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WO2003079003A2 - Procede de saisie de biopolymeres macromoleculaires au moyen d'un transistor a effet de champ, biocapteur et ensemble circuit comportant un biocapteur et un circuit d'analyse associe - Google Patents

Procede de saisie de biopolymeres macromoleculaires au moyen d'un transistor a effet de champ, biocapteur et ensemble circuit comportant un biocapteur et un circuit d'analyse associe Download PDF

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Publication number
WO2003079003A2
WO2003079003A2 PCT/DE2003/000888 DE0300888W WO03079003A2 WO 2003079003 A2 WO2003079003 A2 WO 2003079003A2 DE 0300888 W DE0300888 W DE 0300888W WO 03079003 A2 WO03079003 A2 WO 03079003A2
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Prior art keywords
transistor
molecules
region
biosensor
organic
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English (en)
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WO2003079003A3 (fr
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Thomas Haneder
Hagen Klauk
Günter Schmid
Roland Thewes
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Infineon Technologies AG
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Infineon Technologies AG
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
    • G01N33/5438—Electrodes
    • 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
    • G01N27/4145—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS specially adapted for biomolecules, e.g. gate electrode with immobilised receptors
    • 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
    • G01N27/4148—Integrated circuits therefor, e.g. fabricated by CMOS processing
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00497—Features relating to the solid phase supports
    • B01J2219/00527—Sheets
    • B01J2219/00529—DNA chips
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • B01J2219/0061—The surface being organic
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • B01J2219/00623—Immobilisation or binding
    • B01J2219/00628—Ionic
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • B01J2219/00623—Immobilisation or binding
    • B01J2219/0063—Other, e.g. van der Waals forces, hydrogen bonding
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • B01J2219/00632—Introduction of reactive groups to the surface
    • B01J2219/00635—Introduction of reactive groups to the surface by reactive plasma treatment
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • B01J2219/00632—Introduction of reactive groups to the surface
    • B01J2219/00637—Introduction of reactive groups to the surface by coating it with another layer
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00653—Making arrays on substantially continuous surfaces the compounds being bound to electrodes embedded in or on the solid supports
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/0068—Means for controlling the apparatus of the process
    • B01J2219/00702—Processes involving means for analysing and characterising the products
    • B01J2219/00704—Processes involving means for analysing and characterising the products integrated with the reactor apparatus
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00718—Type of compounds synthesised
    • B01J2219/0072—Organic compounds

