Digital sensor device for detecting an analyte in a sample

Abstract

The invention relates to a sensor device (6) for detecting the presence and / or concentration and / or amount of an analyte (90) in a sample (9), comprising a sensor (1), a connection electronics (60) and a housing (62), wherein the sensor (1) is configured for converting chemical and / or biochemical information of the analyte (90), preferably a virus (902), in the sample (9) into an electrical signal, wherein the sensor (1) comprises a test cantilever (2) having a base (20) and a deformable portion (22), wherein at least on the deformable portion (22) a receptor layer (24) for selectively receiving the analyte (90) is applied, wherein the sensor comprises a reference cantilever (3) having a base (30) and a deformable portion (32), wherein on the deformable portion (32) a reference layer (34) for selectively not receiving the analyte (90) is applied.

Description

Technical Field

[0001] The present invention relates to a sensor device for detecting one or more analytes in a sample, so as to derive qualitative and / or quantitative conclusions about the presence and / or concentration of one or more analytes in the sample. Background Technology

[0002] A highly sensitive method for detecting and analyzing analytes in samples involves applying microscopic deformation induced by the analyte in a miniaturized elastic element, known as a cantilever, to measure the presence of the analyte in the sample. Specifically, the analyte-induced deformation is achieved by providing a receptor layer on one side of the cantilever, the receptor layer having binding molecules that specifically bind to the specific analyte to be examined, thereby causing a change in surface stress on one side of the cantilever. Here, the deformation of the cantilever is converted into an electrically detectable magnitude, particularly by an electrical converter or transducer applied to the cantilever, to quantitatively measure the presence of the analyte. Such an elastic element is described, for example, in DE 10 2020107 918 A1.

[0003] WO 2007 / 088018 A1 proposes an elastic element for use in biosensors, such as for DNA analysis.

[0004] For example, in Rasmussen, PA, Hansen, O., & Boisen, A. (2005) "Cantilever surface stress sensors with single-crystalline silicon piezoresistors" Applied Physics Letters, 86(20), 203502. https: / / doi.org / 10.1063 / 1.1900299 The paper describes the cantilever deformation caused by different surface stresses. Summary of the Invention

[0005] Based on known existing technologies, the object of this invention is to provide an improved sensor device for detecting analytes in samples.

[0006] The objective is achieved by a sensor device according to the invention for detecting analytes in a sample. Advantageous improvements are derived from the invention.

[0007] Correspondingly, a sensor is proposed for converting the chemical and / or biochemical information of an analyte into an electrical signal in a sample. The sensor includes a test cantilever having a substrate and a deformable portion, wherein a receptor layer for selectively receiving the analyte is applied at least on the deformable portion, the test cantilever having a test converter layer including a passive test converter on the substrate and an active test converter on the deformable portion, and wherein a test function layer is disposed between the test converter layer and the receptor layer. Furthermore, the sensor includes a reference cantilever having a substrate and a deformable portion, wherein a reference layer for selectively not receiving the analyte is applied on the deformable portion, the reference cantilever having a reference converter layer including a passive reference converter on the substrate and an active reference converter on the deformable portion, and wherein a reference function layer is disposed between the reference converter layer and the reference layer. Here, the active and passive reference converters, as well as the active and passive test converters, are configured to output an electrical signal corresponding to the presence and / or concentration and / or amount of one or more analytes in the sample.

[0008] The substrate of the test cantilever and / or the substrate of the reference cantilever can be configured as a rigid substrate. A rigid substrate is understood herein as one in which no deformation, or substantially no deformation, occurs in the corresponding cantilever, i.e., the deformable portion of the test cantilever and / or the reference cantilever relative to the deformable portion of the corresponding cantilever. A rigid substrate is, for example, connected to, supported by, or fabricated from a substrate. Conversely, the deformable portion of the test cantilever and / or the reference cantilever is not supported by a substrate, but rather extends beyond the edge of the substrate and is correspondingly freely configured.

[0009] The deformable portion of the test cantilever and / or reference cantilever can be configured, for example, to be deflectable. Here, the deflection of the corresponding cantilever can be achieved, for example, around a curved edge formed in the transition region between the substrate and the deflectable region. The curved edge here is, for example, the edge of the substrate along which the cantilever is divided into the substrate and the deformable portion.

[0010] However, the deformation of the corresponding cantilever in its deformable part is not limited to convex or concave deformation; the cantilever itself can also deform, for example, arching or forming a wave or twist.

[0011] Here, a sample refers to a finite amount of substance extracted from a relatively large quantity of matter, such as from a reservoir, where the composition of the sample represents the composition of the substance in the reservoir and correspondingly, the presence of the corresponding substance in the reservoir can be inferred from the presence and composition of the substance in the sample.

[0012] For example, a sample can be a saliva sample, or a blood sample, or lymph fluid, or urine, or sweat, or interstitial fluid, or a swab, especially a throat swab, a nasal swab, or a sinus swab, or a extracted tissue. Samples especially include any type of biological sample, i.e., especially animal samples.

[0013] The sample can also be a non-biological sample, such as a sample of chemical substances.

[0014] An analyte is a substance whose presence in a sample is to be qualitatively and / or quantitatively demonstrated or to be detected by means of a sensor. An analyte may be present directly in the sample, dissolved in the sample, or adhered to the sample or a portion thereof, particularly sample particles. An analyte may also interact chemically, biologically, and / or physically with the sample, such that the analyte can only be detected indirectly through the corresponding interaction.

[0015] In particular, one sample form can be transformed into another, enabling the detection of analytes or their presence in a simple and reliable manner. For example, a swab can be dissolved in a liquid, making the swab dissolved in the liquid the actual sample, which is then examined against the analyte.

[0016] The analytes in the sample can also be chemically pretreated, for example—if the analyte is a virus—to break down the viral envelope and obtain the nucleocapsid antigen. Furthermore, this pretreatment can be used to "label" the analyte to amplify the measurement signal. For this purpose, conjugated antibodies can, for example, bind to the antigen of the analyte to produce the largest possible deformation on the cantilever system.

[0017] Therefore, a sample contains chemical and / or biochemical information about the analyte. Chemical information may include, for example, the type of analyte, its concentration, presence, weight, reactivity, and density. Biochemical information includes the same characteristics as the chemical information; however, the substance may be produced, for example, through biological processes. In particular, biochemical information is discussed if the analyte has a specific effect on biological cycles, such as metabolism or the immune system.

[0018] The test cantilever and reference cantilever each include a test converter layer and a reference converter layer, respectively. Passive test converters, active test converters, active reference converters, and passive reference converters are embedded in the test converter layers and reference converter layers. The test converter layers and reference converter layers are primarily configured for electrically contacting the passive test converters and / or active test converters and passive reference converters and / or active reference converters. The converter layers may also be constructed from multiple different layers and materials. Furthermore, the test converter layers and reference converter layers may include other functionalities, which will be discussed in detail later.

[0019] Preferably, a passive test converter is disposed within a test converter layer on the substrate of the test cantilever, and an active test converter is disposed on a deformable portion of the test cantilever. A passive reference converter is disposed within a reference converter layer on the substrate of the reference cantilever, and an active reference converter is disposed on a deformable portion of the reference cantilever. The active and passive reference converters, as well as the active and passive test converters, are configured to output an electrical signal corresponding to the presence and / or concentration and / or amount of the analyte in the sample.

[0020] Converting chemical and / or biochemical information into electrical signals. This can mean that the electrical signal can be altered or established by the chemical composition of the analyte. This can, for example, involve the conductivity of a circuit. For instance, a first biochemical information may be present when the circuit is conductive, while a second biochemical information may be present when the circuit is non-conductive or has reduced conductivity.

[0021] However, in addition to the direct accessibility of such information, such as information about conductivity, it is also possible to infer biochemical information via physical and / or chemical processes and / or interactions.

[0022] For the stated purpose, the proposed sensor includes a reference cantilever and a test cantilever. Here, the cantilever is an elastic element having a base and a deformable portion. Correspondingly, the base is the immovable portion of the cantilever that is fixedly disposed on a substrate at a particular location. The deformable portion of the cantilever is disposed at the base and extends beyond the base.

[0023] In particular, the substrate and the cantilever can be constructed as a single piece. In other words, the deformable portion of the cantilever is suspended from the substrate on one side. Extending from the substrate, the deformable portion of the cantilever can be bent, deflected, and stretched. The following spatial boundary, referred to as the bending edge, is the starting point from which the cantilever can bend or transition from the substrate into the deformable portion. When the cantilever extends from the substrate, the bending edge is typically the edge of the substrate.

[0024] If the cantilever bends, measurable material stresses and forces are generated in or on the material of the cantilever. The bending of the cantilever can be deduced from these material stresses and / or forces, provided they can be measured.

[0025] The converter serves the purpose of determining or measuring the deformation of the cantilever. Active converters are positioned on the deformable portion of the cantilever, while passive converters are positioned on the base of the cantilever, for example, on the substrate. In particular, the electrical characteristics of the circuit can be influenced via the converter.

[0026] For example, deformation of the cantilever can cause an increase in the resistance of the converter, such as an active converter, while no deformation of the cantilever will cause no change in the resistance of the converter. This can be achieved, for example, through a converter configuration based on the principle of strain gauges, whereby the corresponding deformation of the cantilever is reflected in the change in the length of the strain gauge applied to it, and thus the bending of the cantilever can be detected directly by the change in the resistance of the strain gauge.

[0027] Therefore, the chemical and / or biochemical information of the analyte can be detected by the deformation of the cantilever, followed by recording by the transducer, and finally by changes in the electrical properties of the circuit.

[0028] Deformation of the cantilever can be specifically induced by a suitable coating material. For this reason, the reference cantilever has a reference layer for selectively not receiving the analyte, while the test cantilever has a receptor layer for receiving the analyte.

[0029] The acceptor layer is a substance that can interact with the analyte. This means that the acceptor layer is specifically selected for each analyte. Similarly, the reference layer is a substance that cannot interact with the analyte. Therefore, the reference layer is also specifically selected for each analyte.

[0030] In this context, the interaction means that the analyte is in a chemical and / or biochemical and / or physical interaction with the receptor layer. In particular, the interaction can exist in the binding of the analyte to the receptor layer. The interaction can also exist in the absorption or adsorption of the analyte or its non-specific adhesion to the receptor layer.

[0031] Regarding potential interference effects, the acceptor layer and the reference layer are preferably chemically identical, and the difference is preferably only in their interaction with the analyte. Substances that are not analytes interact with the acceptor layer in the same strong or the same weak manner as the reference layer.

