Method for detecting an analyte and / or the activity of an analyte by adjusting the polarization state of a ferroelectric material of a measuring device

Abstract

The invention relates to a method for detecting an analyte and / or the activity of an analyte in an electrolyte by means of a measuring device. For this purpose, a measuring device is provided which comprises a reference electrode and a sensor surface comprising a ferroelectric material. Furthermore, the polarization state of the ferroelectric material is adjusted on the basis of the analyte to be detected and / or the activity of the analyte to be detected. The electrolyte is then brought into contact with the sensor surface in order to detect the analyte and / or the activity of the analyte. The invention further relates to a measuring device for detecting an analyte and / or the activity of an analyte in an electrolyte, to a method for determining an optimized polarization state for the measuring device, and to uses of the measuring device.

Description

[0001] METHOD FOR DETECTING AN ANALYTE AND / OR AN ACTIVITY OF AN ANALYTE BY SETTING A POLARIZATION STATE OF A FERROELECTRIC MATERIAL OF A MEASURING DEVICE

[0002] DESCRIPTION

[0003] The invention relates to a method for detecting an analyte and / or the activity of an analyte in an electrolyte using a measuring device. For this purpose, the measuring device comprises a reference electrode and a sensor surface comprising a ferroelectric material. Furthermore, the polarization state of the ferroelectric material is adjusted depending on the analyte and / or its activity to be detected. Subsequently, the electrolyte is brought into contact with the sensor surface to detect the analyte and / or its activity.

[0004] Furthermore, the invention relates to a measuring device for detecting an analyte and / or an activity of an analyte in an electrolyte, a method for determining an optimized polarization state for the measuring device and uses of the measuring device.

[0005] Background and state of the art

[0006] The detection of analytes and / or the activity of an analyte, such as ions, biomolecules and / or cell signals, in a liquid plays a crucial role in many biomedical applications.

[0007] Methods are known for measuring, for example, ion concentrations and cell signals (e.g., action potentials of neurons) in which electrolyte-oxide-semiconductor field-effect transistors (EOSFETs) with dielectric oxides as sensor surfaces are used. Historically, EOSFETs are also frequently referred to as ion-sensitive field-effect transistors (ISFETs).

[0008] The measuring principle of EOSFETs is based on a change in their threshold voltage due to a change in potential differences. These changes in potential differences can be caused by various factors, as explained in more detail below. For example, a change in potential difference can occur due to current flow in a liquid electrolyte or due to a change in an electrochemical double layer.

[0009] In Fromherz (2012), the mathematical relationships between potential difference changes and changes in the threshold voltage of an EOSFET with a dielectric sensor area are examined in detail. In particular, it is derived that a change in the EOFET's threshold voltage is equivalent to a change in the EOFET's gate voltage, i.e., the voltage between a gate terminal and a bulk terminal of the EOSFET. Fromherz (2012) further demonstrates that, for example, current flow in the electrolyte and changes in the electrochemical double layer due to interaction of the dielectric sensor area with prototons can lead to a change in the threshold voltage. Furthermore, changes in the interface polarization can also influence the EOSFET's threshold voltage.

[0010] For measuring ions other than protons, as well as for detecting biomolecules such as glucose, the dielectric sensor surface of EOSFETs is often modified with a functional coating. For ion detection, so-called ion-sensitive membranes are applied to the dielectric sensor surface. For biomolecule detection, immobilized enzymes (e.g., glucose oxidase) are frequently used.

[0011] Methods for detecting ions and biomolecules that require an additional coating on the dielectric sensor surfaces of the EOSFET have the disadvantage of increased manufacturing effort and limited long-term stability. Furthermore, the functional coating is not reversible in many applications, which restricts the flexibility and applicability of the underlying EOSFETs. For example, the ion sensitivity of a dielectric sensor surface can only be irreversibly maximized or minimized by coating. Similarly, the ion sensitivity of uncoated dielectric sensor surfaces cannot be selectively and reversibly influenced. In addition, the time drift of the EOSFET signals (with and without coating) is a common problem that impairs measurement accuracy.

[0012] Furthermore, methods are known in the prior art that enable the detection of cell signals other than neuronal action potentials. One example of such alternative cell signals is the sealing noise that arises during the adhesion of cells to a sensor surface. EP 1717574 B1 describes a method for determining the sealing impedance of a gap filled with an electrically conductive liquid between a substance and a support. The support comprises at least one first electrode, which is wholly or partially covered by the substance in the liquid. A noise voltage is then determined to measure the impedance between the first electrode and a second electrode, which is also in contact with the electrically conductive liquid. The sealing impedance can then be determined based on this noise voltage.However, targeted adjustment of the sealing impedance as well as reversible adjustment of the sealing impedance is not possible.

[0013] CN 117269280 A discloses a biosensor in the form of a field-effect transistor (FET). Among other things, the use of graphene as a channel material between the drain and source of the FET is proposed. Due to its physical properties, such as particularly high electron mobility and conductivity, graphene is especially well-suited for this purpose. The biosensor disclosed therein also includes a substrate made of ferroelectric material, which is used for the electrostatic doping of the graphene in order to modulate the electrical properties of the graphene channel and thus increase the detection sensitivity of the sensor. Furthermore, it is described that the polarization of the ferroelectric material generates an electric field that exerts a force on charged particles in a sample and thereby influences the distribution of the particles.Furthermore, it is disclosed that the positive and negative charges can be controlled by the polarization state. However, a method for specifically adjusting the polarization state depending on the sample under investigation is not disclosed. CN 112697843 B describes another field-effect transistor (FET) that utilizes the properties of a ferroelectric material in the negative capacitance regime to achieve an amplified measurement signal. The use of carbon nanotubes as the channel material between the drain and source of the FET is also discussed. The carbon nanotubes are intended to enable more efficient charge transport and faster switching speeds compared to commonly used semiconductor materials. The characteristic hysteresis loop of ferroelectric materials is discussed, but no active adjustment of a polarization state depending on the type of sample under consideration is described.

[0014] CN 108231901 A relates to a field-effect transistor (FET) that utilizes the concept of negative capacitance through the use of a ferroelectric material to achieve an improved measurement signal and, in particular, an increased switching speed of the FET through internal voltage amplification. Furthermore, CN 108231901 A describes a method for fabricating such a FET. In certain embodiments, the disclosed FET serves as a sensor for biomarkers in which the ferroelectric material is in direct contact with the analyte under investigation.

[0015] US 2020 0194592 A1 discloses an ion-sensitive field-effect transistor (ISFET) for measuring the concentration of an analyte. A reference electrode applies an electrical potential to the analyte. The analyte is in contact with a sensor surface whose surface charge depends on the analyte concentration. In this way, the gate electrode of a conventional FET is replaced by the combination of a reference electrode and the analyte under investigation. Additionally, a ferroelectric capacitor consisting of two electrodes and a ferroelectric material is used. By selectively changing the polarization, the ferroelectric material is designed to have a negative capacitance, thereby internally amplifying the voltage across the reference electrode.In particular, switching the polarization of the ferroelectric material between polarization states is intended to enable an increased voltage difference through the effect of negative capacitance. The change in the polarization state is mediated by a periodic bias voltage. The property of ferroelectric materials to exhibit negative capacitance at certain changing electrical polarizations is thus to be advantageously utilized in the FETs to amplify the measurement signals and increase the detection sensitivity. Setting the polarization state of the ferroelectric material depending on the analyte to be detected is not performed.

[0016] German patent application DE 102020132756 B3 discloses a biochip that can, in particular, stimulate biological material. For this purpose, the biochip preferably has a coupling arrangement with coupling surfaces for the electrical stimulation of biological material, for example, nerve cells. The biochip is characterized by having at least one layer with ferroelectric properties, which is bounded by the coupling surface. The coupling surface of the ferroelectric layer preferably defines the biochip in a region in which the biological material, preferably the nerve cells, is located. To stimulate the biological material, in particular the nerve cells, a time-varying voltage can preferably be applied to an electrode, which contains an electrolyte or...The biological material is contacted, and an electrode layer is applied, which is located opposite the ferroelectric layer and preferably on a support structure. Advantageously, the layer with the ferroelectric properties should make an additional contribution to the electrical stimulation of the biological material, which originates from the ferroelectric polarization in the layer. This additional contribution occurs alongside the contribution caused by the known purely capacitive stimulation and can be significantly higher. DE 102020132756 B3 also uses the dielectric properties of the ferroelectric layer in the context of electrical measurements of the biological material, preferably nerve cells. However, DE 102020132756 B3 does not disclose how a polarization state of the ferroelectric layer can be set depending on the biological material under investigation.

[0017] Although the state of the art offers a variety of approaches for detecting an analyte and / or its activity in an electrolyte, there is potential for optimizing the sensitivity of the measuring device. Therefore, there is a need for alternative, improved methods or measuring devices for detecting an analyte and / or its activity in an electrolyte.

[0018] Object of the invention

[0019] The object of the invention is to provide a method and a measuring device that eliminate the disadvantages of the prior art. In particular, it is an object of the invention to provide a method and a measuring device that are characterized by targeted, reliable and highly sensitive detection of an analyte and / or the activity of an analyte in an electrolyte, preferably also enabling high flexibility with regard to the measurement of different analytes and / or their activity using simple means.

[0020] Summary of the invention

[0021] The object of the invention is achieved by the independent claims. Advantageous embodiments of the invention are disclosed in the dependent claims.

[0022] In a first aspect, the invention relates to a method for detecting an analyte and / or an activity of an analyte in an electrolyte by means of a measuring device comprising the following steps: a) providing the measuring device comprising a reference electrode and a sensor surface comprising a ferroelectric material, b) setting a polarization state of the ferroelectric material of the sensor surface depending on the analyte to be detected and / or the activity of the analyte to be detected, c) bringing the electrolyte into contact with the sensor surface and detecting the analyte and / or the activity of the analyte.

[0023] The description of the steps of the method according to the invention is preferably not limited to a specific sequence. For example, it may be preferred that step b) takes place entirely before step c), i.e., that preferably a polarization state of the ferroelectric material of the sensor surface is first set depending on the analyte to be detected and / or the activity of the analyte to be detected, and then the electrolyte is brought into contact with the sensor surface and the analyte and / or the activity of the analyte is detected. It may also be preferred, for example, that step c) takes place wholly or partially before step b), i.e.,In particular, the process begins with bringing the electrolyte into contact with the sensor surface, followed by adjusting the polarization state of the ferroelectric material of the sensor surface depending on the analyte to be detected and / or its activity, and subsequently detecting the analyte and / or its activity. A person skilled in the art will understand which sequence of the (partial) steps of the method according to the invention may be preferred depending on the application.

[0024] The method according to the invention is characterized in particular by the possibility of setting a polarization state for the ferroelectric material of the sensor surface. Here, a polarization state can be selectively set by means of the ferroelectric material, which optimizes a measurement signal with respect to an analyte to be detected and / or its activity. For this purpose, it may be particularly preferred to set a polarization state that maximizes or minimizes the sensitivity of the sensor surface for the detection of the analyte and / or the activity of the analyte.

[0025] For example, by selecting a polarization state for the sensor surface, the displacement of analytes, such as ions, biomolecules, or cells, towards the sensor surface can be selectively increased or decreased. If, for instance, the detection of a biomolecule, such as glucose, is desired, it may be advantageous to selectively induce biomolecules to adhere to the sensor surface via dipole-dipole interactions by setting a specific polarization state, thereby increasing their influence on interfacial polarization. Similarly, ions can preferably be selectively attracted or repelled by the sensor surface by appropriately adjusting its polarization state to increase or decrease measurement sensitivity.

[0026] The sensitivity of the method for detecting analyte activity, such as cell activity, can also be selectively increased or decreased by adjusting the polarization state. For example, a polarization state can be chosen to minimize or maximize the distance between adherent cells and the sensor surface. As explained in more detail elsewhere, this makes it possible to influence a so-called sealing resistance, which correlates with the measurement sensitivity for cell activity, such as an action potential in the case of neurons.

[0027] Optimizing the measurement signal can preferably also involve optimizing the signal-to-noise ratio (SNR). As explained in more detail below, in preferred embodiments the measurement signal itself can be a noise signal from the measuring device. Noise or a noise signal from the measuring device in an electrolyte is, in particular, also a functional of the polarization state of the ferroelectric material and can therefore be specifically optimized by adjusting the polarization state accordingly. With a view to improving the SNR, the noise signal can thus be maximized or minimized to enable effective detection of an analyte and / or the activity of an analyte in an electrolyte.

[0028] It can also be advantageous to select a polarization state such that, for example, the sensitivity of the sensor area with respect to one type of analyte is specifically increased, while the sensitivity for detecting another type of analyte is specifically decreased. With regard to the detection of ions in the electrolyte, for example, the sensitivity for positive ions can be specifically increased by adjusting the polarization state, while the sensitivity for negative ions is decreased.

[0029] Likewise, the polarization state can preferably be set in such a way that, for example, the attachment of biomolecules to be detected is promoted, while the influence of ions in the electrolyte on the measurement signal is avoided.

[0030] Therefore, with regard to analyte detection and / or activity, targeted signal optimization is easily achieved simply by adjusting the polarization state. The separate application of analyte-sensitive coatings, for example, for immobilizing biomolecules or attracting ions using specific ion-sensitive membranes, can be advantageously avoided.

[0031] Instead, it was recognized that by using a ferroelectric material for a sensor surface, an additional degree of freedom in the form of a polarization state can be provided, which enables more sensitive detection of a desired analyte and / or a desired activity of an analyte in an electrolyte.

[0032] A key advantage of the method according to the invention is that, depending on the analyte to be detected and / or its activity, the polarization state of the sensor surface can be adjusted easily and quickly, for example, by applying a suitable voltage polarity. No design modifications are necessary. Instead, the same measuring device can be used. Furthermore, no coating needs to be applied to the sensor surface to increase the sensitivity of the measuring device for detecting specific analytes. Instead, the same ferroelectric material is used, but its properties, in the form of a polarization state, can be advantageously adjusted for optimal measurement of the analytes in question by applying a suitable voltage polarity.

[0033] In this way, the reversibility of the polarization state of the ferroelectric material can be exploited in particular, thus maintaining a high degree of flexibility.

[0034] A further advantage of the method according to the invention is the long-term stability of the measuring device. While coatings of the sensor surfaces for the more specific detection of analytes usually exhibit reduced long-term stability or their specificity decreases over longer periods and / or measurements, the sensor surface for the method according to the invention can be provided by means of an extremely stable ferroelectric layer, which on the one hand exhibits high chemical and mechanical stability with respect to the electrolyte and / or the analytes contained therein. On the other hand, the reversibility of the polarization state of the ferroelectric material, or its adjustability, is also advantageously extremely stable over the long term, whereby, within the framework of a corresponding hysteresis curve, a desired polarization state can be reliably set even over a large number of polarization changes and / or a long period of time.A permanent setting option for the polarization state of the ferroelectric material allows for a permanent optimization of sensitivity. Therefore, the measuring device can be used reliably for measuring a wide variety of analytes or their activity over extended periods, even several years.

