WO2003079016A1 - Biocapteur pour la detection de biopolymeres macromoleculaires et son procede de production - Google Patents

Biocapteur pour la detection de biopolymeres macromoleculaires et son procede de production Download PDF

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Publication number
WO2003079016A1
WO2003079016A1 PCT/DE2003/000892 DE0300892W WO03079016A1 WO 2003079016 A1 WO2003079016 A1 WO 2003079016A1 DE 0300892 W DE0300892 W DE 0300892W WO 03079016 A1 WO03079016 A1 WO 03079016A1
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Prior art keywords
biosensor
biosensor according
semiconducting
detection
evaluation circuit
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PCT/DE2003/000892
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German (de)
English (en)
Inventor
Thomas Haneder
Hagen Klauk
Günter Schmid
Roland Thewes
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Infineon Technologies Ag
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Publication of WO2003079016A1 publication Critical patent/WO2003079016A1/fr

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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
    • 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
    • H—ELECTRICITY
    • H10—SEMICONDUCTOR DEVICES; ELECTRIC SOLID-STATE DEVICES NOT OTHERWISE PROVIDED FOR
    • H10K—ORGANIC ELECTRIC SOLID-STATE DEVICES
    • H10K10/00—Organic devices specially adapted for rectifying, amplifying, oscillating or switching; Organic capacitors or resistors having potential barriers
    • H10K10/40—Organic transistors
    • H10K10/46—Field-effect transistors, e.g. organic thin-film transistors [OTFT]
    • H10K10/462—Insulated gate field-effect transistors [IGFETs]
    • H10K10/466—Lateral bottom-gate IGFETs comprising only a single gate
    • H—ELECTRICITY
    • H10—SEMICONDUCTOR DEVICES; ELECTRIC SOLID-STATE DEVICES NOT OTHERWISE PROVIDED FOR
    • H10K—ORGANIC ELECTRIC SOLID-STATE DEVICES
    • H10K19/00—Integrated devices, or assemblies of multiple devices, comprising at least one organic element specially adapted for rectifying, amplifying, oscillating or switching, covered by group H10K10/00

Definitions

  • the invention relates to a biosensor for detecting macromolecular biopolymers and a method for producing a biosensor for detecting 0 macromolecular biopolymers.
  • Optical methods are mostly used today for examining, for example, the expression pattern of a cell using nucleic acids or generally for detecting 5 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, a few 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
  • Fluorescent dye contains labeled nucleic acids, pumped over this surface.
  • nucleic acids with capture molecules complementary to them can form double-stranded hybrid molecules on the surface of the carrier substrate. After excitation of the fluorescence marking by means of a laser and subsequent measurement of the optical fluorescence signal, it is determined on the basis of the detected, emitted light beams whether or not a DNA strand to be detected with the correspondingly predetermined sequence is contained in the analyte.
  • Proteins can also be detected using optical detection methods based on the immobilization of a capture molecule on a surface of any substrate e.g. made of glass, silicon dioxide, other oxides, metal or plastics, e.g. Hydrocarbons such as polyethylene, polypropylene or polystyrene, polyesters such as polyethylene naphthalate or terephthalate, polycarbonates, polyurethanes, polyacrylates, epoxy resins, biodegradable polylactates, plastics which are stable at high temperatures, such as polyimides, polybenzoxazoles or imidazoles, are based. Any composite materials, such as glass fiber reinforced epoxy resins or coated metal surfaces, are also suitable.
  • 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]).
  • the sensor 200 has two electrodes 201, 202 made of gold, which are embedded in an insulator layer 203 made of insulator material. Electrode connections 204, 205 are connected to the electrodes 201, 202, to which the electrical potential applied to the electrode 201, 202 can be supplied. The electrodes 201, 202 are arranged as planar electrodes. DNA probe molecules 206 are immobilized on each electrode 201, 202 (cf. FIG. 2a). The immobilization takes place with the help of the so-called gold-thiol bond. The analyte 207 to be examined is applied to the electrodes 201, 202.
  • the analyte can, for example be an electrolytic solution with different DNA molecules.
  • the coupling of the DNA molecules is not limited to the gold-thiol bond, but in principle any strong metal-ligand coupling can be used (Ni-amine ligands, Mo-sulfur or Mo-phosphorus, etc.)
  • the analyte 207 contains DNA strands 208 with a sequence that is complementary to the sequence of the DNA probe molecules 206, these DNA strands 208 hybridize with the DNA probe molecules 206 (cf. FIG. 2b).
  • Hybridization of a DNA probe molecule 206 and a DNA strand 208 only takes place if the sequences of the respective DNA probe molecule 206 and the corresponding DNA strand 208 are complementary to one another. If this is not the case, no hybridization takes place.
  • a DNA probe molecule of a given sequence is only able to bind a specific one, namely the DNA strand with a complementary sequence, i.e. to hybridize with it.
  • FIGS. 4 a to 4 c show a biosensor 400 with a first electrode 401 and a second electrode 402, which are applied to a substrate 403 as an insulator layer.
  • a holding area designed as a holding layer 404, is applied to the first electrode 401 made of gold.
  • the holding area serves to immobilize DNA probe molecules 405 on the first electrode 401.
  • the sensor 400 is brought into contact with a solution 406 to be examined such that in the solution to be examined 406 any DNA strands contained can hybridize with the complementary sequence to the sequence of the DNA probe molecules 405.
