example, 2,3-dihydroxypropyl methacrylate, glycerol methacrylate (GMA), etc.).
- Poly-HEMA tends to have a higher water content when it is a copolymer.
- the PVP may be a homopolymer of N-vinyl-2-pyrrolidone (NVP), which is a copolymer obtained by polymerizing NVP as a main component and adding a crosslinking agent with HEMA, methyl methacrylate (MMA) or the like. May be.
- NVP N-vinyl-2-pyrrolidone
- MMA methyl methacrylate
- Paper is manufactured by gluing plant fibers and other fibers.
- Plant fibers are composed of cellulose, hemicellulose, and lignin.
- Cellulose has a property in which a large number of hydroxyl groups are bonded to each other by hydrogen bonding, whereby plant fibers constituting the paper adhere to each other.
- other fibers include fibers made of minerals, metals, synthetic resins, etc. From the viewpoint of more firmly fixing the identification substance, paper made of plant fibers (cellulose) is used. preferable.
- SAP is a polymer that can absorb and retain water from several hundred times to several thousand times its own weight.
- a polymer of acrylic acid can be used. Since a polymer of acrylic acid has a large number of carboxyl groups, it has a high hydrophilicity and is further crosslinked to a fine structure to form a gel having a high water absorption when it is in the form of a sodium salt.
- hydrophilic polymers include cellulose derivatives such as 2-methacryloyloxyethyl phosphorylcholine (MPC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (CMC-Na), hydroxyethylcellulose (HEC); alginic acid, hyaluronic acid, agarose , Starch, dextran, pullulan and other polysaccharides and derivatives thereof; homopolymers such as carboxyvinyl polymer, polyethylene oxide, poly (meth) acrylamide, poly (meth) acrylic acid, and copolymers of the homopolymer and polysaccharides , And a copolymer of the monomer constituting the homopolymer and other monomers; proteins such as collagen and gelatin and derivatives thereof; heparin, hyaluronic acid, chondroitin sulfate, Mention may be made of glycosaminoglycans such as dermatan sulfate, dextran sulfate
- 1-vinyl-2-pyrrolidinone, propenoic acid 2-methyl ester, monomethacryloyloxyethyl phthalate, ammonium sulfatoethyl methacrylate, N-vinylpyrrolidone, N, N-dimethylacrylamide, 2- (methacryloyloxyethyl) ) -2- (Trimethylammonioethyl) phosphate and other hydrophilic polymers may be used.
- hydrophilic polymers exemplified above may be used alone or in combination of two or more.
- a known radical polymerization accelerator can be appropriately selected and used as the polymerization initiator.
- those having water solubility or water dispersibility and uniformly contained in the entire system are preferably used.
- water-soluble peroxides such as potassium peroxodisulfate and ammonium peroxodisulfate, water-soluble azo compounds such as VA-044, V-50, and V-501 (all of which are Wako Pure Chemical Industries, Ltd.)
- a mixture of Fe 2+ and hydrogen peroxide can be used.
- N, N'-methylenebisacrylamide, ethylene glycol dimethacrylate, vinyl methacrylate, or the like can be used as the crosslinking agent.
- Phenylboronic acid can be used as the identification substance.
- the phenylboronic acid contained in the identification film has an equilibrium based on the diol bond of the saccharide as shown in the following (Chemical Formula 4).
- the boron atom changes from a nonionic state lacking an electron to a negatively charged state by ester bonding with the diol compound.
- the identification film as a characteristic substance, for example, the sialic acid Lewis X sugar chain or the sialic acid Lewis A sugar chain as sugars binds to phenylboronic acid as an identification substance, thereby discharging negative charges. Prompt.
- the discharged electric charges are charged in the gate insulating film 28.
- the measuring apparatus 10A can measure the property of the sample 20 with higher sensitivity by measuring the change in the gate voltage.
- the characteristic substance includes the first metabolite to be measured for blood cell stem cells such as hematopoietic stem cells and leukemia stem cells.
- blood cell stem cells such as hematopoietic stem cells and leukemia stem cells.
- BCAA valine, leucine, isoleucine
- alanine glutamine
- glycine glycine
- H + Na
- ions such as + , K + , Ca 2+ , NH 4+ , Cl ⁇ and HCO 3 ⁇ .
- the identification film (molecular template) using phenylboronic acid as an identification substance, an oxide film, a polymer film containing ion-sensitive crown ether in polyvinyl chloride (PVC), and the like can be applied. Since the oxide film has a hydroxyl group in the solution, it has excellent hydrogen ion responsiveness.
- hematopoietic stem cells for transplantation include uric acid
- leukemia stem cells include physiologically active phospholipids such as histamine and PGE2.
- canceration can be estimated from the difference in the charge amount of the functional group.
- identification film molecular template
- phenylboronic acid as an identification substance
- oxide film that captures a change in hydrogen ion concentration due to the difference in the amount of charge of phospholipid.
- one measurement unit 39 may include a plurality of FETs 40.
- different identification films may be provided on at least some of the gate insulating films 28 of the FETs 40.
- the measuring apparatus 10B can measure the electric charge discharged
- the measurement apparatus 10A has been described as including one measurement unit 12, but the present invention is not limited to this.
- the measurement apparatus 10 ⁇ / b> C may include a plurality of measurement units 42.
- the plurality of measurement units 42 shown in this figure are arranged in an array.
- the measurement unit 42 is provided with four electrodes 44 so as to surround one sample 20.
- the electrode 44 is formed in a cylindrical shape.
- An FET 43 is formed at the center bottom surrounded by the electrode 44.
- An AC voltage having a predetermined frequency is applied between the electrodes 44 so as to generate a dielectrophoretic force that attracts the sample 20 to the FET 43.
- a flow path (not shown) is formed on the plurality of measurement units 42 arranged in an array so that a liquid containing the sample 20 flows.
- the measuring apparatus 10C when the sample 20 reaches the measuring unit 42, the sample 20 is attracted to the FET 43 between the electrodes 44 by the dielectrophoretic force and is captured between the electrodes 44.
- the charges are discharged from the sample 20, the charges are charged on the gate insulating film (not shown in the figure).
- the charge density on the gate insulating film changes.
- the FET 43 measures a change in gate voltage accompanying a change in charge density on the gate insulating film.
- the measuring apparatus 10 ⁇ / b> C can measure the property of the sample 20.
- the measurement apparatus 10C according to this modification can measure the charges of the plurality of samples 20 at a time by arranging the measurement units 42 in an array.
- the measuring apparatus 10C can sort by separating only the specific sample 20 from the measuring unit 42 according to the measurement result.
- the measuring apparatus 10 ⁇ / b> C stops the voltage applied between the electrodes 44 capturing the specific sample 20.
- the specific sample 20 moves away from the measurement unit 42, rides on the liquid flow, and flows downstream.
