Classifications

• • 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
  • G01N33/551—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being inorganic
  • G01N33/552—Glass or silica
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
  • C12Q1/001—Enzyme electrodes
  • C12Q1/005—Enzyme electrodes involving specific analytes or enzymes
• • 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
  • 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
  • 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
  • G01N33/551—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being inorganic
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
  • G01N2333/90—Enzymes; Proenzymes
  • G01N2333/902—Oxidoreductases (1.)
  • G01N2333/904—Oxidoreductases (1.) acting on CHOH groups as donors, e.g. glucose oxidase, lactate dehydrogenase (1.1)
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
  • G01N2333/90—Enzymes; Proenzymes
  • G01N2333/902—Oxidoreductases (1.)
  • G01N2333/908—Oxidoreductases (1.) acting on hydrogen peroxide as acceptor (1.11)

Definitions

• the invention relates to a transistor-based sensor with a specially designed gate electrode for the highly sensitive detection of analytes.
• sensors based on silicon-based microelectronic components have received great attention, since the sensor and the evaluation electronics can be integrated monolithically on a chip and the experience of silicon CMOS technology can be used.
• the coordination between the sensitivity of the component and the sensor is always fraught with problems.
• the component on the electronic side of the sensor is the MOSFET. Due to its importance in microelectronics, this component has been undergoing continuous development for two decades. The critical component dimensions and the electronic properties have been and continue to be reduced and improved. By reducing the size, the transistors not only become faster, they also become more sensitive. At the beginning of the 1990s, the limit was below 1 micrometer. Today's components standard channel lengths of 180 nanometers. This measure will soon be reduced to 130 nanometers in production.
• FD-SOI fully depleated silicon-on-insulator
• DG double gate transistor
• the current-carrying layer which is just a few nanometers thick, is located on a buried oxide layer; in the case of a DG-MOSFET, the current-carrying layer is controlled from both sides by a control electrode.
• the space requirement per component advantageously decreases, which means more throughput and thus more profit for industrial applications with the same effort.
• the small dimensions mean higher sensitivity, ie with smaller inputs output signals, the same output signals can be achieved. This property is generally of great importance for use in sensor technology.
• sensors are currently divided into the following groups. Enzymatic biosensors (e.g. glucose, urea), affinity biosensors (e.g. immunosensors, DNA sensors), whole-cell biosensors (microbes, tissues, nerve cells).
• affinity biosensors e.g. immunosensors, DNA sensors
• whole-cell biosensors microbes, tissues, nerve cells.
• the following structures are usually used for signal conversion: impedance structures, acoustic wave structures, calorimetric sensors, electrochemical cells, optical sensors and semiconductor-based sensors.
• a receptor for the analyte is located locally on a very small area of the detection electrode.
• the local immobilization of the receptor on such small areas is, however, disadvantageously only possible with a great deal of work and expense.
• the object of the invention is therefore to provide a sensor which does not have the deficiencies shown in the prior art.
• the compa given to CMOS standard processes and at the same time the detection of at least one analyte by means of conversion or binding to a receptor.
• the solution is that a gate electrode is arranged between a detection electrode made of an electrically insulating material and a gate oxide of a transistor designed as a dielectric.
• the gate electrode has a large contact area A sens for the detection electrode and a small contact area Ag ate to the gate oxide of the adjacent sub-micrometer or nanotransistor.
• the receptor for binding or converting the analyte is immobilized on the surface of the detection electrode.
• Analytes in particular mean biomolecules such as nucleic acids (RNA, DNA), antigens and substrates of immobilized enzymes.
• receptors includes all molecules that can bind or convert such an analyte, whereby the analyte is detected.
• the large area of the detection electrode ensures that the receptor can be immobilized on its surface in a technically simple manner.
• the sensor according to the invention always comprises a series connection of two capacitors through the use of insulating materials.
• the first capacitor is arranged between the detection electrode and the gate electrode material