[0035] Furthermore, the method is advantageously applicable to the detection of different analytes with minimal effort. In addition, the manufacturing effort for the measuring device can be kept low, as, as explained, no additional application of analyte-sensitive coatings is necessary to detect specific types and / or activities of an analyte, for example, specific ion types and / or specific biomolecules.

[0036] A further advantage is that a drift signal can be reduced or avoided by temporarily adjusting the polarization state. In this case, adjusting or changing the polarization state preferably involves changing an electric field, which can influence the movement and / or direction of charge carriers in the electrolyte and, in particular, resolve any unwanted deposits that could distort the measurement results as a drift signal.

[0037] The method according to the invention is particularly useful for the detection of an analyte and / or the activity of an analyte.

[0038] The detection of the analyte and / or activity can mean whether an analyte and / or activity is present or not. Detection can preferably also refer to quantified detection, i.e., the determination of a quantity and / or measure of an analyte and / or activity.

[0039] The detection of the analyte and / or its activity preferably refers to a qualitative, semi-quantitative, and / or quantitative analysis to assess the presence of an analyte and / or its activity in the electrolyte. In a qualitative analysis, a preferred outcome may be the determination of whether a specific analyte and / or its activity is detectable in the electrolyte. Therefore, a qualitative analysis may preferably initially only clarify whether an analyte is present in the electrolyte, i.e., whether it exhibits at least a concentration above a detection threshold, or whether a corresponding analyte activity is detectable, i.e., preferably also above a detection threshold.In a semi-quantitative analysis, it is preferably determined whether the analyte and / or its activity is detectable above a predefined threshold (which is preferably many times higher than the detection threshold). In a quantitative analysis, the result is preferably a numerical value indicating a measured quantity, for example, the amount and / or concentration of an analyte to be detected and / or the (signal) strength of the analyte's activity. Quantitative analysis can preferably be a relative measurement, in which, for example, the time course of an analyte concentration in the electrolyte is quantitatively determined. Likewise, a quantitative analysis can preferably also include the determination of absolute quantities, such as the absolute concentration of the analyte.Preferably, as explained elsewhere herein, a reference and / or calibration measurement may be used for this purpose.

[0040] The detection of an analyte and / or an activity of an analyte according to the invention can preferably include qualitative, semi-quantitative and / or quantitative analysis as well as mixed forms thereof.

[0041] The term "analyte" preferably refers to the material to be detected, which is present in the electrolyte. In a preferred embodiment, the material to be detected is a chemical and / or biological material. Particularly preferably, the analyte is selected from the group consisting of ions, biomolecules, and cells.

[0042] The term "biomolecule" as used here refers preferably to any chemical compound isolated from a living organism, as well as to analogues (including genetically engineered and / or synthetic analogues), derivatives, mutants or variants, and / or biologically active fragments thereof. The biomolecule may be, for example, a protein, a nucleic acid, a nucleotide, a carbohydrate, or a lipid.

[0043] A biomolecule can be selected, for example, from a group consisting of DNA (including genes and / or plasmids), RNA (e.g., mRNA, siRNA, miRNA), proteins (e.g., enzymes, antibodies, and / or receptors), peptides (especially antimicrobial peptides), lipids (e.g., phospholipids, triglycerides, and / or sterols), carbohydrates (saccharides, polysaccharides, and / or glycoproteins), metabolites (e.g., primary metabolites, especially glucose and / or ATP, secondary metabolites), vitamins (e.g., vitamin C, D), cofactors (e.g., NAD+ / NADH, FAD / FADH2), nucleotides (e.g., ATP and / or cAMP), and signal transduction molecules (e.g., cytokines and / or hormones), without being limited to these.

[0044] In preferred embodiments, the biomolecule to be detected exhibits a dipole moment. This electric dipole moment generally arises when the centers of charge of a substance do not coincide, regardless of the total charge of the substance, in this case, the biomolecule. Therefore, the electric dipole moment can influence the response to the electric field of the sensor surface, since the polarization of the sensor surface, comprising a ferroelectric material, is also associated with an electric field. For example, as explained in more detail elsewhere herein, the detection of biomolecules with a dipole moment, such as glucose, can be enabled via interface polarization.

[0045] The term "ion" used herein has the meaning common in the prior art and refers in particular to an electrically charged atom or molecule. An ion can be an anion or a cation, where an anion is a negatively charged ion and a cation is a positively charged ion. In particular, the ions can be selected from a group consisting of monatomic ions, such as a proton (H₂). + ), potassium ion (K + ) or a chloride ion (Cl-), or polyatomic ions, such as ammonium ions (NH₄⁺) 4+ ), sulfide ions (SO4 2 ) or hydrogen phosphates (HPO4) 2-The term "cell" as used here refers preferably to all biological cells, in particular somatic cells, as well as all types of cells in tissues or organs, all types of stem cells, such as pluripotent stem cells and progenitor cells, including all types of cells such as egg cells, sperm cells, and germ cells. The cell may be present in isolated or non-isolated form, e.g., in a cell-containing body fluid, a tissue, or an organ morphology.

[0046] A cell can be selected, for example, from a group consisting of stem cells, red blood cells (erythrocytes), white blood cells (leukocytes), platelets (thrombocytes), nerve cells (neurons), glial cells, muscle cells (myocytes), cartilage cells (chondrocytes), bone cells, skin cells, endothelial cells, epithelial cells, fat cells (adipocytes), and germ cells (gametes), without being limited to these examples. In particular, cells can also be animal, plant, or bacterial cells.

[0047] The activity of the analyte preferably refers to an electrochemical activity of the analyte; more preferably, the activity of the analyte includes the formation of an electrical potential by or in the analyte.

[0048] For example, the activity of the analyte can involve a change in the membrane potential of a cell. The membrane potential preferably refers to an electrical voltage that arises due to charge differences between two separate compartments within the cell. This separation of charge differences preferably results from the cell membrane, which is permeable only to certain ions. There are different ion concentrations on each side. Therefore, the membrane potential preferably refers to the electrical voltage between the inside and outside of a semipermeable cell membrane.

[0049] If the cell in question is a nerve cell (neuron), the membrane potential can also be referred to as an action potential. Therefore, the activity of the analyte to be detected, and in particular the activity of a cell, can relate to the action potential of a nerve cell or its changes. The action potential primarily refers to a nerve impulse responsible for the transmission of stimuli. The transmission of stimuli takes place in nerve cells (neurons) and manifests itself as a change in the membrane potential. Specifically, the electrical voltage across the cell membrane increases compared to the resting potential. This change in voltage occurs through the opening and closing of voltage-gated ion channels in the membrane. When an electrical stimulus reaches a nerve cell, the voltage changes and the ion channels open.This triggers an action potential that can be transmitted to the next nerve cell. In the context of the invention, the change in the action potential of a nerve cell can preferably be determined by means of an electric current flow within the electrolyte, as explained in more detail elsewhere.

[0050] The activity of an analyte can also relate to other reactions of the analyte. For example, if the analyte is an adherent cell, such as a cancer cell, its activity can also relate to adhesion, which, as explained elsewhere herein, can be measured by the method according to the invention by measuring a change in sealing resistance. Preferably, a measuring device is provided comprising a reference electrode and a sensor surface, wherein the sensor surface comprises a ferroelectric material. The measuring device refers in particular to a structural component that includes at least the aforementioned components, comprising a reference electrode and a sensor surface comprising a ferroelectric material. A measurement signal can preferably be acquired by means of the sensor surface.

[0051] The fact that the measuring device includes a reference electrode means, in particular, that at least one reference electrode is provided and preferably brought into contact with the electrolyte during the detection process, for example, by being immersed in the electrolyte. It may also be preferred that the measuring device includes one or more further electrodes which are brought into contact with the electrolyte during the detection process. For example, two or more reference electrodes can be brought into contact with the electrolyte. Particularly in measurements with a potentiostat, it may be preferred to provide a counter electrode in addition to the reference electrode and bring it into contact with the electrolyte.

[0052] The measuring device may preferably include further components, for example, an electronic component and / or a support structure. The electronic component may preferably be a transistor, an analog-to-digital converter, and / or a digital-to-analog converter. A measurement signal is preferably read out by means of the electronic component. A support structure preferably refers to a component of the measuring device that serves to mount the sensor area comprising a ferroelectric material.

[0053] A support structure can preferably be formed by a transistor substrate of a transistor on which the sensor area is applied.

[0054] It may also be preferred that the support structure forms a separate structure on which the sensor area is mounted. The support structure, as a preferred separate structure, may preferably be connected to the electronic component. Thus, the support structure may preferably be mechanically and / or electrically connected to the electronic component. Particularly preferably, the support structure enables an electrical connection, for example by means of a conductor track or conductor path, between the sensor area and the electronic component. Preferably, the electronic component may be formed by a transistor or components of a transistor, for example, a transistor substrate, source terminal, and / or drain terminal. The measurement signal may, particularly when a transistor is used, be a transistor signal.

[0055] The measuring device may also include other components, such as an electronic circuit for controlling the components of the measuring device, for example for setting a polarization of the sensor area or setting an operating voltage on a transistor, and / or for evaluating the measurement signal.

[0056] The measurement signal allows for inferences about the analyte and / or its activity. Therefore, a measurand can preferably be determined using the measurement signal, wherein the measurand comprises one or more parameters that enable detection (preferably qualitative, semi-quantitative, or quantitative) of the analyte and / or its activity. The measurand can thus be, for example, the concentration or quantity of the analyte.

[0057] The measurement signal can be, in particular, an electrical signal, for example, an electrical voltage, an electrical current, and / or a charge carrier density. The measurement signal can also be a noise signal; for example, the measurement signal can be (static) noise from an electrical signal, such as an electrical voltage or an electrical current. If the measuring device includes a transistor, it is preferred that the measurement signal is essentially generated by a transistor signal.

[0058] In preferred embodiments, the measurement signal is therefore a transistor signal, particularly if the measuring device includes a transistor. The transistor signal preferably denotes a signal that is detected by means of the transistor of the measuring device. The measurement signal can preferably be a transistor current, preferably a current between source and drain (ID or IDS), or a transistor voltage, preferably a voltage between the electrode as gate and a bulk or substrate (Vc or Vcs) of the transistor.

[0059] A transistor is known as a device that enables the control and / or amplification of an electrical signal. In particular, a transistor is a field-effect transistor comprising a source terminal and a drain terminal. In a field-effect transistor, preferably only one type of charge is involved in the electric current, i.e., preferably electrons or (electron) holes.

[0060] The sensor area can preferably be arranged on a support structure, the support structure being selected particularly according to how the measurement signal is to be read out. It may be preferred that the support structure is a transistor substrate, in particular a semiconductor substrate, of a transistor. Preferably, the sensor area is arranged on the transistor substrate and forms an insulating ferroelectric layer of the transistor.

[0061] The support structure can also be a component for mounting the sensor area, which is used separately from a transistor in the measuring device. It may be preferred that the support structure provides a mechanical support for the sensor area and also allows an electrical connection between the sensor area and an electronic component, preferably a transistor.

[0062] Furthermore, the measuring device comprises a sensor surface. The sensor surface preferably designates a section of the measuring device that has an active interaction with the analyte and / or the analyte's activity, enabling detection. This active interaction can preferably refer to a (permanent or temporary) spatial displacement, concentration, or deposition of the analyte, for example, a (bio)mechanical or electrostatic bond, such as through dipole-dipole interactions or adhesive forces. The active interaction can also preferably refer to an electrical interaction, for example, an interaction via an electric current resulting from the activity of an analyte in the electrolyte, which leads to a potential difference measurable at the sensor surface. According to the invention, the sensor surface comprises a ferroelectric material.A ferroelectric material is characterized by ferroelectric behavior, which can also be referred to as ferroelectricity. Ferroelectricity specifically refers to spontaneous electric polarization, i.e., the occurrence of a surface charge density without an external electric field. This preferably occurs below a certain transition temperature, the Curie temperature or Curie point. The term is derived from the analogous behavior in the magnetic case (ferromagnetism). It preferably involves the spontaneous alignment or formation of elementary electric dipoles by an internal electric field. An external electric field, for example, applied to the sensor surface, causes the ferroelectric polarization to increase sharply and reach a saturation value when all dipoles are aligned.When the electric field is switched off, the polarization does not disappear completely; instead, a stable polarization state exists, which corresponds to a maximum positive or negative polarization when saturated.

[0063] Polarization can be eliminated by an opposing field, i.e., it can be brought to a state of non-existent polarization (random orientation of the dipoles). Further increasing the opposing field reverses the polarization direction. This behavior of the polarization as a function of the field is called a hysteresis loop or hysteresis curve. It is a characteristic of ferroelectric materials, also known as ferroelectrics or electrets. These materials lose this property above the Curie temperature and transition into the normal paraelectric phase, in which no spontaneous polarization exists, but dielectric polarization can be generated by applying an electric field. The ferroelectric materials according to the invention preferably have a Curie temperature higher than room temperature (approx. 25°C), preferably significantly higher, preferably more than approx. 50°C, approx. 100°C, approx. 200°C or more.

[0064] In the context of the invention, the term ferroelectric material also includes antiferroelectric material and ferrielectric material. These materials exhibit antiferroelectric or ferrielectric behavior, respectively. In antiferroelectricity, electric dipoles of equal strength align themselves spontaneously in antiparallel to each other, analogous to magnetic dipoles in antiferromagnetism. If the antiparallel pairs consist of two dipoles of different sizes, ferrielectricity arises. Furthermore, antiferroelectricity can also refer to a reversible, field-dependent phase transition into a ferroelectric phase. Within the framework of the method according to the invention, a polarization state of the ferroelectric material of the sensor surface is preferably set depending on the analyte to be detected and / or the activity of the analyte to be detected.

[0065] As explained above, the polarization state of the ferroelectric material changes when an electric field is applied. An electric field can be applied, in particular, by applying an electric voltage across the sensor surface, preferably temporarily, for example, between a reference electrode and a bulk terminal of a transistor, provided the sensor surface forms a layer of the transistor. This allows for targeted adjustment of the polarization state. For example, by applying a voltage, such as a time-dependent voltage signal U(t) with one or more voltage peaks, a maximum positive remanent polarization state (+P) can be achieved. r ,max) or a maximum negative polarization state (-P r ,max) can be set. Likewise, a polarization state between the +P r ,max and the -P r,max possible, which in particular also includes a polarization state of P r = 0 (unpolarized) belongs.

[0066] Preferably, the polarization state of the ferroelectric material of the sensor surface is adjusted depending on the analyte to be detected and / or its activity. The measuring device, comprising a reference electrode and a sensor surface comprising a ferroelectric material, is provided specifically for a single measurement process.