  • 4b shows the case in which the DNA strands 407 to be detected are contained in the solution 406 to be examined and are hybridized to the DNA probe molecules 405.
  • the DNA strands 407 in the solution to be examined are marked with an enzyme 408, with which it is possible to cleave the molecules described below into partial molecules.
  • DNA probe molecules 405 Usually, a significantly larger number of DNA probe molecules 405 is provided than DNA samples to be determined. Strands 407 are contained in the solution 406 to be examined.
  • the biosensor 400 is rinsed, as a result of which the non-hybridized DNA strands are removed and the biosensor 400 from it investigating solution 406 is cleaned.
  • An electrically uncharged substance is added to this rinsing solution used for rinsing or to another solution 412 which is supplied in a further phase and contains molecules 409 which, by means of the enzyme on hybridized DNA strands 407, result in a first sub-molecule of a negative first electrical charge and in a second sub-molecule of a positive second electrical charge can be split.
  • the negatively charged partial molecules are drawn to the positively charged anode, as indicated by arrow 411 in FIG. 4c.
  • the negatively charged first partial molecules 410 are oxidized on the first electrode 401, which has a positive electrical potential as the anode, and are oxidized as the oxidized partial molecules 413 on the negatively charged cathode, i.e. pulled the second electrode 402 where they are reduced again.
  • the reduced sub-molecules 414 in turn migrate to the first electrode 401, ie to the anode. In this way, an electrical circuit current is generated which is approximately proportional to the number of charge carriers generated by the enzymes 408 in each case.
  • the biosensors used for the above processes are based on substrates / chips which are produced from inorganic semiconducting materials such as silicon.
  • the semiconducting material can either be used as a pure carrier material for the sensors, or integrated circuits are used in the semiconductor manufacturing process in addition to detection units such as electrodes, e.g. manufactured using CMOS technology.
  • the latter type of sensor can also be called active sensors due to the integrated circuits.
  • passive sensors these sensors have the advantage of being able to amplify, process and process even weak sensor signals directly on-chip. With this e.g. enable active sensors with a significantly smaller sensor area and / or significantly higher sensitivity to passive variants to be manufactured.
  • CMOS processes are required to manufacture such active semiconductor sensors. This makes them seem unsuitable for certain biotechnological and biochemical applications, because these applications usually require a sensor that only once is used and should therefore be inexpensive.
  • One reason for the one-time use of sensors is that one wants to exclude possible chemical / biological cross-contamination of the used areas from trial to trial and the resulting wrong results.
  • 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 elimination e.g. a CMOS process reduces the manufacturing costs of such biosensors compared to active semiconductor chips.
  • CMOS process reduces the manufacturing costs of such biosensors compared to active semiconductor chips.
  • sensors cannot fundamentally achieve the performance of sensors with active chips.
  • the requirements for the external devices required for operation and reading are much greater, and the susceptibility to interference due to irradiated electromagnetic radiation e.g. due to nearby power supplies of commercially available electronic devices is larger.
  • a microfluidic chamber that is open to the surface and into which the analyte can be pumped is attached above the circuit board. Electrical connections go from the individual electrodes to the edge of the printed circuit board, where contacts are located.
  • the connection to a separate electronic reading device can be established [cf. 8,9].
  • the reading device makes a difference in the reading current between them Can detect electrodes on which a reaction has taken place and those on whose surface no reaction has taken place.
  • the principle of the eSENSOR is due to the external arrangement of the measuring electronics, however, firstly much less sensitive and secondly less robust to electromagnetic interference than a sensor in which signal processing takes place on the sensor.
  • the electrode areas must be relatively large in order to obtain a measurable signal that can be derived from the sensor.
  • [24] discloses a method for producing a biosensor with a planarized surface, which prevents the risk of tearing of biological or biochemical membranes.
  • [26] discloses a chloride-free process for the production of alkylsilanes, suitable for microelectronic applications.
  • [27] discloses a measuring circuit with a biosensor using an ion-sensitive field effect transistor.
  • Field effect transistor which ion sensor is designed to determine an ion concentration of a sample liquid to be examined.
  • [30] discloses a method of manufacturing a CMOS integrated circuit with an ISFET and with an evaluation MISFET in polysilicon technology.
  • the problem underlying the invention is to provide an alternative sensor for the detection of macromolecular biopolymers.
  • Biopolymer is a sensor with at least one unit for immobilizing macromolecular biopolymers, with at least one detection unit for detecting a detection signal with which the existence of macromolecular biopolymers is indicated, and with one with
  • Detection unit coupled evaluation circuit for the signal, the evaluation circuit at least one component having a semiconducting layer with an organic material.
  • the present method is based on the knowledge that the use of electrical components with at least one semiconducting layer with an organic material, for example a layer with an organic semiconducting material, has a number of advantages in an evaluation circuit.
  • Such sensors can be manufactured with considerably less process engineering effort than sensors based on inorganic semiconductors. The number of process steps required can be reduced from approximately 300 for silicon-based sensors to approximately 50 for the sensors present.
  • the use of an evaluation circuit located on the sensor offers the advantage of “on-chip ⁇ V signal processing, which offers high sensitivity when measuring by active electrical components in the immediate vicinity of the detection units. Compared to sensors based on an inorganic
  • the semiconducting layer of the component can be a layer which has an organic inert polymer material as an (electrically inert) matrix material, in which inorganic semiconducting particles are embedded. With this layer, the semiconductor properties are consequently fulfilled by inorganic semiconducting materials.