- the measurement unit 39 shown in FIG. 4 may be applied to the measurement unit 42 of the measurement apparatus 10C shown in FIG. Thereby, the measuring apparatus can measure the electric charge discharged
- a measuring device with an identification film was actually manufactured, and it was verified whether the properties of cancer cells and normal cells could be measured as samples.
- the FET used IGZO as a semiconductor substrate, ITO as a source / drain, SiO 2 as a gate insulating film, and a channel area of 20 ⁇ 10 ⁇ m 2 .
- the electrode was formed using gold.
- an identification film was formed of a base material made of HEMA and MPC and an identification substance made of phenylboronic acid.
- the DEP liquid was allowed to flow at a flow rate of 3.3 cm / s while an AC voltage of 10 V and 1.4 MHz was applied between the electrodes.
- a DEP solution was prepared by adding 8.5 g of sucrose, 0.3 g of D-glucose, and 0.1 g of BSA to 100 ml with pure water. The FET was measured for 100 ⁇ s (10 4 times / s). Samples were flowed at 10 / s intervals. The results are shown in FIGS. 6A and 6B. In this figure, the horizontal axis shows time (sec) and the vertical axis shows the change in surface potential (mV) which is the gate voltage. From the result of FIG. 6A, the negative charge was measured 6 times when cancer cells were flowed.
- the measurement device can measure the negative charge generated by the binding of the sugar chain present in the cell membrane of the cancer cells in the liquid flowing at a predetermined flow rate to the phenylboronic acid. It was confirmed that the cells could be measured.
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Abstract
Provided are a measurement apparatus and a measurement method that can achieve further simplification. A measurement apparatus (10A) provided with a measurement unit (12) for measuring charges is characterized in that the measurement unit (12) has: at least two electrodes (16) that draw a sample (20) near a gate insulating film (28) by means of dielectrophoresis force; and a field effect transistor (14) for measuring charges outputted from the sample (20) through the gate insulating film (28).
Description
本発明は、測定装置及び測定方法に関し、特に流路を流れる試料を測定するための測定装置に関する。
The present invention relates to a measuring apparatus and a measuring method, and more particularly to a measuring apparatus for measuring a sample flowing in a flow path.
測定装置の一例として、流路中を流れる細胞や微生物などの試料に、レーザー光を照射し、当該試料から発せられた蛍光や散乱光の強度を検出することで、試料の性質を定量化するフローサイトメーターが知られている（例えば、特許文献１）。このフローサイトメーターにより、試料を個々に測定したり、分取したりすることができる。フローサイトメーターは、試料にレーザー光を照射するレーザー照射部と、１つ１つの試料毎に、当該試料から発せられた蛍光や散乱光の強度を検出する光学検出器が必要である。
As an example of a measuring device, a sample such as a cell or microorganism flowing in a flow path is irradiated with a laser beam, and the properties of the sample are quantified by detecting the intensity of fluorescence or scattered light emitted from the sample. A flow cytometer is known (for example, Patent Document 1). With this flow cytometer, the sample can be individually measured or separated. The flow cytometer requires a laser irradiation unit that irradiates a sample with laser light and an optical detector that detects the intensity of fluorescence or scattered light emitted from the sample for each sample.
上記したフローサイトメーターは、レーザー照射部や、光学検出器が流路毎に必要になるため、装置が大型化してしまう、という懸念がある。
The above-mentioned flow cytometer requires a laser irradiation part and an optical detector for each flow path, and there is a concern that the apparatus will be enlarged.
そこで本発明は、より簡素化することができる測定装置及び測定方法を提供することを目的とする。
Therefore, an object of the present invention is to provide a measuring apparatus and a measuring method that can be further simplified.
本発明に係る測定装置は、電荷を計測する測定部を備える測定装置において、前記測定部は、誘電泳動力によりゲート絶縁膜付近に試料を引き寄せる少なくとも２つの電極と、前記試料から排出される電荷を、前記ゲート絶縁膜を通じて計測する電界効果トランジスタとを有することを特徴とする。
The measurement apparatus according to the present invention is a measurement apparatus including a measurement unit that measures charges, wherein the measurement unit includes at least two electrodes that draw the sample near the gate insulating film by a dielectrophoretic force, and charges discharged from the sample. And a field-effect transistor that measures through the gate insulating film.
本発明に係る測定方法は、誘電泳動力によりゲート絶縁膜付近に液体中の試料を引き寄せるステップと、前記試料から排出される電荷を、前記ゲート絶縁膜を通じて計測するステップとを備えることを特徴とする。
The measurement method according to the present invention includes a step of drawing a sample in a liquid near a gate insulating film by a dielectrophoretic force, and a step of measuring charges discharged from the sample through the gate insulating film. To do.
本発明によれば、流路の底部に形成された測定部によって電気的に試料の性質を測定することにより、従来の光学的測定装置のようにレーザー照射部や、光学検出器を省略できるので、その分、簡素化することができる。
According to the present invention, since the properties of the sample are electrically measured by the measurement unit formed at the bottom of the flow path, the laser irradiation unit and the optical detector can be omitted as in the conventional optical measurement device. Therefore, it can be simplified.
以下、図面を参照して本発明の実施形態について詳細に説明する。
Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings.
（全体構成）
図１に示す測定装置１０Ａは、測定部１２と、試料２０を含む液体を前記測定部１２上に供給する流路１８とを備える。試料２０は、細胞や微生物などの生体微小粒子、マイクロビーズなどである。測定部１２は、ゲート絶縁膜２８を有し、試料２０から排出される電荷を計測する電界効果トランジスタ（ＦＥＴ：Field Effect Transistor）１４と、誘電泳動力により前記ゲート絶縁膜２８付近に前記試料２０を引き寄せる２つの電極１６とを有する。流路１８の内空間の大きさは、適宜選択することができるが、例えば幅及び高さがいずれも２０μｍ～１００μｍ程度が好ましい。流路１８の内空間は、幅方向断面が、四角形であるだけでなく、円形であってもよい。電極１６は、流路１８の短手方向に対向して設けられ、平面視において略台形状を有し、流路の側部から中心に向かって先細となるように形成されている。液体としては、ＤＥＰ（Dielectrophoresis）液、細胞培養溶液、ｐＨ７程度の緩衝溶液を用いることができる。 (overall structure)
Ameasurement apparatus 10A shown in FIG. 1 includes a measurement unit 12 and a flow path 18 that supplies a liquid containing a sample 20 onto the measurement unit 12. The sample 20 is a living body microparticle such as a cell or a microorganism, a microbead, or the like. The measurement unit 12 includes a gate insulating film 28, and a field effect transistor (FET) 14 that measures the charge discharged from the sample 20, and the sample 20 near the gate insulating film 28 by a dielectrophoretic force. And two electrodes 16 for attracting each other. The size of the inner space of the flow path 18 can be selected as appropriate. For example, both the width and the height are preferably about 20 μm to 100 μm. The inner space of the flow path 18 may have a circular cross section in the width direction as well as a quadrangle. The electrode 16 is provided so as to face the short direction of the flow path 18, has a substantially trapezoidal shape in plan view, and is formed so as to taper from the side of the flow path toward the center. As the liquid, a DEP (Dielectrophoresis) solution, a cell culture solution, or a buffer solution having a pH of about 7 can be used.