[0067] Preferably, the polarization state of the ferroelectric material is set before the measurement process. Furthermore, the polarization state is preferably kept essentially constant for the duration of the measurement process. In other words, it is preferred to maintain a permanent polarization state for the entire measurement process. Preferably, the polarization state is set for an expected analyte to be detected and / or the expected detectable activity of the analyte. Therefore, it is preferred that the polarization state be set to a specific state for the duration of the measurement process. In particular, it is preferred not to continuously change the polarization state of the ferroelectric material, as is proposed in the prior art to exploit the negative capacitance of ferroelectric materials.

[0068] By adjusting the polarization state, the measurement signal can be optimized for a specific analyte or its activity, as explained herein. In particular, sensitivity can be maximized or minimized by adjusting the polarization state. This allows for the measurement of a macroscopic charge distribution on the surfaces of the ferroelectric material. The macroscopic charge distribution on the surface preferably represents a measure of the polarization state, for example, a positive polarization state +P. r or negative polarization state +P r The polarization state or polarization can preferably be expressed in the SI unit C / m². 2 (Coulomb per square meter) can be specified, with a value in pC / cm² also being an option. 2 (microcoulombs per square centimeter) may be preferred.

[0069] Furthermore, the electrolyte is brought into contact with the sensor surface to enable the detection of the analyte and / or its activity. The electrolyte preferably refers to a chemical compound that is dissociated into ions in the solid, liquid, or dissolved state and that moves in a directed manner under the influence of an electric field. In particular, the electrolyte acts as a conductor for charge carriers, especially with regard to signal transmission from the reference electrode to other components of the measuring device, for example, an electronic component, preferably a transistor.

[0070] Preferably, the electrolyte is an ion-containing liquid comprising the analyte. In the context of the invention, the electrolyte comprising the analytes can also be referred to as a sample in which the analyte or its activity is to be detected. For example, an electrolyte can be any ion-containing liquid whose pH value is to be determined, for example, by detecting hydrogen ions or protons. In the case of biomolecules or cells as analytes, the electrolyte can also be, for example, any biologically compatible buffer solution, such as a phosphate-buffered saline solution (PBS).

[0071] The contacting process can in particular include applying the electrolyte to the sensor surface or inserting the sensor surface into the electrolyte.

[0072] The electrolyte can be applied, for example, by depositing a liquid electrolyte in droplet form onto the sensor surface, such as via a pipetting process. In a pipetting process, the electrolyte is preferably applied to the sensor surface using a pipette, in order to subsequently detect the analyte and / or its activity within the electrolyte. This method advantageously allows for the application of a precisely measured amount of electrolyte to the sensor surface. Examples of suitable pipettes include, but are not limited to, dropper pipettes, microliter pipettes, milliliter pipettes, multipipettes, open pipettes, piston-stroke pipettes, and / or multichannel pipettes.The volume of the electrolyte as a sample droplet can be selected depending on the extent of the sensor area and the penetration depths to be preferably set, for example to ensure detection over a predominant part of the applied electrolyte.

[0073] It may also be preferred that the sensor surface of the measuring device is immersed in the electrolyte. For this purpose, the measuring device, in particular the transistor, can be immersed, for example, in a container containing the electrolyte or installed in a container containing the electrolyte or through which the electrolyte flows. For example, in-situ detection of an analyte in corresponding pipelines can be carried out in this way. It may also be preferred to implement the in-situ detection within an implant system or wearable device. Likewise, it may be preferred to test a large number of samples using the method according to the invention by pipetting small volume drops of the electrolyte or the sample onto corresponding sensor surfaces. The contacting can thus be carried out flexibly, depending on the application of the detection method.

[0074] The contacting of the electrolyte with the sensor surface can preferably refer to physical contact between the electrolyte and the sensor surface. However, this contacting is not limited to physical contact but also preferably includes functional contact involving an interaction between the electrolyte and the sensor surface. This interaction can manifest itself, in particular, through the formation or modification of an electrochemical double layer at the interface between the electrolyte and the sensor surface. As explained in more detail elsewhere herein, the electrochemical double layer preferably forms as a result of electrostatic interactions between the electrolyte and the sensor surface.The type and / or concentration of an analyte in the electrolyte can alter the structure, composition, and / or charge distribution of the electrochemical double layer, which can be used in the context of the measurement procedure for the analyte measurement. For example, a measurable change in the potential of the electrochemical double layer correlates with a change in the presence of ions in the electrolyte. The term "contacting" therefore preferably also includes such electrochemical interactions.

[0075] In a further preferred embodiment, the method is characterized in that the measuring device comprises a transistor, wherein the sensor area forms a layer of a transistor and wherein the transistor has a transistor substrate as well as a source terminal and a drain terminal.

[0076] Preferably, the transistor layer, which encompasses the sensor area, is formed from a ferroelectric material, comparable to the insulating layer of an insulated-layer field-effect transistor. The drain and source terminals are preferably located within the transistor substrate. An electric current flows between the source and drain terminals, which can serve as a measurement signal via the transistor.

[0077] In the preferred embodiment, in which the sensor surface forms a layer of a transistor and the transistor has a transistor substrate, the transistor substrate preferably forms a support structure on which the sensor surface comprising a ferroelectric material is applied.

[0078] In a further preferred embodiment, the method is characterized in that the measuring device comprises a transistor, wherein the sensor area is electrically connected to a gate terminal of the transistor. The gate terminal can preferably be a metal-oxide-semiconductor field-effect transistor (MOSFET).

[0079] Preferably, the sensor surface is mounted on a support structure that forms a component of the measuring device. The support structure can, in particular, serve to mechanically stabilize the sensor surface and / or to establish an electrical connection between the sensor surface and an electronic component, for example, a transistor. Preferably, the support structure comprises an electrically conductive material, more preferably an electrode, on which the ferroelectric sensor surface is mounted. The support structure can also preferably include an electrical connection, for example, in the form of a conductor path or a conductive track, which ensures an electrical connection between the sensor surface and a gate terminal of a transistor.As explained in more detail below, the support structure may preferably comprise a semiconductor substrate, preferably manufactured using CMOS technology, which, for example, has a conductor path in the form of several metal layers.

[0080] Therefore, in the context of the invention, there are several possibilities for providing a support structure on which the sensor surface can be applied.

[0081] In a preferred embodiment, the support structure comprises a transistor substrate on which the sensor area, comprising a ferroelectric material, is applied. Preferably, in these embodiments, the sensor area is located above (i.e., in the direction of the electrolyte) a conduction channel of the transistor substrate, which includes a source terminal and a drain terminal. Preferably, in these embodiments, the sensor area serves as an insulating layer of a transistor. In this respect, the sensor area is preferably arranged directly on the transistor substrate, which forms a support layer for the sensor area.

[0082] In a further embodiment, the support structure comprises a structure on which the sensor surface, comprising a ferroelectric material, is applied, and which preferably provides an electrical connection between the sensor surface and an electronic component. The electronic component can, in particular, comprise a transistor substrate or a separate transistor.

[0083] In a preferred embodiment, the support structure comprises, in particular, an electrically conductive material, which especially forms an electrode. The electrically conductive material can, in particular, be embedded on or in a semiconductor substrate and, especially, be located below the sensor surface. Preferably, in this embodiment, the electrode forms a support layer for the sensor surface.

[0084] The electrode can in turn preferably be connected to an electronic component, for example a transistor, by means of an electrical connecting means, for example by means of a conductor track and / or a conductor path.

[0085] Furthermore, the support structure can preferably comprise a support substrate that stabilizes the conductive material, for example, an electrode, a conductor track, and / or a conductor path. The support substrate of the support structure can, for example, be a semiconductor substrate, preferably enabling the fabrication of the support structure using CMOS technology.

[0086] It may also be preferred that the support substrate of the support structure comprises, for example, a dielectric and / or biocompatible material, such as polyimide, epoxy resin, and / or parylene. Particularly preferably, in these embodiments, the support substrate may be formed by a material that can be used as a substrate in printed circuit boards (PCB material). Preferably, the support substrate may be formed, for example, from a material, preferably a PCB material, selected from the group comprising plastics (e.g., polyimides), fiber-reinforced plastics (e.g., glass fiber-reinforced plastics such as GRP), hard paper (a material comprising paper and a phenolic and / or epoxy resin), FR4, and / or FR5, without being limited to these examples.

[0087] In a preferred embodiment, the transistor is an electrolytic ferroelectric semiconductor field-effect transistor (EFSFET).

[0088] Since ferroelectric materials always also have dielectric properties (but not vice versa), EFSFETs preferably also have the properties of conventional EOSFETs (electrolytic oxide semiconductor field-effect transistor) with dielectric sensor surfaces.

[0089] The electrolytic ferroelectric semiconductor field-effect transistor, or EFSFET, preferably refers to a special type of field-effect transistor with an insulated gate terminal. The measuring principle and operating principle of the EFSFET are comparable to those of an insulated-film field-effect transistor, in which current flow between the source and drain terminals is preferably controlled by charge carrier induction via the electrically insulated gate terminal. Preferably, the gate terminal is formed, among other things, by the reference electrode. In discussions of the EFSFET's gate terminal, it can preferably also be said that the gate terminal of the EFSFET is formed by the reference electrode and the electrolyte. Thus, a connection to the reference electrode can also be considered a gate terminal.The design of the gate terminal distinguishes the EFSFET from conventional metal-oxide-semiconductor field-effect transistors (MOSFETs), in which the gate terminal is provided by a metal layer formed on a preferred transistor substrate. In contrast, for an EFSFET, the gate is formed by a combination of a reference electrode and an electrolyte.

[0090] In an EFSFET, a current preferably flows between the source and drain terminals, analogous to a MOSFET, and this current can be influenced by a gate voltage. Furthermore, it is also preferred that the EFSFET has a bulk or substrate terminal.

[0091] The transmission path between the source and drain terminals of the EFSFET can also be called a channel. The gate terminal, in particular the reference electrode and the preferred bulk terminal, allows for current or signal control by applying a voltage between these terminals, thus influencing the channel.

[0092] It is preferred that the EFSFET comprises a transistor substrate. The transistor substrate preferably comprises an electrically conductive material and / or a semiconductor material.

[0093] In particular, the transistor substrate can be a semiconductor substrate. This is also referred to as bulk. It may also be preferred that a processed substrate, especially with regard to the material to be used and / or the geometric design for the provision of the EFSFET, is referred to as bulk.

[0094] In preferred embodiments, the sensor area is located on a support structure comprising a semiconductor structure manufactured using CMOS technology. The EFSFET is configured such that the electrolyte with reference electrode and the adjacent ferroelectric layer are connected to the gate of a conventional MOSFET via an electrical connection, for example, a metallic path within the semiconductor structure. This enhanced embodiment of the transistor can also be referred to as an enhanced EFSFET or eEFSFET.

[0095] The procedure is explained below using the example of a simpler EFSFET.

[0096] Preferably, the source and drain terminals are located within the bulk of an EFSFET. The source and drain terminals particularly comprise sections within the bulk that are more heavily doped than the remaining bulk. Furthermore, the source and drain terminals preferably have a doping composition that is opposite to a preferred doping composition of the bulk.

[0097] For example, if p-type silicon, i.e., p-doped silicon, is used as bulk material, it is preferred that the source and drain terminals include n-type doping. In particular, p-type silicon is then preferably present as the material between the source and drain terminals. Accordingly, an npn structure is formed by the source terminal, the bulk material (or, in this example, the p-type silicon), and the drain terminal. The charge carriers for signal or current transmission between the source and drain terminals are provided by electrons. This is referred to as an n-channel when electrons are transferred between the source and drain terminals, especially when the source and drain terminals include an n-doped section.

[0098] Conversely, it may also be preferred to use an n-doped substrate or bulk for the EFSFET. With an n-doped substrate or bulk, it is preferred that the source and drain terminals comprise p-doped sections formed within the bulk. In particular, the n-doped substrate or bulk material is then located between the two p-doped sections providing the source and drain terminals. This results in an npn structure. The charge carriers for signal or current transmission between the source and drain terminals are provided by holes or holes. This is referred to as a p-channel when holes are transmitted between the source and drain terminals, especially when the source and drain terminals comprise p-doped sections.

[0099] The channel, which can also be referred to as a conduction channel, and which can be formed by either an n-channel or a p-channel, is located within the transistor substrate or the bulk. It is particularly preferred that the channel is located below the sensor area comprising a ferroelectric material. It is especially preferred that the sensor area adjoins the channel. The ferroelectric material is simultaneously dielectric, i.e., electrically insulating, and thus the sensor area comprising the ferroelectric material provides insulation between the channel and / or the source terminal and the drain terminal from the electrolyte and / or the reference electrode.

[0100] Preferably, the source terminal and / or the drain terminal are contacted with and / or comprise an electrically conductive material in order to tap the current between the source terminal and the drain terminal, particularly with regard to the respective intended use, and in the context of the invention, especially to receive, for example, a transistor signal as the measurement signal in order to enable detection of the analyte and / or the activity of the analyte. The electrically conductive material can, in particular, be formed by an electrode.

[0101] Preferably, the drain terminal and the source terminal extend along a first (e.g., horizontal) direction of the EFSFET, while preferably a connecting line between the gate terminal and the bulk terminal is directed substantially perpendicular to this in a second (e.g., vertical) direction. In a model representation, the arrangement comprising the gate terminal and the bulk terminal corresponds to an arrangement comprising two capacitor plates. The sensor area comprising the ferroelectric material is located between the gate terminal, i.e., the reference electrode, and the bulk terminal, wherein the ferroelectric material is particularly also dielectric. In the model description, the arrangement comprising the gate terminal, the bulk terminal, and the sensor area comprising a ferroelectric material thus corresponds to a parallel-plate capacitor comprising two plates with an intermediate ferroelectric.

[0102] The model-based description of the capacitor allows the operation of the EFSFET to be explained using a field effect. In particular, by applying a voltage, the gate voltage—specifically the voltage between the reference electrode and a bulk terminal of the EFSFET—the channel or the current in the channel can be controlled.

[0103] If, for example, an n-channel is used, applying a positive gate voltage charges the capacitor comprising the gate terminal, the sensor area comprising the ferroelectric material, and the bulk terminal. The resulting electric field causes minority carriers (electrons in this example) in the p-substrate to migrate to the interface and recombine with the majority carriers, which form holes in the p-substrate. This process displaces the holes, a phenomenon also known as "depletion." A space charge region with a negative space charge forms at the interface with the sensor area. Above the threshold voltage, the displacement of holes is so significant that they are no longer available for recombination with electrons. A buildup of minority carriers (electrons) occurs, causing the p-doped substrate near the sensor layer to become n-type. This state is called strong "inversion."Explained in terms of the band model, the increased gate voltage leads to a band bending of the conduction and valence bands at the interface. Above the critical voltage or threshold voltage, the Fermi level lies closer to the conduction band than to the valence band. The semiconductor material or transistor substrate is thus inverted. The resulting n-type channel now connects the two n-regions, the source terminal and the drain terminal, allowing charge carriers to flow (almost) unimpeded from source to drain.