  • inorganic semiconducting material there any known inorganic semiconducting material can be used. However, for reasons of cost, among others, common semiconductor materials such as silicon, silicon carbide, germanium, gallium arsenide, gallium nitride, indium phosphide, cadmium selenide or mixtures thereof are preferably used in the present invention.
  • a particularly preferred material is polycrystalline silicon, which is generated, among other things, as waste in the production of silicon single crystals during zone melting and which only has to be comminuted here for use as an inorganic semiconductor material.
  • the semiconductor material can be doped or undoped.
  • the particle size of the inorganic semiconducting material used here is generally between 100 ⁇ m and 1 nm, preferably between 50 ⁇ m and 0.1 ⁇ m or 0.05 ⁇ m.
  • n- and p-conductive nanoparticles, as described in [10], which are embedded in an organic matrix, are also used.
  • any of the polymer materials which are mentioned below as polymer materials for forming the gate dielectric in transistors or as a carrier material of the biosensor can be used as the electrically inert organic matrix material.
  • the layer in which the inorganic semiconducting particles are embedded in an organic matrix material can also contain a supporting semiconducting organic material (as matrix material).
  • This material can be the above-mentioned organic semiconducting polymers such as polythiophene, polyaniline, poly-p-phenylene and the like. , his.
  • monomeric or low molecular weight, Supporting (semiconducting) organic additives such as pentazene or oligothiophenes (for example with 1 to 10 thiophene units, preferably 6 thiophene units) can be contained as such organic material.
  • the proportion of such supporting polymers and additives in the semiconducting layer is generally about 0.5 to 25% by volume, preferably at most 10% by volume.
  • the semiconducting layer of the component of the evaluation circuit can have an organic semiconducting material, i.e. in this case the
  • Matrix containing semiconductor materials can be included.
  • the component of the evaluation circuit with the organic semiconducting layer can be a passive component such as a resistor or a capacitor as well as an active component such as a diode or a transistor.
  • the evaluation circuit can also have a plurality of passive and / or active components with at least one organic layer.
  • a diode can, for example, have only one layer with an n- or p-semiconducting organic material or both a layer of an n-type and a layer of a p-type organic semiconductor material (cf. [11, 12]).
  • suitable p-semiconducting organic materials are the polymer polyvinylcarbazole (cf.
  • polythiophene especially the regional regulators, such as RR-poly-3-hexyl-thiophene or RR-poly-3-octyl-thiophene, phthalocyanines such as copper phthalocyanine or p-semiconductors based on condensed aromatic ring systems such as pentazene, anthracene or tetracene can be used.
  • Suitable n-semiconducting organic materials are based, for example, on electron-poor aromatic compounds.
  • amido derivatives of naphthalene tetracarboxylic acid dianhydride or fluorinated derivatives of phthalocyanine or thiophene such as, for example, bis (Nl, 1-dihydropentadecafluorooctyl) naphthalene bisimide or bis (Nl, 1-dihydroheptafluoroproyl) naphthalene 14-bisadferlafine [13].
  • 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 [11]. As described in [11], these (passive) components can be manufactured using inkjet techniques. In general, however, these can also be produced using standard lithography and metallization processes.
  • the at least one component of the evaluation circuit is a transistor.
  • a transistor is preferred in which the layer with the organic semiconducting material Area of the transistor forms.
  • a transistor is preferred for the evaluation circuit, which is an organic thin film transistor.
  • the body area is understood to mean the area in which the channel of the transistor can form.
  • Such transistors are principally e.g. known from [15] to [17]. On the one hand, they can be transistors in which there is only one layer with semiconducting organic material, such as e.g. described in [15] and [16].
  • a metallic gate electrode e.g. made of nickel
  • a suitable substrate see Fig. 1
  • the dielectric can consist of an inorganic insulator material such as silicon dioxide or silicon nitride.
  • Form plastic material such as polyvinylphenol, polyvinylidene fluoride etc. or polyvinyl alcohol.
  • the contacts (electrodes) for source and drain can be made of palladium or platinum, for example. Between source and drain is located (as a single organic electrically active layer), a layer of the organic semiconductor, pentacene, which consequently forms the body- 0 / channel region of the transistor. If necessary, a passivation layer made of an electrically insulating inorganic material such as
  • Silicon dioxide or an insulating polymer material such as polyvinyl alcohol, polyvinylphenol, polyvinylidene fluoride, etc. may be formed.
  • the transistors can also be formed entirely from organic materials, preferably organic polymer and oligomer materials.
  • gate and drain electrode made of an electrically conductive polymer material such as poly (3,4-ethylenedioxythiophene) doped with polystyrene sulfonic acid (PEDOT / PSS).
  • the body area can in turn, e.g. be made from pentazene or an oligomer material such as poly (9, 9-dioctylfluorene-cobithiophene) (F8T2).
  • the layer of the gate dielectric of both these transistors and that of the transistors described above, in which organic and inorganic materials are combined, can consist of a dielectric organic polymer material.
  • polymer materials that can be used here are common dielectric synthetic plastics such as epoxy resins, polyalkylenes such as polyethylene or
  • Polypropylene resins polyvinyl alcohols, polystyrenes, polyurethanes, polyimides, polybenzoxazoles, polythiazoles, polyethers, polyether ketones, polyacrylates, polyterephthalates, polyethylene naphthalate, polycarbonates of all types and other known plastics of this type, as described, for example, in
  • the organic polymers used can preferably be dryable and curable materials, preferably IR- and / or UV-curable polymers such as polystyrenes, epoxy resins, polyalkylenes, polyimides, polybenzoxazoles, polyacrylates.