• the second capacitor is arranged between the gate electrode material and the silicon substrate.
• the capacitance of the gate electrode as the control electrode of the transistor is correspondingly smaller due to the significantly smaller contact area A gate of the gate electrode with the transistor, provided that the thicknesses of the insulation layers d sens and d gte do not differ or differ only slightly.
• the capacitance of the gate electrode C gate can also be approximated using the above formula.
• the gate capacitance is significantly smaller than that of the detection electrode in the dimensions of the submicron or nanotransistor used. Because the relationship between the capacitance and the voltage across a capacitor
• the use of a sensor with the above-mentioned dimensions for the gate electrode means that even a few molecules of an analyte can be detected on the surface of the detection electrode, provided that a change in the charges on the detection electrode by the receptor, which binds the analyte or with this reacts, takes place.
• the analyte is first brought into contact with the brought on immobilized receptor. This leads to a change in the electrical charge on the surface of the detection electrode.
• the charge is transferred to the transistor via the series connection of the two capacitors, the charge density being increased in the direction of the transistor by the dimensions of the gate electrode at the contact areas to the detection electrode A sens and to the gate oxide A gate (see relationship 3).
• the concentration of the analyte to be detected is determined by measuring the change in current.
• the ratio of areas Ag a _ is preferably te: A se ns 1:10 to 1: 500,000.
• the detection electrode consists of an insulating material.
• the detection electrode can consist of Si0 2 , for example. Si0 2 is a good insulator.
• the material can also be applied in very thin layers. Smallest changes in charge on the surface of the detection electrode due to the binding of an analyte to an immobilized receptor molecule can thus with high sensitivity via the first capacitor in the direction of the transistor are transmitted.
• biomolecules such. B. nucleic acids, antibodies and enzymes as receptors via methods which form prior art within silane chemistry, can be immobilized well on Si0 2 .
• Ta 2 0 5 , Al 2 0 3 or Si 3 N 4 are also particularly suitable. These materials are also good insulators. They are also particularly suitable as pH-sensitive materials for the detection of substrates as analytes which are reacted in the course of a reaction with an immobilized enzyme, for example with dehydrogenases. This leads to a demonstrable local change in the pH value at the detection electrode, whereby the analyte is detected.
• highly conductive polysilicon is used as the gate electrode material. This advantageously has the effect that the gate electrode material is capacitively coupled to the detection electrode. Good signal transmission from the detection electrode to the gate electrode is ensured.
• the material of the gate electrode is not limited to polysilicon. Rather, all materials with good conductivity can be used for the gate electrode.
• the gate electrode and the detection electrode can be connected to one another via one or more layers.
• a silicide layer can be arranged as the surface of the gate electrode.
• the silicide layer can e.g. B. generated by sputtering tungsten onto the polysilicon and subsequent annealing.
• a layer of titanium silicide can also be arranged as the surface of the gate electrode after sputtering titanium.
• the suicides mentioned are very good ladders. They prevent ion flow to the transistor and increase the durability of the transistor.
• a layer sequence of polysilicon, tungsten silicide and SiO 2 is present to form a first capacitor.
• the layer of tungsten silicide, which forms the surface of the gate electrode, is arranged on the polysilicon.
• Polysilicon and tungsten silicide together form the gate electrode.
• Such a layer sequence with Si0 2 as an insulating material for the detection electrode leads to the capacitive connection of the gate electrode to the detection electrode.
• the gate oxide of a sensor according to the invention consists of a dielectric in accordance with the specifications of the nanotransistor.
• Figure 1 shows the cross section through a sensor according to the invention based on a field effect transistor. The dimensions in Fig. 1 are not shown to scale.
• drain contact area 2 On a silicon substrate 1 there is a drain contact area 2, a source contact area 8, and a gate oxide 4, consisting of a dielectric such as. B. Si0 2 , with a certain area.
• Substrate 1, drain contact region 2, source contact region 8 and gate oxide 4 consist of materials as are known from the prior art for producing sub-micrometer and nanotransistors.