[0104] A physically equivalent mode of operation results in a p-channel, where, however, a negative gate voltage is applied and the majority carriers form electrons, while the minority carriers are provided by holes.

[0105] The voltage between the gate and bulk terminals allows for precise channel dimensional control. Specifically, the vertical portion of the channel can be adjusted by this voltage. This, in turn, allows for control of the charge carrier density and, consequently, the current between the source and drain terminals. Therefore, the field effect of the EFSFET can cause the channel to expand or contract via the gate voltage, particularly when a voltage is applied between the reference electrode and the bulk terminal. Furthermore, as explained in more detail below, the presence of an analyte in the electrolyte or its activity leads to potential differences that influence the transistor's threshold voltage and thus also affect the field effect, specifically the expansion or contraction of the conducting channel in the substrate.A signal, in particular an electric current and / or a charge carrier density between the source and drain terminals, can thus constitute a measurement signal that allows conclusions to be drawn about the analyte or its activity in the electrolyte. Signals from the transistor, especially the EFSFET, can also be referred to as transistor signals. These transistor signals can also function as measurement signals to allow conclusions to be drawn about a measured quantity.

[0106] The above explanations relating to a simple EFSFET, in which the sensor area preferably forms a ferroelectric (insulating) layer of the transistor and is located on a transistor substrate which serves as a support structure, are preferably transferred essentially analogously to an extended EFSFET or further embodiments in which the sensor area is located on a (separate) support structure and does not necessarily form an insulating layer of the transistor.

[0107] As explained above, it may be preferred, for example, that the sensor area is located on a support structure that electrically connects the sensor area to a gate terminal of a transistor, preferably a conventional MOSFET. The support structure may preferably be a semiconductor structure manufactured using CMOS technology. Preferably, the support structure may include an electrically conductive path, for example in the form of conductor tracks and / or vias within a semiconductor structure, which provides the electrical connection between the sensor area and an insulating layer of a (conventional) field-effect transistor.

[0108] The support structure can also be formed, for example, by a printed circuit board which has an electrode on which the sensor area is applied as a ferroelectric layer and which is connected by means of conductor tracks to a separate transistor, preferably a conventional MOSFET, which is installed, for example, as a chip on the printed circuit board.

[0109] In these embodiments as well, the presence of an analyte in the electrolyte or its activity can lead to potential differences which influence a threshold voltage of the transistor and also affect the field effect or the widening or constriction of a conducting channel in a transistor substrate, preferably the conventional MOSFET.

[0110] Preferably, the principle of capacitive voltage division can be used to detect the analyte and / or its activity. A first capacitance is preferably defined by the sensor area, which is located, for example, on an electrode. A second capacitance can be defined by the insulating layer or the gate terminal of the transistor. Preferably, the first capacitance is larger than the second capacitance, so that a predominant voltage is present across the transistor, and the measurement signal, preferably a transistor signal, can be detected with high sensitivity depending on the presence of an analyte and / or its activity.

[0111] Terms such as "essentially", "approximately", "about", etc. preferably describe a tolerance range of less than ± 20%, more preferably less than ± 10%, even more preferably less than ± 5%, and particularly less than ± 1%. Statements of "essentially", "approximately", "about", etc., always disclose and include the exact value stated. In a further preferred embodiment, the method is characterized in that the polarization state of the ferroelectric material of the sensor surface is adjusted such that the sensitivity of the sensor surface for the detection of the analyte and / or the activity of the analyte is maximized or minimized.

[0112] The sensitivity of the sensor area is in particular the sensitivity of the transistor, since, as described above, the sensor area forms a section of the transistor of the measuring device.

[0113] Sensitivity preferably refers to the ratio of the change in the measurement signal to the underlying change in the measured quantity. The greater the change in the measurement signal, for example, due to a change in the measured quantity (e.g., the concentration of an analyte), the greater the sensitivity. The measurement signal is preferably an electrical signal from the transistor, i.e., a transistor signal, preferably a transistor current or a transistor voltage. The cause of a change in the measurement signal preferably lies in the change in the measured quantity, i.e., in the context of the invention, in particular a change in the concentration or amount of an analyte and / or an activity of an analyte in the electrolyte.

[0114] The measurement signal is acquired via the interaction between the sensor surface and the analyte and / or the analyte's activity, as described above, to enable detection. According to the invention, the sensor surface comprises a ferroelectric material. As described above, the ferroelectric material preferably exhibits a spontaneous electrical polarization that can be reversed by an external electric field. This polarization is not permanent and can change under the influence of an external electric field, which can preferably be predetermined by applying an electrical voltage. Thus, the polarization or polarization state of the ferroelectric material can be adjusted by applying a corresponding voltage.

[0115] Advantageously, the polarization state of the ferroelectric material can again be used to maximize or minimize the sensitivity, thereby enabling more reliable detection of the analyte and / or the analyte activity.

[0116] Maximizing sensitivity may be advantageous, for example, when a specific type of analyte, such as an ion type (see Fig. 3A), is to be detected. In this case, the polarization state can preferably be selected such that the influence of the ions to be detected on the conduction channel between the source and drain terminals in the substrate is maximized. This means that, due to a field effect that is particularly dependent on the ion concentration in the electrolyte, as described above with regard to the operation of a preferred EFSFET as a transistor, a transistor signal (e.g., a transistor current between the source and drain terminals) will change significantly. With respect to a specific polarization state, a charge distribution preferably forms at the interfaces of the ferroelectric material such that the sensitivity of the sensor area is maximized.The transistor's polarization for ion detection is increased. A polarization state optimized for analyte detection or its activity can be generated, for example, by applying a voltage and the resulting remanent polarization state (see Fig. 3B). Since the ferroelectric material is characterized by its hysteresis curve, two (maximum) remanent polarization states of the ferroelectric material can be established, provided the voltage is sufficiently high.

[0117] Remanent polarization states exist when the external electric field is switched off. Depending on whether a voltage signal has previously caused a positive or negative alignment of the dipole moments of the ferroelectric material, these states differ in their orientation. Therefore, one can also speak of reversed remanent polarization states, or of positive and negative remanent polarization. If a voltage signal is chosen that does not lead to saturation of the orientation, so that the hysteresis curve is not driven in the positive or negative direction towards maximum alignment of the dipole moments, remanent polarization states can also be established that lie between the maximum, negative, and positive (remanent) polarization states.The intermediate states can be set in particular by appropriately choosing a voltage peak, whereby, starting from a lower dipole moment alignment when the voltage is switched off, i.e., no external electric field, a remanent polarization state with essentially the same or slightly reduced dipole moment alignment remains.

[0118] By setting a positive or negative remanent polarization state, the sensitivity for detecting a particular analyte type or its activity can preferably be optimized.

[0119] Depending on the type of ion, i.e., specifically whether it is a cation or anion, higher sensitivity can be achieved by setting a negative or positive residual polarization state. Similarly, a positive or negative polarization state can influence the adhesion of biomolecules or cells to the sensor surface, thus maximizing sensitivity with respect to the detection of specific biomolecules or cell activity.

[0120] Maximizing sensitivity allows for a greater change in a measurement signal (with the same change in the measured quantity), which advantageously improves the signal-to-noise ratio and reduces statistical uncertainty regarding the detection of the analyte and / or the activity of the analyte.

[0121] Similarly, it may be preferable to select a polarization state that, on the one hand, exhibits particularly high sensitivity with regard to the detection of the analyte and / or its activity, but without necessarily achieving maximum sensitivity. This is because, for example, an intermediate polarization state can be used to achieve a significantly reduced sensitivity to any interfering signal. This can be advantageous, for instance, if the electrolyte contains multiple ion species, but the detection of a specific ion species is desired, while minimizing the influence of a potentially dominant ion species that cannot be detected on the measurement signal.

[0122] The ability to set different polarization states offers a high degree of flexibility for a wide variety of measurement configurations.

[0123] In certain measurement configurations, it may be preferable, for example, to minimize the sensitivity of the sensor area for detecting an analyte and / or its activity. This is particularly the case when the measuring device has a bidirectional interface, comprising a sensor area and a stimulation area. Here, an electric current can preferably be injected into the electrolyte via a stimulation area, as explained in more detail below, whereby a measurement signal, preferably in the form of a voltage signal, can be obtained at the sensor area. Preferably, an oscillating current signal can be injected into the electrolyte, wherein the amplitude and / or phase of the measurable oscillating voltage signal at the sensor area allows conclusions to be drawn about the impedance of the electrolyte.Since such an impedance measurement is also influenced by the presence of an analyte and / or the activity of an analyte in the electrolyte, this measurement signal can be used for detection.

[0124] Minimizing the sensitivity of the sensor area with respect to analyte detection and / or analyte activity, in this case, means specifically minimizing a transistor signal that arises from a gate voltage between the source and drain terminals due to the influence of the analyte and / or its activity in the electrolyte. Since the measurement of the analyte and / or its activity in the electrolyte, when using the measuring device as a bidirectional interface, depends primarily on the described impedance measurement, other signals that do not correlate with the injected current in the stimulation area can also be reduced.

[0125] In a further preferred embodiment, the method is characterized in that the method comprises determining a polarization state of the ferroelectric material in which the sensitivity of the sensor area for detection of the analyte and / or the activity of the analyte is maximal or minimal, wherein preferably a measurement signal, preferably a transistor signal, is acquired for at least two different polarization states of the ferroelectric material for a reference electrolyte with a known concentration of an analyte and / or a known activity of an analyte.

[0126] Preferably, the determination of an optimized polarization state of the ferroelectric material, preferably with which a maximization or minimization of the sensitivity for the analyte and / or the activity of the analyte is carried out before the actual (detection) procedure for the detection of the analyte and / or an activity of the analyte in an electrolyte or a sample to be measured.

[0127] It is preferred that a reference electrolyte with a known concentration of an analyte to be detected and / or a reference electrolyte with a known activity of the analyte is provided. A measurement signal, preferably a transistor signal, for example a transistor current or a transistor voltage, is preferably applied to the reference electrolyte for at least two different polarization states. These can, for example, be two different polarization states selected from the group comprising a maximum positive remanent polarization state (+P). r ,max), a maximum negative remanent polarization state (+P r ,min) and / or one or more arbitrary intermediate states, in particular also an unpolarized polarization state (P=0).

[0128] Based on the specific measurement signal, for example a transistor signal, it is possible to determine which of the two different polarization states yields a higher measurement signal and thus a higher sensitivity.

[0129] Preferably, the measurement for the at least two different polarization states can also be carried out for a plurality of reference electrolytes with known but different concentrations of the analyte or activities of the analyte in order to be able to evaluate the influence of the polarization state on the sensitivity more precisely over different measuring ranges (see Fig. 3A).

[0130] Advantageously, the preferred method allows the sensitivity of the measuring device for the detection of specific analytes and / or activities to be optimized by adjusting the polarization state of the ferroelectric material. It is not strictly necessary to apply functional coatings, such as an ion-sensitive membrane. Instead, by optimizing the sensitivity—for example, by maximizing or minimizing it—a favorable measurement signal is provided by adjusting the polarization state of the ferroelectric material.

[0131] In preferred embodiments, 3, 4, 5, 10 or more polarization states can also be set for one or more reference electrolytes, each with a known concentration of an analyte or known activity of the analyte, in order to approximately determine a polarization state at which the sensitivity is maximal or minimal based on the obtained measurement signal(s), preferably the transistor signal(s).

[0132] Determining a polarization state at which the sensitivity is maximal or minimal means, in particular, determining a polarization state as a selection from at least two different polarization states, whereby selecting a polarization state with a higher sensitivity corresponds to maximizing the sensitivity, while selecting a polarization state with a lower sensitivity corresponds to minimizing the sensitivity. Thus, maximum or minimum sensitivity is preferably not to be understood as an absolute value, but rather as a relative value. The term "maximum" therefore preferably means the highest possible sensitivity, i.e., preferably the highest sensitivity compared to other possible sensitivities for the measured polarization states. The term "minimal" therefore preferably means the lowest possible sensitivity, i.e.,preferably in comparison to other possible sensitivities at measured polarization states, preferably lowest sensitivity.

[0133] After determining the optimized polarization state, the actual (detection) method can preferably be carried out, beginning with the adjustment of the ferroelectric material of the sensor surface to the determined polarization state. Subsequently, using the previously determined (optimal) polarization state, a (sample) electrolyte is brought into contact with the sensor surface. The (sample) electrolyte preferably has an unknown concentration of an analyte and / or an unknown activity of the analyte, and the analyte and / or its activity can be detected using the method according to the invention, as described herein.

[0134] In a further preferred embodiment, the method is characterized in that the analyte and / or the activity of the analyte is detected using a measured transistor signal, wherein the transistor signal comprises an electric current, an electric current density, an electrical conductivity and / or a charge carrier density between the source terminal and the drain terminal.

[0135] A transistor signal can preferably be a signal for controlling the transistor and / or a signal that is detected by means of the transistor, for example a voltage and / or a current and / or a charge carrier density between the terminals of the transistor, in particular between the source terminal and drain terminal, between gate terminal and source terminal and / or between gate terminal and a bulk terminal.

[0136] Electric current can be supplied, for example, by electrons or holes (electron defects). In particular, the specification of an electric current refers to its current intensity. Current density is defined as the ratio of the current intensity to the cross-sectional area available to the current flowing perpendicularly. Electrical conductivity is defined as the constant of proportionality between current density and electric field strength. Charge carrier density refers specifically to the number of charge carriers present in a given volume, relative to that volume.

[0137] As explained above, in particular by applying a voltage between a gate terminal and a bulk terminal of a transistor, especially an EFSFET transistor, the signal, in particular the current, between the source terminal and the drain terminal can be controlled.

[0138] In particular, the voltage between the gate terminal and the bulk terminal VG, the voltage between the source terminal and the drain terminal VD and the threshold voltage VT can influence the channel, especially with regard to widening or constriction, in a transistor.

[0139] If the voltage VG is below a threshold voltage VT, the transistor is in a cutoff region where there is virtually no current flow. Current flow between the source and drain terminals ID can occur if the voltage between the gate and bulk terminals VG is above the threshold voltage: VG S VT. Preferably, the voltage between the source and drain terminals VD < VG-VT. This region can also be called the active region, where there is a linear relationship between the current flow ID and the source voltage VD.

[0140] In the saturation region, the current between the source and drain terminals (ID) and the voltage (VD) run approximately parallel to the Vo axis. Increasing the voltage between the drain and source terminals has little effect on the current. The threshold at which this behavior becomes apparent is D, satur = G - T.

[0141] As explained in more detail below, it is preferable to choose the operating point of the transistor such that it is located in an active region.

[0142] In a further preferred embodiment, the method is characterized in that the measuring device comprises a transistor and a change in the threshold voltage of the transistor as a function of the polarization state of the ferroelectric material is effected by i) a change in a potential drop in the electrolyte, ii) a change in a potential drop across an electrochemical double layer and / or iii) a change in an interfacial polarization at an interface between the sensor surface and the electrolyte.