  • IR- and / or UV-curable polymers such as polystyrenes, epoxy resins, polyalkylenes, polyimides, polybenzoxazoles, polyacrylates.
  • transistors which consist partly or completely of organic materials, offers the The advantage that they and therefore also the corresponding circuits can be produced by printing techniques such as inkjet printing, which considerably simplifies the manufacturing process and also reduces the costs.
  • the use of such transistors offers the possibility of high operating voltages of, for example, conventional silicon transistors. > 10 V.
  • This is advantageous in the case of the biosensor disclosed here in that it enables electrophoretic processes to be used in the detection of the macromolecular biopolymers, the voltages required for this being able to be handled easily by the available components, since these can also be used relatively high voltages. This is e.g. no longer the case with standard transistors in modern CMOS processes, the operating voltages for the standard devices are below 2 V.
  • any organic material can be used as an organic semiconducting material in the biosensor described here can be used that shows electrical properties and behavior of a semiconductor material.
  • the semiconducting organic material is selected from the group consisting of pentazene, anthracene, tetrazene, oligothiophene, polythiophene, polyaniline, poly-p-phenylene, poly-p-phenylvinylene, polypyrrole, phthalocyanine, porphyrin and derivatives thereof.
  • the semiconducting material can be a “molecular system” such as pentazene, anthracene, tetracene, phthalocyanine, porphyrin or oligothiophene or a “polymer system” (one or more polymer compounds) such as polythiophene, polyaniline, poly-p-phenylene , Poly-p-phenylvinylene, polypyrrole.
  • a “molecular system” such as pentazene, anthracene, tetracene, phthalocyanine, porphyrin or oligothiophene
  • a “polymer system” one or more polymer compounds
  • a molecular system in monomer form are the fullerenes such as C 60 -, C 7 o ⁇ , C 7 6- (Buckminster) fullerenes.
  • suitable derivatives of one of the above materials are the aforementioned poly (9, 9-dioctylfluorene-co-bi hiophene) or poly (3-alkyl tiophene) such as poly (3-hexylthiophene) or poly (3-octylthiophene).
  • An example of oligothiophenes are compounds with 1 to 10 thiophene units, preferably 6 thiophene units.
  • semiconducting phthalocyanines or porphyrins are the corresponding (organometallic) complexes of copper such as copper phthalocyanine or
  • Perfluorokupferphthalocyanin For the purposes of the invention, it is possible to use the semiconducting organic materials on their own or, if desired, as mixtures of at least two such materials.
  • the entire evaluation circuit consists of transistors with at least one layer made of an organic semiconducting material.
  • a circuit can contain, for example, approximately 10 or a few 10 transistors if, as described in [19], only simple switching matrices are to be built.
  • the evaluation circuit can contain between approximately 50 and a few 100 transistors. Examples of such evaluation circuits are disclosed in [20].
  • detection is understood to mean both the qualitative and quantitative detection of macromolecular biopolymers in an analyte (to be examined). This means that the term "capture” also includes determining the absence of macromolecular biopolymers in the analyte.
  • a biopolymer to be detected can be a molecule that is captured by means of a capture molecule that is located on a unit for immobilizing macromolecular biopolymers.
  • a molecule to be detected can also be applied from a sample / analyte to an immobilization unit and then detected with a molecule which has (specific) binding affinity for the molecule to be detected using the biosensor disclosed here.
  • a “detection unit for detecting a detection signal” is understood here to mean a unit that is able to detect a detection signal with which the existence of macromolecular biopolymers is indicated. Such a signal is generated indirectly or directly by the formation of a complex of those to be detected macromolecular biopolymer and a suitable one Catcher molecule evoked.
  • An example of a directly produced detection signal is a change in capacitance, which is caused between two electrodes by a complex formation of the capture molecule and the molecule to be detected (e.g. formation of a double-stranded nucleic acid molecule or an antigen-antibody complex) (see Fig. 2).
  • An example of a detection signal that is indirectly caused by complex formation is fluorescence radiation that is emitted by a label located on one of the two binding partners, or an electrical circuit current that is initiated by a redox-active label (see FIG. 4 ).
  • any suitable unit can be used as the detection unit in the biosensor of the invention, which unit can preferably detect a detection signal physically or chemically and can forward it to an evaluation circuit for further evaluation.
  • detection units examples include electrodes, e.g. can be used for impedance measurements or measurements of an electrical circuit current mentioned above.
  • Other examples are photodiodes or charge coupled devices (CCDs, CCD cameras) which can be used to detect emitted radiation such as fluorescence or chemiluminescence radiation.
  • an electrical signal is used to detect the biopolymers, which is the result of the first stage of the detection unit, which converts an optical signal such as a fluorescence or chemiluminescence signal into an electrical signal.
  • This electrical signal (in) the detection unit is preferably an electrical current such as a photocurrent or a voltage such as a photo voltage at the photodiode. The detection of this optical signal and the subsequent evaluation by means of the evaluation circuit can take place, for example, by integrating the electrical signal over several minutes.
  • the photodiode used as the detection unit has a semiconducting organic material (as the “active” material).