[0032] The test cantilever selectively receives the force induced by the analyte, which then acts on the cantilever through the analyte, allowing the cantilever to respond sensitively to the analyte. Conversely, other substances in the sample besides the analyte only contribute to the background noise at the test cantilever, which is essentially curved. For example, the higher the concentration of the analyte in the sample or the faster the surface of the cantilever is occupied by the analyte, the faster the force acting on the test cantilever increases. With the cantilever fully occupied, the maximum possible force for the corresponding configuration is achieved.

[0033] Conversely, selectively excluding the analyte-induced forces at the reference cantilever prevents the analyte from acting on the reference cantilever, so that non-analyte substances only contribute to the background noise of the reference cantilever in a fundamentally curved form.

[0034] The force applied can induce deformation in the deformable portion of the test cantilever, while the deformable portion of the reference cantilever remains unchanged. The basis for the deflection of the cantilever is the change in surface stress caused by interaction with the analyte. This change in surface stress causes stretching or contraction of the upper (or lower) surface of the cantilever. The different stretching or contraction at the upper and lower sides induces internal forces or material stresses in the material, which in turn cause deformation.

[0035] According to existing technology, the reference cantilever lacks a receptor layer that sensitively responds to the analyte. While this allows for the determination of effects in the sample, such as turbulence and thermal drift of the sensor system, the analyte can, for example, bind to the reference layer of the cantilever via non-specific binding. Thus, the analyte itself contributes to background noise. Therefore, in sensors according to existing technology, it is necessary to perform reference measurements in a reference sample, i.e., a sample without the analyte. Only in this way can the effects of non-specific binding of substances that are not analytes be determined.

[0036] In the sensor according to the invention, the measurement method is strongly simplified by selectively not receiving analytes at the reference cantilever, since the reference cantilever is insensitive to analytes and therefore does not contribute to background noise. Only substances that are not analytes contribute to the background noise of the reference cantilever. By selectively not receiving analytes at the reference cantilever, it is possible to induce the reference cantilever to experience, to a certain extent, the same turbulence, the same thermal drift, and the same effects as in the reference sample from all substances that are not analytes. However, the difference lies in the fact that the reference signal is determined directly in the sample liquid.

[0037] In particular, compared to a reference cantilever without a receptor layer, a reference cantilever with a reference layer and a test cantilever with a receptor layer result in significantly more specific analysis of the analyte, because not only the reference layer but also the receptor layer has specific interactions or non-interactions with the analyte.

[0038] The construction of a sensor with a reference cantilever and a test cantilever offers the following advantages: two measurements can be performed simultaneously in a sample, with the measurement at the reference cantilever calibrating the measurement at the test cantilever. This reduces environmental influences on the corresponding measurements, such as chemical, thermal, mechanical, electrical, and fluid interferences, allowing the presence of the analyte to be inferred from a comparison of measurements at the test and reference cantilever points.

[0039] The forces or material stresses acting on the cantilever, such as tension or contraction, can ultimately be detected by a transducer, which detects stresses of different intensities through tension or contraction of varying strengths.

[0040] In the sensor presented here, the measurement method is significantly simplified by selectively not receiving the analyte at the reference cantilever, since the reference cantilever is insensitive to the analyte and therefore does not contribute to background noise. Here, only substances that are not analytes contribute to the background noise of the reference cantilever. By selectively not receiving the analyte at the reference cantilever, it is possible to induce the reference cantilever to experience, to a certain extent, the same turbulence, thermal drift, and effects as the test cantilever and as in the reference liquid, from all substances that are not analytes. The difference, however, is that the reference signal is determined directly in the sample liquid.

[0041] In other words, it is no longer necessary to calibrate the reference cantilever in a limited reference sample; instead, measurements can be performed directly in the sample to be analyzed using both the test cantilever and the reference cantilever.

[0042] In particular, compared to a reference cantilever without a receptor layer, a reference cantilever with a reference layer and a test cantilever with a receptor layer result in significantly more specific analysis of the analyte, because not only the reference layer but also the receptor layer has specific interactions or non-interactions with the analyte.

[0043] By placing an active converter on the deformable portion of the cantilever, a measure of the intensity of the interaction between the analyte and the deformable portion can be obtained via the active converter. Conversely, by placing a passive converter on the base of the cantilever, the interaction is reduced to those interactions that do not primarily cause deformation of the deformable portion.

[0044] The construction of a sensor with a reference cantilever and a test cantilever offers the following advantages: two measurements can be performed simultaneously in a sample, with the measurement at the reference cantilever calibrating the measurement at the test cantilever. This reduces environmental influences on the corresponding measurements, such as chemical, thermal, mechanical, electrical, and fluid interferences, allowing the presence of the analyte to be inferred from a comparison of measurements at the test and reference cantilever points.

[0045] In particular, it is feasible to optimize the geometry of the reference cantilever for specific disturbance effects, so that these disturbance effects can be specifically considered during evaluation. Furthermore, it is feasible to identify different disturbance effects using different reference cantilever designs.

[0046] In other words, a sensor construction with a test cantilever and at least two reference cantilever is also proposed, wherein different reference cantilevers are then preferably optimized for different interference effects.

[0047] By selectively receiving the analyte through the receptor layer and selectively not receiving the analyte-preferred virus through the reference layer, a relative deflection of the test cantilever relative to the reference cantilever can be caused, wherein the presence of the analyte-preferred virus is inferred by comparing the force detected by the transducer, and preferably the magnitude of the presence is inferred.

[0048] According to the proposed sensor, the sensor includes a test functional layer and / or a reference functional layer, which are disposed between the test converter layer and the receptor layer and / or between the reference converter layer and the reference layer.

[0049] The functional layer can fulfill several different functions, such as improving the sensor's sensitivity by moving the neutral axis, thereby improving the tension at the corresponding transducer location, or improving the surface quality for applying the acceptor or reference layer, or adjusting the surface energy so that different acceptor and reference layers can be applied to detect different analytes accordingly. The functions exemplarily mentioned below are described in detail.

[0050] The functional layer may also be deposited on the test converter layer and / or the reference converter layer for overlay, such that the functional layer is located between the test converter layer or the reference converter layer and the receptor layer or the reference layer.

[0051] The deposition and structuring of functional layers can be performed using a variety of methods, such as electron beam evaporation, sputtering deposition, electron beam lithography, plasma-assisted chemical vapor deposition (PECVD), chemical vapor deposition (CVD), atomic layer deposition (ALD), spin coating using a paint spinner, inkjet printing, electroplating, and / or other methods.

[0052] Typical materials used for functional layers may include binary silicon compounds (SiOx, SiN) and / or metal oxides (AlOx).

[0053] In particular, inorganic materials can be used as materials for the functional layer, such as at least one of the following: diamond, 3C-SiC, 6H-SiC, Si3N4, SiO2, SCSi(100), SCSi(110), polycrystalline silicon, tungsten, aluminum, nickel, copper, titanium, gold and / or Ni-Fe.

[0054] In particular, organic materials such as SU8, polyimide, polyamide, PVDF, PMMA and / or SAM (self-assembled monolayers) can also be used as materials for functional layers.

[0055] Functional layers can also be fabricated by electron beam evaporation using the following materials: Al, AlSiCu, Au, Cr, Ge, In, Mg, Mo, Ni, Pd, Pt, Ti, W, Si, and SiO.

[0056] Functional layers can also be fabricated by DC sputtering using the following materials: Al, AlCu (96 / 4), Co, Cr, CrNi (50 / 50), Cu, Mo, Ni, NiV7, Si, Sn, Ti, W, WTi (90 / 10), MoSi / SiC.

[0057] Dielectric layers made of the following materials can also be applied as functional layers: Si3N4, SiO2, DLC, AlN, a-Si.

[0058] Preferably, the complete test converter layer and / or reference converter layer are fully covered by test function layers and / or reference function layers, thereby covering all converters. Alternatively, the coverage by function layers may also include only a portion of the converter layers, wherein preferably, at least one converter of the corresponding cantilever is covered.

[0059] If the test converter layer and / or reference converter layer are covered by a corresponding functional layer, the acceptor layer or reference layer designed to absorb the analyte cannot be directly applied to the test converter layer or reference converter layer, because otherwise no contact would occur between the acceptor layer or reference layer and the sample, and thus with the analyte. Correspondingly, in order to enable the sensor to detect the analyte, including the functional layer according to this disclosure, the corresponding acceptor layer or reference layer is applied to the outer surface of the test functional layer or reference functional layer. This has a particular advantage: the functional layer can be optimized with respect to the acceptor layer or reference layer deposited thereon. Details of this will be discussed later.

[0060] The converter layer is protected from direct contact with any surrounding substances, i.e., liquids or gases, by means of a functional layer covering it. Without the functional layer covering it, the surrounding substances, i.e., liquids or gases, would be in direct contact with the converter layer.

[0061] External influences include, for example, the humidity of the (air) surrounding the converter layer, temperature changes in the environment surrounding the converter layer, or the pH value or salt / ion concentration of the medium surrounding the converter layer. Generally, any polar substances in the solution affect the dielectric properties of the solution, thus falling under the category of external influences. Furthermore, the influence of air gases in the air surrounding the converter layer or analytes dissolved in the sample should also be mentioned. In particular, the final conductivity of the solution surrounding the converter layer and in which the analyte is dissolved should be mentioned. Typically, contact between the converter layer, especially the transducer embedded therein, and the conductive medium causes significant noise in the sensor and should therefore be preferably avoided.

[0062] In the absence of a functional layer, the aforementioned influences particularly cause increased drift in the sensor signal. This sensor signal drift means that, although the presence or concentration of the analyte remains unchanged, the detectable electrical variable of the transducer changes over time due to changes in external influences on the transducer. In other words, changes in the sensor signal can be accompanied by changes in external influences other than those on the analyte. This can lead to erroneous inferences about the presence or concentration of the analyte, or even the inference that the analyte is absent. By incorporating one or more functional layers as presented herein, this drift in the sensor signal due to external influences can be reduced or avoided, thereby improving the accuracy and reliability of analyte detection.

[0063] External influences can also cause stronger noise in the sensor, thereby worsening the signal-to-noise ratio or even causing the sensor to lose its sensitivity. By using one or more functional layers proposed, the signal-to-noise ratio can be kept more constant or constant.