[0143] Preferably, the threshold voltage denotes a voltage value above which the transistor becomes electrically conductive, thus enabling the transfer of an electric current between a source terminal and a drain terminal. In particular, it is therefore preferably necessary to set a voltage between the gate terminal and the source terminal of the transistor for an operating point of the device, which is at least equal to the threshold voltage, so that a current flows between the source terminal and the drain terminal. Accordingly, the threshold voltage can be determined in a characteristic curve of the transistor at the point above which a current is possible between the source terminal and the drain terminal.

[0144] In a further preferred embodiment, the method is therefore characterized in that the measuring device comprises a transistor and a change in the threshold voltage can be measured by means of a change in the gate voltage of the transistor and / or by means of a change in an electric current between a source terminal and a drain terminal. The gate voltage can preferably be an electric voltage between the reference electrode and a bulk terminal of an EFSFET transistor, in which the sensor area preferably forms an insulating layer of the transistor. Likewise, the gate voltage can preferably refer to a gate voltage at a separate transistor, for example, a conventional MOSFET, for instance, if the transistor is an extended EFSFET.

[0145] The change of a threshold voltage ÖVT EFS(which, as explained in more detail below, depends on the properties of the electrolyte or analyte) is in particular equivalent to a change in a gate voltage eVc. sens :

[0146] (1) public transport G sens = - Public transport T EFS

[0147] The subscript G denotes the gate terminal (for example, the connection to the reference electrode), while sens stands for the sensor. The subscript T denotes the threshold voltage, and EFS is an abbreviation for an EFSFET transistor. Advantageously, as explained in more detail below, the threshold voltage depends on the analyte or its activity in the electrolyte, so that determining the change in the threshold voltage, preferably based on a change in the transistor signal, can be used to detect the analyte and / or its activity.

[0148] The factors influencing the threshold voltage can be derived in particular by considering the total potential, which corresponds to the potential difference between the electrical potential in the electrolyte E and the substrate, for example a semiconductor substrate Sj: <p~ E - <p~ Si

[0149] The difference in electrical potentials is determined by (i) a potential drop in the electrolyte, (ii) a potential jump between the interface between the electrolyte and the dielectric sensor surface (for example, an oxide), (iii) a potential drop in the dielectric sensor surface, (iv) a potential jump across the sensor surface / substrate interface, and (v) a potential drop in the substrate (preferably a semiconductor).

[0150] The threshold voltage depends in particular on a plurality of potentials and parameters.

[0151] The change in the threshold voltage for an EOSFET with dielectric sensor surfaces can be described from the above potential differences according to Fromherz (2012) by

[0152] (2) Public transport T EOS = - öA <p« E

[0153] - ö(Acp Gouy + öAcp stern )

[0154] - Ö(AX OX,E - Ax E Ox ), where öA <p~ E describes a change in the potential in the electrolyte E, ö(A) <p Gouy + öAcp stern ) a change in the potential of an electrochemical double layer and ö(Ax) Ox E - Ax E Ox ) describes a change in potential due to interfacial polarization between a dielectric material and the electrolyte E.

[0155] The index "Ox" preferably stands for the oxide layer and the index "E" for the electrolyte.

[0156] According to the invention, it was recognized that a change in the threshold voltage ÖVT EFSThe behavior of an EFSFET, in turn, depends on the polarization P. FE of the ferroelectric material FE of the sensor surface. In particular, the change in the threshold voltage ÖVT EFS therefore also a functional of polarization P FE of the ferroelectric material F. Since an EFSFET always also has the properties of an EOSFET, relationship (2) can be generalized to

[0157] (3) Public transport T EFS [P FE ] = - öA <p« E [P FE ]

[0158] - ö(Acp Gouy + öAcp stern ) [P FE ]

[0159] - Ö(A X F E - A X E F ) [P FE ].

[0160] In particular, by appropriately choosing a polarization state P FEThe influence of one of the aforementioned terms on the threshold voltage, and thus on the measurement signal, can be adjusted. The subscript "E" continues to stand for the electrolyte. The subscript "F" denotes the ferroelectric layer.

[0161] The individual terms on the right-hand side of equation (2) or (3) correlate in particular with specific types of an analyte and / or its activity, so that detection is possible by determining the change in the threshold voltage. In particular, it is also possible to infer the analyte and / or its activity with respect to a measured quantity, such as the analyte concentration or the (electrical) signal strength of an electrochemically active analyte.

[0162] In a further preferred embodiment, the method is characterized in that the measuring device comprises a transistor and a change in the potential in the electrolyte is measured by means of a change in the threshold voltage of the transistor, which correlates with a current flow in the electrolyte, wherein the current flow has a dependence on an activity of the analyte, particularly preferably an action potential of a neuron.

[0163] The change in potential in the electrolyte is described by the term εAcp~ E [P FE ] described. The change in potential in the electrolyte ΔAcp~ E This correlates particularly with an electric current flow in the electrolyte. This allows, for example, the detection of the activity of an electrochemically active analyte, since the electric current flow is determined by the change in the potential in the electrolyte ΔAcp~. EThis, in turn, correlates with the activity of the analyte. For example, a cell's membrane potential, preferably an action potential of a neuron, can cause an electric current in the electrolyte, so that the change in electrolyte potential can be used to determine the ΔAcp. E a direct inference about the cell's membrane potential or the neuron's action potential is possible.

[0164] In particular, the sealing resistance of a neuron adhered to the sensor surface can also be determined via an extracellular voltage Vj. The extracellular voltage is generated by cellular currents and is related to a gap conductance (see, among others, Fig. 2). As described below, the gap conductance influences the spectral power density of the electrical noise, from which a sealing resistance can in turn be determined to enable the detection of an analyte and / or its activity.

[0165] In a further preferred embodiment, the method is characterized in that a change in the potential of an electrochemical double layer is measured by means of a change in the threshold voltage of a transistor, which correlates with the presence of the analyte in the electrolyte, wherein the analyte is preferably an ion.

[0166] The electrochemical double layer preferably refers to the formation of two interface layers between the sensor surface and the electrolyte. Typically, two charge layers with opposite signs face each other at the phase boundary in the charged state. The "thickness" of the charged layers, i.e., the average extent perpendicular to the surface of the sensor area, is preferably about 0.1 nm to 10 nm and can be described in particular by the Debye length. In the context of the invention, the electrochemical double layer can be described by a Stern double layer (hence the subscript Stern in equations (2) and (3)), in particular by the Stern model, which combines the models of the Helmholtz layer and the Gouy-Chapman double layer (hence the subscript Gouy in equations (2) and (3)). The change in potential through the two interface layers, respectively, is described by the change in potential across the two interface layers.The electrochemical double layer is represented in equations (2) and (3) by the term ö(A). <p. Gouy + Acp stern ) described. In the Stern model of the Stern double layer, a layer in the electrolyte comprises a rigid layer and an adjacent diffuse layer. The Stern model takes into account that electrically charged particles, especially ions, have a finite size.

[0167] Therefore, a shift of charged particles, especially ions, towards the sensor surface, particularly through ion attachment, causes a change in the potential of the electrochemical double layer. Thus, the change in the potential of the electrochemical double layer allows conclusions to be drawn, in particular, about the presence of ions in the electrolyte.

[0168] In a further preferred embodiment, the method is characterized in that a change in interfacial polarization at an interface between the sensor surface and the electrolyte is measured by means of a change in a threshold voltage of the transistor, which preferably correlates with an adsorption of the analyte at the interface, wherein the analyte is preferably a biomolecule.

[0169] Interface polarization refers specifically to a polarization that results from the attachment of particles with a dipole moment to the sensor surface. Interface polarization is represented in equations (2) and (3) by the term (Ax). Ox,E - Ax E,Ox ) or (Ax FE - Ax E F ) described. The change in interface polarization θ(Ax) Ox E - Ax E Ox ) or ö(Ax) F E - Ax E FThis correlates particularly with the adsorption of analytes exhibiting a dipole moment at the sensor surface, for example, one or more biomolecules. The presence of biomolecules with a dipole, such as glucose, alters the polarization at the interface, which can influence a measurable transistor signal.

[0170] Thus, a change in the potential of the interfacial polarization can advantageously allow conclusions to be drawn about, for example, biomolecules in the electrolyte.

[0171] In a further preferred embodiment, the method is characterized in that the polarization state of the sensor surface is set by applying an electrical voltage across the sensor surface, for example between the reference electrode and a bulk terminal of the transistor.

[0172] As described above, it is advantageously possible to optimize the sensitivity of the sensor area with respect to a detectable analyte or its activity by adjusting the polarization state of the ferroelectric material. The polarization state can be adjusted, in particular, by applying an external electric field to establish a desired polarization state. The applied electric field correlates, in particular, with the electrical voltage between the reference electrode and a bulk terminal of the transistor via the relationship

[0173] Electric field strength = voltage / distance of the charge distribution.

[0174] Therefore, the electric field strength is directly proportional to the applied voltage, so that the electric field strength and, in turn, the polarization of the ferroelectric material can be adjusted via the voltage.

[0175] The hysteresis of the polarization of the ferroelectric material allows, in particular, a reversal of the polarization state to be achieved, thus maximizing or minimizing sensitivity. Without the voltage or electric field, the remanent polarizations, or the maximum or minimum polarization, are maintained to adjust the sensitivity. However, the hysteresis curve shows that an increase or decrease in polarization, and therefore also in sensitivity, is possible until saturation of the hysteresis curve is reached. This is also referred to as saturation polarization. Saturation polarization occurs with opposite electric fields. For example, positive saturation polarization can occur with a positive electric field, while negative saturation polarization can occur with a negative electric field.

[0176] For example, the operating range of the applied voltage for adjusting the polarization can be between -5 V and +5 V, specifically including 0 V, which correlates with the absence of an external electric field and at which positive or negative remanent polarization is present. The voltage can be designed as a time-varying signal with one or more voltage peaks.

[0177] In a further preferred embodiment, the method is characterized in that, in addition to a polarization state of the ferroelectric material, a gate voltage of a transistor, preferably a voltage between the reference electrode and a bulk terminal and / or a voltage between a source terminal and a drain terminal of a transistor, is set to maximize or minimize the sensitivity of the transistor for the detection of the analyte and / or the activity of the analyte.

[0178] The polarization state of the ferroelectric material can be adjusted, as described herein, to optimize the sensitivity of the sensor area. Further operating parameters can be set via a transistor, specifically through its terminals, between which an electrical voltage can be applied. These parameters can further contribute to optimizing the sensitivity, particularly with regard to maximizing or minimizing it. These additional operating parameters of the transistor include, in particular, an electrical voltage between the drain terminal and the source terminal VD.

[0179] Therefore, at least three operating parameters, namely the polarization state of the ferroelectric material, the voltage between the reference electrode and the bulk terminal, and the electrical voltage between the source and drain terminals, can be selected to maximize or minimize sensitivity. This allows, preferably, the setting of an optimal operating point for particularly reliable detection of the analyte and / or its activity.

[0180] Preferably, the applied electrical voltage is applied to a gate terminal, more preferably between a reference electrode and a bulk terminal, above a threshold voltage of the transistor. The threshold voltage is the voltage value above which, in particular, a signal or current flow (holes or electrons) can be transmitted between the source and drain terminals. Preferably, the voltage between the source and drain terminals is below a saturation voltage, which is preferably a voltage at which the current flow between source and drain is maximum, but the voltage drop is minimal. In the characteristic curve of the transistor, there is a substantially constant relationship between current and voltage above the saturation voltage, so that a change in the concentration or activity of the analyte leads to no or only a small change in the measurable current.

[0181] Applying voltages in the aforementioned regions advantageously ensures particularly good functionality of the transistor for analyte detection and / or analyte activity measurement. One or more characteristic curves can exist within these regions, within which analyte detection and / or analyte activity is performed. For example, a linear characteristic curve can be selected, which is suitable for particularly reliable measurement of the analyte or its activity. However, it may also be preferable to select a non-linear voltage curve, such as an exponential curve, between the gate terminal and a bulk terminal of the transistor.

[0182] In preferred embodiments, an optimized operating point of a preferred transistor of the measuring device can also be influenced by setting a polarization state or reversing the polarization. For example, the operating point for positive remanent polarization may not be identical to the operating point for negative remanent polarization. In particular, if the sensor area is applied to an electrically conductive material that is electrically connected to a (separate) transistor as an electronic component, the ratio between the sensor area and the area of ​​the gate terminal of the (separate) transistor can preferably be selected such that the operating point changes only within desired limits or essentially not at all.

[0183] In a further preferred embodiment, the method is characterized in that the method includes a calibration to determine a calibration factor gM between a change in current ID with respect to a change in voltage VG. EFS

[0184] Preferably, for calibration, a polarization state of the ferroelectric material of the sensor surface is first set such that the sensitivity of the sensor surface for the detection of the analyte and / or the activity of the analyte is maximized, and both the calibration and the actual (detection) procedure are carried out in the polarization state.

[0185] Calibration is preferably performed at that operating point (among other things with regard to a polarization state P). FE , a voltage VG EFSbetween the gate terminal and a bulk terminal or a voltage VD between the source and drain terminals), in which the detection procedure is also carried out.

[0186] Therefore, in a calibration measurement, for example, the change in current ID is measured in relation to a change in voltage VG. EFS between the reference electrode and a bulk connection, determined by a proportionality factor g m , the calibration factor, relationships:

[0187] ÖID KAL = gm ÖVG EFS

[0188] Preferably, an operating point of the transistor (preferably P) was selected. FE , G EFS and D) such that in a measuring range around VG EFS a linear relationship between a change in current flow between Source and ÖID KAL and Drain lo KAL and a change in gate voltage ÖVG EFS is present. The calibration factor g mIn this case, it corresponds to a linear proportionality factor and can be called a gain.

[0189] However, a voltage-dependent calibration factor g is also possible. m (Vc EFS ) conceivable, where, for example, a non-linear relationship exists between ÖVG EFS and ÖID KAL is available.

[0190] Preferably, the calibration is performed around an operating point (P). FE , VG EFS and VD) in a measuring range of ÖVG EFS , which is caused by sample- or electrolyte-dependent changes in the threshold voltage ÖVT EFS That would be expected.

[0191] Preferably, the calibration can be performed using the electrolyte to be measured itself or a comparable reference electrolyte. A comparable reference electrolyte refers in particular to an electrolyte with a similar basic composition, e.g., a similar ion-containing liquid, and a substantially similar concentration of an analyte to be detected.

[0192] Preferably, a multiple measuring points for different ÖVG are used for a calibration measurement. EFS recorded, for example 2, 3, 4, 5, 10 or more, especially to gain an operating point VG EFS , within an expected measurement range, for example ± 10%, ± 20%, ± 30%, ± 50% or more.

[0193] This allows for a particularly accurate determination of the calibration factor g. m This enables, and preferably allows for simultaneous verification of whether a linear curve is indeed present over the expected measuring range.