  • This material can be an organic polymer compound such as poly-p-phenylene vinylene (PVP) and another mentioned above in connection with the semiconducting body materials Be a polymer compound or be a molecule / "molecular system” such as PV-oligomers, fluorene derivatives and the like (see above).
  • PVP poly-p-phenylene vinylene
  • the photodiode also has a filter layer which serves to reduce or to keep the excitation radiation off. It is also possible to form the filter layer over the entire surface of the sensor and not only over the individual photodiodes. It is also possible to use the filter layer to completely cover the area of the sensor in which photodiodes are implemented.
  • organic materials such as organic dyes are preferably used for this filter layer.
  • Example suitable for forming a filter layer Materials are nitro and nitroso, azo, di and triaryl methane, xanthene, acridine, phenoxazine, phenothiazine, phenazine or indigo dyes.
  • the filter effect depends on the excitation radiation used and can be adapted to the selected system. In general, the excitation radiation is in the range from 250 nm to 900 ⁇ m.
  • the filter layer is therefore designed in such a way that it is impermeable to the respectively selected area.
  • Light / electromagnetic radiation with a wavelength of less than 500 nm or 550 nm is preferably transmitted through the
  • Filter layer held / shielded i.e. the filter layer is preferably designed as a "blue filter”.
  • unit for immobilization is understood to mean an arrangement which has a surface on which first molecules, which can either be capture molecules or molecules to be detected, can be immobilized, i.e. a surface to which capture molecules can bind through physical or chemical interactions. These interactions include hydrophobic, ionic or electrostatic interactions and covalent and complexing bonds.
  • suitable surface materials that can be used for at least one immobilization unit are metals such as gold, plastics such as polyethylene or polypropylene or inorganic substances such as silicon dioxide. If the surface of the immobilization unit is not in itself suitable for immobilizing the first molecules, it can be modified for the immobilization by suitable functionalization. Such functionalization can e.g. through the formation and derivatization of a monolayer as in [3] on page 25, line 2 to page 31, line 5 or
  • the surface the unit for immobilization can still be activated by processes such as plasma etching, vapor deposition of suitable materials (for example by chemical or physical deposition, (CVD; PVD) [cf. 3, page 19]. If conductive polymer materials are used for the units for immobilization, immobilization can be carried out also as described in [22].
  • immobilization agent is a plastic material that is used for the production of microtiter plates (e.g. polypropylene).
  • linker chemistry any suitable linker chemistry (cf. e.g. [21,
  • the first molecules can be both capture molecules and macromolecular biopolymers to be detected.
  • the at least one immobilization unit is arranged on a detection unit.
  • the detection unit is at the same time as the at least one
  • This embodiment is particularly preferred when one or more electrodes, for example for Impedance measurement or one or more field effect transistors can be used as a detection unit.
  • the electrode serving as a detection and immobilization unit can consist of an electrode array.
  • the electrode serving as the detection unit can be designed as an interdigital structure. This embodiment is particularly advantageous when using the redox and impedance methods for reading out.
  • an electrode of the biosensor can be produced from any material that is biocompatible in the sense that it is inert to biological media and that also conducts the electrical current and is eventually compatible with a substrate material of the biosensor.
  • the electrode can preferably be gold, palladium, platinum, titanium, TiN, silver or another conductive metal such as Cu or
  • Nickel however, also have an electrically conductive organic material.
  • organic materials that can be used for the formation of electrodes are organic doped semiconductors such as polyaniline or doped with champhersulfonic acid
  • Polystyrene sulfonic acid doped polythiophenes such as PEDOT / PSS, which can also be used as a conductive material for the source, drain and gate electrodes of the transistors used here (see above).
  • Evaluation circuit can of course also be done using the electrically conductive material just listed, by forming a connection between the detection unit and the evaluation circuit using these materials.
  • the electrodes can be designed so that they react sensitively to the pH of the solution.
  • electrodes made of PEDOT / PSS can be used for this purpose.
  • Various electrode arrangements can be used as the detection unit of the biosensor, which may have at least one immobilization unit or are designed as such. Examples of usable here
  • Electrode arrangements are electrically conductive grids or networks, electrically conductive porous materials, plate electrode arrangement or an interdigital electrode arrangement, e.g. is known from [5].
  • an interdigital electrode arrangement several or all “fingers” of the arrangement can be provided with units for immobilization or can even be designed as these units.
  • the electrodes can be configured as cylindrical elements, which are each arranged concentrically around one another and are electrically isolated from one another, for example by means of a suitable dielectric, so that an electric field between the electrodes Forms electrodes.
  • the biosensor has a plurality of detection units with a coupled one
  • Evaluation circuit the detection units preferably in a regular arrangement, an array, are arranged. This configuration is preferably used for multiple and / or parallel determinations.
  • each individual detection unit can be controlled individually to detect the detection signal. This will falsify the measurement result e.g. avoided by incoming interference signals from neighboring sensor fields.
  • the design of the biosensor disclosed here does not only offer a simplified structure due to the omission of a detection device, such as a confocal microscope, which is arranged outside the reaction area. Rather, the structure described here enables continuous measurement for each registration unit. This is particularly advantageous if e.g. Processes that affect reaction dynamics or kinetics should be investigated.
  • the biosensor also has a reference electrode (control electrode).
  • a reference electrode control electrode
  • This configuration is particularly necessary when carrying out detection methods in which absolute electrical potentials are to be applied or measured on an electrode serving as a detection unit.