[0064] Furthermore, the aforementioned external influences can cause transducer aging effects, which persistently alter the corresponding electrical measurement variables used as parameters for detecting analytes in a sample, rendering safe or reliable sensor operation no longer feasible. The transducer aging effects can also be reduced or avoided through one or more of the proposed functional layers, enabling the sensor to achieve more reliable detection of analytes.

[0065] Correspondingly, through protective functional layers, especially through suppressed oxygen contact and air humidity, the covered transducer does not have aging effects or does not have significant aging effects, such as sensor signal drift and / or signal-to-noise ratio degradation.

[0066] Furthermore, the functional layer protects the converter layer from external influences, such as those caused by the reactive medium surrounding the converter layer, particularly acids or reactive gases. This specifically prevents the so-called chemiluminescence characteristic of the converter. Chemiluminescence here means that the material changes its resistance in response to a chemical environment in the vicinity or in contact with the material.

[0067] However, the use of porous functional layers characterized by providing partial permeability to specific substances is not excluded. Correspondingly, chemiluminescent properties can be utilized in a targeted manner: the transducer covered by the porous functional layer obtains targeted sensitivity regarding one or more analytes that can pass through the porous functional layer to reach the transducer. Here, for example, different functional layers with different characteristics regarding their partial permeability can also be used.

[0068] Preferably, the functional layers are made of an electrically insulating material with high insulation resistance. This is particularly preferred for one or more functional layers that are in direct contact with the converter and / or electrodes. Furthermore, the test functional layer and the reference functional layer can be made of the same material.

[0069] To operate the converter, and especially to read out the electrical measurement variable to be detected, a voltage drop across the converter's electrodes is typically required. In the absence of a test or reference functional layer with insulation covering the test or reference converter layer, the voltage-related potential has a direct impact on the test or reference converter layer, particularly at the converter's electrodes.

[0070] Because the transducer layer, which lacks an insulating functional layer for the sensor's ability to detect analytes, must also include a receptor layer or reference layer for selectively receiving or not receiving the analyte to be detected, the binding molecules of the receptor layer (e.g., antibodies) or reference layer, as well as the analytes bound to the transducer layer, are similarly affected by the potential present in the transducer layer, for example, in their binding properties (specificity, binding rate, binding capacity, etc.).

[0071] For example, if a test cantilever and / or reference cantilever with a test converter layer and / or reference converter layer and acceptor layer and / or reference layer comes into contact with a sample without a protected test functional layer and / or reference functional layer, the voltage drop across the electrodes of the active and / or passive sensors causes a small but limited leakage current, in addition to the current flowing through the sensor. This leakage current flows, for example, through the high but limited resistance of the sample material, such as a liquid solution. The chemicals present in the sample, as well as the bound molecules (which are themselves chemicals) of the acceptor and / or reference layers, then experience voltage or leakage current that can induce electrochemical reactions in the chemicals involved. Correspondingly, the electrochemical changes induced by these chemicals can affect the electrical signal of the converter.

[0072] The insulating functional layer covering the converter layer now has the decisive advantage that electrochemical reactions that would occur in the absence of an insulating functional layer, particularly at the electrodes of the converter, through direct contact between the converter and the sample, are suppressed. In other words, the surface of the functional layer, through which subsequent layers (e.g., acceptor layers or reference layers) are correspondingly designed to receive or not receive specific analytes, is essentially without potential, thus eliminating electrochemical reactions.

[0073] In the converter layer, the absence of electrochemical reactions means the converter's electrical signal is no longer affected by these reactions, and changes in the electrical signal caused by the analyte are no longer superimposed on the electrochemically induced signals. This improves the converter and thus the sensor's sensitivity. In particular, the sensor's noise characteristics are improved, thereby enhancing the sensor's signal-to-noise ratio.

[0074] By setting a test functional layer and / or reference functional layer between the test converter layer and / or reference converter layer and the receptor layer and / or reference layer, the receptor layer and / or reference layer, and their bound molecules, especially proteins such as antibodies, are isolated from the voltage dropped on or along the converter layer. Correspondingly, the voltage-induced effects on the receptor layer and / or reference layer and their bound molecules are suppressed due to electrochemical reactions.

[0075] When a cantilever is coated with a receptor layer or a reference layer, where the receptor layer or reference layer is in direct contact with the corresponding converter layer and thus with the active and / or passive converter, interference with the converter can occur. This interference is suppressed by the coating when a functional layer is used between the converter layer and the receptor layer or reference layer.

[0076] The area of ​​the converter layer covered by the functional layer can also serve as protection against electrostatic discharge effects within the converter layer. Converter layers without a protective functional layer, exposed to the environment, are particularly susceptible to discharges, especially in the case of conductive layers used for converter electrical contacts, which can be derived from the possible potential in the surrounding environment directly adjacent to the converter layer. The insulating functional layer covering the converter layer prevents such discharges via the conductive layers of the converter layer or via the electrodes of the converter. This protection is particularly evident in embodiments with high insulation resistance of the functional layer, and prevents discharges even under high potential conditions.

[0077] In a particularly preferred embodiment, the converter layer is implemented as a conductive layer structured as electrodes, allowing the active and passive converters to be electrically contacted from the outside. A particular advantage of the functional layer covering the converter layer is that non-inert materials are also suitable as conductive layers, since there is no exposure to the environment through the functional layer, and oxidation of reactive materials is particularly suppressed.

[0078] In addition to the conductive layer described above, the converter layer may also include an activation layer configured to induce increased surface stress along the converter layer. This can be achieved by using a covered functional layer, or by using a non-inert material as the activation layer.

[0079] In a particularly preferred embodiment, the converter layer, implemented as an activation layer, can simultaneously function as a conductive layer for electrical contact with the converter. Correspondingly, the activation layer can be made of a conductive material, particularly gold, wherein an adhesion promoter, such as titanium, is typically used between the gold layer and the cantilever material due to the negligible wetting properties of gold on the cantilever surface. However, as mentioned above, non-inert materials are also suitable as a protective functional layer. Correspondingly, the selection of materials for the activation layer is significantly increased, and adhesion promoters can be omitted if suitable material selection is made.

[0080] Another function of the functional layer is to improve the variability of the sensor with respect to the appropriate receptor layer or reference layer for specific detection or non-detection of analytes in the sample, and to improve the sensitivity of the sensor.

[0081] This objective is also achieved through a functional layer positioned between the converter layer and the receptor layer or reference layer.

[0082] In the absence of a functional layer, the cantilevered converter layer must have specific properties so that the subsequent acceptor layer or reference layer wets the converter layer below it, thereby ensuring proper adhesion between the layers.

[0083] The adhesion / wetting of layers requires that the surface energy of the layer to be wetted be significantly greater than the surface energy of the layer to be wetted. Correspondingly, in the absence of a functional layer, the converter layer, in addition to its activation and / or conductivity and / or inertness properties, must also possess surface energy to allow subsequent acceptor or reference layers to adhere to the corresponding converter layer. This significantly limits the selection of suitable materials for the converter layer and the acceptor or reference layer.

[0084] If the functional layer is correspondingly disposed between the converter layer and the acceptor layer or reference layer, then only the surface energy of the functional layer must match the surface energy of the acceptor layer or reference layer to ensure proper wetting / adhesion between the layers. This significantly increases the feasibility of selecting the converter layer, as already explained above, but also significantly increases the feasibility of selecting the acceptor layer or reference layer. In particular, the functional layer can be matched to any acceptor layer or reference layer.

[0085] In a typical implementation, a passivation layer can be applied to the lower surface of the cantilever. The passivation layer is configured to minimize non-specific adhesion of analytes on the lower side of the cantilever.

[0086] However, in a preferred embodiment, it is also feasible to have the receptor layer for selectively receiving the analyte on the functional layer and on the underside of the corresponding cantilever, wherein the surface stress of the upper layer is altered by binding the analyte to the receptor layer in the opposite direction to the change in surface stress of the lower layer.

[0087] According to the described embodiment, the deformation is enhanced by the analytes bound to the receptor layer on the upper and lower surfaces of the cantilever, thereby also enhancing the electrical signal generated by the active test converter, thereby improving the sensitivity of the sensor.

[0088] Furthermore, the mechanical stress state of the cantilever can be specifically set through the proposed structure.

[0089] In a particularly preferred embodiment, under the same cantilever deformation, the stress field of the cantilever is configured such that the stretching / contraction is maximized at the location of the active test converter and / or the active reference converter, thereby maximizing the electrical signal of the active test converter and / or the active reference converter.

[0090] Here, "together" includes not only longitudinal stretching but also transverse stretching of the cantilever, as well as any combination of both. Correspondingly, the transducer is preferably configured to be sensitive to both stretching directions. Here, the term stretching or deformation correspondingly includes longitudinal stretching, transverse stretching, and mixed stretching.

[0091] A neutral plane corresponds to a virtual surface profile within a material, such as a cantilever, along which the material does not experience stretching / contraction due to surface stress. The neutral plane unfolds through two mutually perpendicular neutral axes. Here, the neutral axes correspond to virtual lines along the longitudinal or transverse direction that do not experience stretching / contraction due to longitudinal or transverse stress along the surface of the cantilever. Correspondingly, locations particularly far from the neutral plane or axis are subjected to particularly large stretching / contraction.

[0092] The cantilever stretch distribution can also be additionally set by setting it on the converter to cover the functional layer of the converter or the segmented converter.

[0093] If the tension is observed exemplarily along a chosen direction, such as the longitudinal direction of the cantilever, the position of the longitudinal neutral axis along said direction can be given quantitatively. Correspondingly, this relates to the geometric position of the neutral axis for a structure consisting of two layers with thicknesses h1 and h2. It can be represented as

[0094]

[0095] Where λ = h1 / h2 is the layer thickness ratio, and E1 and E2 represent the elastic modulus of the layer. For isotropic materials with the same elastic modulus, the position of the transverse neutral axis is correspondingly equivalent, resulting in a flat profile of the plane (provided the layer thickness is uniform). However, anisotropic materials with correspondingly anisotropic elastic moduli cause a non-typical profile of the neutral plane.

[0096] Correspondingly, according to the above equation, the elastic modulus of the functional layer can be selected, for example, such that the neutral plane or neutral axis of the cantilever shifts downwards, i.e., away from the converter layer or transformer, maximizing the tension at the location of the converter under deformation. For this embodiment, the elastic modulus of the functional layer must therefore be chosen to be sufficiently smaller than the average elastic modulus of the layers below it. The stress in the cantilever caused by the different elastic moduli of the different layers is also called inherent prestress or internal stress.