• a specially designed gate electrode according to the invention comprising an area 6 with a contact area Ag ate for the gate oxide 4 and with an area 5 with a contact area A aens for the detection electrode 7, is thus arranged between the gate oxide 4 and the detection electrode 7.
• the contact area Ag ate is smaller than the contact area A sens - the channel below
• the gate oxide 4 for example, has a length of only 0.01 to 1 micrometer. This results in very small capacitor areas between the gate electrode material and the silicon substrate.
• the contact area A gene to the detection electrode 7 can for example have a length of 1 to 1000 micrometers.
• the contact area A gate to the gate oxide 4 can thus be, for example, 10 "3 square micrometers.
• the contact area A sen s to the detection electrode 7 can be, for example, 500 square micrometers. This increases the charge density by a factor of 500,000. Of course, the areas are not open the specified dimensions are limited.
• the cross-section of the gate electrode is T-shaped in the present case. However, you are not limited to a T shape in the selection of the shape. Rather, any shape can be selected for the gate electrode 5, 6, which results in a larger contact area Age n s with the detection electrode 7 compared to the contact area Ag ate with the gate oxide 4.
• the material of the gate electrode 5, 6 consists of polysilicon.
• a further layer of tungsten silicide, not shown in FIG. 1, is located on the gate electrode in the area 5 to the detection electrode 7 as the surface of the gate electrode.
• the detection electrode 7 made of silicon dioxide is arranged thereon.
• Tungsten silicide is a very good conductor and advantageously prevents ion flow from the detection electrode 7 to the gate oxide 4. The durability of the transistor is through increased. This function can also be performed by a layer of titanium silicide.
• drain contact area 2, source contact area 8 and gate electrode and detection electrode 7 is in an insulator 3, z. B. embedded in a silicon dioxide layer. This serves to protect the sensor. Si 3 N 4 can also be used instead.
• a nucleic acid is preferably covalently or electrostatically immobilized on the detection electrode 7. If the analyte (here: a nucleic acid complementary to the immobilized nucleic acid: RNA, DNA) binds, then the charges on the surface of the detection electrode change via the additionally bound negative charges of the phosphate groups of the analyte nucleic acid. These charges are transferred to the transistor via the series connection of the two capacitors. The current change at the transistor generated in this way is measured and can be converted quantitatively into the concentration of the bound analyte, as well as used qualitatively for simple detection of the analyte. Duplication of the DNA by PCR is no longer necessary in the case of a nanotransistor. According to this principle, an anti-body-antigen reaction can also be detected or measured.
• An enzyme e.g. B. a dehydrogenase or a glucose oxidase in combination with a horseradish peroxidase, e.g. B at Ta 2 0 5 as a detection electrode 7, immobilized.
• the substrate is converted by the enzymatic reaction, the surface of the detection electrode 7 being protonated or deprotonated locally as a function of the pH.
• the change in charge is converted into a change in current by the series connection of the capacitors and measured.
• the conversions of all those enzymes in which there is a local change in the pH at the surface of the detection electrode 7 due to the reaction mechanisms can be detected or measured.

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• Health & Medical Sciences (AREA)
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• Biochemistry (AREA)
• General Health & Medical Sciences (AREA)
• Biotechnology (AREA)
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• Microbiology (AREA)
• General Physics & Mathematics (AREA)
• Medicinal Chemistry (AREA)
• Food Science & Technology (AREA)
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• Proteomics, Peptides & Aminoacids (AREA)
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• Investigating Or Analyzing Materials By The Use Of Electric Means (AREA)
• Apparatus Associated With Microorganisms And Enzymes (AREA)
• Insulated Gate Type Field-Effect Transistor (AREA)

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• 2001
  • 2001-12-21 DE DE10163557A patent/DE10163557B4/de not_active Expired - Fee Related
• 2002
  • 2002-12-14 EP EP02795005A patent/EP1456636A1/de not_active Withdrawn
  • 2002-12-14 US US10/499,751 patent/US7632670B2/en not_active Expired - Fee Related
  • 2002-12-14 JP JP2003556796A patent/JP4768226B2/ja not_active Expired - Fee Related
  • 2002-12-14 WO PCT/DE2002/004594 patent/WO2003056322A1/de active Application Filing

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