WO2002027319A1

WO2002027319A1 - Device for the detection of charged macromolecules

Info

Publication number: WO2002027319A1
Application number: PCT/DE2001/003660
Authority: WO
Inventors: Max Lemme; Margarete Odenthal; Wolfgang Henschel
Original assignee: Santron Ag
Priority date: 2000-09-27
Filing date: 2001-09-27
Publication date: 2002-04-04
Also published as: DE10048997A1

Abstract

The device for the detection of charged macromolecules, in particular of polynucleotide sequences, in an electrically conducting solution, is based on a capacitance measurement of a layer system, comprising a test solution with the solvent, an insulator and a semi-conductor. An insulating layer (3) is located on the surface of the doped semiconductor (1). A partial region of the surface of the insulation layer (3) is in the form of a sensor surface (9) for the selective adsorption of the macromolecule for detection. A drop (5) of the test solution is applied to the sensor surface (9). An electrically conducting structure (7) is located on the insulation layer (3), directly adjacent to the sensor surface (9), which establishes an electrical contact with said drop (5). A restraining means (13) is provided on the sensor surface (9) to fix the spatial extent of the drop (5). The sensor surface (9) is spatially limited and a measuring device (9) is provided for determining capacitance changes in the capacitance system formed by the semiconductor (1) / insulation layer (3) / sensor surface (9) and drop (5).

Description

Name: Device for the detection of charged macromolecules

The subject of the present patent application is a device for the detection of macromolecules in a sample solution according to the preamble of the main claim.

A variety of methods are known for the detection of macromolecules in a sample solution. Some of these methods are based on a specific reaction of the macromolecules to be detected with so-called capture molecules, this reaction having a high specificity for the macromolecules to be detected. Such is e.g. observed in a hybridization reaction of macromolecules that have a double-stranded equilibrium conformation. An example of this is e.g. the hybridization of a DNA sequence in which two complementary single strands combine to form a double-stranded molecule. Furthermore, a high specificity also occurs, for example, in antibody-antigen reactions.

The detection methods mentioned are usually based on the fact that the macromolecules to be detected are provided with suitable markings and are enriched at this interface by means of specific reactions with labeled detection molecules which are fixed at an interface and are therefore present in a concentration which is a detection of the marking make possible. For example, a stimulated light emission of the fluorescent markers from the interface can be observed or the radioactive radiation resulting from the decay of the radioactive markers can be monitored. be shown.

However, such labeling of the macromolecules to be detected has disadvantages. Methods for marking the macromolecules to be detected must be developed. The marking may change the molecular properties as little as possible. Furthermore, the marking makes additional work steps necessary as part of the verification procedure. Newer detection methods focus on using intrinsic molecular properties for detection in order to make labeling unnecessary.

For example, US Pat. No. 5,164,319 discloses a capacitive detection method for macromolecules in solution, which is based on the observation that many macromolecules are in dissociated form in solution and thus sometimes have a high charge (depending on the size of the macromolecule up to a few thousand elementary charges) can wear. Through a specific detection reaction with capture molecules fixed on a carrier surface, a strong accumulation of charged macromolecules on the carrier surface can be achieved, which can be detected with a capacitive measuring method. The disclosure content of US Pat. No. 5,164,319 is hereby fully made the subject of the present patent application, and reference is also made explicitly to the documents mentioned in US Pat. No. 5,164,319.

A layer system consisting of a doped semiconductor and an insulator located thereon is used as the carrier. The (electrically conductive) sample solution is in contact with the insulator. The entire semiconductor / isolator / test solution system forms a capacitor whose capacitance can be detected using suitable measuring methods which are already known from the prior art. An example of this is the publication by Hewlett Packard, Application Note 322, Analysis of Semiconductor Capacitan ce characteristics, e.g. Called BS2. This also shows the CU characteristic curve (capacitance C versus applied voltage U) of such a capacitor consisting of a semiconductor / insulator / conductor transition.