[0097] Preferably, the elastic modulus of the functional layer can be selected to be particularly small, especially smaller than the elastic modulus of the underlying converter layer and / or the matrix of the cantilever. However, the elastic modulus of the functional layer can generally be arbitrarily selected to induce or define a specific stress distribution in the cantilever under deformation.

[0098] The thickness of the functional layer can also be used, according to the above equation, to influence the position of the cantilever's neutral plane or axis. With increasing thickness, the neutral plane moves towards the functional layer, i.e., towards the converter layer. Conversely, a smaller thickness should be chosen for the opposite effect.

[0099] Correspondingly, in another embodiment, the stress distribution along the converter layer, particularly at the location of the active converter, caused by the deformation of the deformable portion of the cantilever, can be maximized through appropriate structuring of the functional layers. Here, structuring of the functional layers refers to targeted alteration of the height profile of the functional layers.

[0100] For example, the functional layer at the converter location can be structured, wherein the height profile of the functional layer is modified to maximize the stress state at the converter location. This can be done, for example, by reducing the thickness of the functional layer through targeted local etching at the converter location, causing the neutral plane of the corresponding cantilever to move away from the converter at that location, thereby increasing the tensile stress at the converter location under deformation.

[0101] By applying an activation layer, the corresponding cantilever can also have the following stress state: the stress state causes a strong inherent prestress, causing the corresponding cantilever itself to bend strongly in equilibrium, i.e., when the analyte is not bound to the acceptor layer or reference layer.

[0102] Advantageously, in the aforementioned situation, the stress state can be transformed into a neutral, preferably uniform, equilibrium state of the cantilever. This can be achieved via an additional functional layer by setting the material properties of the functional layer, particularly its thickness and / or modulus of elasticity, so that the bending state of the cantilever is transformed into a neutral, preferably straight, state.

[0103] In addition, appropriate structuring of functional layers can be used to achieve a stress-free state of the cantilever in equilibrium, i.e., to counteract any possible inherent prestress in the cantilever.

[0104] To further optimize, especially to maximize, the tension or length change of the cantilever, particularly at the location of the converter, in another embodiment, the structure of the converter itself can also be affected to set the stress state of the converter in the event of cantilever bending.

[0105] What is meaningful for this is that the structurally constrained resistance change of the quantizer is quantized. The value of k, also known as the response factor, is a proportionality constant between the stretching of the converter and its resistance change:

[0106]

[0107] Where ΔR is the change in converter resistance, R is the converter resistance when the cantilever is not bent, and ΔL l and ΔL t It refers to the longitudinal and lateral length changes of the converter, while L l and L t These are the longitudinal and lateral lengths of the converter when the cantilever is not bent. The length changes, which are orthogonal to each other, are achieved here through a weighting factor G. L and G R The weighting is determined by the geometric configuration of the converter. In particular, all other measurement variables proportional to the k-value or resistance, such as, for example, conductivity, can also be measured.

[0108] In anisotropic materials, the value of k can also be direction-dependent.

[0109] On one hand, the converter can be structured in the plane of the converter layer with respect to its shape. By changing the shape of the converter in the plane, a voltage distribution can be generated that produces a larger electrical signal during cantilever deformation. Correspondingly, the structuring can be chosen to maximize the change in length of the converter at the location during cantilever deformation.

[0110] Specifically, according to the above equation, the geometric weighting factor G L and G T The structure of the converter can be directly influenced as described above. Depending on the desired sensitivity along the longitudinal and / or lateral directions, the converter can be appropriately structured to increase or decrease the weighting factor.

[0111] On the other hand, the converter can also be structured with respect to its height profile. In this case, the height profile of the converter is specifically designed to deviate from a flat profile. By structuring the height profile of the sensor, it is possible to influence the voltage state of the converter in a very targeted manner. As described above, the varying thickness of the converter resulting from the structuring causes a shift in the neutral plane or axis, and when the cantilever undergoes externally induced bending, this results in a change in the voltage state or length at the location of the converter.

[0112] Similarly, it is also possible to structure the converter with respect to its structure in the plane of the converter layer as well as with respect to its height profile in order to achieve the desired voltage distribution in the converter.

[0113] Reference cantilever and test cantilever can have another layer including a self-organizing monolayer.

[0114] Self-organized monolayers can reduce surface roughness and compensate for chemical changes, making it feasible to create a uniform coating of the cantilever using a receptor or reference layer. Therefore, the uniform surface properties of the cantilever ultimately improve the binding properties of the receptor layer and the analyte.

[0115] Correspondingly, the self-organizing monolayer can be set between the test functional layer and / or the reference functional layer and the receptor layer and / or the reference layer.

[0116] The transducer can be configured and set up to determine the deformation of the deformable portions of the test cantilever and the reference cantilever, preferably detecting the forces applied to the base and deformable portions of the test cantilever and the reference cantilever respectively during deformation.

[0117] If a sensor consisting of a reference cantilever with a reference layer or a receptor layer and a test cantilever is exposed to a sample containing an analyte, an interaction can exist where the analyte binds to the receptor layer.

[0118] By binding the analyte to the receptor layer, the surface stress on the receptor-occupied side of the test cantilever changes, causing a force to act on the test cantilever. Conversely, no force acts on the reference cantilever via the analyte. For example, the higher the concentration of the analyte in the sample or the faster the surface of the cantilever is occupied by the analyte, the faster the force acting on the test cantilever increases. Therefore, to measure the concentration of the analyte, for example, the slope of the continuous force change over time can be measured on the cantilever. The maximum force feasible for the corresponding configuration is achieved when the cantilever is fully occupied.

[0119] The interaction can induce deformation in the deformable portion of the cantilever, while the deformable portion of the reference cantilever does not bend.

[0120] The basis for the deflection of the cantilever is the change in surface stress caused by its interaction with the analyte. This change in surface stress causes stretching or contraction of the upper (or lower) surface of the cantilever. The different stretching or contraction at the upper and lower sides induces internal forces or material stresses in the material, which in turn cause deformation.

[0121] The force or material stress, and especially tension or contraction, can ultimately be detected by a transducer, wherein different intensities of stress are detected by the transducer through tension or contraction of varying degrees. The corresponding transducer changes its resistance according to the tension or contraction, thus enabling the transducer to be used for detecting tension or contraction in the aforementioned manner.

[0122] The force to be detected can be a bending force and / or a tensile force and / or a contractile force and / or a shear force and / or based on the elastic modulus of the reference cantilever and the test cantilever. Therefore, the force to be detected is typically caused by surface stress on the surface of the cantilever.

[0123] Bending forces can cause changes in the geometry of a cantilever, especially when a curvature different from that of an unloaded cantilever is applied. This curvature can induce bending moments or tensions, thereby generating bending stresses, which can be determined using a corresponding transformer.

[0124] Changes in surface stress and the resulting tensile forces can cause changes in the length of the cantilever in the region. In particular, the stretching at the upper surface of the cantilever can differ from that at the lower surface. Surface stretching can occur parallel to the base of the cantilever (so-called transverse stretching), perpendicular to the base of the cantilever (so-called longitudinal stretching), or a combination of both. The magnitude of the stretching is strongly related to the geometry of the cantilever and other layers disposed on the surface, such as electrodes, allowing for optimal detection of the analyte by optimizing the orientation and cantilever geometry. The length, width, and thickness profiles of all involved layers of the cantilever are particularly important. The corresponding length changes can vary depending on the orientation of the cantilever's lattice.

[0125] In an unstructured converter, the relative deformation and / or relative change of surface stress occur in the longitudinal direction of the test cantilever and / or reference cantilever (i.e., in the direction of longitudinal tension), wherein the longitudinal direction is perpendicular to the base extension of the test cantilever and / or reference cantilever, wherein preferably, the active test converter and / or passive test converter and / or active reference converter and / or passive reference converter are oriented in the longitudinal direction and are thus most sensitive along said direction.

[0126] However, the case of the converter described above is particularly preferred, wherein the relative deformation and / or the relative change in surface stress extends in the longitudinal and / or lateral directions of the test cantilever and / or the reference cantilever, wherein preferably, the active test converter and the passive test converter and / or the active reference converter and the passive reference converter are optimized in both directions with respect to their sensitivity through appropriate geometric structuring.

[0127] If the tensile forces at the upper and lower surfaces are different, the force acting is also called shear force.

[0128] In the case of a curved cantilever, bending forces take effect. Consequently, the upper surface of the cantilever is stretched, and this stretching is particularly greater than the stretching at the lower surface of the cantilever (which is particularly contracted), causing an overall shear force to act on the cantilever. In the case of a (hypothetically) uniform cantilever, the stretching at the upper side is as large as the contraction at the lower side. In the case of an asymmetrical cantilever construction, through the proposed layer system, the stretching at the upper side has a different value than the contraction at the lower side.

[0129] The forces mentioned above are all based on the so-called elastic modulus of the cantilever. The elastic modulus of the cantilever is a material constant specific to the material used in the cantilever. By selecting the material or material composition, or by processing the material, the elastic modulus can be set within a certain range, allowing optimization of the measured effect for each configured transducer. Conversely, it is also possible to match the transducer to the current elastic modulus of the material and optimize its sensitivity.

[0130] Preferably, the cantilever can be a multilayer cantilever, for example, a cantilever consisting of a gold layer, a silicon nitride layer, and a functional layer on the gold layer. A cantilever thus constructed consists of material layers that collectively have a defined stress state. For example, the state can be stress-free, minimizing inherent mechanical stress. However, it is also possible that the multilayer cantilever is pre-stressed, making the cantilever particularly sensitive to changes in surface stress. Furthermore, it is also possible to coat a uniform cantilever with different layers on the upper and lower sides to achieve the effects described by the multilayer cantilever.

[0131] By comparing the deformation and / or force detected by the transducer, the presence of the analyte can be inferred by selectively receiving the effect on the test cantilever caused by the analyte. Preferably, the magnitude of the presence can be inferred.

[0132] In particular, the passive converter on the substrate of the cantilever only detects the primary non-deflection effect because the substrate is fixedly coupled to the substrate. Therefore, the measurement signal from the passive converter yields a fundamental signal, which is specific to the corresponding cantilever.

[0133] For example, the substrate of the reference cantilever can cause the first electrical state of the passive reference converter through the influence of environmental conditions, while the interaction between the test cantilever and the sample causes the second electrical state of the passive test converter.

[0134] Conversely, the active transducer on the deformable portion of the cantilever indicates a measure of the force of deformation or action, and thus indirectly indicates a measure of the interaction between the reference or acceptor layer and other substances in the analyte and sample.