  • the reference electrode whose potential is measured without current, supplies the reference potential here. In pure electrochemical processes (e.g. redox recycling) such an electrode is absolutely necessary for measurement.
  • This reference electrode is preferably made of AgCl, for example in the form of a chlorinated silver wire or a chlorinated one Silver electrode. On the one hand, this can be applied directly to the substrate material or integrated into it. On the other hand, this reference electrode can also be mounted in a housing of the sensor or in a separate chamber, which separates the detection unit from the evaluation circuit, for example.
  • the possibility of applying such a silver electrode on the substrate material of the biosensor represents a significant advantage over the conventional sensors based on semiconducting inorganic materials. For example, silver or gold is only very difficultly compatible with the manufacturing processes of active CMOS sensors (chips), however without further ado with the materials and manufacturing processes used here for components with semiconducting organic materials as well as the methods for forming the detection units.
  • the detection unit is arranged in a microfluidic chamber. This not only separates the detection unit from the evaluation circuit, but also allows special biochemical detection reactions to be carried out. Especially in long-term tests or tests at higher temperatures (eg> 90 ° C), a separation of the evaluation circuit from polymer transistors and the detection units can prove to be beneficial.
  • the reference electrode described above can also be integrated into this chamber. In the case of the configuration in the form of an array comprising a plurality of detection units, compartments of any design can also be formed within the area of the “active” sensor surface, ie the detection units.
  • microfluidic unit can be used, for example, to pump the analyte over the surface of the detection unit during the hybridization process or subsequently to remove non-bound analyte molecules from the surfaces of the detection units using a rinsing or cleaning solution before the readout process takes place.
  • the at least one unit for immobilizing macromolecular biopolymers of the biosensor is preferably integrated in a substrate and / or applied to this substrate.
  • the at least one detection unit can be embedded in a substrate, preferably applied thereon and / or integrated in the substrate.
  • the evaluation circuit is likewise applied or integrated on the same substrate on which the detection and / or immobilization unit is also located.
  • any material on which the various units of the sensor can be permanently applied can be used here as substrate material (carrier material) for the biosensor.
  • suitable substrate materials are insulators such as paper, plastic films, ceramics, or glass, furthermore with an insulator or metal coated with plastic.
  • substrate materials made of 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 kinds.
  • biodegradable materials are also suitable. The surface properties of such a polymer or glass substrate can easily be changed, so that hydrophilic or hydrophobic surfaces are created. This is desirable for many biochemical sensors.
  • nucleic acids, oligonucleotides, proteins or complexes of nucleic acids and proteins as well as whole cells can be detected as macromolecular biopolymers with the present sensor.
  • Macromolecular biopolymers are understood here to mean, for example, (longer-chain) nucleic acids such as DNA molecules, RNA molecules, PNA molecules or cDNA molecules or shorter oligonucleotides with, for example, 10 to 50 bases, in particular 10 to 30 bases.
  • the nucleic acids can be double-stranded, but also have at least single-stranded regions or, for example by preceding thermal denaturation (strand separation) for their detection, can be present as single strands.
  • the sequence of the nucleic acids to be detected can be at least partially or completely predetermined, ie known.
  • Other macromolecular biopolymers are proteins or peptides. These can be built up from the 20 amino acids usually found in proteins, but can also contain naturally not occurring amino acids or be modified, for example, by sugar residues (oligosaccharides) or contain post-translational modifications.
  • 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 immobilization unit by covalent bonds.
  • DNA molecules nucleic acids or oligonucleotides
  • 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.
  • the senor at hand it is of course possible to use the sensor at hand to not only detect a single type of biopolymer in a single series of measurements. Rather, several macromolecular biopolymers can be recorded simultaneously or one after the other. For this purpose, several types of capture molecules can be placed on the immobilization unit, each of which has a (specific) binding affinity for a specific one to be detected
  • Has biopolymer are bound and / or several units can be used for immobilization, only one type of capture molecule being bound to each of these units.
  • the method for producing a biosensor for detecting macromolecular biopolymers has the steps of at least one unit for on or in a substrate Immobilization of macromolecular biopolymers is formed, at least one detection unit for detecting a detection signal, with which the existence of macromolecular biopolymers is indicated, is formed, and an evaluation circuit coupled to the detection unit is applied for the signal, the evaluation circuit comprising at least one component with a semiconducting layer with an organic material.
  • layers can be formed which consist of organic semiconducting material, as well as layers in which an inorganic semiconductor material is embedded in a matrix of polymer material.
  • the component of the detection circuit is preferably a transistor.
  • the layer with the semiconducting material preferably forms the body region of the transistor.
  • the method of the invention is advantageously designed so that it is carried out entirely by means of printing techniques similar to ink jet printing. This is the case, for example, if all the biosensor units (detection units, evaluation circuit, etc.) are based on organic materials. However, the processing of metals such as gold and nickel, for example by sputtering, vapor deposition or electrochemical deposition, can be carried out easily and simply and is also compatible with printing techniques. Overall, compared to sensors based on inorganic semiconductors, this leads to a significant reduction in the process steps and the manufacturing costs, while the performance features of the evaluation circuit and / or the biosensor disclosed here continue to be sufficient. It is also sufficient if the Metals are printed in the form of a hardenable suspension.
  • the gate structures (102) are produced by printing a colloidal palladium starter solution onto a polyethylene naphthalate substrate at the locations at which the gate structures are to be formed later. After this printing process, the printed palladium seeds are electrolessly reinforced with nickel to the desired layer thickness (approx. 10-50 nm). The gate dielectric (103) can then be printed on directly.