図１に示す測定装置１０Ａは、測定部１２と、試料２０を含む液体を前記測定部１２上に供給する流路１８とを備える。試料２０は、細胞や微生物などの生体微小粒子、マイクロビーズなどである。測定部１２は、ゲート絶縁膜２８を有し、試料２０から排出される電荷を計測する電界効果トランジスタ（ＦＥＴ：Field Effect Transistor）１４と、誘電泳動力により前記ゲート絶縁膜２８付近に前記試料２０を引き寄せる２つの電極１６とを有する。流路１８の内空間の大きさは、適宜選択することができるが、例えば幅及び高さがいずれも２０μｍ～１００μｍ程度が好ましい。流路１８の内空間は、幅方向断面が、四角形であるだけでなく、円形であってもよい。電極１６は、流路１８の短手方向に対向して設けられ、平面視において略台形状を有し、流路の側部から中心に向かって先細となるように形成されている。液体としては、ＤＥＰ（Dielectrophoresis）液、細胞培養溶液、ｐＨ７程度の緩衝溶液を用いることができる。 (overall structure)
A
試料２０から排出される電荷としては、細胞膜や細胞から排出されるイオン・イオン性分子、細胞以外の粒子から排出されるイオンなどが挙げられる。細胞膜から排出されるイオン・イオン性分子は、例えば、細胞膜に存在する糖鎖、具体的には癌細胞に多く発現するシアリル酸を含む糖鎖がある。また再生医療用の軟骨細胞表面に存在する硫酸基を有するプロテオグリカン、癌細胞の膜タンパク質で、特にE-cadherin発現量が腫瘍における細胞の多様化と転移に関わる膜たんぱく質がある。細胞から排出されるイオン・イオン性分子は、例えば、細胞の呼吸により排出されるＣＯ２濃度変化がもたらす水素イオン、細胞の代謝で排出される乳酸、白血病幹細胞から排出されるヒスタミンなどがある。細胞以外の粒子から排出されるイオンは、例えば、マイクロビーズ表面での抗原・抗体反応、ＤＮＡ分子認識反応、種々の生体分子認識反応などによって排出されるイオンがある。
Examples of the electric charges discharged from the sample 20 include ions and ionic molecules discharged from cell membranes and cells, ions discharged from particles other than cells, and the like. Examples of ionic / ionic molecules discharged from the cell membrane include sugar chains present in the cell membrane, specifically, sugar chains containing sialic acid that is highly expressed in cancer cells. There are also proteoglycans having sulfate groups present on the surface of cartilage cells for regenerative medicine, and membrane proteins of cancer cells. In particular, there are membrane proteins whose E-cadherin expression level is involved in cell diversification and metastasis in tumors. Examples of ion / ionic molecules excreted from cells include hydrogen ions brought about by changes in CO 2 concentration excreted by cell respiration, lactic acid excreted by cell metabolism, and histamine excreted from leukemia stem cells. Examples of ions ejected from particles other than cells include ions ejected by antigen / antibody reaction on the microbead surface, DNA molecule recognition reaction, various biomolecule recognition reactions, and the like.
ＦＥＴ１４は、流路１８の幅方向の略中央に形成されており、流路１８の上流側にソース２４、下流側にドレイン２６が配置されている。ＦＥＴ１４上にゲート絶縁膜２８を介して電極１６が形成されている。電極１６は、ＦＥＴ１４のチャネルを挟んで、流路１８の幅方向の両側にそれぞれ設けられている。電極１６は、高い導電性を有する材料で形成することが好ましく、例えば、金、銀、銅などで形成することができる。電極１６は、図示しないが、特定の周波数の交流電圧を印加する電源に電気的に接続されている。電極１６に電源から特定の周波数の交流電圧が印加されることにより、電極１６間に不均一な電場、すなわち電場強度に勾配を有する電場が生じる。
The FET 14 is formed substantially at the center in the width direction of the flow path 18, and a source 24 is disposed on the upstream side of the flow path 18, and a drain 26 is disposed on the downstream side. An electrode 16 is formed on the FET 14 via a gate insulating film 28. The electrodes 16 are provided on both sides in the width direction of the flow path 18 across the channel of the FET 14. The electrode 16 is preferably formed of a material having high conductivity. For example, the electrode 16 can be formed of gold, silver, copper, or the like. Although not shown, the electrode 16 is electrically connected to a power source that applies an alternating voltage having a specific frequency. When an AC voltage having a specific frequency is applied to the electrode 16 from the power source, a non-uniform electric field, that is, an electric field having a gradient in electric field strength is generated between the electrodes 16.
測定部１２は、図２に示すように、流路１８の底部に形成されている。ＦＥＴ１４は、半導体基板２２と、半導体基板２２の表面に形成されたソース２４及びドレイン２６と、ソース２４及びドレイン２６上に形成されたゲート絶縁膜２８とを備える。ＦＥＴ１４は、ｎ－ＭＯＳ、ｐ－ＭＯＳのいずれも使用することができる。
The measurement part 12 is formed in the bottom part of the flow path 18, as shown in FIG. The FET 14 includes a semiconductor substrate 22, a source 24 and a drain 26 formed on the surface of the semiconductor substrate 22, and a gate insulating film 28 formed on the source 24 and the drain 26. The FET 14 can use either n-MOS or p-MOS.
半導体基板２２は、Ｓｉ、Ｇａ、Ａｓ、ＩＴＯ、ＩＧＺＯ、ＩＺＯ等で形成してもよいし、有機半導体、炭素半導体（例えば、カーボンナノチューブ、グラフェン半導体、ダイヤモンド半導体等）等を用いてもよい。ゲート絶縁膜２８は、ＳｉＯ２、Ｓｉ３Ｎ４（ＳｉＮｘ）、Ｔａ２Ｏ５、Ａｌ２Ｏ３等の酸化物又は窒化物で形成することができる。
The semiconductor substrate 22 may be formed of Si, Ga, As, ITO, IGZO, IZO, or the like, or an organic semiconductor, a carbon semiconductor (for example, a carbon nanotube, a graphene semiconductor, a diamond semiconductor, or the like) may be used. The gate insulating film 28 can be formed of an oxide or nitride such as SiO 2 , Si 3 N 4 (SiN x ), Ta 2 O 5 , Al 2 O 3 .