[0194] If a measurement is performed for an electrolyte with an unknown concentration of an analyte and / or the activity of the analyte, the calibration factor can be used to determine the value based on a change in the measured current ID. SENS , where the change is made by ÖID SENS is described as inferring the change in threshold voltage via the relationship between oil D SENS = - g m public transport T EFS .

[0195] The determined calibration factor can therefore be used to derive the ÖID. SENS on a change in the gate voltage ΔVc sens or threshold voltage ÖVT EFS can be concluded, since these are equivalent (see equation (1) with eVc sens = - ÖVT EFS Furthermore, it may also be preferred to perform a reference measurement for a plurality of reference electrolytes with known but different concentrations of the analyte or activities of the analyte before the actual measurement.

[0196] For example, a reference measurement (measurement of an öVc) can sens ) to perform measurements for 2, 3, 5, 10 or more reference electrolytes, each with a known concentration of an analyte or a known activity of the analyte. Such a reference measurement can be performed analogously to the measurement series illustrated in Fig. 3, wherein the reference measurement is only carried out for a selected polarization state.

[0197] This allows, preferably, the determination of a further (reference) parameter k, which describes the relationship between a measured quantity (e.g., a concentration of the analyte, ΔCn) and a measured ΔVc. sens characterizes, where ö c sens = k* ÖCanaiyt ' . The characteristic value can preferably depend on the measured quantity or represent a function of the measured quantity.

[0198] Using such a reference measurement, it is advantageously possible to perform an absolute quantification of the measured quantity in a (sample) electrolyte, for example, the concentration of an analyte.

[0199] The described calibration, as well as an optional reference measurement (for determining absolute quantities), can be particularly advantageous, for example, when the measurement process aims to detect the concentration of a specific ion species. The ion sensitivity Si on (i) The sensor area per decade for a specific ion type i can be determined via the relationship

[0200] (4) ö(Acp Gouy + öAcp stern ) [P FE ] = Sion® [P FE ] ölog (ci on ®), are star-shaped, where ci on ® denotes the concentration of the ions (ion) of the ion type i.

[0201] It is preferred, as explained above, to select a polarization state in which the sensor area exhibits maximum sensitivity to the ion type. A calibration measurement is preferably performed for this polarization state.

[0202] In a further preferred embodiment, the method is characterized in that the measuring device, in addition to the sensor surface, has a stimulation surface, preferably comprising one or more microelectrodes, and an electric current is introduced into the electrolyte by means of the stimulation surface, and a measurement signal caused by the electric current, preferably a transistor signal, is measured by means of the sensor surface in order to detect the analyte and / or the activity of the analyte preferably by means of an impedance measurement of the electrolyte.

[0203] The stimulation area of ​​the measuring device preferably designates a section from which an electric current can be introduced into the electrolyte. With regard to the stimulation area in the context of the invention, one can also speak of an injection of the electric current into the electrolyte.

[0204] Preferably, the stimulation area comprises one or more microelectrodes. A microelectrode is defined as an electrode manufactured using semiconductor and / or microsystems technology and / or having dimensions in the pm range, for example, between 10 pm and 10,000 pm, preferably between 100 pm and 1,000 pm. The surface of the microelectrode is preferably planar. Its cross-sectional shape is preferably circular or rectangular, but is not limited to this. Preferably, the stimulation area has a ferroelectric layer, analogous to the sensor area. Preferred embodiments of the ferroelectric layer or ferroelectric material disclosed with respect to the sensor area therefore also preferably apply to the stimulation area.The ferroelectric material is particularly advantageous in that, in addition to the contribution of capacitive stimulation itself, a further contribution arises from the polarization of the ferroelectric material. This additional contribution occurs alongside the contribution caused by the known purely capacitive stimulation.

[0205] After injecting an electric current into the electrolyte, a measurement signal can be obtained at the sensor surface. This signal can be obtained, in particular, as a voltage signal across the transistor, i.e., a transistor signal. Preferably, an oscillating current signal is injected into the electrolyte beforehand, the amplitude and / or phase of the measurable oscillating voltage signal at the sensor surface allowing conclusions to be drawn about the impedance of the electrolyte. Since such an impedance measurement is also influenced by the presence and / or activity of an analyte in the electrolyte, this measurement signal can be used for detection. Here, "impedance measurement" preferably refers to the measurement of electrical impedance.

[0206] In a preferred embodiment, the method is characterized in that, for the measurement, a polarization state of the ferroelectric material of the sensor surface is set, which minimizes the sensitivity of the sensor surface for the detection of the analyte and / or the activity of the analyte. Minimizing the sensitivity is particularly advantageous when the measuring device has a bidirectional interface, in which the measuring device, as described above, comprises a sensor surface and a stimulation surface.

[0207] Minimizing the sensitivity of the sensor area with respect to analyte detection and / or analyte activity, in this case, means specifically minimizing a transistor signal that arises from a gate voltage between the source and drain terminals due to the influence of the analyte or its activity in the electrolyte. Since the measurement of the analyte or its activity in the electrolyte, when using the measuring device as a bidirectional interface, depends primarily on the impedance measurement described above, other signals that do not correlate with the injected current in the stimulation area can be reduced. This applies particularly to signals caused by the analyte and / or its activity itself. This further reduces the risk of distorting the measurement results.

[0208] Impedance, i.e., the resistance to alternating current, correlates particularly with molecules located in the bulk of the electrolyte, which is especially true for glucose, for example. Here, impedance measurement preferably refers to the measurement of electrical impedance. Electrical impedance denotes an alternating current resistance, i.e., a resistance when an alternating current is introduced into the electrolyte.

[0209] Preferably, the electric current introduced via the stimulation surface is an oscillating signal, wherein the oscillating signal is preferably a sine signal, a cosine signal, a square wave signal, a pulse signal, a triangle signal or a sawtooth signal.

[0210] In a further preferred embodiment, the method is characterized in that a noise signal, preferably a noise voltage or a noise current, is measured, wherein a total impedance is determined using the noise signal and a sealing impedance of the analyte and / or the activity of the analyte, in particular of one or more ions, biomolecules and / or cells, is determined using the total impedance.

[0211] The noise signal can preferably be a measurement signal from the measuring device. For example, the noise signal can be a noise voltage or noise current between the reference electrode and a bulk terminal of a transistor.

[0212] In particular, the noise signal can refer to the noise of an electrical signal that can be measured using a transistor. Specifically, this is an electrical voltage or an electrical current. The corresponding noise signal is therefore also referred to as noise voltage or noise current. More generally, the noise itself preferably refers to the temporal fluctuation of a quantity. These fluctuations are characterized by their non-deterministic behavior; that is, a temporal prediction of the signal is not possible. The fluctuations are of spontaneous origin, meaning they do not originate from an external source but arise from the system or the process itself and cannot be avoided or suppressed.

[0213] In particular, an electrical impedance also exhibits inherent noise. More precisely, a time-fluctuating electrical quantity can be measured at the ends of an electrical impedance, independent of external voltages and / or fields. This will be described below using the noise voltage as an example. Those skilled in the art will recognize that the corresponding explanations also apply, in a physically equivalent way, to the noise current. Thus, a noise voltage V(t) can be measured independently of external quantities. The noise between two electrodes, both in contact with the electrolyte, increases as the impedance of the electrolyte rises.

[0214] In particular, the total impedance can function as a measurement signal to enable the detection of the analyte and / or its activity. For impedance measurement, it is preferred to minimize the sensitivity for determining the total impedance by polarizing the ferroelectric material to ensure reliable detection. This reduces the influence of other signals and / or the analyte and / or its activity on the detection measurement signal. The total impedance Z refers to the impedance resulting from one or more terminals of the transistor in contact with the electrolyte. In this case, these are specifically the reference electrode and a bulk terminal of the transistor. Furthermore, the total impedance includes the impedances of the electrolyte and the impedance of the seal.

[0215] Through active or spontaneous adhesion of the analyte to the sensor surface, a gap with an electrical impedance, known as the sealing impedance, is created between the sensor surface and the analyte. The adhered analyte seals a surface of the sensor from the surrounding electrolyte. This results in an increase in the impedance between the two transistor terminals that are in contact with the electrolyte.

[0216] The noise signal can be used to determine another quantity, such as the real part of the generally complex-valued impedance between the electrodes. The impedance determined in this way can either be the desired quantity directly or, using a suitable sealing model, can be used to determine other parameters, such as the gap width. Thus, the electrical noise of the impedance can be used to determine the sealing of the analyte at the sensor surface.

[0217] The sealing of the analyte preferably refers to a gap between the sensor surface and the analyte filled with the electrolyte. The gap encompasses the space between the analyte and the sensor surface, and preferably also all structures between the analyte and the sensor surface, as well as structures within the analyte and / or the electrolyte that can contribute to sealing the analyte to the sensor surface. For example, the sealing of a living cell to the sensor surface can be increased by the incorporation of substances into the space between the analyte and the sensor surface. Another example of structures that contribute to sealing but are not part of the geometric space between the analyte and the sensor surface are so-called tight junctions, which connect living cells.

[0218] The smaller or denser the gap, the greater the contact between the analyte and the sensor surface, and the greater the sealing of the analyte to the sensor surface. The greater the sealing, the greater the impedance of the gap. Gap impedance and sealing impedance are therefore synonymous terms. Without any substance on the sensor surface, there is no gap and therefore no sealing impedance.

[0219] Given that an increase in noise correlates with greater sealing, impedance measurement can be used to determine the sealing of analytes on a sensor surface. Thus, the sealing can be determined from the noise or noise signal, particularly a noise voltage, with the sealing being greater the stronger the noise. Typically, the sealing impedance for the adhesion of, for example, single cells in a normal culture medium is 500 kΩ to 10 Ω, for dense cell layers such as epithelial cells 500 kΩ to 50 Ω, and for actively pressed-on materials 1 Ω to 1 GO.

[0220] Depending on which parameters of the analyte to be detected, e.g., of a cell, a cell cluster, or a cell membrane, are known, conclusions can be drawn about the state and / or changes of the analyte on the sensor surface from the sealing or sealing impedance.

[0221] In a further preferred embodiment, the method is characterized in that a spectral power density is determined from the noise signal, wherein the sealing impedance is determined from the spectral power density.

[0222] The noise voltage V(t) of a (generally complex-valued) impedance Z has the spectral power density (see also EP 1 717 574 B1)

[0223] Sv© = 4*kβ*T*Re(Z), where kβ is the Boltzmann constant, T is the absolute temperature, and Re(Z) is the real part of the impedance. The noise voltage, as a noise signal, can preferably be measured by a noise signal at the transistor of the measuring device. For this purpose, it may be advantageous to connect suitable amplifiers to the transistor to enable simple detection of the noise voltage as a noise signal.

[0224] The relationship for the power density Sv© applies generally to electrical impedances, regardless of the transport mechanism, the type of charge carriers, and external voltages and fields. It is strictly valid in thermodynamic equilibrium and also a good approximation for many non-equilibrium states, especially current-carrying impedances. The cause of the voltage noise can be attributed to the Brownian motion of the charged particles (ions in the electrolyte, electrons in metals) or to fundamental thermodynamic equations. Both perspectives are physically equivalent.

[0225] To describe the noise signal, it may be preferable to use the so-called power density. For a given time-dependent quantity a(t), one can calculate its spectral power density (also power spectral density or simply power density) S. a (f) define as

[0226] S a (f) = lim T1 / (2T) I Each i2TTft a(t) dt | 2

[0227] In the context of the invention, the total impedance is composed in particular of the impedances of the terminals that are in contact with the electrolyte, the electrolyte and the seal:

[0228] Total — Z connections + Z electrolyte + Z sealing

[0229] Therefore, the following applies to the spectral power density:

[0230] Sv(t) = 4*kß*T*Re (Ztotal)

[0231] — 4 kß T Re (ZAnschlüsse + Zßelektrolyt + ZAbdichtung)

[0232] The noise and its measurement are therefore advantageously unaffected by an imaginary impedance (i.e., without a real part), such as that which occurs with purely capacitive electrodes. An imaginary impedance does not enter the measurement and therefore does not interfere with it. Thus, capacitive connections, whose impedance is almost exclusively imaginary, can be miniaturized for use in the preferred method (up to the limits of what is technically possible), since the increase in imaginary impedance associated with the miniaturization does not interfere with the measurement.

[0233] Furthermore, it may be preferred that the sealing is determined from the integral of the spectral power density over a predetermined frequency range fi to f2 or / and from the square root of the integral of the spectral power density over a predetermined frequency range fi to f2:

[0234] V rms = f f i f2 S v (f) df

[0235] The square root of the integral of the spectral power density over a predetermined frequency range fi to f2 is also called V. rm This is called the s-value. It is preferred that the V rm The s-value is determined by filtering a predetermined frequency range fi to f2 from the noise voltage signal, e.g. via a bandpass filter to select the frequency range of interest, and then by calculating the RMS value of the square of the voltage in a predetermined time interval.

[0236] In another preferred embodiment, an autocorrelation function is determined from the noise voltage and then a seal is determined from the autocorrelation function.

[0237] The autocorrelation function for a time-dependent quantity a(t) is defined as

[0238] P(T) = 1 / (2T) LT +Ta(t)*a(t+T) dT is another representation of the spectral power density. The spectral power density is the Fourier transform of the autocorrelation function (and vice versa).

[0239] The gap conductivity gj is determined by gj = n*dj / (Aj*pj), where dj denotes the height of the gap, Aj the cross-sectional area of ​​the adhesion surface, pj the specific resistance of the electrolyte in the gap, and q a dimensionless geometric parameter, preferably taking into account the geometric shape of the gap. Advantageously, the sealing resistance can be specifically adjusted by setting the polarization state of the ferroelectric material of the sensor surface.

[0240] In a cancer cell (see Fig. 3A), the sealing resistance contributes to electrical noise. The ferroelectric material allows for targeted adjustment of the polarization state with regard to the sealing resistance.

[0241] In another preferred embodiment, the method is characterized in that a temporary polarization reversal of the ferroelectric material is performed to reduce drift signals.

[0242] Drift signals preferably refer to signals that can be detected by the movement of charge carriers. They manifest themselves in particular as an electron or ion current with a drift velocity proportional to the electrical voltage. These can have an undesirable influence on the measurement during the preferred process steps for determining the analyte and / or the analyte's activity.

[0243] Advantageously, the ferroelectric material of the sensor surface allows for a reversal of the polarization state, and thus also of the charge distribution, which is caused by the polarization of the ferroelectric material, through appropriate signals. This is particularly possible when a corresponding electrical voltage is applied between the reference electrode and a bulk terminal of the transistor. A temporary polarization reversal results in a corresponding reversal of the electric field generated by the sensor surface. This counteracts or resets unwanted drift, for example, caused by the deposition of analytes to be detected, which can distort measurement results.

[0244] Preferably, the temporary polarization reversal occurs for a period of less than 100 ms (milliseconds), preferably less than 10 ms, and particularly preferably less than 1 ms. These preferred times are advantageously easy to implement by applying a suitable voltage between the reference electrode and a bulk substrate. It is preferred that an original polarization state is restored. In other words, a repeating pattern for setting the polarization state is preferably established, resulting, for example, in the repeated generation of an electrochemical double layer to reduce or reset unwanted drift signals, such as in ion detection.