Definitions

  • the invention relates to a method for detecting macromolecular biopolymers by means of a field effect transistor, a biosensor and a circuit arrangement with a biosensor and an evaluation circuit coupled therewith.
  • Optical methods are mostly used today for examining, for example, the expression pattern of a cell using nucleic acids or generally for detecting nucleic acids.
  • small amounts of different single-stranded nucleic acid molecules serving as capture molecules are preferably immobilized in a punctiform manner in an ordered grid (array) of, for example, some 10, 100 or 1000 points (dots) on a surface, for example made of glass, plastic, gold or other materials (see for example [1], [2]).
  • An analyte ie a liquid to be examined
  • nucleic acids labeled with a fluorescent dye is then transferred pumped this surface.
  • nucleic acids with capture molecules complementary to them can form double-stranded hybrid molecules on the surface of the support.
  • Proteins can also be detected using optical detection methods which are based on the immobilization of a capture molecule on a surface of a support made of glass, plastic, silicon dioxide or metal.
  • markings that emit an optical signal such as a fluorescence signal are detected with the aid of an excitation unit such as a laser and an external detection unit for the emitted radiation (cf. e.g. [3], [4]).
  • Biosensors based on passive semiconductor chips i.e. Sensors that do not have integrated circuit elements require large-area detection elements in order to be able to guarantee a certain degree of sensitivity and dynamics.
  • the omission of on-chip signal preprocessing with the help of integrated circuits e.g. based on a CMOS process reduces the manufacturing costs of such biosensors compared to active semiconductor chips. In principle, however, such sensors cannot be used.
  • This type of immobilization can take place, for example, if the immobilization agent is a plastic material that is used for the production of microtiter plates (for example polypropylene or
  • Fluoroalkylnaphthalinbis id (n-semiconductors, [19]), while the side facing the sensor consists of an N-amino acid-substituted naphthalene bisimide.
  • the dielectric can be inorganic in nature, such as silicon dioxide, silicon nitride, or an organic dielectric, such as Polyvinyl alcohol, which can be used as passivation of the transistor as described above.
  • organic dielectric such as Polyvinyl alcohol, which can be used as passivation of the transistor as described above.
  • all connections that can be deposited or processed above the channel region material can be used for the modification. It goes without saying that neither the deposition nor the structuring of this material may damage the underlying layers and materials of the transistor.
  • Detection signal not on a current measurement or the like rests, i.e. no electrically conductive connection between the detection unit and analyte (electrolyte), in particular the capture molecules, their reaction partners or possibly additional markers, is necessary.
  • analyte electrophilyte
  • this further layer is a metal such as gold. This embodiment is advantageous if, on the one hand, a galvanic separation between the analyte (a sample to be examined) is desired, the biochemical reaction to be examined on another
  • the transistor of the biosensor is a folded (polymer) transistor shown in FIG. 8, which provides an order of magnitude of the electrical parameters to be evaluated that is optimal for measurement and circuit technology.
  • folding is understood to mean that several individual transistors are connected in parallel, so that their electrical modeling can be considered as a single overall transistor with a very large width.
  • the drain and source areas are used on both sides of their longitudinal edges, which leads to an area-efficient implementation of such components.
  • the biosensor has a plurality of transistors, which are preferably arranged in a regular arrangement, an array, on the (common) carrier or embedded therein.
  • any material on which the various units of the sensor can be permanently applied can be used as the carrier material for the biosensor.
  • suitable carrier materials are insulators such as paper, plastic films, ceramics or glass, and also metal coated with an insulator or metal coated with plastic.
  • carrier materials made from suitable organic polymer materials are common dielectric synthetic plastics such as epoxy resins, polyalkylenes such as polyethylene or polypropylene resins,
  • Polyesters polystyrenes, substituted polystyrenes such as poly-o-hydroxystyrene, polyvinyl compounds such as polyvinyl alcohols or polyvinyl carbazoles, polyurethanes, polyimides, polybenzoxazoles, polythiazoles, polyethers, polyether ketones, polyacrylates, polyterephthalates, polyethylene naphthalates or polycarbonates of all types.
  • biodegradable polymers are also suitable, such as poly-degradable polymers , The surface properties of such a polymer material or glass support can easily be changed, so that hydrophilic or hydrophobic surfaces are created. This is desirable for many biochemical sensors.
  • These can be made up of the 20 amino acids usually found in proteins, but can also contain naturally occurring amino acids or e.g. be modified by sugar residues (oligosaccharides) or contain post-translational modifications. Furthermore, complexes from several different macromolecular biopolymers can also be detected, for example complexes from nucleic acids and proteins.
  • proteins or peptides are to be detected as macromolecular biopolymers with the biosensor, ligands which can specifically bind the proteins or peptides to be detected are preferably used as capture molecules.
  • the capture molecules / ligands are preferably linked to the detection area by covalent bonds.