In the specific detection reaction of the macromolecules to be detected, which are dissolved in the sample solution and dissociated in solution, with capture molecules fixed to the insulator surface, charges accumulate strongly on the insulator surface. This enrichment leads to a shift of charge carriers in the semiconductor and thus to a change in the capacitance of the capacitor consisting of semiconductor / insulator / sample solution, which can be detected. There is a shift in the capacitor C-U characteristic which can be easily detected, e.g. by detecting the capacitance of the capacitor at an appropriately selected operating point. For this purpose, a point of high slope of the C-U characteristic is advantageously chosen as the operating point. For this purpose, details are given in the context of the exemplary embodiments; details can also be found in US Pat. No. 5,164,319.

The device known from US Pat. No. 5,164,319 for carrying out the capacitive measuring method mentioned works with sensor surfaces which are applied to the surface of a surface-oxidized, doped silicon carrier. Each sensor surface is provided with an individual electrode on the back. Such an electrode / semiconductor / insulator layer system is introduced with the conductive sample solution, which also contains an inert counter electrode. The C-U characteristic of the aqueous condenser system formed in this way can be determined by means of suitable measuring methods, which can be found in detail in US Pat. No. 5,164,319.

In order to achieve a high efficiency of the detection method, it is known from the prior art to use an array of suitable devices to process the method simultaneously with a large number of different capture molecules. cool on a sample solution to be examined together. For this purpose, from US 5164,319 an array of the above-mentioned capacitors is known for individual sensor surfaces, each of which has electrodes on the rear and are electrically insulated from one another. At the front, the entire array surface is uniformly covered by the sample solution and contacted by means of a counter electrode common to all capacitors.

This device has a number of disadvantages. A large amount of sample solution is required to cover the entire array, which in many cases is not available. The detection sensitivity achieved, which is in the range of micromoles / liter of the macromolecules to be detected, is clearly too low to enable the device to be e.g. to be able to use in analytical medicine. Furthermore, wet chemical work, more precisely electro chemical work here. This makes simple use in a laboratory more difficult.

The relatively large amount of sample solutions mentioned is required for a single experiment. This has the disadvantage that individual developments cannot be checked in detail or studied in subsequent measurements. It has been shown that deposits of various types can occur on the individual sensor surfaces that cannot be studied individually. A zero measurement without molecules to be detected and only with the solvent requires an entire arrangement with a complete array.

It was therefore an object of the present invention to provide a device which has a significantly increased sensitivity to detection compared to the previously known device and which also requires a reduced amount of sample solution for carrying out the detection method. Finally, the device should be suitable for building an array. she should be easy to handle.

This object is achieved by a device with the features of the main claim.

With this device and with the method that arises when using the device, it is possible to work specifically with a very small amount of sample solutions. Only the sensor surface including at least part of the electrically conductive structure is wetted. In any case, greater wetting is not necessary. This means that the respective amount of sample solutions can be very small.

In this way, different test solutions can be tested, which is in complete contrast to the prior art mentioned. The pure solvent can be used as a test solution. A mixture of solvent and the macromolecules to be detected can then be used as the sample solution. Furthermore, any additive can be added to the pure solvent as a test solution, and any additive can also be added to a test solution composed of solvent and macromolecules. Different temperatures can be used. Overall, the measurement can therefore be made much more differentiated than is possible according to the prior art.

The individual drops of sample solution are each applied to the sensor surfaces and the electrically conductive structures immediately following them. A complete liquid cell as in the prior art is not required. This also eliminates all electrochemical measures associated with a larger liquid cell than in the prior art.

The sensor surface together with the part, the electrically conductive structure structure that is wetted by the drop of sample solution is referred to below as the wetting surface. The sensor area together with the electrically conductive structure is referred to as the total area. The wetting area is at most as large as the total area. The entire surface is closed off in a ring shape, preferably designed by hydrophobes, of the region of the insulator layer surrounding the entire surface. At this point, the insulator layer is preferably also covered with a thick cover layer.