ソース２４とドレイン２６は、電源３４及び電流計３６が電気的に接続されており、ソース２４からドレイン２６へ流れるドレイン電流を計測するように形成されている。ゲート絶縁膜２８上の電荷密度が変化すると、ドレイン電流の大きさが変化する。すなわちドレイン電流を一定に保つためには、ゲート絶縁膜２８上の電荷密度の変化に伴いゲート電圧を変化させる必要がある。ＦＥＴ１４は、このゲート電圧の変化を計測することにより、ゲート絶縁膜２８上の電荷密度の変化を電気的に計測する。
The source 24 and the drain 26 are electrically connected to a power source 34 and an ammeter 36, and are configured to measure a drain current flowing from the source 24 to the drain 26. When the charge density on the gate insulating film 28 changes, the magnitude of the drain current changes. That is, in order to keep the drain current constant, it is necessary to change the gate voltage as the charge density on the gate insulating film 28 changes. The FET 14 electrically measures the change in the charge density on the gate insulating film 28 by measuring the change in the gate voltage.
この際、本図に示すように参照電極３２が用いられる。参照電極３２は、ＦＥＴ１４における基準電位であり、流路１８において液体と電気的に接続される。
At this time, a reference electrode 32 is used as shown in FIG. The reference electrode 32 is a reference potential in the FET 14 and is electrically connected to the liquid in the flow path 18.
（作用及び効果）
上記のように構成された測定装置１０Ａにおいて、無数の試料２０を含む液体を流路１８上流から下流に向かって所定の流速で流す。試料２０は所定の間隔をあけ、一列で流路１８を通って測定部１２付近に到達する。電極１６間には、印加された特定周波数の交流電圧によって不均一な電場が生じている。測定部１２付近に到達した試料２０は、電場によって分極し、周囲の液体の分極と電場の勾配によって生じた誘電泳動力により、電極１６間に引き寄せられ、チャネルのゲート絶縁膜２８に近づく（図３）。誘電泳動力は、電場の不均一の程度、すなわち一対の電極１６間の電場強度勾配、つまり電気力線の密度の変化量で決まる。 (Function and effect)
In themeasurement apparatus 10A configured as described above, a liquid containing an infinite number of samples 20 is flowed from the upstream side of the flow path 18 to the downstream side at a predetermined flow rate. The sample 20 reaches the vicinity of the measurement unit 12 through the flow path 18 in a row at a predetermined interval. A non-uniform electric field is generated between the electrodes 16 due to the applied AC voltage having a specific frequency. The sample 20 that has reached the vicinity of the measurement unit 12 is polarized by the electric field, and is attracted between the electrodes 16 by the dielectrophoretic force generated by the polarization of the surrounding liquid and the gradient of the electric field, and approaches the gate insulating film 28 of the channel (FIG. 3). The dielectrophoretic force is determined by the degree of non-uniformity of the electric field, that is, the electric field intensity gradient between the pair of electrodes 16, that is, the amount of change in the density of the electric field lines.
上記のように構成された測定装置１０Ａにおいて、無数の試料２０を含む液体を流路１８上流から下流に向かって所定の流速で流す。試料２０は所定の間隔をあけ、一列で流路１８を通って測定部１２付近に到達する。電極１６間には、印加された特定周波数の交流電圧によって不均一な電場が生じている。測定部１２付近に到達した試料２０は、電場によって分極し、周囲の液体の分極と電場の勾配によって生じた誘電泳動力により、電極１６間に引き寄せられ、チャネルのゲート絶縁膜２８に近づく（図３）。誘電泳動力は、電場の不均一の程度、すなわち一対の電極１６間の電場強度勾配、つまり電気力線の密度の変化量で決まる。 (Function and effect)
In the
試料２０がゲート絶縁膜２８に近づき、当該試料２０から電荷が排出されている場合、当該電荷がゲート絶縁膜２８に帯電する。ゲート絶縁膜２８表面に電荷が帯電することにより、ゲート絶縁膜２８上の電荷密度が変化する。ＦＥＴ１４は、ゲート絶縁膜２８上の電荷密度の変化に伴うゲート電圧の変化を計測する。これにより測定装置１０Ａは、当該試料２０の性質を測定することができる。
When the sample 20 approaches the gate insulating film 28 and charges are discharged from the sample 20, the charges are charged on the gate insulating film 28. When the charge is charged on the surface of the gate insulating film 28, the charge density on the gate insulating film 28 changes. The FET 14 measures a change in gate voltage accompanying a change in charge density on the gate insulating film 28. Thereby, the measuring apparatus 10A can measure the property of the sample 20.
液体は所定の流速で流れているので、試料２０は、誘電泳動力によりチャネルのゲート絶縁膜２８に一旦近づいた後、再び液体の流れに乗って下流へと流れる。測定装置１０Ａは、所定の間隔で流路１８を流れてくる無数の試料２０に対し、所定の間隔で１つずつ連続的に測定する。なお、測定装置１０Ａは、電極１６間に印加されている電圧を止めることにより、試料２０を液体の流れに乗って下流へと流すこととしてもよい。これにより測定装置１０Ａは、誘電泳動力によりチャネルのゲート絶縁膜２８に一旦近づけた試料２０を、液体の流れにより円滑に戻すことができる。
Since the liquid is flowing at a predetermined flow velocity, the sample 20 once approaches the gate insulating film 28 of the channel by the dielectrophoretic force, and then flows on the liquid flow again downstream. The measuring device 10A continuously measures one sample at a predetermined interval for the countless samples 20 flowing through the flow path 18 at a predetermined interval. Note that the measurement apparatus 10 </ b> A may stop the voltage applied between the electrodes 16 and cause the sample 20 to flow downstream along the liquid flow. As a result, the measuring apparatus 10A can smoothly return the sample 20 once brought close to the gate insulating film 28 of the channel by the dielectrophoretic force by the flow of the liquid.
本実施形態に係る測定装置１０Ａは、流路１８の底部に形成された測定部１２によって電気的に試料２０の性質を測定することにより、従来の光学的測定装置のようにレーザー照射部や、光学検出器を省略できるので、その分、簡素化することができる。
The measurement apparatus 10A according to the present embodiment electrically measures the property of the sample 20 by the measurement unit 12 formed at the bottom of the flow path 18, so that a laser irradiation unit, a conventional optical measurement apparatus, Since the optical detector can be omitted, it can be simplified accordingly.