  • Low-molecular enzyme agonists or enzyme antagonists, pharmaceuticals, sugars or antibodies or other suitable molecules which have the ability to specifically bind proteins or peptides are suitable as ligands for proteins and peptides.
  • DNA molecules nucleic acids or oligonucleotides of a given nucleotide sequence are detected with the biosensor described here, they are preferably detected in single-stranded form, i.e. if necessary, they are converted into single strands before the detection by denaturing as explained above.
  • DNA probe molecules with a sequence complementary to the single-stranded region are then preferably used as capture molecules.
  • the DNA probe molecules can in turn
  • oligonucleotides or longer nucleotide sequences as long as they do not form any of the intermolecular structures that prevent hybridization of the probe molecule with the nucleic acid to be detected.
  • DNA-binding proteins or agents as the capture molecule.
  • any evaluation circuit that can be coupled to the sensor or a transistor of the sensor and that can further process a signal received by the sensor, e.g. compares the result of the first electrical measurement with that of the second electrical measurement and thus records macromolecular biopolymers.
  • the evaluation circuit has at least one component with a semiconducting layer with an organic material.
  • Such a diode can have, for example, a layer with an n- or p-semiconducting organic material or both a layer made of an n-conducting and a layer of a p-conducting organic semiconductor material (see [20, 21]).
  • a layer with an n- or p-semiconducting organic material or both a layer made of an n-conducting and a layer of a p-conducting organic semiconductor material (see [20, 21]).
  • Suitable n-semiconducting organic materials are based, for example, on electron-poor aromatic compounds.
  • Resistors or capacitors with organic semiconducting materials can e.g. be constructed analogously to the resistors or capacitors described in FIG. 4 or FIG. 6 of [21].
  • these passive components are manufactured using inkjet techniques. In general, however, these can also be produced by standard lithography and metallization.
  • the at least one component of the evaluation circuit is a transistor.
  • This transistor is preferably a "polymer transistor" as described above and can be used in the biosensor and method of the invention.
  • the circuit arrangement has a multiplicity of biosensors.
  • a circuit arrangement is particularly preferred in which one or more of the biosensors with the associated coupled evaluation circuit are applied to a common carrier.
  • Figures 4a to 4c a symbolic representation of the field effect transistor according to the invention (Fig.4a) and two different electrical equivalent circuit diagrams (Fig.4b, Fig.4c);
  • Figure 5 shows an evaluation circuit of the invention
  • Figure 6 shows an evaluation circuit of the biosensor of the invention according to a second embodiment of the
  • Figure 8 shows an embodiment of the biosensor, which is based on a folded polymer transistor.
  • Fig.l shows various configurations of a field effect transistor 100 which can be used in the invention.
  • a carrier 101 e.g. consists of polyethylene naphthalate
  • a gate region 102 which consists of nickel.
  • a layer 103 made of a dielectric material such as silicon dioxide, which separates the gate region 102 from the first source / drain region 104 and the second source / drain region 105, which are made of palladium.
  • a layer 106 made of pentacene as a semiconducting organic material.
  • the layer 106 forms the body region of the transistor 100.
  • the body region 106 can also be formed from a layer of inert polymeric matrix material in which inorganic semiconducting particles are embedded.
  • a functional layer 107 e.g. consists of octadecyltrichlorosilane molecules can be generated as follows.
  • the pentacene layer is then functionalized with a short oxygen plasma treatment (1 to 2 seconds).
  • the functionalization is preferably completed by a rinsing step with deionized water, but the normal air humidity is also sufficient for the functionalization).
  • the reaction is then carried out with silane-functionalized oligonucleotides to remove the capture molecules (see, for example, FIG. 2, for example 206). to dock.
  • silane-functionalized oligonucleotides to remove the capture molecules (see, for example, FIG. 2, for example 206). to dock.
  • silane-functionalized oligonucleotides to remove the capture molecules (see, for example, FIG. 2, for example 206). to dock.
  • less reactive alkoxysilanes are also suitable.
  • other coupling methods such as amide, ester or glycosidic bonds, ionic or complexing bonds can also be used.
  • layer 107 can also consist of a gold layer which enables coupling via the gold-sulfur bond.
  • 107 may also include a dielectric.
  • the field effect transistor 100 initially has a layer 106 of semiconducting organic material on the carrier 101. This layer 106 forming the body region of transistor 100 has e.g. Tetracene on.
  • the transistor 100 also has a first and a second source / drain region 104, 105 made of platinum. A layer 103 is located above the source / drain regions 104, 105 or the body region 106
  • the gate area 102 also has a layer 108 of gold, which forms the detection area, on which either macromolecular biopolymers to be detected or capture molecules are immobilized. Alternatively, the gate area can be formed directly and completely from gold. The gate area then also directly represents the detection area.
  • the field effect transistor 100 according to FIG. 1g to Fig.li basically has the same structure as the transistor according to Fig.la to Fig.lc. However, there is an additional layer 108 in the transistor 100 according to FIGS. which can be used as an additional electrode for immobilizing biopolymers if, for example, the body area is not to be functionalized directly to form an immobilization unit.