  • Source (104) and drain (105) contacts are formed using a palladium suspension (particle size 1 ⁇ m) in polystyrene.
  • the organic semiconductor (106) can then be formed over the entire surface. If the individual transistors are sufficiently far apart, this layer does not need to be structured (e.g. pentacene by evaporation).
  • Another gold electrode for immobilization of the nucleotides can then be deposited using a shadow mask.
  • FIGS. 2a and 2b show a sketch of two planar electrodes, by means of which a method is explained, which can be carried out with the biosensor of the invention for detecting the presence of DNA molecules in an electrolyte (FIG. 2a) or their non-existence (FIG. 2b);
  • FIGS. 3a and 3b show two embodiments of the biosensor disclosed here
  • FIGS. 4a to 4c sketches of a biosensor according to the prior art, on the basis of which individual conditions are explained in the context of the redox recycling process;
  • FIG. 5 shows a functional curve of a circulating current, as can be used in the context of a redox recycling process for the detection of macromolecular biopolymers
  • FIGS. 6a and 6b show a further embodiment of the biosensor of the invention.
  • FIG. 7 shows another embodiment of the biosensor of the invention
  • FIG 8 shows yet another embodiment of the biosensor of the invention
  • Figure 9 shows another embodiment of the biosensor of the invention
  • Figure 10 shows yet another embodiment of the biosensor of the invention.
  • Fig.l shows various configurations of a field effect transistor 100, which can be used as a component in the evaluation circuit of the invention.
  • a substrate 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 is located on the gate region 102
  • 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. Between the source / drain regions 104, 105 there is a layer 106 made of pentacene as a semiconducting organic material. Layer 106 forms the body region in which the channel of transistor 100 can form.
  • the field effect transistor 100 initially has a layer 106 of semiconducting organic material on the substrate 101.
  • This layer 106 which forms the body region of the transistor 100, has tetrazenes.
  • the transistor 100 also has a first and a second source / drain region 104, 105 made of platinum. Above the source / drain regions 104, 105 or the body region 106 there is a layer 103 of silicon dioxide as a dielectric, on which the gate region 102 made of nickel is applied.
  • the field effect transistors according to Fig.l with the layer with semiconducting organic material can be produced, for example, with the method described in [15].
  • the deposition of the source / drain regions 104 is performed in the embodiments shown in Fig.la, Fig.lc and Fig.lf, 105 before the 'deposition of the semiconducting layer 106, while, in the embodiments according to Fig.lb, Fig.ld and Fig.le the semiconducting layer 106 is applied in front of the source / drain regions 104, 105.
  • FIG. 3a shows as a first embodiment of the biosensor of the invention a biosensor 300.
  • transistors of the evaluation circuit are applied to a substrate 301 made of polyethylene naphthalate.
  • a substrate 301 made of polyethylene naphthalate.
  • only one transistor 302 is shown. This
  • Transistor 302 has a structure analogous to FIG. 1 with a gate region 303 made of nickel, a layer 304 made of a dielectric material such as silicon dioxide, a first source / drain region 305 and a second source / drain region 306, both of which consist of palladium, and a layer 307 forming the channel region with pentacene as a semiconducting organic material.
  • the transistor 302 also has a passivation layer 308 made of polyvinyl alcohol.
  • the biosensor 300 also has an electrode made of gold as the detection unit 309, which at the same time has a monomolecular self-organizing layer (not shown for the sake of clarity), so that catcher molecules 310 bind to the self-organizing layer by means of gold-sulfur coupling and thus to the electrode 309 be immobilized.
  • the detection unit 309 also serves as an immobilization unit.
  • the capture molecules are 310 Oligonucleotides so that they can be used to detect nucleic acids.
  • the capture molecules 310 can also be proteins such as antibodies or, for example, the so-called protein A.
  • the detection unit 309 is connected to the transistor 302 of the evaluation circuit via a conductive connection 311, e.g. coupled with a gold or copper track.
  • a conductive connection 311 e.g. coupled with a gold or copper track.
  • the coupling with the source / drain region 305 takes place. Alternatively, the coupling can also take place via the gate region 302.
  • the biosensor 300 has a compartment 312 made of a polymer such as poly (meth) acrylate, i.e. Plexiglass can exist. This compartmentalization separates the detection unit with the associated sample / reaction space 313 from the evaluation circuit.
  • FIG. 3b shows a top view of a further embodiment of the biosensor 300.
  • a transistor 302 of the evaluation circuit which is constructed as described above with at least one layer with a semiconducting organic material, is shown on the substrate 301.
  • the transistor is connected via an electrically conductive connection 311, which consists of gold, to a ring electrode serving as detection unit 309.
  • an electrically conductive connection 311, which consists of gold to a ring electrode serving as detection unit 309.
  • FIG. 3b there are further components 314 of the detection unit, which include both transistors 302 and e.g. Diodes or resistors with semiconducting organic layers can be shown schematically.
  • FIG. 6 illustrates a further embodiment of the biosensor.
  • FIG. 6 a shows a sectional view of the biosensor 600, in which transistors 602 with a structure of the invention analogous to the embodiment of FIG. 3a are applied to a glass substrate 601.
  • the transistors 602 form part of the schematically illustrated evaluation circuit 603 (cf. FIG. 6b).