[0245] The temporary polarization reversal is achieved in particular by a voltage signal applied to the sensor surface. Preferably, an oscillating voltage signal is applied, for example, a triangle wave, a sine wave, and / or a square wave. The voltage signal can be applied across the sensor surface. For example, in the embodiment of an EFSFET, a voltage signal can be applied between the reference electrode and a bulk terminal of a transistor.

[0246] In a further preferred embodiment, the method is characterized in that the ferroelectric material is selected from a group consisting of hafnium oxide, aluminum scandium nitride, zirconium oxide and / or compounds and / or alloys thereof.

[0247] The aforementioned preferred materials, as ferroelectric materials for the sensor area, have proven particularly advantageous in the context of the invention. In particular, these preferred materials are compatible with known processes and / or techniques from semiconductor and / or microsystems technology for providing the sensor area as a section of the transistor. Specifically, these preferred materials are compatible with CMOS technology. Therefore, it does not require significant effort for the average person skilled in the art to provide a sensor area on the transistor using these preferred materials.

[0248] In further preferred embodiments, the aforementioned preferred ferroelectric materials can be doped. The dopant material can be selected from the group consisting of silicon, aluminum, germanium, yttrium, gadolinium, lanthanum, strontium, and zirconium. The aforementioned preferred dopants can improve the properties of the ferroelectric material, particularly with regard to increasing the remanent polarization.

[0249] Preferably, the ferroelectric material has a remanent polarization of at least 10 pC / cm². 2 , at least 20 pC / cm 2 , at least 30 pC / cm 2 , at least 40 pC / cm² 2 , at least 50 pC / cm² 2 , at least 60 pC / cm² 2 , at least 70 pC / cm² 2 , at least 80 pC / cm² 2 , at least 90 pC / cm² 2 , at least 100 pC / cm² 2or more. In particular, aluminum scandium nitride, for example, exhibits a polarization of 100 pC / cm. 2 (microcoulombs per square centimeter).

[0250] In another preferred embodiment, the measuring device comprises a support structure on which the sensor surface is applied.

[0251] The support structure preferably refers to the component of the measuring device on which the sensor area is mounted. In preferred embodiments, the support structure can form a component of a transistor; for example, the support structure can be formed by a transistor substrate. Preferably, the transistor substrate can be a semiconductor substrate.

[0252] However, it may also be preferred that the support structure forms a structure on which the sensor area is applied, wherein the support structure preferably forms an electrical connection between the sensor area and a separate transistor, preferably a conventional MOSFET. The support structure may preferably comprise a semiconductor substrate.

[0253] The semiconductor substrate can preferably comprise a wafer in the context of chip manufacturing. In particular, the semiconductor substrate or wafer can be manufactured using CMOS technology and contain other (active and passive) electrical components such as transistors, capacitors, diodes, analog-to-digital converters, filters, amplifiers, etc.

[0254] The semiconductor substrate may preferably comprise a material selected from the group consisting of monocrystalline silicon, polysilicon, silicon dioxide, silicon carbide, silicon germanium, silicon nitride, nitride, germanium, carbon, gallium arsenide, gallium nitride, indium phosphide and glass.

[0255] These materials are easy and inexpensive to process in semiconductor and / or microsystem manufacturing and are suitable for large-scale production.

[0256] The transistor substrate, preferably a semiconductor substrate, comprises or includes, in particular, a source terminal and a drain terminal. In this respect, the transistor substrate enables current transmission between the source terminal and the drain terminal by forming a (conducting) channel, as explained above.

[0257] As explained above, the channel can be either a p-channel or an n-channel. For an n-channel, a p-doped transistor substrate is preferably used. The source and drain terminals comprise n-doped regions in the transistor substrate. In an n-channel, the majority charge carriers are electrons. Similarly, for a p-channel, an n-doped transistor substrate is preferably used. The source and drain terminals comprise p-doped regions in the transistor substrate. In an n-channel, the majority charge carriers are holes.

[0258] In a further aspect, the invention relates to a measuring device for detecting an analyte and / or an activity of an analyte in an electrolyte by means of a method according to the above described, comprising a reference electrode and a sensor surface comprising a ferroelectric material, and wherein the measuring device is designed to adjust a polarization state of the ferroelectric material of the sensor surface depending on the analyte to be detected and / or the activity of the analyte to be detected.

[0259] The average person skilled in the art recognizes that technical features, definitions and advantages disclosed for the method according to the invention or preferred embodiments thereof also apply to the measuring device according to the invention, and vice versa.

[0260] In a preferred embodiment, the measuring device is characterized in that the measuring device comprises an electronic circuit which is configured to adjust the polarization state of the ferroelectric material depending on the analyte to be detected and / or the activity of the analyte to be detected.

[0261] An electronic circuit can preferably function as a control unit which preferably sets a polarization state of the ferroelectric material depending on the analyte to be detected and / or the activity to be detected.

[0262] It may be preferable for a corresponding signal to be transmitted from the electronic circuit to terminals of the measuring device or a transistor, for example to a reference electrode and a bulk terminal, in order to provide a corresponding voltage signal with regard to a corresponding polarization state of the ferroelectric material for optimizing the sensitivity of the sensor area. Thus, the electronic circuit can preferably assume the functions of a control unit to adjust the polarization state of the ferroelectric material.

[0263] Preferred electronic circuits include, without limitation, an integrated circuit (IC), an application-specific integrated circuit (ASIC), a programmable logic circuit (PLC), a field-programmable gate array (FPGA), a microprocessor, a microcomputer, a programmable logic controller and / or any other electronic circuit, preferably programmable.

[0264] In preferred embodiments, the electronic circuit can also be configured to process the measurement signals acquired by the measuring device with regard to the detection of an analyte or the activity of an analyte. Data processing preferably means that the electronic circuit is configured to perform calculations and / or computational steps, for example, with respect to the acquired measurement signals, preferably transistor signals. The electronic circuit can thus be configured as an evaluation, readout, and / or control unit that enables control of the heating element, readout of the sensor component, and / or evaluation of the measurement data. If evaluation is performed, the electronic circuit can also be referred to as a processing unit.

[0265] The term "computing unit" preferably refers to any device or unit that can be configured to perform computational operations. Preferably, the computing unit is, for example, a processor, a processor chip, a microprocessor, and / or a microcontroller, preferably configured to evaluate the temperature response. The computing unit can also preferably be a programmable printed circuit board. The computing unit can also preferably comprise a computer-usable or computer-readable medium, such as a hard drive, random access memory (RAM), read-only memory (ROM), flash memory, etc.

[0266] Process steps for setting a polarization state of the ferroelectric material or for evaluating the measurement signal to detect an analyte or the activity of an analyte, as described herein, are preferably performed by the electronic circuit. The phrase "is configured to do so" preferably means that computer code and / or software is installed on the electronic circuit or processing unit to perform a process step, set and / or determine the polarization state of the ferroelectric material.

[0267] The computer code and / or software for evaluating the modulation of the heat field can be written in any programming language or model-based development environment, e.g., in C / C++, C#, Objective-C, Java, Basic / VisualBasic, MATLAB, Simulink, StateFlow, Lab View, Python and / or Assembler.

[0268] The computer code and / or software, which is preferably installed on the electronic circuit or computing unit, can be considered technical features, since there is a direct physical effect of the measuring device, for example the supply of a signal to set a polarization state of the ferroelectric material.

[0269] Functional descriptions of the computer code and / or software can therefore be considered preferred and defining embodiments of the invention.

[0270] The electronic circuit may preferably also include a memory unit. A memory unit allows for the backup and / or temporary storage of data. Non-limiting examples of memory, preferably semiconductor memory, are volatile memory, (RAM) memory, or non-volatile memory such as ROM memory, EPROM memory, EEPROM memory, or flash memory, and / or other memory technologies.

[0271] In preferred embodiments, reference data can also be stored on the electronic circuit or storage unit itself, or on an external data processing unit connected to the electronic circuit. This reference data preferably enables a correlation of the polarization state of the ferroelectric material with the analyte and / or the activity of the analyte for maximizing or minimizing sensitivity. Typically, the reference data can be stored on a computer-accessible or computer-readable medium within the electronic circuit, the storage medium, or an external data processing unit. Any industry-standard format can be used. The reference data can be stored in a separate file and / or integrated into the computer code or software (e.g., the source code), which is preferably installed on the electronic circuit.

[0272] The reference data can be provided, for example, as a lookup table, parameters, or as ranges for a mathematical relationship that allows a correlation of physical quantities for determining the analyte and / or its activity. The reference data can be obtained, for example, by performing suitable calibration experiments. A suitable value for the polarization state and / or a target or tolerance range for the polarization state can preferably be provided by reference data.

[0273] To determine suitable values ​​for the polarization state and / or a target or tolerance range, not only statistical analyses or model-based calculations, but preferably also artificial intelligence algorithms can be used.

[0274] In preferred embodiments, reference data for a suitable polarization state, in particular for a target or tolerance range of the polarization state, can be determined using artificial intelligence algorithms, preferably machine learning algorithms comprising supervised learning, unsupervised learning and / or reinforcement learning.

[0275] In a further aspect, the invention relates to a method for determining a polarization state for optimizing the sensitivity of a measuring device depending on an analyte to be detected and / or an activity of the analyte, comprising the following steps: a) providing the measuring device comprising a reference electrode and a sensor surface comprising a ferroelectric material, b) bringing the measuring device into contact with a reference electrolyte in which the analyte to be detected and / or an activity of the analyte to be detected is present, c) determining a measurement signal for at least two different polarization states of the ferroelectric material for the reference electrolyte, d) determining a polarization state of the ferroelectric material in which the sensitivity of the sensor surface for detection of the analyte and / or the activity of the analyte is maximal or minimal.

[0276] The average person skilled in the art recognizes that the technical features, definitions and advantages of the method or measuring device for detecting an analyte and / or an activity of an analyte apply to the method for determining a polarization state for optimizing the sensitivity of a measuring device, and vice versa.

[0277] In a preferred embodiment, the measuring device comprises a transistor. If a transistor is present, the measuring signal can in particular be generated by a transistor signal. The transistor signal is a signal that is detected at the transistor, in particular a current between a source terminal and a drain terminal and / or a voltage between a gate terminal and a bulk terminal.

[0278] In another aspect, the invention relates to the use of the measuring device according to the method described above for the detection of an analyte and / or the activity of an analyte in an electrolyte as part of a wearable system, a neural implant system, a lab-on-a-chip system and / or an in-vitro biosensor platform.

[0279] The average person skilled in the art recognizes that the technical features, definitions and advantages of the method for detecting an analyte and / or an activity of an analyte and the measuring device and the method for adjusting a polarization state to optimize the sensitivity of a measuring device also apply to the use of the measuring device, and vice versa.

[0280] The measuring device according to the invention can advantageously be implemented in a variety of applications to detect the analyte and / or the activity of the analyte.

[0281] A wearable system preferably refers to a portable computer system that can be worn on a user's body during use. For example, a wearable system can include a smartwatch, smart glasses, a smartband, smart contact lenses, or be integrated into the user's clothing, without being limited to these examples. Advantageously, a measuring device according to the invention, integrated into a wearable system, can be used, for example, for the continuous detection of analytes or their activity in a wearer of the wearable system.

[0282] A neural implant system preferably refers to a system that provides an interface between the nervous system and an electronic component for clinical application and medical technology research. The neural implant system may, for example, comprise multiple individual microelectrodes or electrode arrays to correct or restore impaired, pathological, or lost functions of the nervous system, or to improve normal functions. For example, the measuring device in this context may preferably be used to detect the activity of nerve cells and / or to stimulate them.

[0283] A lab-on-a-chip (also known as a chip laboratory or lab-on-a-chip device) is a microfluidic system that integrates the entire functionality of a macroscopic laboratory onto substrates of relatively small dimensions, for example, in the centimeter range. This technology allows for the complete and automated analysis of small quantities of a sample or electrolyte (a few picoliters to microliters) of a liquid on a single chip. Sample transport between the various reaction and analysis chambers can be achieved using capillary action. A measuring device can preferably be a component of such a lab-on-a-chip and, as a single sensor or as part of a larger set of sensors, measure a multitude of samples or electrolytes in an extremely compact space.The measuring device can also be used as a biochip or biosensor, preferably an in vitro biosensor, to detect, for example, biological processes or biomolecules in vitro.

[0284] Figures

[0285] The aspects of the invention will be explained below by way of example using figures, without being limited to these figures.

[0286] Brief description of the characters

[0287] Fig. 1 Schematic representation of a preferred embodiment of the measuring device

[0288] Fig. 2 Schematic representation of a detection of cancer cells and neurons

[0289] Fig. 3 Illustration of the measurement principle for maximizing sensitivity for concentration measurement

[0290] Detailed description of the figures

[0291] Fig. 1 shows a preferred embodiment of the measuring device for detecting an analyte and / or the activity of an analyte in an electrolyte 3. The measuring device 1 according to the illustrated embodiment comprises an EFSFET transistor with a source terminal 5, a drain terminal 7, and a reference electrode 9. The EFSFET transistor additionally has a sensor area 11 comprising a ferroelectric material 13. The measuring device 1 is designed to adjust the polarization state of the ferroelectric material 13 of the sensor area 11 depending on the analyte and / or the activity of the analyte to be detected. The sensor area 11 is positioned on a support structure 21 in the form of a transistor substrate 17.

[0292] For example, by selecting a polarization state for the sensor surface 11, the displacement of analytes, such as ions, biomolecules, or cells, towards the sensor surface 11 can be selectively increased or decreased. If, for instance, the detection of a biomolecule, such as glucose, is desired, it may be preferable to selectively induce the attachment of biomolecules by dipole-dipole interaction through a specific polarization state of the sensor surface 11, thereby increasing their influence on interfacial polarization. Similarly, ions can preferably be selectively attracted to or repelled from the sensor surface 11 by appropriately adjusting its polarization state to increase or decrease measurement sensitivity.

[0293] The sensitivity for detecting analyte activity, such as cell activity, can also be selectively increased or decreased by adjusting the polarization state. For example, a polarization state can be chosen to minimize or maximize the distance between adherent cells and the sensor surface 11. This allows for influencing the so-called sealing resistance, which correlates with the measurement sensitivity for cell activity, such as an action potential in the case of neurons. It can also be advantageous to select a polarization state such that, for example, the sensitivity of the sensor surface 11 is selectively increased with respect to one type of analyte, while the sensitivity for detecting another type of analyte is selectively decreased.With regard to the detection of ions in the electrolyte, for example, sensitivity for positive ions can be specifically increased by adjusting a polarization state, while sensitivity for negative ions is reduced.

[0294] Likewise, the polarization state can preferably be set in such a way that, for example, the attachment of biomolecules to be detected is promoted, while an influence of ions in the electrolyte 3 on the measurement signal is avoided.