The fixation agent is located on the sensor surface. A suitable agent, which can be derived from the prior art for the respectively selected sample solution and holds on the insulator layer, is provided here.

In a preferred embodiment of the invention, the wetting area is limited by mechanical measures. This is to be understood in particular as a circumferential wall and overall a circumferential edge, by means of which the drop is forcibly delimited locally.

Further features and advantages result from the subclaims and the following exemplary embodiments, which are explained with reference to the drawing, in which:

1 is a perspective view of a sensor device according to the invention,

2: a representation corresponding to FIG. 1 of a total of seven sensors on a common substrate,

3: a perspective view like FIG. 1 of an individual sensor device, but now with a drop of a sample solution,

4: a representation of an optical microscopy image of an array of photolithographically produced detection devices according to the invention in supervision, a detail is shown, 5 shows a diagram for the dependence of the capacitance C in pF on the voltage U in V and

6: a diagram for three measuring points for the ribbon voltage Ufb in V with three different sample solutions, namely once pure water, once single-stranded DNA ss in the solvent water and once double-stranded DNA ds in the solvent water.

In the context of the embodiment according to 1, a device with the following structure was realized:

An n- or p-doped silicon cuboid serves as the semiconductor 1, the conductivity of which is typically set to 1 to 100 ohmmeter. The thickness of the silicon cuboid is approximately 550 micrometers. On the back a full-surface metallic counter electrode 15 made of a typical electrode material is applied, e.g. a thermally vapor-deposited or sputtered, coherent Al film with a thickness of about 200 nm, the thickness of which is in any case sufficient to form metallic properties. It is connected to a connection of a measuring device 27. An HP 4280 A device from Hewlett Packard is used.

The top of the silicon cuboid is oxidized to a depth of approximately 20 nm, so that a non-conductive SiO 2 insulator layer 3 is located on the surface of the silicon wafer. The methods required for this are known from the prior art.

A metallic layer is applied to the entire surface of the insulator layer 3, which is then suitably structured using photolithographic methods, so that a conductive structure 7 forms on the surface of the insulator layer 3. The metallic layer is, for example, an evaporated or sputtered aluminum, titanium, chromium, gold, silver or platinum film with a thickness that is at least sufficient to remove formation of metallic properties is considered. Typical film thicknesses are in the range of a few hundred nanometers.

Photolithographic methods are preferably used to structure the metallic layer, i.e. after the full-surface evaporation of a metal film made of aluminum with a thickness of 200 nm, application of a photoresist to the entire surface of this metal film, exposure of the photoresist through a suitably structured mask, removal of the exposed photoresist, subsequent etching of the exposed surface with an etching solution suitable for metal removal and, if appropriate, removal of the remaining photoresist. Corresponding methods are also known from the prior art. As an alternative to this, other structuring methods such as electron beam or ion beam exposure are also possible, the choice of the suitable structuring method depends primarily on the structure sizes to be achieved. Ion implantation is also suitable for producing the structure 7.

FIG. 1 shows a ring shape for the structure 7, the outside diameter of which is approximately 0.5 to 1 millimeter. The ring width is approximately 100 to 300 micrometers, so that in the center of the ring structure there is a sensor surface 9 with a diameter of approximately 500 micrometers, in which the surface of the insulator layer 3 is freely accessible.

Capture molecules 17, which show a specific chemical reaction with the macromolecules to be detected, can now be applied to this sensor surface 9 by means of suitable method steps, which are also known from the prior art. This can be, for example, the complementary sequence to a single-stranded polynucleotide sequence to be detected. The capture molecules 17 are preferably chemically fixed on the surface of the insulator layer 3, for example by chemical reaction of specific chemical end Groups with a, preferably chemically absorbed, linker layer 19 applied to the sensor surface 9. Details on this are known from the prior art and are based primarily on the chemical properties of the insulator layer 3 and the available end groups of the capture molecules 17. The Insulator layer 3 in the center of the electrically conductive structure 7, that is to say the sensor surface 9, together with the catcher molecules 17 applied or fixed thereon is referred to as the prepared sensor surface 9.