[0135] For example, the reference cantilever can bend at a first magnitude through interaction with the sample, causing a deflection in the active reference converter to induce a third electrical state, while the test cantilever can bend at a second magnitude through interaction with the sample, and at a third magnitude through additional interaction with the analyte in the sample, which induces a fourth electrical state in the active test converter.

[0136] A comparison of the electrical states of the passive and active converters illustrates the measurement of cantilever deformation, where the electrical signal of the active converter is calibrated to the fundamental signal of the passive converter on the substrate. Simultaneously, a comparison of the measured signals of the active or passive converters yields a measure of the difference in cantilever deformation. From this, it is feasible to infer the specific influence of the analyte on the tested cantilever.

[0137] The configuration with four transducers has the following advantages: it allows for local calibration of the sensor at locations where the influence of the sample and analyte is present.

[0138] The deformable portions of the reference cantilever and the test cantilever can have the same geometric dimensions, wherein the width of the deformable portions of the reference cantilever and the test cantilever preferably corresponds to the length of the deformable portions of the reference cantilever and the test cantilever.

[0139] Therefore, the deformation of the cantilever can generate a particularly large force on the active converter.

[0140] The bases of the reference cantilever and the test cantilever can be set on the same integral base. In particular, the test cantilever and the reference cantilever share a common base.

[0141] This allows passive converters to operate at a similar baseline level, or reduces the impact on the specific characteristics of a separate substrate. This can lead to greater measurement accuracy.

[0142] Therefore, the reference cantilever and the test cantilever can be positioned particularly close to each other, for example, smaller than the width of the cantilever.

[0143] This allows the same disturbance effects to act on the cantilever, which are caused, for example, by temperature differences in the sample, and especially by convection or other fluid dynamics.

[0144] Furthermore, this also allows for the fabrication of multiple cantilevers from (silicon) wafers.

[0145] Furthermore, the spacing of the cantilever toward the manufacturing boundary can be optimized. The manufacturing boundary is typically given by the spotting-abstand, which is an important measure when manufacturing the reference and acceptor layers, see below.

[0146] The bases for the reference cantilever and the test cantilever can be constructed as a single piece.

[0147] This allows for further reduction of substrate-specific effects, resulting in greater measurement accuracy. Furthermore, it simplifies the fabrication of one or more cantilever pairs.

[0148] Therefore, the deformable portions of the reference cantilever and the test cantilever can have the same geometric dimensions, wherein the width of the deformable portions of the reference cantilever and the test cantilever corresponds to the length of the deformable portions of the reference cantilever and the test cantilever, and the bases of the reference cantilever and the test cantilever are disposed on the same integral base, and the base is preferably constructed in one piece.

[0149] The reference cantilever and test cantilever may include Si3N4, SiO2, Si3N4 / SiO2, SiC, Si, or be composed of Si or include polymers.

[0150] By using silicon-based reference and test cantilever arms, manufacturing methods known from the semiconductor industry can be employed, enabling the proposed sensor to be manufactured on a large industrial scale. Polymers can also be manufactured on a large industrial scale and offer the advantage that the material properties of the polymer can be largely predetermined.

[0151] The converters can have the same inherent physical characteristics, wherein the converters are configured to adjust their electrical characteristics according to the forces acting on the reference cantilever and the test cantilever, preferably a resistance or another value proportional to the value of k (see the equation above).

[0152] The same inherent physical properties here include those that bear the measurement characteristics of the converter on the cantilever. This particularly relates to the voltage that can be dropped across the converter, i.e., the converter's resistance or conductivity. Resistance is especially related to the converter's geometry, such that in the case of uniform conductivity in different converters, the converter's geometry must be correspondingly identical. However, non-uniform conductivity in different converters can also be generated by altering the nanomaterial properties of the converter material.

[0153] However, physical characteristics also involve the way and method by which the measured signal changes as a response to the applied force. In particular, each converter should respond identically to the same force applied or the deformation of the cantilever, so that no nonlinear deviations occur between different converters.

[0154] The inherent physical properties are determined, in particular, by the nanostructure of the converter. The nanostructure is preferably identical for all converters, such that the same geometric configuration provides the same physical properties.

[0155] Extremely high sensitivity can be achieved by making the metal particles in the converter as small as possible.

[0156] Therefore, a reliable manufacturing process for the converter can ensure that all converters respond identically to the effects of force or external disturbances, so that the deviation of different measured forces is based solely on the external action on the cantilever and is not related to the inherent physical characteristics.

[0157] In particular, the bending states of the individualized reference and test cantilever arms can be inferred from the electrical characteristics of the transducer, especially the presence of analytes selectively received through the receptor layer. The transducer, which indirectly senses the interaction with the analyte via the cantilever arms, alters its measurement characteristics according to the applied force.

[0158] The spacing between the active reference transformer or test transformer and the passive reference transformer or test transformer can be less than 100 μm, wherein the transformer can be placed against a curved edge.

[0159] By placing transducers as close to each other as possible, the spatial impact of the sample on the transducers is reduced. For example, if the presence of an analyte in the sample is subject to a concentration gradient, it is advantageous to perform the measurement at a point along the gradient whenever possible.

[0160] When the converter rests against a curved edge, the minimum possible spacing is achieved. The curved edge here is the edge of the substrate along which the cantilever divides the substrate into a base and a deformable portion. For example, an active converter can rest against the curved edge with its lower edge, while a passive converter can rest against the curved edge with its upper edge.

[0161] In particular, the optimal distance between the active converter and the curved edge can be correlated with the precise geometry of the sensor. Correspondingly, the distance from the curved edge can be selected such that surface stretching causes the maximum change in the electronic state of the converter.

[0162] In particular, the optimal distance between the passive converter and the curved edge is achieved when the electronic state of the passive converter is changed as little as possible by testing the deflection of the cantilever.

[0163] However, active and passive converters should ideally be positioned close to each other so that, in manufacturing processes such as those based on scanning electron microscopy or electron lithography, they can be easily and quickly manufactured together in a single step, without requiring the mechanical movement of the XYZ feed device to move the wafer. This, in particular, enables significantly faster, more accurate, and cost-effective manufacturing of sensors.

[0164] In particular, the orientation and geometry of the converter determine whether to measure the longitudinal, lateral, or mixed tension of the cantilever. If the longitudinal axis of the converter extends parallel to the base, it is preferable to measure the lateral tension of the cantilever. If the longitudinal axis of the converter is oriented perpendicular to the base, it is preferable to measure the longitudinal tension of the cantilever. However, the longitudinal axis of the cantilever can also have any orientation with respect to the base, and correspondingly, mixed tension (a superposition of longitudinal and lateral tension) can be measured. Therefore, it is particularly feasible to form a rectangular, square, circular, or elliptical converter so that the sensitivity of the converter is matched to the geometry of the cantilever.

[0165] The reference cantilever and test cantilever, as well as the active and passive reference transformers and test transformers, can be set up in a mirror-symmetric manner relative to each other.

[0166] Mirror symmetry can particularly involve a mirror axis positioned between a reference transformer and a test transformer.

[0167] A mirror-symmetric construction can reduce, for example, the influence of voltage on the converter, or at least guide it symmetrically relative to each other. This can improve measurement accuracy and reduce susceptibility to interference.

[0168] The test converter layer and reference converter layer of the sensor may include electrodes, preferably four electrodes, which are configured to electrically contact an active test converter and / or a passive test converter and a passive reference converter and / or an active reference converter.

[0169] Here, the electrode is a conductive layer, such as a conductive layer made of gold, or a metal wire or cable, which can establish a conductive connection from the converter's connection terminal to external devices such as current or voltage sources or to corresponding measuring devices. In principle, any conductive connection between the converter and external devices can be understood as an electrode. However, a portion of the electrical connection of the contact sensor is specifically regarded as an electrode here.

[0170] Typically, the sensor is electrically connected to an external source or measuring device via electrical terminals. Here, the electrical connection connector contacts a cable or wire on a pad, where the wire is fixedly soldered, for example, by ultrasonic means. The electrical connection then extends directly from the pad to the transducer. The equipotential surface between the transducer and the pad is referred to hereinafter as an electrode.

[0171] Electrodes are used in electrical contact transducers, and in particular, enable the feasibility of guiding electrical signals from sensors to measuring devices.

[0172] In particular, the electrodes can be at different potentials and interact with each other. Therefore, in order to minimize the mutual influence of current and voltage in the electrodes, it is advantageous that the electrodes also have a symmetrical shape, so that the corresponding interferences are at least uniformly distributed throughout the system. This can be achieved, in particular, by using an even number of electrodes or, in the case of four converters, only four electrodes.

[0173] Therefore, it is feasible through electrode geometry design to achieve a basic signal level of less than 1.1V at the electrode due to the possible potential difference, making electrical packaging of the electrode unnecessary. Here, electrical packaging can be understood, for example, as electrical insulation, covering, or shielding of the electrode and bonding wires. This simplifies the manufacturing process and improves measurement accuracy.

[0174] The spacing between electrodes can be minimized.

[0175] Here, the spacing is minimal when the electrodes are not in contact, i.e., connected to each other without conducting electricity. In other words, the conductivity between the electrodes is significantly smaller than the conductivity of the converter.

[0176] By minimizing the spacing between electrodes, multiple electrodes can be placed on the wafer, making more cost-effective manufacturing processes feasible. However, this also allows for a reduction in converter size, further minimizing the impact of non-uniform environmental conditions on the converter.

[0177] The converter can be electrically connected in a full-bridge configuration, which is used to establish a bridge transverse voltage, especially when the electrical characteristics of the converter change asymmetrically.

[0178] A full bridge is a measuring device used to measure resistance or small changes in resistance. Full bridges are also known by the names Wheatstone'sche Messbrücke, H-bridge, symmetrical full bridge, or thermally symmetrical full bridge.

[0179] For example, the active and passive converters of the reference and test cantilever arms are connected in a full-bridge configuration, with one connection contact of each active converter placed on a common potential via a first electrode. Furthermore, one connection contact of each passive converter is placed on a common potential via a third electrode. A voltage (DC or AC) can be applied via the first and third electrodes, where the combination of the active or passive converters acts as a voltage divider corresponding to the resistors of the respective converters.

[0180] Furthermore, on each cantilever, another contact point of the active converter is connected to another contact point of the passive converter via the second electrode in the test cantilever or the fourth electrode in the reference cantilever. Correspondingly, a bridge transverse voltage is established on the second and fourth electrodes as long as the resistance ratio of the active to passive converter in the reference cantilever is not equal to the resistance ratio of the active to passive converter in the test cantilever.