測定装置１０Ａは、所定の流速で流れる液体中の試料２０を、誘電泳動力によりＦＥＴ１４で電荷を測定できるようにチャネルのゲート絶縁膜２８に近づけることにより、試料２０を傷つけずに測定することができる。また測定装置１０Ａは、試料２０を、誘電泳動力によりチャネルのゲート絶縁膜２８に一旦近づけて電荷を計測した後、再び液体の流れに乗って下流へと流すので、短時間で試料２０毎の性質を測定することができる。
The measurement apparatus 10A can measure the sample 20 without damaging the sample 20 in the liquid flowing at a predetermined flow rate by bringing the sample 20 close to the channel gate insulating film 28 so that the charge can be measured by the FET 14 by the dielectrophoretic force. it can. Further, the measurement apparatus 10A measures the electric charge by once bringing the sample 20 close to the channel gate insulating film 28 by the dielectrophoretic force, and then again flows on the liquid flow and flows downstream. Properties can be measured.
（変形例）
本発明は上記実施形態に限定されるものではなく、本発明の趣旨の範囲内で適宜変更することが可能である。 (Modification)
The present invention is not limited to the above-described embodiment, and can be appropriately changed within the scope of the gist of the present invention.
本発明は上記実施形態に限定されるものではなく、本発明の趣旨の範囲内で適宜変更することが可能である。 (Modification)
The present invention is not limited to the above-described embodiment, and can be appropriately changed within the scope of the gist of the present invention.
例えば、チャネルにおけるゲート絶縁膜２８上に、試料２０の性質を特徴づける特徴物質と結合し、電荷を排出する識別物質を有する識別膜（図示しない）を設けてもよい。特徴物質は、癌細胞の表面に存在するシアリル酸ルイスＸ糖鎖（下記（化１））や、シアリル酸ルイスＡ糖鎖（下記（化２））が適用される。
For example, on the gate insulating film 28 in the channel, an identification film (not shown) having an identification substance that combines with a characteristic substance that characterizes the properties of the sample 20 and discharges electric charges may be provided. As the characteristic substance, sialic acid Lewis X sugar chain (the following (Chemical Formula 1)) or sialic acid Lewis A sugar chain (the following (Chemical Formula 2)) existing on the surface of the cancer cell is applied.
なお、上記化学式中、NeuAcはN-acetylneuramic acid(siarylic acid), Galはgalactose, GlcNAcはN-acerylglucosamine, Fucはfucoseである。
In the above chemical formula, NeuAc is N-acetylneuramic acid (siarylic acid), Gal is galactose, GlcNAc is N-acerylglucosamine, and Fuc is fucose.
識別膜は、いわゆる分子鋳型であって、基材と識別物質とを有する。基材は、親水性ポリマーで形成されている。親水性ポリマーとは親水性の官能基（水酸基、カルボキシル基）を有するポリマーであり、ハイドロゲル、紙、高吸水性ポリマー（ＳＡＰ：Superabsorbent Polymer）等である。
The identification film is a so-called molecular template and has a base material and an identification substance. The base material is formed of a hydrophilic polymer. The hydrophilic polymer is a polymer having a hydrophilic functional group (hydroxyl group, carboxyl group), such as hydrogel, paper, superabsorbent polymer (SAP).
ハイドロゲルは、親水性高分子鎖間が架橋されて多量の水を保持し、吸水性に優れるゲル状材料であり、例えば、ポリヒドロキシエチルメタクリレート（Ｐｏｌｙ－ＨＥＭＡ、ポリメタクリル酸２－ヒドロキシエチルとも称する。）、ポリビニルピロリドン（ＰＶＰ）、ポリビニルアルコール（ＰＶＡ）等が挙げられる。Ｐｏｌｙ－ＨＥＭＡは、ヒドロキシエチルメタクリレート（ＨＥＭＡ）のホモポリマーであってもよく、他のモノマー（例えば、２，３－ジヒドロキシプロピルメタクリレート、グリセロールメタクリレート（ＧＭＡ）等）とのコポリマーであってもよい。なお、Ｐｏｌｙ－ＨＥＭＡは、コポリマーとした方がより含水率が高くなる傾向にある。また、ＰＶＰとしては、Ｎ－ビニル－２－ピロリドン（ＮＶＰ）のホモポリマーであってもよく、ＮＶＰを主成分として、ＨＥＭＡ、メチルメタクリレート（ＭＭＡ）等と架橋剤を加えて重合したコポリマーであってもよい。
Hydrogel is a gel-like material in which hydrophilic polymer chains are cross-linked and retains a large amount of water and is excellent in water absorption, for example, polyhydroxyethyl methacrylate (Poly-HEMA, polyhydroxymethacrylate 2-hydroxyethyl). And polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), and the like. Poly-HEMA may be a homopolymer of hydroxyethyl methacrylate (HEMA) or a copolymer with other monomers (for example, 2,3-dihydroxypropyl methacrylate, glycerol methacrylate (GMA), etc.). Poly-HEMA tends to have a higher water content when it is a copolymer. The PVP may be a homopolymer of N-vinyl-2-pyrrolidone (NVP), which is a copolymer obtained by polymerizing NVP as a main component and adding a crosslinking agent with HEMA, methyl methacrylate (MMA) or the like. May be.
紙は、植物繊維その他の繊維を膠着させて製造される。植物繊維は、セルロース、ヘミセルロース、リグニンから構成される。セルロースは、多数有する水酸基同士が水素結合により結合する性質を有しており、これにより紙を構成する植物繊維同士がくっつき合う。また、その他の繊維としては、鉱物、金属、合成樹脂等を繊維状にしたもの等が挙げられるが、識別物質をより強固に固定するという観点から、植物繊維（セルロース）で形成された紙が好ましい。
Paper is manufactured by gluing plant fibers and other fibers. Plant fibers are composed of cellulose, hemicellulose, and lignin. Cellulose has a property in which a large number of hydroxyl groups are bonded to each other by hydrogen bonding, whereby plant fibers constituting the paper adhere to each other. Examples of other fibers include fibers made of minerals, metals, synthetic resins, etc. From the viewpoint of more firmly fixing the identification substance, paper made of plant fibers (cellulose) is used. preferable.
ＳＡＰは、自重の数百倍から数千倍までの水を吸収及び保持することができる高分子である。ＳＡＰとしては、アクリル酸の重合体を用いることができる。アクリル酸の重合体は、カルボキシル基を多数有するため、親水性が高く、さらに細目構造に架橋させ、ナトリウム塩の形とすると高い吸水性を持つゲルとなる。
SAP is a polymer that can absorb and retain water from several hundred times to several thousand times its own weight. As the SAP, a polymer of acrylic acid can be used. Since a polymer of acrylic acid has a large number of carboxyl groups, it has a high hydrophilicity and is further crosslinked to a fine structure to form a gel having a high water absorption when it is in the form of a sodium salt.