In the outside area, the electrically conductive (ring) structure 7 is connected to a connection surface 23 via a feed line 21. The second connection line of the measuring device 27 for detecting changes in capacitance is connected to this connection area. Terminal area 23 and feed line 21 are likewise produced photolithographically, preferably in one operation with the production of the electrically conductive structure 7.

FIG. 2 shows an array arrangement of the device according to the invention shown in FIG. 1, which can advantageously be produced by means of photolithographic processes. An array arrangement can be used for the massively parallel analysis of individual drops of a sample solution for a large number of different macromolecules. A corresponding procedure is e.g. known from the detection of polynucleotide sequences by means of labeling with fluorescent dyes. Overall, the array arrangement can also be introduced into a sufficiently large volume of sample solution.

FIG. 3 shows the device according to the invention shown in FIG. 1 in contact with a drop of sample solution 5. This drop has a defined volume of typically a few nanoliters. Drops of this size can be generated using standard pipetting methods. The drop 5 is preferably produced using an automated positioning device positioned and deposited on the sensor surface 9.

In order to obtain an exact positioning of the drop 5 on the sensor surface 9, a fixing means is provided which essentially fixes the position of the drop 5 on the sensor surface 9. In the exemplary embodiment under discussion, the surface of the insulator layer 3 located outside the electrically conductive structure 7 can be removed by the targeted application of a hydrophobic monolayer, e.g. of OTS, hydrophobized so that a drop 5 of the sample solution applied to this area has a high contact angle, preferably greater than 45 °, in particular in the range of 90 ° and above.

The surface of the electrically conductive structure 7 is preferably metallic, which generally results in good wettability by aqueous solutions. Many clean metal surfaces, e.g. of precious metals, show complete wettability by water, characterized by a contact angle of 0 °.

The sensor surface 9 is preferably also hydrophilized by targeted application of a monolayer of suitable molecules, so that a low to vanishing contact angle of the sample solution is also formed on the sensor surface 9. Overall, the surface of the electrically conductive structure 7 and the sensor surface 9 is thus made hydrophilic, whereas the surrounding free surface of the insulator layer 3 is made hydrophobic, ie there is a targeted wetting contrast between the electrically conductive structure 7 and the sensor surface 9 on the one hand and the free surface of the insulator layer 3 on the other hand set. Provided that the volume of the drop applied does not exceed a certain value, which depends on the geometry and the wetting properties of the device according to the invention, the drop 5 of the sample solution can largely be completely applied to the sensor surface 9 and the electrical rically conductive structure 7 are set. The entirety of the wetting properties with the monolayers that may be applied to the surface of the insulator layer thus represents the fixing agent according to the invention in this embodiment. The hydrophilic formation of the sensor surface 9 is preferably carried out before the capture molecules 17 are applied, but it can also be carried out afterwards.

As an alternative to this, for example, the drop 5 can be fixed on the sensor surface 9 by means of a geometric “confinement”, ie for example the free surface of the insulator layer 3 is covered with a passivation layer 25 of great thickness (for example a few 100 nanometers PMMA (polymethyl methacrylate), which a covering of the surface of the insulator layer 3 with the sample solution due to a wall or an embankment (flank) is geometrically prevented or such a large distance between the drop and the semiconductor / insulator layer system that those parts of the drop 5 that are on the passivation layer 25 sit, no longer contribute to the capacitive measurement signal.