  • the field effect transistors according to Fig.l with the layer with semiconducting organic material or the layer with the polymeric matrix material, in which inorganic semiconducting particles are embedded, can be produced with the method described in [12].
  • the deposition of the source / drain regions 104, 105 takes place before the deposition of the semiconducting layer 106 in the embodiments according to FIGS. 1c, 1c and Fig. Le, while in the embodiments according to FIGS. 1b, 1d and 1d If the semiconducting layer 106 is applied in front of the source / drain regions 104, 105.
  • the transistor 300 has a carrier 301, which consists of polyethylene naphthalate, a gate region 302 made of nickel, and a dielectric layer 303 made of silicon dioxide arranged thereover. Furthermore, the transistor 300 has a first source / drain region 304 and a second source / drain region 305 made of platinum as well as a layer 306 made of pentazen between the source / drain regions 304, 305 as a semiconducting organic material. Layer 306 forms the body region of transistor 300 and is at the same time modified by, as described above with reference to FIG.
  • Layer 306 has one Pot or tub shape to facilitate the absorption of liquid analytes.
  • first oligonucleotide molecules 307 (FIG. 3a) and second ones
  • Pyrimidine bases thymine (T) or cytosine (C) can in each case complement sequences of the DNA strands complementary to the sequences of the probe molecules in the usual manner, i.e. hybridize by base pairing via hydrogen bonds between A and T or between C and G.
  • T thymine
  • C cytosine
  • RNA molecules for example uridine (U)
  • U uridine
  • Fig.3c and Fig.3d show the transistor at the time when an analyte (not shown) with the detection area, i.e. here layer 306, the transistor, is brought into contact.
  • the analyte contains DNA molecules 309 which have a predetermined first nucleotide sequence which is complementary to the sequence of the first DNA capture molecules
  • the DNA molecules 309 complementary to the first DNA probe molecules 307 hybridize with the first DNA probe molecules 306, which are applied to the detection region of the semiconducting layer (the body region) 306.
  • the conditions under which the hybridization is carried out are (stringent) selected so that only the Hybridize sequences of DNA strands with the specific (perfectly) complementary sequence. Therefore, the DNA molecules 309 complementary to the first DNA probe molecules do not hybridize with the second DNA probe molecules 308.
  • a first electrical measurement is carried out with the transistor 300.
  • the current flowing through the transistor is measured.
  • the molecules immobilized during hybrid formation modulate an electric field which acts on the body region of the transistor and which thus influences the channel current of the field-effect transistor.
  • the current through the transistor is a direct measure of the amount of charge immobilized on the detection area 306.
  • a second electrical measurement is therefore carried out after contacting the analyte, in which the transistor current is determined.
  • the comparison of the two electrical measurements is used to detect the nucleic acid molecules. If the difference determined in the comparison exceeds a (predetermined) threshold value, it is concluded from this that DNA molecules 309 were present in the sample that are (perfectly) complementary to the capture molecules 307, and possibly in what concentration (cf. .3e). If there is a difference below the threshold value, it is concluded that no DNA molecules were present. This is the case with the example here in that the statement can be made that there were no DNA molecules that were among the given ones
  • Hybridization conditions are complementary to the capture molecules 308. This classification according to the threshold value can also be carried out in the other methods disclosed here.
  • the reaction can be detected.
  • the hybridization or, in general, the complex formation between the two binding partners changes the gate capacitance or - as described here primarily by way of example - the substrate steepness (this term is borrowed from the MOS transistor) or the substrate penetration and thus the transfer characteristic of the transistor. This change in the transfer characteristic is used here to detect complex formation and biopolymers.
  • Another way to operate the sensor of the invention is continuously, for example during contacting the analyte with the sensor surface or also during an optional washing step after the measurement. Changes to the sensor surface can then be tracked transiently.
  • mismatch i.e. to determine a hybridization between not perfectly complementary nucleic acids
  • the complementarity influences the properties of the field effect transistor, and thus e.g. influences the current flow through the transistor (cf. [10]).
  • FIGS. 4 a to 4 c show a symbol 400 for the field effect transistor 100 according to the invention with the following four connections (see FIG. 4 a):
  • a first source / drain region 401 A first source / drain region 401,
  • 4b and 4c show two different electrical equivalent circuit diagrams for the field effect transistor 100 according to the invention shown in FIG.
  • Field effect transistor 411 and a second field effect transistor 412 which have different properties in their electrical parameters, such as for example, their threshold voltage, their steepness, etc., can be approximated sufficiently well and can thus be replaced in the equivalent circuit.
  • This equivalent circuit assumes that the gate connection and the body connection each control a transistor independently of one another.
  • the second electrical equivalent circuit diagram 420 shown in FIG. 4c is more suitable for describing the electrical behavior, since in this case it is assumed that the control effect of the control electrodes, i.e. of the gate connection 403 and the body connection 404 extends to the entire volume of the body material.