その他の親水性ポリマーとしては、２-メタクリロイルオキシエチルホスホリルコリン（ＭＰＣ）、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）、カルボキシメチルセルロースナトリウム（ＣＭＣ－Ｎａ）、ヒドロキシエチルセルロース（ＨＥＣ）などのセルロース誘導体；アルギン酸、ヒアルロン酸、アガロース、デンプン、デキストラン、プルラン等の多糖類及びその誘導体；カルボキシビニルポリマー、ポリエチレンオキサイド、ポリ（メタ）アクリルアミド、ポリ（メタ）アクリル酸等のホモポリマー、当該ホモポリマーと多糖類等との共重合体、及び当該ホモポリマーを構成するモノマーと他のモノマーとの共重合体；コラーゲン、ゼラチン等のタンパク質及びその誘導体；ヘパリン、ヒアルロン酸、コンドロイチン硫酸、デルマタン硫酸、デキストラン硫酸、ケラタン硫酸、ヘパラン硫酸等のグリコサミノグリカン、キチン、キトサン等の多糖類やムコ多糖類を挙げることができる。
Other hydrophilic polymers include cellulose derivatives such as 2-methacryloyloxyethyl phosphorylcholine (MPC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (CMC-Na), hydroxyethylcellulose (HEC); alginic acid, hyaluronic acid, agarose , Starch, dextran, pullulan and other polysaccharides and derivatives thereof; homopolymers such as carboxyvinyl polymer, polyethylene oxide, poly (meth) acrylamide, poly (meth) acrylic acid, and copolymers of the homopolymer and polysaccharides , And a copolymer of the monomer constituting the homopolymer and other monomers; proteins such as collagen and gelatin and derivatives thereof; heparin, hyaluronic acid, chondroitin sulfate, Mention may be made of glycosaminoglycans such as dermatan sulfate, dextran sulfate, keratan sulfate and heparan sulfate, polysaccharides such as chitin and chitosan, and mucopolysaccharides.
さらには、１－ビニル－２－ピロリジノン、プロぺノン酸２－メチルエステル、モノメタクリロイルオキシエチルフタレート、アンモニウムスルファトエチルメタクリレート、Ｎ－ビニルピロリドン、Ｎ，Ｎ－ジメチルアクリルアミド、２－（メタクリロイルオキシエチル）－２－（トリメチルアンモニオエチル）ホスフェート等の親水性ポリマーを用いてもよい。
Furthermore, 1-vinyl-2-pyrrolidinone, propenoic acid 2-methyl ester, monomethacryloyloxyethyl phthalate, ammonium sulfatoethyl methacrylate, N-vinylpyrrolidone, N, N-dimethylacrylamide, 2- (methacryloyloxyethyl) ) -2- (Trimethylammonioethyl) phosphate and other hydrophilic polymers may be used.
上記例示した親水性ポリマーは、単独で用いてもよく、２種類以上を併用してもよい。
The hydrophilic polymers exemplified above may be used alone or in combination of two or more.
重合開始剤としては、公知のラジカル重合促進剤を適宜選択して用いることができる。好ましくは水溶性または水分散性を有し、系全体に均一に含まれるものが好ましく用いられる。具体的には、重合開始剤として、水溶性の過酸化物、例えばペルオキソ二硫酸カリウムやペルオキソ二硫酸アンモニウム、水溶性のアゾ化合物、例えばＶＡ－０４４、Ｖ－５０、Ｖ－５０１（いずれも和光純薬工業株式会社製）の他、Ｆｅ２＋と過酸化水素との混合物等を用いることができる。
A known radical polymerization accelerator can be appropriately selected and used as the polymerization initiator. Preferably, those having water solubility or water dispersibility and uniformly contained in the entire system are preferably used. Specifically, as a polymerization initiator, water-soluble peroxides such as potassium peroxodisulfate and ammonium peroxodisulfate, water-soluble azo compounds such as VA-044, V-50, and V-501 (all of which are Wako Pure Chemical Industries, Ltd.) In addition to Yakuhin Kogyo Co., Ltd., a mixture of Fe 2+ and hydrogen peroxide can be used.
架橋剤としては、Ｎ，Ｎ’－メチレンビスアクリルアミド、エチレングリコールジメタクリレート、メタクリル酸ビニル等を用いることができる。
As the crosslinking agent, N, N'-methylenebisacrylamide, ethylene glycol dimethacrylate, vinyl methacrylate, or the like can be used.
識別物質は、フェニルボロン酸を用いることができる。
フ ェ ニ ル Phenylboronic acid can be used as the identification substance.
基材としてＨＥＭＡを用いた識別膜の構成を下記（化３）に示す。
The structure of the identification film using HEMA as the substrate is shown below (Chemical Formula 3).
識別膜に含まれるフェニルボロン酸は、下記（化４）に示すように、サッカライドのジオール結合を基に平衡が成り立っている。ホウ素原子は電子を欠いた非イオン状態からジオール化合物とエステル結合することで負電荷を帯びた状態へと変化する。
The phenylboronic acid contained in the identification film has an equilibrium based on the diol bond of the saccharide as shown in the following (Chemical Formula 4). The boron atom changes from a nonionic state lacking an electron to a negatively charged state by ester bonding with the diol compound.
このようにして識別膜は、特徴物質として例えば糖として上記したシアリル酸ルイスＸ糖鎖や、シアリル酸ルイスＡ糖鎖が、識別物質としてのフェニルボロン酸と結合することにより、負電荷の排出を促す。排出された電荷はゲート絶縁膜２８に帯電する。測定装置１０Ａは、ゲート電圧の変化を計測することにより、より高感度で試料２０の性質を測定することができる。
In this way, the identification film, as a characteristic substance, for example, the sialic acid Lewis X sugar chain or the sialic acid Lewis A sugar chain as sugars binds to phenylboronic acid as an identification substance, thereby discharging negative charges. Prompt. The discharged electric charges are charged in the gate insulating film 28. The measuring apparatus 10A can measure the property of the sample 20 with higher sensitivity by measuring the change in the gate voltage.
特徴物質としては、造血幹細胞および白血病幹細胞等の血球系幹細胞について、計測する最初の代謝産物が挙げられる。例えば、定常状態・移植等のストレス時や、白血病における代謝産物として、ピルビン酸、乳酸、アミノ酸(アスパラギン酸やＢＣＡＡ(バリン、ロイシン、イソロイシン)、アラニン、グルタミン、グリシン、リジン)、Ｈ＋、Ｎａ＋、Ｋ＋、Ｃａ２＋、ＮＨ４＋、Ｃｌ－、ＨＣＯ３－などの各種イオンがある。この場合、識別物質としてフェニルボロン酸を用いた上記識別膜（分子鋳型）、酸化膜、ポリヴィニルクロライド(PVC)にイオン感応性のクラウンエーテルを含む高分子膜などを適用することができる。酸化膜は、溶液下で水酸基を持つので水素イオン応答性に優れる。
The characteristic substance includes the first metabolite to be measured for blood cell stem cells such as hematopoietic stem cells and leukemia stem cells. For example, pyruvate, lactic acid, amino acids (aspartate, BCAA (valine, leucine, isoleucine), alanine, glutamine, glycine, lysine), H + , Na as metabolites in steady state / transplantation stress or leukemia There are various ions such as + , K + , Ca 2+ , NH 4+ , Cl − and HCO 3− . In this case, the identification film (molecular template) using phenylboronic acid as an identification substance, an oxide film, a polymer film containing ion-sensitive crown ether in polyvinyl chloride (PVC), and the like can be applied. Since the oxide film has a hydroxyl group in the solution, it has excellent hydrogen ion responsiveness.