Such a confinement is already achieved in the embodiment according to FIG. 1 in that the sensor surface 9 is located within the structure 7, which has a certain thickness. The edge of this structure therefore forms a flank that runs around and that inevitably holds the drop 5. The electrical contact of this side surface of the structure 7 with the drop 5 is sufficient to produce the electrical contact.

FIG. 4 finally shows a top view of an optical microscopy image of an array of phototrophotographically produced devices according to the invention, the structure of which corresponds to that of FIG. 1 (200 nm Al structure on 20 nm SiO 2 on 550 micrometers p-Si). In this experimental implementation, the fixing agent 13 is covered by the (optically visible) electrically conductive structure 7 and a (non-visible) hydrophilic coating on the inside. Ren the electrically conductive structure 7 in connection with the hydrophobic unbound surface (contact angle about 30 °) of the insulator layer 3 is formed. If a drop of 5 aqueous sample solution is placed on the structure shown, the drop spreads out to the outer edge of the hydrophilic, electrically conductive structure 7, that is to say over the entire surface. The interior of the electrically conductive structure 7, which is designed as a sensor surface 9, is completely covered by the drop 5.

Pre-dimensions on empty structures

The measurement methods and measurement structures on which the invention is based were first verified by measurements with solvents of different pH values. There were no macromolecules in the solvent.

Depending on the proton concentration (pH = - log aH + with a = activity), the surface potential of the isolator varies due to a shift in the protolysis balance. For the present case of an insulator layer 3 made of SiO 2, the surface potential is determined by the following reactions:

SiOH + H ⁺ ^ SiOH ₂ ⁺ SiOH + OH- <-> SiO- + H ₂ O Accumulations or cleavages of the protons from terminal OH groups of the oxide cause the surface to charge, which in turn causes a shift in the flat band potential. With the help of Nernst's equation, the pH dependence of the flat band potential can be determined as 59 mV / pH:

E = E ₀ + 0.059 log a _H ,

The measurements were carried out in sodium hydrogen phosphate buffer (10 mm) at pH values of 5, 7 and 9 and a volume of 500 nL. In the voltage range from -5 V to 1 V, the capacitance was ner AC voltage with 20 mV amplitude and a frequency of 100 kHz measured. The CU characteristic curves obtained for the doped semiconductor 1, insulator layer 3 made of SiO2 and buffered aqueous solution are shown in FIG. 5.

All measurements show a clear shift of the entire characteristic curve compared to the reference measurement on an unwetted, dry structure. A small spread of the individual measurements is observed. Even within the measurement series, a change in the ribbon tension depending on the pH value is clearly recognizable.

This shows that a change in the surface charge in the area of the sensor surface 9 leads to a shift in the entire C-U characteristic of the above. Condenser system leads. If one selects an operating point of fixed voltage on the flank of the CU characteristic curve, in particular the turning point to be observed there, and observes the change in the capacitance due to adsorption of charged macromolecules on the sensor surface 9, a high detection sensitivity can be achieved by simply measuring the change in capacitance of the overall system , Within certain adsorbed amounts of charge, i.e. The number of particles in the macromolecules to be detected can result in a linear or quadratic relationship between the number of particles and the change in capacity.

Preparation of nucleic acids:

Production of the nucleic acids:

Starting from an insert sequence +1 to 646, which was inserted in the polylinker of plasmid pl56, single-stranded and double-stranded DNA was produced enzymatically. As a template for a single-strand or double-strand PCR, linearized plasmid 156 was isolated in a polylinker Hind III in a con- concentration of 10 ng / μl. The primers 65 and 19 used for the synthesis were present in a working solution with a concentration of 10 μM.

The PCR reactions were carried out in a PTC 200 from MJ Research Inc.