  • One of the transistors 602 is connected via an electrically conductive material 604, such as a copper track or a layer of PEDOT / PSS, to a ring electrode 605, which serves as a detection unit and unit for immobilization.
  • FIG. 7 shows another embodiment of the biosensor of the invention.
  • transistors 702 with a structure corresponding to FIG. 3
  • an evaluation circuit 704 and detection and immobilization units 703 designed as electrodes are applied to a substrate 701 made of polyethylene naphthalate.
  • the evaluation circuit is connected to the detection units via an electrically conductive material 705.
  • the biosensor 700 has a lockable microfluidic chamber 706 with a cover 707 and a side wall 708, which encloses one or more of the detection units 703.
  • a reference electrode made of silver or Ag / AgCl (not shown) can be integrated into the side wall 708 of the microfluidic chamber 706.
  • Chamber 706 further includes a port 709 for a microfluidic pumping system, i.e. a system with which (small) liquid volumes in the ⁇ l range or smaller can be transferred into the chamber 706 and onto the detection units 703.
  • the biosensor 800 is made of a substrate 801 Polystyrene applied an evaluation circuit 802 made of polymer transistors (ie transistors with at least one layer with an organic semiconducting material).
  • the evaluation circuit 802 is coupled to the detection unit 803, which is designed as an array of electrodes made of gold, via a conductive connection 804.
  • the electrodes also serve as immobilization units.
  • the biosensor 900 has a substrate 901 made of polyethylene naphthalate.
  • a multiplicity of electrodes as detection units 902, which at the same time function as units for immobilization, with a coupled evaluation circuit 903 are applied to the substrate 901 in a regular arrangement.
  • the biosensor 900 is preferably used for the parallel detection of a large number of macromolecular biopolymers.
  • the biosensor 1000 has a substrate
  • the photodiode 1002 consists of an ITO electrode
  • ITO-coated PEN substrates are commercially available
  • a poly (phenyl-vinylene) polymer and C 50 are commercially available
  • the top electrode is made of aluminum (an overview of the spectral sensitivities when choosing the appropriate one
  • the biosensor 1000 is used for the detection of macromolecular biopolymers by means of an optical detection signal, for example by means of fluorescent radiation, which is generated by a fluorophore as a marker.
  • a material such as gold can be applied to an area of the photodiode that serves as a unit for immobilizing macromolecular biopolymers.
  • the excitation wavelength of the fluorescent dye is usually orders of magnitude higher than the intensity of the emitted fluorescent radiation
  • the excitation wavelength will preferably be masked out during detection.
  • a filter layer is formed on at least a partial area of the sensor or on a photodiode.
  • organic molecules disclosed here has the advantage that the spectral sensitivity of the photodiode can be modified over the entire spectral range by material and diode structure (for literature, see e.g. [23]).
  • fluorescent dye e.g. oc-RED excitation 488 nm, emission 670 nm; PE-Cy7 excitation 488 nm,
  • a suitable semiconducting organic polymer e.g. PPV (poly-p-phenylene vinylene)) or molecule (PV oligomers, fluorine derivatives and others) can be found from which the sensor diode can be built.
  • PPV poly-p-phenylene vinylene
  • PV oligomers, fluorine derivatives and others can be found from which the sensor diode can be built.
  • organic dyes nitro and nitroso, azo, di- and triarylmethane, xanthene, acridine, phenoxazine, phenothiazine, phenazine, indigo dyes
  • additional optical filter layer which is applied to the entire carrier, a region of the carrier or only to the photodiode itself, allows the photodiode to be further shielded from the excitation wavelength.
  • the optical density can be infinitely adjusted by the concentration of the dye in the polymer layer. Mixtures of dyes are also suitable.
  • the present invention opens the way to a widely applicable and at the same time inexpensive biosensor.

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Abstract

L'invention concerne un biocapteur pour la détection de biopolymères macromoléculaires, qui comprend au moins une unité servant à immobiliser des biopolymères macromoléculaires, au moins une unité de détection servant à détecter un signal de détection indiquant l'existence de biopolymères macromoléculaires, ainsi qu'un circuit d'évaluation, couplé à l'unité de détection, pour le signal. Le biocapteur selon l'invention est caractérisé en ce que le circuit d'évaluation comprend au moins un composant ayant une couche semi-conductrice qui présente un matériau organique.
PCT/DE2003/000892 2002-03-18 2003-03-18 Biocapteur pour la detection de biopolymeres macromoleculaires et son procede de production WO2003079016A1 (fr)

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DE10211900A DE10211900A1 (de) 2002-03-18 2002-03-18 Biosensor zum Erfassen von makromolekularen Biopolymeren und Verfahren zur Herstellung eines Biosensors zum Erfassen von makromolekularen Biopolymeren

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CN106525921A (zh) * 2015-09-09 2017-03-22 香港城市大学 一种电化学检测器及其制造方法和检测目标物质的方法

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ITBO20060771A1 (it) * 2006-11-13 2008-05-14 Alma Mater Studiorum Uni Di Bologna Metodo per il trattamento di un materiale, materiale trattato cosi' ottenuto e dispositivi contenenti tale materiale
DE102015104419A1 (de) 2014-04-02 2015-10-08 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Fluidsensor und Verfahren zur Untersuchung eines Fluids

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CN106525921A (zh) * 2015-09-09 2017-03-22 香港城市大学 一种电化学检测器及其制造方法和检测目标物质的方法

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