また移植用造血幹細胞について尿酸、白血病幹細胞についてヒスタミン、ＰＧＥ２等の生理活性リン脂質が挙げられる。さらに特徴物質として細胞表面の複数種類のリン脂質を適用することにより、官能基の電荷量の相違から癌化を推定することができる。この場合、識別物質としてフェニルボロン酸を用いた上記識別膜（分子鋳型）、リン脂質の電荷量の相違により水素イオン濃度変化を捉える酸化膜を適用することができる。
In addition, hematopoietic stem cells for transplantation include uric acid, and leukemia stem cells include physiologically active phospholipids such as histamine and PGE2. Furthermore, by applying a plurality of types of phospholipids on the cell surface as a characteristic substance, canceration can be estimated from the difference in the charge amount of the functional group. In this case, it is possible to apply the identification film (molecular template) using phenylboronic acid as an identification substance and an oxide film that captures a change in hydrogen ion concentration due to the difference in the amount of charge of phospholipid.
上記実施形態の場合、測定部１２は１個のＦＥＴ１４を有する場合について説明したが、本発明はこれに限らない。例えば、図４に示すように、１つの測定部３９に複数のＦＥＴ４０を備えることとしてもよい。この場合、少なくとも一部のＦＥＴ４０のゲート絶縁膜２８上に、それぞれ異なる上記識別膜（図示しない）を設けてもよい。これにより測定装置１０Ｂは、１つの試料２０から、異なる性質に基づいて排出される電荷を、性質ごとに計測することができる。
In the case of the above embodiment, the case where the measurement unit 12 has one FET 14 has been described, but the present invention is not limited to this. For example, as shown in FIG. 4, one measurement unit 39 may include a plurality of FETs 40. In this case, different identification films (not shown) may be provided on at least some of the gate insulating films 28 of the FETs 40. Thereby, the measuring apparatus 10B can measure the electric charge discharged | emitted from one sample 20 based on a different property for every property.
上記実施形態の場合、測定装置１０Ａは１つの測定部１２を備える場合について説明したが、本発明はこれに限らない。例えば図５に示すように、測定装置１０Ｃは、測定部４２を複数備えることとしてもよい。本図に示す複数の測定部４２は、アレイ状に配置されている。この場合、測定部４２は、１つの試料２０を囲むように４個の電極４４が設けられている。電極４４は円柱状に形成されている。電極４４で囲まれた中央の底部にはＦＥＴ４３が形成されている。電極４４間には、ＦＥＴ４３に試料２０を引き寄せる誘電泳動力を生じるように、所定の周波数の交流電圧が印加されている。アレイ状に配置された複数の測定部４２上を、試料２０を含む液体が流れるように流路（図示しない）が形成されている。
In the case of the above embodiment, the measurement apparatus 10A has been described as including one measurement unit 12, but the present invention is not limited to this. For example, as illustrated in FIG. 5, the measurement apparatus 10 </ b> C may include a plurality of measurement units 42. The plurality of measurement units 42 shown in this figure are arranged in an array. In this case, the measurement unit 42 is provided with four electrodes 44 so as to surround one sample 20. The electrode 44 is formed in a cylindrical shape. An FET 43 is formed at the center bottom surrounded by the electrode 44. An AC voltage having a predetermined frequency is applied between the electrodes 44 so as to generate a dielectrophoretic force that attracts the sample 20 to the FET 43. A flow path (not shown) is formed on the plurality of measurement units 42 arranged in an array so that a liquid containing the sample 20 flows.
測定装置１０Ｃにおいて、試料２０が測定部４２上に到達すると、当該試料２０は誘電泳動力により電極４４間のＦＥＴ４３に引き寄せられ、電極４４間に捕捉される。これにより当該試料２０から電荷が排出されている場合、当該電荷がゲート絶縁膜（本図には図示しない）に帯電する。ゲート絶縁膜表面に電荷が帯電することにより、ゲート絶縁膜上の電荷密度が変化する。ＦＥＴ４３は、ゲート絶縁膜上の電荷密度の変化に伴うゲート電圧の変化を計測する。これにより測定装置１０Ｃは、当該試料２０の性質を測定することができる。しかも本変形例に係る測定装置１０Ｃは、アレイ状に測定部４２が配置されていることにより、１度に複数の試料２０の電荷を計測することができる。
In the measuring apparatus 10C, when the sample 20 reaches the measuring unit 42, the sample 20 is attracted to the FET 43 between the electrodes 44 by the dielectrophoretic force and is captured between the electrodes 44. As a result, when charges are discharged from the sample 20, the charges are charged on the gate insulating film (not shown in the figure). When the charge is charged on the surface of the gate insulating film, the charge density on the gate insulating film changes. The FET 43 measures a change in gate voltage accompanying a change in charge density on the gate insulating film. Thereby, the measuring apparatus 10 </ b> C can measure the property of the sample 20. Moreover, the measurement apparatus 10C according to this modification can measure the charges of the plurality of samples 20 at a time by arranging the measurement units 42 in an array.
測定装置１０Ｃは、測定結果に応じ、当該特定の試料２０のみを測定部４２から引き離すことにより、分取することができる。この場合、測定装置１０Ｃは、特定の試料２０を捕捉している電極４４間に印加されている電圧を止める。これにより当該特定の試料２０は、測定部４２から離れ、液体の流れに乗り、下流へと流れる。
The measuring apparatus 10C can sort by separating only the specific sample 20 from the measuring unit 42 according to the measurement result. In this case, the measuring apparatus 10 </ b> C stops the voltage applied between the electrodes 44 capturing the specific sample 20. As a result, the specific sample 20 moves away from the measurement unit 42, rides on the liquid flow, and flows downstream.
なお、図５に示す測定装置１０Ｃの測定部４２に、図４に示す測定部３９を適用してもよい。これにより測定装置は、複数の試料２０について、異なる性質に基づいて排出される電荷を性質ごとに、１度に計測することができる。
Note that the measurement unit 39 shown in FIG. 4 may be applied to the measurement unit 42 of the measurement apparatus 10C shown in FIG. Thereby, the measuring apparatus can measure the electric charge discharged | emitted based on a different property about the some sample 20 for every property at once.