Single-stranded PCR:

Approach: PCR program

5 µl template DNA (p 156) 95 ° C

2 ul primer 65 [10 ul] 30 "94 ° C

10 ul 10-fold Taq polymerase buffer 30 ^" 64 ° C

5 ul dNTP [1mM] r 72 ° C

77.8 ul H2O 5 ^{^} 72 ° C

0.2 μl Taq polymerase (5 U / μl)

Double-stranded PCR:

Approach: PCR program

2.5 µl template DNA (p 156) 95 ° C

2 ul primer 65 [10 ul] 30 ^" 94 ° C

30 x

2 ul primer 19 30 "64 ° C>

10 ul 10-fold Taq polymerase buffer r 72 ° C

5 ul dNTP [1mM] 5 ~ 72 ° C

77.8 ul H2O

0.2 μl Taq polymerase (5 U / μl) Purification of the nucleic acids:

After the amplification, 10 batches of the single-strand or double-strand PCR were combined and either subjected to a phenol / choroform extraction with subsequent ammonium acetate precipitation or a purification using the Wizzard Purification Kit (Promega). The nucleic acids were taken up in chromatography water from Merck.

Dialysis:

The samples were transferred to QuixSep dialysis vials from Membrane Filtration Products, Inc. The dialysis tubing from Roth used had a pore size of 25 to 50 angstroms. It was dialyzed twice in a 1000-fold volume of chromatography water for 1 hour each.

Concentration determination and control of nucleic acids:

The concentrations were determined spectrophotometrically at a wavelength of 260 nm.

Aliquots of the samples were separated to check the purity of double strands or single strands in a submarine agarose gel electrophoresis at a constant voltage of 80 volts and their running behavior was documented under a UV transilluminator.

Melting curves were also carried out in a GeneAmp 5700 from Perkin Elmer Biosystems to check the purity of the samples. For this purpose, SYBR-Green solution from FMC Bioproducts for the Ali- quots of the samples in a dilution of 1: 10000 and the temperature profile from 95 ° C to room temperature recorded.

Concentrations of the C / U measured samples

Single-stranded DNA Double-stranded DNA (hybrid)

a. 7.5 ng / μl = 50 fmol / μl a. 15 ng / μl = 50 fmol / μl

b. 75 ng / μl = 500 fmol / μl b. 150 ng / μl = 500 fmol / μl

Between 100 nl and 500 nl were used in the C / U measurements.

Solution medium: here chromatography water (see dialysis)

Measurements with a sample solution containing DNA

To measure the hybridization state (single or double strand) of DNA solutions, a 5 * 10 " ⁷ molar DNA solution in H2O with the above-described DNA sequence of 409 bases or base pairs was used. With a volume of only 500 used nL per measurement, only 250 fmol DNA were thus applied to the device according to the invention.

Due to the fact that the macromolecules to be detected, here the above-mentioned polynucleotide sequences dissociate in solution and are thus charged, adsorption of the dissociated polynucloetide sequences on the insulator surface occurs on the prepared sensor surface 9. Depending on the presence of a single-stranded or double-stranded polynucleotide sequence, this sequence carries fewer or more charges which, when adsorbed on the prepa- rated sensor surface 9 to a different degree of change in the amount of charge adsorbed and thus to different shifts in the CU characteristics, ie lead to changes in the capacity of the overall system at the operating point.

In the voltage range from -5 V to 1 V, the capacitance of the capacitor system was measured by adding an AC voltage with an amplitude of 20 mV and a frequency of 100 kHz and the flat band potential was determined.

As FIG. 6 shows, a clear and clearly distinguishable shift of the flat band potential by 16 mV between single and double stranded DNA could be demonstrated with identical DNA concentration and length.

This proves that a device according to the invention according to the above embodiment has sufficient accuracy to detect a total particle count of approximately 250 femtomoles in a drop of approximately 500 nanoliters.

An improvement in the measuring accuracy can also be achieved by measuring a sample solution on a first device according to the invention against a reference solution on a second device according to the invention, ie in FIG. 6 the relative position of the "ss" (single stranded) and "ds" ( double stranded) designated measurement points compared to the measurement point designated "H ₂ O" is determined.