  • a MOS voltage acts on a MOS field-effect transistor 421, which results from the weighted sum of the electrical voltages present at the gate connection 403 and at the body connection 404, these voltages possibly also adding an additive surcharge are provided in order to be able to take into account different work functions and similar effects, as is described, for example, for deriving the threshold voltage in conventional MOS field-effect transistors in [10]. For this reason, the second electrical
  • Equivalent circuit 420 has an adder 422 coupled with its output to the gate connection of the MOS field-effect transistor 421, the first input of which is coupled to the body connection 404 via a first amplifier element 423 and a first voltage source 424 and the second
  • connection is coupled via a second amplifier element 425 and a second voltage source 426 to the gate terminal 403. Evaluation circuits for evaluating the signal provided by the biosensor are described below.
  • FIG 5 shows an evaluation circuit 500 of the biosensor according to the invention based on a polymer transistor according to a first exemplary embodiment of the invention.
  • the transistor 400 according to the invention is
  • FIG. 5 shows the electrical occurring in the analyte at the body connection 404
  • the first source / drain connection 401 is coupled to the ground potential 502.
  • the gate voltage VG present at the gate connection 403 is provided via the symbolically represented gate voltage source 503.
  • the second source / drain region 402 is via a current measuring device 504 with which the current flowing through the transistor 400 is measured, i.e. the electrical flowing through the body region of transistor 400 from first source / drain region 401 to second source / drain region 402
  • FIG. 6 shows an evaluation circuit 600 according to a second exemplary embodiment of the invention.
  • the change in the effective control voltage which is required for the transistor 400 to carry an electrical current of a predetermined current strength is measured.
  • this change may preferably occur at first source / drain region 401, i.e. can be tapped from the source node of transistor 400.
  • transistor 400 is operated as a source follower.
  • the voltage at the first source / drain region 401 is measured by means of a voltage measuring device 601 connected to the first source / drain region, a current source 603 being coupled to the first source / drain region 401.
  • the drain-to-source potential affects the current only slightly, or the influence of the gate-to-source potential is significantly greater than the influence of the drain-to-source potential for maintaining a constant current , if the transistor operating point is placed in the saturation range or the sub-threshold range.
  • FIG. 7 shows an evaluation circuit 700 according to a third exemplary embodiment of the invention.
  • the voltage at one of the control electrodes is measured, which is required for the transistor to carry an electrical current of a predetermined current.
  • a control circuit 701 which controls the gate voltage source 503 in such a way that the current measured by the current measuring device 504 and flowing through the transistor 400 is kept constant.
  • the electrical potential applied to the body connection 404 i.e. the electrical voltage VE provided by the analyte voltage source 501 is kept constant and the gate voltage is regulated accordingly.
  • the evaluation circuit according to the third exemplary embodiment has an electrical voltage acting on the transistor via the analyte, which is symbolized by the analyte voltage source 501 and which is coupled on the one hand to the ground potential 702 and on the other hand to the body connection 404.
  • the first source / drain region 401 is directly coupled to the ground potential. Furthermore, the gate connection 403 is coupled to the gate voltage source 503 and the gate voltage source 503 to the ground potential 702 via the control circuit.
  • the second source / drain region 402 is coupled via the current measuring device 504 to the drain voltage source 505, which in turn is coupled to the ground potential 702.
  • the transistor 412 controlled by the gate connection 403 is preferably “disconnected” by applying a suitable control voltage to the gate connection 403, ie switched into a state in which the second transistor 412 delivers such a small electric current that it does not make a significant contribution and thus has to be taken into account in the signal processing.
  • the electrical voltage at the gate connection 403 should be applied to the same electrical potential before and after the biochemical reaction that has taken place.
  • Polymer transistors can be easily manufactured with very different channel lengths and channel widths from a few ⁇ m and below to a few 100 ⁇ m. For this reason, the size of the reaction area can be chosen, for example, depending on the available sample volume or the required sensitivity.
  • the reaction area can consist of the entire active area of the transistor area or only part of this area.
  • a folded polymer transistor 800 (see FIG. 8) can also be used in order to provide an order of magnitude of the electrical parameters to be evaluated that is optimal for measurement technology and circuit technology.
  • the folding of the polymer transistor 800 leads to an overall transistor with a very large electrical width, it being noted that the relative change in the measured parameters, i. the relative sensitivity of the biosensor does not change.
  • the sensor surface has a pot-like or pan-like shape, i.e. has a compartment. This makes it easier to take up small sample volumes.
  • first oligonucleotide molecules 307 first oligonucleotide molecules (probe molecules) 308 second oligonucleotide molecules (probe molecules) 309 DNA molecules