[0181] In the fundamental state of the full-bridge sensor, the transverse voltage of the bridge is ideally zero because no force, or the same force, acts on all participating transducers. This fundamental state is preferably set during the manufacturing process such that only a small offset voltage appears between the electrodes, which can be canceled out by the construction of the measurement technique.

[0182] Therefore, asymmetrical force changes can preferably be detected from the basic state of the full bridge. For example, if the active test converter of the test cantilever responds to a force acting with a change in its electrical characteristics or its resistance, the ratio of resistances in the full bridge is no longer balanced, resulting in the establishment of a bridge transverse voltage. Finally, the established bridge transverse voltage can be detected using a measuring device.

[0183] In particular, if the forces acting on the active converters of the test and reference cantilever arms are the same, no bridge lateral voltage is established. This is, however, a non-specific force application that does not originate from a specific interaction with the test cantilever arm. Similarly, if the forces acting on the passive converters of the test and reference cantilever arms are the same, no bridge lateral voltage is established either.

[0184] By using the full-bridge implementation scheme, the active reference converter of the reference cantilever induces the calibration of the active test converter of the test cantilever to a certain extent. On the one hand, calibration to the basic state of the full bridge can be achieved through a passive converter; on the other hand, the deflection of the deformable part of the cantilever can be inferred by comparing the active and passive converters.

[0185] The sensor may include a bridge lateral voltage detector configured to detect the bridge lateral voltage across the entire bridge, wherein the presence of an analyte selectively received by the receptor layer is inferred from the detected bridge lateral voltage, preferably the magnitude of the presence.

[0186] In particular, the bridge transverse voltage detector can be any detector capable of detecting voltage. For example, it can be a resistor measuring device, a signal transmitter or a voltage measuring device that displays voltage, or other types of detectors that generate an output signal by detecting voltage.

[0187] The bridge lateral voltage detector can be configured to generate a unique output value, indicating only the presence of the bridge lateral voltage. In particular, the presence of the bridge lateral voltage suggests that the analyte has interacted with the acceptor layer of the test cantilever at a minimum concentration, thereby altering the electrical characteristics of the converter, or at least the electrical characteristics of the active converter in the test cantilever.

[0188] However, the bridge lateral voltage detector can also display different output values, which preferably have a simple functional relationship with the bridge lateral voltage. For example, this could mean that as the bridge lateral voltage increases, the output value of the bridge lateral voltage detector increases. But it could also mean that as the bridge lateral voltage increases, the output value of the bridge lateral voltage detector decreases. Particularly advantageous is that a one-to-one correspondence value of the bridge lateral voltage can be inferred from the detector's output value. In other words, preferably, the output value of the bridge lateral voltage detector follows a bijective function of the bridge lateral voltage.

[0189] Ideally, the change in the bridge voltage is expressed as a ratio to a defined supply voltage, i.e., the voltage being measured. For example, drift in the supply voltage would not subsequently affect the measurement signal.

[0190] Different output values ​​are not limited to the signal amplitude, but can also be limited to the occurrence of the output value over time. For example, a bridge transverse voltage detector can output one pulse per time interval under the first voltage condition, while a bridge transverse voltage detector outputs multiple pulses per time interval during the second voltage condition. Therefore, the strength of the bridge transverse voltage can be indicated by the occurrence of the pulses. Thus, the output value can be encoded.

[0191] The electrical characteristics of the converter can be output via an AD converter, and the AD converter logic can be configured to provide differential and / or absolute measurements of the bending state.

[0192] In particular, the bridge transverse voltage detector is designed in the form of an AD converter, which is a converter electronics that generates digital signals from analog signals. For this purpose, the AD converter samples the signal strength point by point at a certain periodicity and converts the measured voltage into a digital value.

[0193] In particular, an AD converter may include AD converter logic, which can be placed into different operating modes by adjusting the internal interconnects, especially by software adjustment. Through these different operating modes, different voltages (especially AC and / or DC voltages) and measurement signals can be extracted from the electrode circuitry.

[0194] For example, an AD converter can have a so-called differential measurement mode, in which only the change in bending state between the reference cantilever and the test cantilever is detected. In this differential measurement mode, in particular, the transverse voltage of the bridge is truncated, such that the change in the bending state of the cantilever is detected in the form of the resulting transverse voltage of the bridge. The differential measurement mode is a preferred measurement mode for detecting the binding of analytes on the acceptor layer.

[0195] However, it is also feasible for the AD converter to operate in a so-called absolute measurement mode, in which the individual converters are directly accessed via electrodes (Single-Ends-Modus). This allows for the measurement of both half-bridges, for example, for quality assurance, or also for the characterization of the full bridge. Furthermore, it is thus possible to detect the absolute bending state of the cantilever.

[0196] Therefore, an AD converter can generally convert the transverse voltage of a bridge into a digital signal, wherein the AD converter can operate in differential measurement mode and / or absolute measurement mode via AD converter logic.

[0197] In particular, the aforementioned construction method requires only one AD converter, making the manufacturing process cost-effective.

[0198] Furthermore, since a stable and balanced full-bridge design is also feasible, it is possible to keep the AD converter away from the actual converter and cantilever, so that, for example, the waste heat of the AD converter does not affect the measurement results.

[0199] Sensors can be fabricated on a chip.

[0200] This could mean that the sensor is fabricated on a semiconductor structure that allows for further data processing of the bridge transverse voltage or the output value of the AD converter logic. In particular, a chip can also represent a so-called System-on-A-Chip, where all the functional units of the measurement system are integrated onto a single electronic component.

[0201] However, it should be considered that the process chain for manufacturing sensors may include gold, which could impair the manufacturing of AD converter logic using CMOS semiconductor technology.

[0202] Multiple cantilever pairs can be set on a single chip, where the AD converter logic can be configured to provide signal multiplexing for measurement signals.

[0203] The cantilever pair includes a reference cantilever and a test cantilever. Multiple such cantilever pairs, along with active and passive converters, can be mounted on a single chip, and the converters can be read out via an AD converter logic.

[0204] In particular, the first cantilever can specifically respond to the first analyte, and the second cantilever can respond to the second analyte, making it possible to detect different analytes using a sensor.

[0205] However, multiple cantilever pairs may also include a first number of test cantilever arms and a second number of reference cantilever arms. For example, different reference cantilever arms can be particularly sensitive to different interference effects, which together provide a reference for a number of test cantilever arms.

[0206] Cantilever pairs can be operated simultaneously via the corresponding A / D converter logic. Thus, on the one hand, it is feasible to detect multiple different analytes using different acceptor and reference layers. However, on the other hand, it is also feasible to establish statistical significance regarding the measured transverse voltage of the bridge using the same acceptor and reference layers.

[0207] The test converter layer and / or reference converter layer on the upper surface of the test cantilever and / or reference cantilever may include an activation layer, wherein the activation layer is configured to provide greater surface tension compared to the unactivated lower surface of the reference cantilever and test cantilever under the action of forces on the reference cantilever and test cantilever, and wherein the activation layer is made of, for example, gold.

[0208] Activation of the upper surface can mean providing adhesion to another layer by applying an activation layer. This can be because the substrate material of the cantilever is not bonded to the subsequent layer, for example. Here, as further described below, the subsequent layer can be a functional layer.

[0209] In particular, the activation layer may include gold, or may be composed entirely of gold.

[0210] Because the upper surface has an activation layer, the cantilever's structure, especially in terms of height, is non-uniform or asymmetrical, but rather composed of layers. This can decisively affect the cantilever's elasticity or stiffness, resulting in greater surface tension at the upper surface during cantilever deformation, which in turn causes a larger measurement signal.

[0211] Gold cladding on cantilever arms can also be used to construct electrodes for converters due to its excellent conductivity. For this reason, the spacing between electrodes can also be minimized, as the smallest possible surface area of ​​the cantilever is not occupied by gold. Correspondingly, the surface area of ​​the cladding can be maximized, resulting in particularly large deformation.

[0212] The activation layer can also be made of a chromium-gold alloy, as the mechanical properties of the cantilever are thus less affected. In particular, the uniformity of the gold layer grains is achieved by incorporating chromium, which avoids potentially disruptive anisotropic effects caused by the lattice of the hypothetical crystal layer.

[0213] The lower surfaces of the reference and test cantilever arms may be passivated by a passivation layer configured to minimize nonspecific protein adhesion to the reference and test cantilever arms, and wherein the passivation layer comprises trimethoxisilan and / or a blocking substance.

[0214] Unlike the activation layer, the passivation layer is a layer designed to minimize or suppress the interaction between the cantilever and another material. This results in the acceptor or reference layer being bonded only to the upper surface of the cantilever and not to the lower surface during fabrication. Consequently, greater surface stress can be achieved at the upper surface through the bonding of the acceptor or reference layer with the analyte. Furthermore, this enhances the asymmetry of the layer structure, which can lead to improved tensile properties for signal detection.

[0215] In particular, the material trimethoxysilane and the so-called barrier layer are suitable for passivating the lower surface. This passivation layer minimizes so-called nonspecific protein adhesion. Protein adhesion is the adhesion of proteins to a surface. Nonspecific adhesion of proteins or other substances to the cantilever can cause distortions in measurements because the nonspecific substances also interact with the cantilever. By suppressing this nonspecific adhesion, the relative influence of the desired specific adhesion or interaction between the analyte and the cantilever is increased relative to the cantilever's baseline state.

[0216] However, it is also feasible to incorporate the passivation layer with the analyte, but in a manner and method that results in surface stresses that are opposite to those of the activation layer. This allows for greater cantilever deformation.

[0217] The so-called barrier layer can be specifically matched to analytes being examined separately in order to define the measurement window for the analytes. The barrier layer is applied in what is known as a spotting process or a washing process.

[0218] In the washing process, a so-called "sealing layer" protects the hydrated shell of the detector protein during drying, allowing for extended storage. The sealing layer is solublely bound to the matrix, making it soluble in sample liquids such as water. Furthermore, the sealing layer has a certain thickness, mechanically stabilizing the cantilever, which enhances protection during cantilever storage. For example, the sealing layer may contain sugars. Sugar crystals are hydrophilic, thus protecting the protein's hydrated shell. Therefore, so-called protein reconstruction is feasible, where the dried protein is reactivated in the measurement liquid.