For this purpose, it has proven to be particularly advantageous to arrange a first device according to the invention and a second device according to the invention in a Wheatstone bridge and to record only the changes between the two. In particular, hydrophilic adhesion promoters are suitable as fixatives. Examples of fixing agents are: silanes, in particular aminosilanes and epoxysilanes; Polyamines (poly-L-lysine); dextran; chitosan; Polymethacrylic acids; Poly (methacrylol oxypropyl (trimethyl ammonium)) or polyamides. The silanes are hydrophobic, the other substances are hydrophilic.

Examples of the opposite, ie substances for finishing the surfaces in such a way that they do not accumulate, are: polystyrene; Polymethyl methacrylates; Polytetrafluoroethylene, polyfluoroethylene. Hydrophobic substances are particularly suitable for this equipment.

Claims

Name: Device for the detection of charged macromolecules

claims

1) Device for the detection of charged macromolecules, in particular polynucleotide sequences, in an electrically conductive solvent, based on a capacitance measurement on a layer system comprising a sample solution containing the solvent, an insulator and a semiconductor, consisting of a doped semiconductor (1) which is extended over a large area one surface of which contains an insulator layer (3), a portion of the surface of the insulator layer (3) being designed as a sensor surface (9) for selective attachment, in particular adsorption or binding, of the macromolecules to be detected, characterized in that: a ) the sensor surface (9) is provided so that a drop (5) of the sample solution is applied to it, b) an electrically conductive structure (7) is applied to the insulator layer (3) in the immediate vicinity of the sensor surface (9), which is intended to make electrical contact with this drop n (5) to be produced, c) a fixing means (13) is applied to the sensor surface (9) and is intended to determine the spatial position of the drop (5), d) the sensor surface (9) is spatially limited e) and a measuring device (9) for detecting changes in capacitance of the capacitor system formed from the semiconductor (1) / insulator layer (3) / sensor surface (9) and drops (5) is provided, which are caused by accumulation, in particular adsorption and binding, of charged macromolecules on the sensor surface (9).

2) Device according to claim 1, characterized in that the fixing means (13) is formed by a defined wetting contrast for the solvent of the sample solution between the insulator layer (3) on the one hand and the sensor surface (9) on the other hand and optionally an electrically conductive structure (7).

3) Device according to claim 1, characterized in that the fixing means (13) defines the spatial position of the drop (5) on the sensor surface (9) by geometric limitation.

4) Device according to claim 1, characterized in that the electrically conductive structure (7), the sensor surface (9) surrounds in a ring.

5) Device according to claim 1, characterized in that the electrically conductive structure (7) is applied in thin-film technology to the insulator layer (3), preferably in the form of a structured metal film.

6) Device according to claim 2, characterized in that the sample solution wets the sensor surface (9), preferably completely wetted.

7) Device according to claim 2, characterized in that the sample solution wets, preferably completely wets, the surface of the electrically conductive structure (7). 8) Device according to claim 2, characterized in that the surface lying outside the sensor surface (9) and the electrically conductive structure (7) is designed such that it is incompletely wetted, preferably not positively wetted, by the sample solution.

9) Device according to claim 8, characterized in that on the outside of the sensor surface (9) and the electrically conductive structure (7) lying surface of the insulator layer (3) a cover layer (11) is applied, the thickness of which is greater than the thickness of the Insulator layer (3), preferably at least 5 times larger.

10) Device according to claim 1, characterized in that capture molecules (13) are anchored, in particular chemisorbed, on the sensor surface (9) to which the charged macromolecules to be detected can bind specifically.

11) Device according to claim 1, characterized in that the device is provided for the detection of equilibrium double-stranded macromolecules, the catcher molecules (13) being formed by single strands of the macromolecules to be detected.

12) Device according to claim 1, characterized in that the electrically conductive structure (7) has a connection surface (13) for an electrical feed line.