実際に識別膜を備える測定装置を作製し、試料として癌細胞と正常細胞の性質を測定することができるか検証した。ＦＥＴは、半導体基板にＩＧＺＯ、ソース・ドレインにＩＴＯ、ゲート絶縁膜にＳｉＯ２を用い、チャネル面積を２０×１０μｍ２とした。電極は金を用いて形成した。ゲート絶縁膜上には識別膜として、ＨＥＭＡとＭＰＣで形成した基材と、フェニルボロン酸からなる識別物質とで形成した。
A measuring device with an identification film was actually manufactured, and it was verified whether the properties of cancer cells and normal cells could be measured as samples. The FET used IGZO as a semiconductor substrate, ITO as a source / drain, SiO 2 as a gate insulating film, and a channel area of 20 × 10 μm 2 . The electrode was formed using gold. On the gate insulating film, an identification film was formed of a base material made of HEMA and MPC and an identification substance made of phenylboronic acid.
電極間に１０Ｖ、１．４ＭＨｚの交流電圧を印加した状態で、流速３．３ｃｍ／ｓでＤＥＰ液を流した。ＤＥＰ液は、スクロース８．５ｇ、Ｄ－グルコース０．３ｇ、ＢＳＡ０．１ｇを純水で１００ｍｌとし調整した。ＦＥＴは、１００μｓ（１０４回／ｓ）測定した。試料は、１０個／ｓの間隔で流した。その結果を図６Ａ，６Ｂに示す。本図は、横軸が時間（ｓｅｃ）、縦軸がゲート電圧である表面電位の変化（ｍＶ）を示す。図６Ａの結果から、癌細胞を流した場合、負電荷が６回測定された。一方、図６Ｂの結果から、正常細胞を流した場合、負電荷が測定されなかった。この結果から測定装置は、所定の流速で流れる液体中の癌細胞の、細胞膜に存在する糖鎖がフェニルボロン酸と結合することによって生じた負電荷を計測することができ、これにより試料が癌細胞であることを測定できることが確認された。
The DEP liquid was allowed to flow at a flow rate of 3.3 cm / s while an AC voltage of 10 V and 1.4 MHz was applied between the electrodes. A DEP solution was prepared by adding 8.5 g of sucrose, 0.3 g of D-glucose, and 0.1 g of BSA to 100 ml with pure water. The FET was measured for 100 μs (10 4 times / s). Samples were flowed at 10 / s intervals. The results are shown in FIGS. 6A and 6B. In this figure, the horizontal axis shows time (sec) and the vertical axis shows the change in surface potential (mV) which is the gate voltage. From the result of FIG. 6A, the negative charge was measured 6 times when cancer cells were flowed. On the other hand, from the result of FIG. 6B, when normal cells were flowed, no negative charge was measured. From this result, the measurement device can measure the negative charge generated by the binding of the sugar chain present in the cell membrane of the cancer cells in the liquid flowing at a predetermined flow rate to the phenylboronic acid. It was confirmed that the cells could be measured.
１０Ａ、１０Ｂ、１０Ｃ 測定装置
１２、３９、４２ 測定部
１４、４０、４３ ＦＥＴ（電界効果トランジスタ）
１６ 電極
１８ 流路
２０ 試料
２８ ゲート絶縁膜
４４ 電極
10A, 10B, 10C Measuring device 12, 39, 42 Measuring unit 14, 40, 43 FET (field effect transistor)
16Electrode 18 Channel 20 Sample 28 Gate insulating film 44 Electrode
１２、３９、４２ 測定部
１４、４０、４３ ＦＥＴ（電界効果トランジスタ）
１６ 電極
１８ 流路
２０ 試料
２８ ゲート絶縁膜
４４ 電極
10A, 10B,
16
Claims (9)
- 電荷を計測する測定部を備える測定装置において、
前記測定部は、
誘電泳動力によりゲート絶縁膜付近に試料を引き寄せる少なくとも２つの電極と、
前記試料から排出される電荷を、前記ゲート絶縁膜を通じて計測する電界効果トランジスタと
を有することを特徴とする測定装置。 In a measuring device comprising a measuring unit for measuring electric charge,
The measuring unit is
At least two electrodes that draw the sample near the gate insulating film by dielectrophoretic force;
And a field effect transistor for measuring charges discharged from the sample through the gate insulating film. - 前記ゲート絶縁膜の表面に前記試料の性質を特徴づける特徴物質と結合する識別膜が設けられていることを特徴とする請求項１記載の測定装置。 The measuring apparatus according to claim 1, wherein an identification film is provided on the surface of the gate insulating film, which is bonded to a characteristic substance that characterizes the properties of the sample.
- 前記電界効果トランジスタが複数設けられており、前記複数の電界効果トランジスタの少なくとも一部には、異なる前記識別膜がそれぞれ設けられていることを特徴とする請求項２記載の測定装置。 The measurement apparatus according to claim 2, wherein a plurality of the field effect transistors are provided, and the different identification films are provided on at least a part of the plurality of field effect transistors.
- 前記測定部が、アレイ状に設けられていることを特徴とする請求項１～３のいずれか１項記載の測定装置。 The measuring apparatus according to any one of claims 1 to 3, wherein the measuring sections are provided in an array.
- 前記ゲート絶縁膜に前記試料を含む液体を供給する流路を備えることを特徴とする請求項１～４のいずれか１項記載の測定装置。 The measuring apparatus according to claim 1, further comprising a flow path for supplying a liquid containing the sample to the gate insulating film.
- 誘電泳動力によりゲート絶縁膜付近に液体中の試料を引き寄せるステップと、
前記試料から排出される電荷を、前記ゲート絶縁膜を通じて計測するステップと
を備えることを特徴とする測定方法。 Drawing the sample in the liquid near the gate insulating film by dielectrophoretic force;
Measuring the charge discharged from the sample through the gate insulating film. - 前記計測するステップは、１つの前記試料から、異なる性質に基づいて排出される電荷を、前記性質ごとに計測することを特徴とする請求項６記載の測定方法。 The measuring method according to claim 6, wherein in the measuring step, a charge discharged from one sample based on different properties is measured for each property.
- 前記計測するステップは、１度に複数の前記試料の電荷を計測することを特徴とする請求項６又は７記載の測定方法。 The measuring method according to claim 6 or 7, wherein the measuring step measures the charges of the plurality of samples at a time.
- 前記計測するステップの後に、
測定結果に応じて少なくとも一部の前記試料を前記ゲート絶縁膜から引き離すステップを備えることを特徴とする請求項８記載の測定方法。 After the measuring step,
The measurement method according to claim 8, further comprising a step of separating at least a part of the sample from the gate insulating film according to a measurement result.
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| JP6714259B2 (en) | 2020-06-24 |
| JP2018021827A (en) | 2018-02-08 |
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