[0219] In the spotting of receptor proteins, a so-called "buffer" is used to allow for the reconstruction of proteins in the sample liquid. Drying also improves the sensor's storage capacity.

[0220] Active and passive cantilevers can be constructed chemically identically.

[0221] Therefore, the reference and test cantilever have the same layered structure, differing only in that an acceptor layer is applied to the test cantilever, while a reference layer is applied to the reference cantilever. Thus, chemical identity specifically means that the two cantilevers differ only in the reference or test layer.

[0222] This allows the measurement signal, especially in the case of differential measurement of the transverse voltage of the bridge, to be based solely on the effect of the analyte on the cantilever, without being affected by other characteristics of the cantilever.

[0223] In particular, chemical identity involves that the cantilever be varied and adjusted within the range whereby it differs only in its binding or interaction properties with the analyte being measured. For all other substances, the interactions should be as identical as possible or as small as possible.

[0224] In general, the entire layered structure of the cantilever described above can also be inverted. This means that the reference layer and the acceptor layer can also be applied to the lower surface of the cantilever instead of the upper surface. For example, the acceptor layer can also be disposed on the lower side of the cantilever.

[0225] For the cantilever to deform, any chemical bonding on the cantilever should ideally occur on one side. If the analyte bonds on the upper side, nonspecific bonding should not occur on the lower side of the cantilever, because otherwise the surface stress generated from the chemical bonding of the analyte could be offset by nonspecific chemical bonding on the lower side of the cantilever.

[0226] In other words, the chemical bonding on the upper and lower sides must be at least asymmetrical in order to achieve deformation. A stronger bond on the upper side than on the lower side, or a stronger bond on the lower side than on the upper side, correspondingly causes measurable deformation of the cantilever.

[0227] The receptor layer may include antibodies for the antigen, and the reference layer may include antigen-specific isotype control antibodies against the antibodies of the reference layer.

[0228] Antibodies are proteins produced by the body's cells as a product of a reaction to antigens. Antibodies are typically used by the human immune system to bind to antigens such as viruses, thereby labeling the virus and preventing viral infections through the immune system. In particular, antibodies can bind to different antigens, leading to a decrease in antibody specificity. Antibodies can also be configured to bind to non-immune targets such as THC.

[0229] Conversely, isotype control antibodies do not bind to viral antigens, allowing for the high specificity inference of the presence of a specific virus or viral antigen when both antibodies bind to the antigen and isotype control antibodies do not bind to the antigen.

[0230] Antibodies to the antigen can be part of the receptor layer of the test cantilever, while isotype control antibodies to the antigen can be part of the reference layer. This has the advantage that the deflection of the test cantilever can be simultaneously confirmed by the non-deflection of the reference cantilever.

[0231] In other words, the passivation layer can be applied to the lower surface of the reference cantilever and the test cantilever, the activation layer can be applied to the upper surface of the reference cantilever and the test cantilever, the reference layer and the test functional layer can preferably be applied to the activation layer as a self-organized monolayer, and the reference layer or the receptor layer can preferably be applied to the self-organized monolayer of the reference cantilever or the test cantilever, wherein the receptor layer includes an antibody for the antigen, and the reference layer includes an antigen-specific isotype control antibody against the antibody of the receptor layer.

[0232] The layers can be fabricated in an impregnation / spotting process, where spotting can preferably be performed using commercially available machines. Here, small droplets of the corresponding layer are deposited onto the cantilever, creating spatial confinement for functionalization, which in particular allows for cost-effective and independent coating of the cantilever. Drying of very small droplets is prevented by appropriate control of environmental parameters such as temperature, humidity, and dew point. The underside of the cantilever is not activated here, so that the antibody used only contacts the upper surface of the cantilever. The layer is then dried such that elevated or decreased temperatures have little or no effect on the antibody. This allows for long storage capacity, especially long storage capacity in an inert gas atmosphere. The protein layer is applied by the wafer, particularly after the functional layer is applied but before the sensor is separated.

[0233] The receptor layer may include, for example, a Sars-CoV2 antibody, and the reference layer may include a Sars-CoV2-specific isotype control antibody. The Sars-CoV2 antibody preferably binds to the S1 or N antigen of the Sars-CoV2 virus. The antibody is monoclonal, has a reliable sequence, and exhibits high specificity relative to the Sars-CoV2 antigen. In particular, the antibody can be manufactured using a so-called phage display method. Conversely, the Sars-CoV2-specific isotype control antibody may be highly specific relative to the corresponding antigen, but otherwise identical to the active antibody.

[0234] Therefore, rapid detection of the SARS-CoV-2 virus is feasible, for example. In particular, a rapid testing method is provided by electrical measurement and antibody accumulation on a test cantilever, which also has high specificity by comparison with non-accumulation on a reference cantilever.

[0235] The receptor layer typically provides molecule-specific binding forces, while the reference layer does not. This makes it possible to demonstrate specific molecule species.

[0236] The receptor layer may include single-stranded DNA (ssDNA) and / or other DNA fragments that can specifically bind to DNA fragments in the sample. The reference layer may include single-stranded DNA and / or other DNA fragments that do not bind to chemical and / or biochemical and / or physical species in the sample, but are consistent with the receptor layer in characteristic parameters (e.g., chain length, chemical structure).

[0237] The receptor layer may include single-stranded RNA and / or other RNA fragments that can specifically bind to RNA fragments in the sample. The reference layer may include single-stranded RNA and / or other RNA fragments that do not bind to chemical and / or biochemical and / or physical species in the sample, but are consistent with the receptor layer in characteristic parameters (e.g., chain length, chemical structure). It is thus possible to demonstrate specific DNA or RNA and its fragments and / or other oligonucleotides.

[0238] The receptor layer may include antibodies and / or other and / or additional proteins that can specifically bind to the target protein, and the reference layer may correspondingly include species-specific isotype control antibodies and / or other proteins that do not bind to the sample.

[0239] The receptor layer may include an scFv antibody fragment, and the reference layer may include an isotype control antibody specific to the scFv antibody fragment. ScFv antibodies are artificially manufactured antibody fragments. By breaking down the antibody into multiple fragments, the sensor's reactivity can be increased to small sample concentrations.

[0240] The receptor layer and reference layer may include hydrogels.

[0241] Hydrogels are molecular matrices that bind water very well and bulge strongly upon contact with water. Through chemical modification of the hydrogel, particularly the matrix, a strong response to the presence of proteins or other analytes can be achieved, resulting in a significant increase in the mechanical deformation of the cantilever. Therefore, it is particularly feasible to perform pH-sensitive measurements of the analytes. Attached Figure Description

[0242] Preferred further embodiments of the invention are explained in more detail with reference to the following accompanying drawings. As shown herein:

[0243] Figure 1 A schematic diagram showing a first embodiment of the sensor;

[0244] Figure 2A , Figure 2B , Figure 2C , Figure 2D A schematic diagram of the cantilever is shown;

[0245] Figure 3A , Figure 3B A schematic diagram showing a second embodiment of the sensor;

[0246] Figure 4 A schematic diagram showing a third embodiment of the sensor;

[0247] Figure 5A , Figure 5B , Figure 5C Further schematic diagrams illustrating another implementation of the sensor, and a circuit diagram of a full-bridge;

[0248] Figure 6 A schematic diagram of a chip with multiple cantilever pairs is shown;

[0249] Figure 7 A schematic diagram showing the binding of antigen and antibody is shown;

[0250] Figure 8 A schematic diagram of a sensor in the form of a cantilever with a functional layer covering the sensor layer is shown.

[0251] Figure 9A A schematic diagram of the selected layers of a cantilever without functional layers is shown, with a plotted neutral axis.

[0252] Figure 9B A schematic diagram of the selected layers of a cantilever with additional functional layers and a downwardly moving neutral axis is shown.

[0253] Figure 10A schematic diagram of a selected layer with additional structured functional layers and a cantilever of a neutral axis that moves downward at a structured location;

[0254] Figure 11A A top view of a converter layer with cantilevered converters structured in a plane is shown.

[0255] Figure 11B A side view of a selected layer of a cantilever with a structured height profile featuring a transformer is shown. Detailed Implementation

[0256] Preferred embodiments are described below with reference to the accompanying drawings. Here, identical, similar, or functionally equivalent elements are given the same reference numerals in different drawings, and repeated descriptions of these elements are partially omitted to avoid redundancy.

[0257] exist Figure 1 The image schematically illustrates a first embodiment of the proposed sensor 1 for converting chemical and / or biochemical information. The sensor 1 includes a test cantilever 2, which in turn has a substrate 20 and a deformable portion 22. A passive test transducer 200 is disposed on the substrate 20, while an active test transducer 220 is disposed on the deformable portion 22.

[0258] Similarly, sensor 1 also has a reference cantilever 3, which in turn has a base 30 with a passive reference transducer 300 and a deformable portion 32 with an active reference transducer 320.

[0259] Converters 200, 220, 300, and 320 are connected to electronic device 4 via electrodes 40. The electronic device is capable of recording or forwarding measurement signals from converters 200, 220, 300, and 320. At the same time, electronic device 4 is also capable of supplying current and / or voltage to converters 200, 220, 300, and 320.

[0260] Sensor 1 has the function of indicating the presence and / or concentration and / or amount of analyte 90 in sample 9.

[0261] exist Figure 1 In this study, sample 9 is, for example, a liquid prepared by processing a swab from the test subject, particularly a nasal swab or a pharyngeal swab. However, sample 9 may also be saliva, blood, or other bodily fluids. Alternatively, sample 9 may be a mouthwash used by the test subject to rinse their mouth. Sample 9 may also be obtained from tissue samples or other extracted substances from the test subject and / or synthesized. Analyte 90 may be dissolved in the sample or exist undissolved as a suspension, dispersion, or emulsion.

[0262] In any case, the presence and / or concentration and / or amount of analyte 90 in sample 9 should be checked by means of sensor 1. For this purpose, a receptor layer 24 that can interact with analyte 90 or can adsorb or absorb analyte 90 is applied to the test cantilever 2. In the case of adsorption, analyte 90 will adhere to the surface of the receptor layer 24, while in the case of absorption, analyte 90 will penetrate into the interior of the reference layer 90.

[0263] If sample 9 contains analyte 90, the analyte can interact with receptor layer 24. This can cause a change in surface stress in the portion of the deformable part 22 of the test cantilever 2 occupied by receptor layer 24. This change in surface stress can be recorded by active test transducer 220, which is then interpreted as a measurement signal in electronic device 4.