[0295] Therefore, with regard to analyte detection and / or activity, targeted signal optimization is easily achieved simply by adjusting the polarization state. The separate application of analyte-sensitive coatings, for example, for immobilizing biomolecules or attracting ions using specific ion-sensitive membranes, can be advantageously avoided.

[0296] Instead, it was recognized that by using a ferroelectric material 13 for a sensor surface 11, an additional degree of freedom in the form of a polarization state can be provided, which enables a more sensitive detection of a desired analyte and / or a desired activity of an analyte in an electrolyte 3.

[0297] A key advantage of the measuring device 1 is that, depending on the analyte to be detected and / or its activity, the polarization state of the sensor surface 11 can be adjusted easily and quickly, for example, by applying a suitable voltage polarity. No design modifications are necessary. Instead, the same measuring device 1, comprising a transistor with a source terminal 5, a drain terminal 7, and a reference electrode 9, can be used. Furthermore, no coating needs to be applied to the sensor surface 11 to increase the sensitivity of the measuring device for the detection of specific analytes. Instead, the same ferroelectric material 13 is used, but its properties, in the form of a polarization state, can be advantageously adjusted by applying a suitable voltage polarity to optimize the measurement of the analytes in question.

[0298] In this way, in particular, the reversibility of the polarization state of the ferroelectric material 13 can be exploited, thereby maintaining a high degree of flexibility.

[0299] A further advantage of the measuring device 1 is its long-term stability. While coatings on the sensor surfaces 11 for the more specific detection of analytes generally exhibit reduced long-term stability, or their specificity decreases over longer periods and / or measurements, the sensor surface of the measuring device 1 can be provided by means of an extremely stable ferroelectric layer 13, which, on the one hand, exhibits high chemical and mechanical stability with respect to the electrolyte 3 and / or the analytes contained therein. On the other hand, the reversibility of the polarization state of the ferroelectric material 13, or rather its adjustability, is also advantageously extremely stable over the long term, whereby, within the framework of a corresponding hysteresis curve, a desired polarization state can be reliably set even over a large number of polarization changes and / or a long period.A permanent setting option for the polarization state of the ferroelectric material allows for a permanent optimization of sensitivity. This enables long-lasting and reliable measurements, particularly those that can be performed over several years.

[0300] Furthermore, the detection of different analytes is easily accomplished using measuring device 1. In addition, the manufacturing effort for the measuring device can be kept low, as, as explained, no additional application of analyte-sensitive coatings is necessary to detect specific types of an analyte and / or an analyte activity, for example, specific ion types and / or biomolecules.

[0301] A further advantage is that a drift signal can be reduced or avoided by temporarily adjusting the polarization state. In this case, adjusting or changing the polarization state preferably involves changing an electric field, which can influence the movement and / or direction of charge carriers in the electrolyte and, in particular, resolve any unwanted deposits that could distort the measurement results as a drift signal.

[0302] Fig. 2A shows a cancer cell 15 adhered to the sensor surface 11, while Fig. 2B shows a neuron 15 on the sensor surface. The ferroelectric material 13 allows for targeted adjustment of the polarization state with regard to adjusting the sealing resistance.

[0303] The gap conductivity gj is determined by gj = n*dj / (Aj*pj), where dj denotes the height of the gap, Aj the cross-sectional area of ​​the adhesion surface, pj the specific resistance of the electrolyte in the gap, and q a dimensionless geometric parameter, preferably taking into account the geometric design of the gap. Advantageously, the sealing resistance can be specifically adjusted by setting the polarization state of the ferroelectric material 13 of the sensor surface 11.

[0304] In a cancer cell 15 (Fig. 2A), the sealing resistance contributes to the electrical noise. The ferroelectric material 13 allows for targeted adjustment of the polarization state with regard to the sealing resistance.

[0305] In particular, the sealing resistance of a neuron 15 adhered to the sensor surface (Fig. 2B) can also be adjusted by selectively setting the polarization state. The extracellular voltage Vj is generated by cellular currents, and the extracellular voltage is proportional to the sealing resistance. The gap conductance is preferably another representation of the sealing resistance, which in turn can be measured by measuring the spectral power density of the noise.

[0306] Fig. 3A shows an illustration of the measurement principle for determining ferroelectric polarization, maximizing sensitivity for measuring the concentration of an ion species. This involves measuring a change in voltage ΔVc. sensMeasurements were taken between the reference electrode and a bulk connection for a variety of reference electrolytes with different, but known, ion concentrations, specifically at three different polarization states. The dotted curve shows the measurement at a positive remanent polarization +P. r , while the dashed curve represents the measurement at a negative remanent polarization -P r The black, solid curve shows an unpolarized polarization state of the ferroelectric material of the sensor surface. The corresponding hysteresis curve is shown in Fig. 3B.

[0307] The transistor signal can be used to determine which of the different polarization states yields a higher measurement signal and thus higher sensitivity. In the illustrated case, öVc sens for a negative remanent polarization -P rmaximum. In particular, it is clearly evident that public transport sens The slope is highest at negative remanent polarization (dashed curve), depending on the ion concentration. In contrast, the slope is lower at positive remanent polarization (dotted curve), so maximum sensitivity is achieved at negative remanent polarization. Therefore, this polarization state offers maximum sensitivity with respect to the ion species to be detected.

[0308] By maximizing the sensitivity, the polarization state can be chosen such that the influence of the ions to be detected on the conduction channel between the source and drain terminals in the transistor substrate is maximized. This means that, based on a field effect particularly dependent on the ion concentration in the electrolyte, a transistor signal (e.g., a transistor current between the source and drain terminals) will change to a particularly strong degree (see the red curve for -P). r versus blue curve for +P r With respect to a specific polarization state, a charge distribution preferably forms at the interfaces of the ferroelectric material such that the sensitivity of the sensor surface or the transistor for the detection of the ions is increased.

[0309] A polarization state optimized for analyte detection or activity can be generated, for example, by applying a voltage as a remanent polarization state (see Fig. 3B). Since the ferroelectric material is characterized by its hysteresis curve, two (maximum) remanent polarization states of the ferroelectric material can be established, provided the voltage is sufficiently high to saturate the dipole moment alignment.

[0310] Remanent polarization states exist when the external electric field is switched off. Depending on whether a voltage signal has previously caused a positive or negative alignment of the dipole moments of the ferroelectric material, these states differ in their orientation. Therefore, one can also speak of reversed remanent polarization states, or of positive and negative remanent polarization. If a voltage signal is chosen that does not lead to saturation of the orientation, so that the hysteresis curve is not driven in the positive or negative direction towards maximum alignment of the dipole moments, remanent polarization states can also be established that lie between the maximum, negative, and positive (remanent) polarization states.The intermediate states can be set in particular by appropriately choosing a voltage peak, starting from a lower dipole moment alignment when the voltage is switched off, i.e., so that when the external electric field is switched off, a remanent polarization state with essentially the same or slightly reduced dipole moment alignment remains.

[0311] Fig. 4 schematically represents a preferred embodiment of the measuring device comprising an extended EFSFET in CMOS technology.

[0312] The measuring device 1 comprises a support structure 21 and an electronic component, which in this case is a transistor. The support structure 21 mechanically supports the sensor surface 11 and enables an electrical connection between the sensor surface 11 and the transistor as the electronic component. For this purpose, an electrically conductive material is embedded in the support structure 21, forming an electrode 18. The electrode 18 is located below the sensor surface 11. An electrically conductive path 19, preferably a metallic path, enables an electrical connection from the electrode 18, or sensor surface 11, to a gate terminal 23 of the transistor. The transistor can preferably be a conventional MOSFET, wherein the support structure 21 is a semiconductor substrate and is manufactured using CMOS technology.The MOSFET comprises, in a known manner, a source terminal 5, a drain terminal 7, and a gate terminal 23, which are located in a transistor substrate 17. The transistor substrate 17 can be formed by the semiconductor substrate of the support structure 21 or by a separate semiconductor substrate.

[0313] The EFSFET comprises a CMOS chip preferably designed such that the electrolyte with reference electrode and the adjacent sensor area 11 with ferroelectric layer 13 is connected to the gate terminal 23 of the conventional MOSFET via the electrically conductive path 19.

[0314] This embodiment of an EFSFET can also be referred to as an extended EFSFET or eEFSFET. In this embodiment as well, the presence of an analyte in the electrolyte 3 or its activity can advantageously lead to potential differences that influence a threshold voltage of the transistor and also affect the field effect or the widening or constriction of a conducting channel in a transistor substrate 17 of the conventional MOSFET.

[0315] The principle of capacitive voltage division can preferably be used to detect the analyte and / or its activity. A first capacitance is preferably defined by the sensor area 11 located on the electrode 18. A second capacitance can be defined by the insulating layer or the gate terminal 23 of the transistor. Preferably, the first capacitance is larger than the second capacitance, resulting in a predominant voltage across the transistor. This allows the measurement signal, preferably a transistor signal, to be detected with high sensitivity depending on the presence of an analyte and / or its activity. (Reference numeral list)

[0316] 1 measuring device

[0317] 3 Electrolyte

[0318] 5 Source connection

[0319] 7 Drain connection

[0320] 9 Reference electrode

[0321] 11 Sensor area

[0322] 13 Ferroelectric material

[0323] 15 cells

[0324] 17 transistor substrate

[0325] 18 electrode

[0326] 19 Electrically conductive path

[0327] 21 Support structure

[0328] 23 Gate connector

[0329] List of sources

[0330] Fromherz, Peter. "Threshold voltage of the EOSFET: Reference electrode and oxide-electrolyte interface." physica status solidi (a) 209.6 (2012): 1157-1162.

Claims

PATENT CLAIMS 1. Method for detecting an analyte and / or an activity of an analyte in an electrolyte (3) by means of a measuring device (1) comprising the following steps: a) provision of the measuring device (1) comprising a reference electrode (9) and a sensor surface (11) comprising a ferroelectric material (13), b) setting a polarization state of the ferroelectric material (13) of the sensor surface (11) depending on the analyte to be detected and / or the activity of the analyte to be detected, c) bringing the electrolyte (3) into contact with the sensor surface (11) and detecting the analyte and / or the activity of the analyte.

2. A method according to the preceding claim characterized in that the analyte is selected from the group consisting of ions, biomolecules and cells and / or the activity of the analyte is a cell activity, preferably a cell signal, and particularly preferably an action potential of a neuron.

3. A method according to one of the preceding claims characterized in that the measuring device (1) comprises a transistor, wherein the sensor area (11) forms a layer of the transistor and wherein the transistor has a transistor substrate as well as a source terminal (5) and a drain terminal (7), wherein the sensor area (11) is electrically connected to a gate terminal of the transistor and / or, wherein the transistor is an electrolytic ferroelectric semiconductor field-effect transistor (EFSFET) or the transistor is an extended EFSFET (eEFSFET) in CMOS technology.

4. Method according to one of the preceding claims characterized in that the adjustment of a polarization state of the ferroelectric material (13) of the sensor surface (11) is carried out in such a way that the sensitivity of the sensor surface (11) for the detection of the analyte and / or the activity of the analyte is maximized or minimized.

5. A method according to one of the preceding claims, characterized in that the method comprises determining a polarization state of the ferroelectric material (13) in which the sensitivity of the sensor area (11) for detection of the analyte and / or the activity of the analyte is maximal or minimal, wherein preferably a measurement signal is provided for at least two different polarization states. of the ferroelectric material (13) for an electrolyte with a known concentration of an analyte and / or known activity of an analyte.

6. Method according to one or more of the preceding claims characterized in that the measuring device (1) comprises a transistor and a change in a threshold voltage of the transistor as a function of the polarization state of the ferroelectric material (13) is effected by i) a change in a potential drop in the electrolyte (3), ii) a change in a potential drop across an electrochemical double layer and / or iii) a change in an interfacial polarization at an interface of the sensor surface (11) to the electrolyte (3).

7. Method according to one or more of the preceding claims characterized in that the measuring device (1) comprises a transistor and a change in the threshold voltage can be measured by means of a change in a gate voltage of the transistor and / or a change in a potential in the electrolyte (3) is measured by means of a change in a threshold voltage of a transistor, which correlates with a current flow in the electrolyte (3), wherein the current flow has a dependence on an activity of the analyte, particularly preferably an action potential of a neuron.

8. Method according to one or more of the preceding claims characterized in that the polarization state of the sensor surface (11) is adjusted by applying an electrical voltage across the sensor surface (11).

9. Method according to one or more of the preceding claims characterized in that the measuring device (1) has, in addition to the sensor surface (11), a stimulation surface, preferably comprising one or more microelectrodes, and an electric current is introduced into the electrolyte (3) by means of the stimulation surface, wherein a measurement signal caused by the electric current is measured by means of the sensor surface (11) in order to preferably detect the analyte and / or the activity of the analyte by means of an impedance measurement of the electrolyte.

10. Method according to one or more of the preceding claims characterized in that a noise signal, preferably a noise voltage or a noise current, is measured, wherein a total impedance is determined using the noise signal and by means of The total impedance determines a sealing impedance of one or more ions, biomolecules and / or cells (15).

11. Method according to one or more of the preceding claims characterized in that a temporary polarization reversal of the ferroelectric material (13) is carried out to reduce drift signals, wherein the temporary polarization reversal preferably takes place for a period of less than 100 ms, preferably less than 10 ms, particularly preferably less than 1 ms.

12. Measuring device (1) for detecting an analyte and / or an activity of an analyte in an electrolyte (3) by means of a method according to the preceding claims comprising a reference electrode (9) and a sensor surface (11) comprising a ferroelectric material (13) and wherein the measuring device is designed to adjust a polarization state of the ferroelectric material (13) of the sensor surface (11) depending on the analyte to be detected and / or the activity of the analyte to be detected.

13. Measuring device (1) according to the previous claim, characterized in that the measuring device (1) comprises an electronic circuit which is configured to adjust the polarization state of the ferroelectric material (13) depending on the analyte to be detected and / or the activity of the analyte to be detected.

14. Method for determining a polarization state for optimizing the sensitivity of a measuring device (1) as a function of an analyte to be detected and / or an activity of the analyte, comprising the following steps: a) providing the measuring device (1) comprising a reference electrode (9) and a sensor area (11) comprising a ferroelectric material (13), b) bringing the measuring device (1) into contact with a reference electrolyte in which the analyte to be detected and / or an activity of the analyte to be detected is present, c) determining a measurement signal for at least two different polarization states of the ferroelectric material (13) for the reference electrolyte is recorded, d) determining a polarization state of the ferroelectric material (13) at which the sensitivity of the sensor area (11) for detection of the analyte and / or the activity of the analyte is maximal or minimal.

15. Use of a measuring device (1) according to one of the preceding claims 1-11 or 12-13 for detecting an analyte and / or the activity of an analyte in an electrolyte (3) as part of a wearable system, a neural implant system, a lab-on-a-chip system and / or an in-vitro biosensor platform.

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