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Abstract

L'invention concerne un biocapteur comprenant les éléments suivants : un support, une zone porte située sur le support, une première et une deuxième zone drain/source, ces zones étant placées sur la zone porte, une zone corps disposée entre la première et la deuxième zone drain/source, cette zone corps comportant une matière organique, une connexion corps se trouvant sur la zone corps, cette connexion corps étant façonnée de telle sorte que des biopolymères macromoléculaires peuvent y être immobilisés.
PCT/DE2003/000888 2002-03-18 2003-03-18 Procede de saisie de biopolymeres macromoleculaires au moyen d'un transistor a effet de champ, biocapteur et ensemble circuit comportant un biocapteur et un circuit d'analyse associe Ceased WO2003079003A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10211901.5 2002-03-18
DE2002111901 DE10211901A1 (de) 2002-03-18 2002-03-18 Verfahren zum Erfassen von makromolekularen Biopolymeren mittels eines Feldeffekt-Transistors, Biosensor und Schaltungsanordnung mit Biosensor und damit gekoppelter Auswerteschaltung

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WO2003079003A2 true WO2003079003A2 (fr) 2003-09-25
WO2003079003A3 WO2003079003A3 (fr) 2003-11-13

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005036156A1 (fr) * 2003-10-10 2005-04-21 Cambridge University Technical Services Limited Detection d'interaction moleculaire au moyen d'une structure de diode semiconductrice isolante metallique
WO2005095938A1 (fr) * 2004-04-01 2005-10-13 Nanyang Technological University Microcircuit adressable a transistors pour la conduite d'essais
WO2007084077A1 (fr) * 2006-01-20 2007-07-26 Agency For Science, Technology And Research Cellule de biocapteur et réseau de biocapteurs
US7455795B2 (en) 2003-12-30 2008-11-25 Infineon Technologies Ag Charge transfer complexes including an electron donor and an electron acceptor as basis of resistive memories
CN103842817A (zh) * 2010-09-29 2014-06-04 得克萨斯系统大学评议会 具有改进的灵敏度和特异性的鳍型fet生物传感器
CN116735881A (zh) * 2023-06-15 2023-09-12 天津大学 一种有机场效应晶体管生物传感器及其制备方法和应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102007034331A1 (de) * 2007-07-24 2009-01-29 Robert Bosch Gmbh Vorrichtung und Verfahren zur Detektierung von Substanzen

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DE3876602T2 (de) * 1987-10-13 1993-07-01 Taiyo Yuden Kk Ionensensor.
KR930002824B1 (ko) * 1990-08-21 1993-04-10 손병기 감이온 전계효과 트랜지스터를 이용한 바이오 센서용 측정회로
DE4115397A1 (de) * 1991-05-10 1992-11-12 Fraunhofer Ges Forschung Verfahren zum herstellen einer integrierten cmos-schaltung mit einem isfet und mit einem auswertungs-misfet in polysiliziumtechnologie
DE4115398A1 (de) * 1991-05-10 1992-11-12 Fraunhofer Ges Forschung Verfahren zum herstellen eines biosensors
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US6203981B1 (en) * 1996-04-17 2001-03-20 Motorola, Inc. Transistor-based molecular detection apparatus and method
US5827482A (en) * 1996-08-20 1998-10-27 Motorola Corporation Transistor-based apparatus and method for molecular detection and field enhancement
US6335539B1 (en) * 1999-11-05 2002-01-01 International Business Machines Corporation Method for improving performance of organic semiconductors in bottom electrode structure

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005036156A1 (fr) * 2003-10-10 2005-04-21 Cambridge University Technical Services Limited Detection d'interaction moleculaire au moyen d'une structure de diode semiconductrice isolante metallique
US7455795B2 (en) 2003-12-30 2008-11-25 Infineon Technologies Ag Charge transfer complexes including an electron donor and an electron acceptor as basis of resistive memories
WO2005095938A1 (fr) * 2004-04-01 2005-10-13 Nanyang Technological University Microcircuit adressable a transistors pour la conduite d'essais
US8138496B2 (en) 2004-04-01 2012-03-20 Nanyang Technological University Addressable transistor chip for conducting assays
WO2007084077A1 (fr) * 2006-01-20 2007-07-26 Agency For Science, Technology And Research Cellule de biocapteur et réseau de biocapteurs
CN103842817A (zh) * 2010-09-29 2014-06-04 得克萨斯系统大学评议会 具有改进的灵敏度和特异性的鳍型fet生物传感器
CN116735881A (zh) * 2023-06-15 2023-09-12 天津大学 一种有机场效应晶体管生物传感器及其制备方法和应用
CN116735881B (zh) * 2023-06-15 2024-01-23 天津大学 一种有机场效应晶体管生物传感器及其制备方法和应用

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