[0264] Changes in the surface stress of the portion of the deformable part 22 of the test cantilever 2 occupied by the acceptor layer 24 may also cause deformation of the deformable part 22 of the test cantilever 2. Therefore, the active test transducer 220 can also record the deformation of the deformable part of the test cantilever 2, which is then interpreted as a measurement signal in the electronic device 4.

[0265] However, due to the interaction with the sample liquid 9, it has been possible to record the force exerted by the active test transducer 220, for example, by the surface stress of the liquid acting solely on the deformable portion 22 of the test cantilever 2. Therefore, in this case, the presence of the analyte 90 does not lead to the corresponding deformation or change in surface stress.

[0266] To determine the magnitude of the fundamental effect of sample 9 on test cantilever 2, reference cantilever 3 is also in contact with sample 9 simultaneously with test cantilever 2. For this purpose, reference cantilever 3 has a reference layer 34 that does not interact with analyte 90 or does not adsorb or absorb analyte 90. Interaction with analyte 90 should be avoided here so that a difference in measurement signal with test cantilever 2 can be achieved.

[0267] By interacting with sample 9 not only by test cantilever 2 but also by reference cantilever 3, the two cantilever arms 2 and 3 interact with sample 9 in a similar manner and method. However, the difference lies in that test cantilever 2 can additionally interact with the analyte 90 that may be present via its reference layer 24. Correspondingly, the measurement signals of active converters 220 and 320 will differ whenever analyte 90 is present in sample 9. Therefore, in the simplest case, the amount of analyte 90 present in sample 9 can be inferred from the magnitude of the difference in the measurement signals.

[0268] However, the presence of analyte 19 in sample 9 is measured at different locations using test cantilever 2 and reference cantilever 3. Different environmental conditions, such as temperature fluctuations or concentration gradients, can occur at different locations on the sample. These different environmental conditions can be measured using passive transducers 200 and 300.

[0269] Passive converters 200 and 300 are mounted on a substrate and preferably do not detect measurement signals when the deformable portions 22 and 32 of the reference or test cantilever 2 and 3 deform or when surface stress changes. However, the basic level of the measurement signals of the passive converters 200 and 300 may be affected by the different environmental conditions. By providing each measurement value of the active converters 220 and 320 via the passive converters 200 and 300 with a separate comparative value taking into account environmental conditions, the influence of environmental conditions on the measurement signals of the active converters 220 and 320 can be determined and reduced, or calculated or isolated.

[0270] Therefore, the presence of analyte 90 in sample 9 can be analyzed independently via sensor 1 by reducing and isolating the effects of interactions not associated with analyte 90 through multiple measurement points on reference cantilever 3 and test cantilever 2. This enables high measurement accuracy of the presence of analyte 90 in sample 9.

[0271] exist Figure 2A The diagram shows a comparison of the deformable portions 32 and 22 of the reference cantilever and test cantilever 3, 2 under deformation and longitudinal tension. The deformable portion 32 of the reference cantilever 3 has an upper surface 360 ​​and a lower surface 362. Similarly, the deformable portion 22 of the test cantilever 2 has an upper surface 260 and a lower surface 262. Whenever the analyte 90 of the sample 9 interacts with the test cantilever 2 or with the receptor layer 24, a change in surface stress occurs from the fixed portion of the deformable portion 22 (transitioning into the substrate of the test cantilever) toward the freely movable portion, thereby causing, for example, deformation of the deformable portion 22. The deflection L shown here is derived from the relative deflection between the deformable portion 32 of the reference cantilever 3 and the deformable portion 22 of the test cantilever 2 due to the interaction with the analyte 90.

[0272] exist Figure 2BThe deformation of the deformable portion 22 of the test cantilever 2 is shown. This is because the upper surface 260 and lower surface 262 of the test cantilever 2 are stretched at different strengths. Due to the large stretch D at the upper surface 260, the active converter 220 applied thereto can record changes in surface stress and / or tensile force F. These recorded changes in surface stress and / or tensile force F can be converted into electronic signals or influence existing electronic signals, such as applied voltage, by the active converter 220. This can be achieved, for example, by the converter changing its resistance whenever it is subjected to tensile force F, which in turn causes the converter 220 to stretch.

[0273] The transducer can also detect the shrinkage of the surface on which it is positioned. However, in the illustrated embodiment, the transducer is always positioned at the surface on which stretching is expected.

[0274] However, the changes in tensile and / or surface stress and / or force detected by the transducer can also be bending or shear forces, or can be caused by bending or shear forces, or in general can be based on the elastic modulus of the corresponding cantilever. In particular, the bending curve is oriented along the bending curve by the force acting on the deformable portions 22, 32 due to the change in surface stress of the tested cantilever, obtained by the fastening of the deformable portions 22, 32 to the bases 20, 30. The resulting bending curve is obtained, in particular, by the geometry of the cantilever, especially the surface moment of inertia, and by the mass and elastic modulus of the cantilever. The bending curve can be described, for example, according to beam theory.

[0275] The cantilever exhibits the described deformation or stretching corresponding to the different surface stresses on its lower and upper sides.

[0276] Beam theory, for example, might predict where the tension D is greatest in the deformable portions 22 and 32. It is feasible to place active converters 220 and 320 at these locations to achieve an optimal signal-to-noise ratio and to respond as sensitively as possible to tension. However, other boundary conditions should also be considered in the case of precise converter positioning.

[0277] In particular, the orientation of the converter plays a crucial role relative to the orientation of the cantilever. Figure 2C An example of an undeflected cantilever is shown. If the cantilever comes into contact with the analyte, the surface stress changes and the material deforms, as shown in [the example]. Figure 2D As shown. In Figure 2DAs shown, the cantilever undergoes deformation perpendicular to the base 20 or the curved edge. This is accompanied by a longitudinal stretch Dl on the upper surface. Simultaneously, deformation occurs parallel to the base 20 or the curved edge, accompanied by a transverse stretch Dq on the upper surface. The geometry of the cantilever determines which direction causes the larger stretch D. The transducer can be oriented in particular along this direction to generate a particularly large measurement signal.

[0278] The signal determined by the converter can be further improved by mechanically stretching the converter too high at the location of the converter. This stretching can be achieved, for example, through the arrangement and shape of the electrodes.

[0279] exist Figure 3A Another embodiment of sensor 1 is shown. In particular, reference cantilever 3 and test cantilever 2 have the same geometric dimensions, with the height, width, and thickness of reference cantilever 3 corresponding specifically to the height, width, and thickness of test cantilever 2. Thus, the same tension D is generated on the upper surfaces 260 and 360. Because the geometric dimensions of cantilever 2 and 3 are the same, the same correlation between the measured signal and the tension is also expected accordingly.

[0280] Preferably, the width B of the cantilever is equal to the height H of cantilever 2 and 3, thereby enabling a particularly large stretch D at the upper surfaces 260 and 360 of cantilever 2 and 3. For example, the cantilever here is less than 100 μm wide, less than 100 μm long and less than 1 μm thick, especially 50 μm wide, 50 μm long and 0.3 μm thick.

[0281] Furthermore, in the embodiment of sensor 1 in Figure 3, the bases 30 and 20 of the reference cantilever and test cantilever 3, 2 are disposed on the same integral base. Correspondingly, there is a direct mechanical connection and interaction between the cantilever and the base throughout the entire base. Thus, the different environmental influences on cantilever 2, 3 can be reduced, for example, because cantilever 2, 3 can be disposed closer to each other. In particular, the bases 30 and 20 of the reference cantilever and test cantilever 3, 2 can also be constructed as a single piece. This ensures that the base also has the same material-specific bonding properties, allowing for good comparison of the measurement results of the passive and active converters 200, 300, 220, 320.

[0282] The distance A between the active converters 320 and 220 and the passive converters 300 and 200 is measured along the height direction H of the cantilever. The distance A is particularly less than 100 μm, thereby ensuring that the converters are placed as close to each other as possible, thereby reducing, for example, the impact on the spatial environment of the converters.

[0283] exist Figure 3B Another embodiment is shown, wherein transducers 200, 220, 300, and 320 are oriented perpendicular to substrates 20 and 30. Still with the transducers along... Figure 3AThe lateral orientation of the curved edge in the middle is used to measure the lateral tension of cantilever 22, 32, while... Figure 3B The longitudinal tension of cantilever 22 and 32 was measured.

[0284] Regarding this, Figure 4 A preferred embodiment is shown, wherein active converters 320, 220 and passive converters 300, 200 are respectively abutted against the curved edges 10 of cantilever 3, 2. By abutting all converters 320, 300, 220, 200 against the curved edges 10, the spacing A of the converters 320, 300, 220, 200 is minimized. Furthermore, in this embodiment, the electrode 40 and the converters 320, 300, 220, 200 are oriented mirror-symmetrically with respect to the mirror symmetry axis S. Therefore, the converters 320, 300, 220, 200 are particularly oriented mirror-symmetrically with respect to each other.

[0285] exist Figure 5A Another embodiment of sensor 1 is shown. Converters 300, 320, 200, and 220 are in contact via electrodes 401, 402, 403, and 404. Specifically, active converter 220 is connected to active converter 320 via electrode 401. Furthermore, passive converter 200 is connected to passive converter 300 via electrode 403. Active converter 220 is also connected to passive converter 200 via electrode 402, while active converter 320 is connected to passive converter 300 via electrode 404. Thus, a total of four electrodes are obtained, through which the converters are electrically contacted with each other. Electrical contact can be achieved in particular by applying the converter to the electrodes, thereby creating a conductive connection. Because the converter has thickness, it is particularly desirable that, when electrodes are subsequently applied, conductive contact with the electrodes will not be achieved at the edges of the converter. This is only ensured when the thickness of the electrodes is greater than the thickness of the converter.

[0286] exist Figure 5B Another embodiment of sensor 1 is shown. The electrodes of contact transducers 200, 220, 300, and 320 are generally constructed in a mirror-symmetric manner. Current flowing through the electrodes or a voltage being applied could cause asymmetrical crosstalk electrical signals on other electrodes if the electrodes were constructed asymmetrically. This mutual interference could potentially generate control signals between the electrodes; however, this can be avoided by the symmetrical construction.

[0287] Converters 200, 220, 300, and 320 are particularly characterized by a so-called full-bridge electrical connection. The full-bridge circuitry... Figure 5CAs shown in the diagram. In the case of a full-bridge configuration, a DC or AC voltage is applied between electrodes 403 and 401. Between these electrodes, the passive and active converters act as voltage dividers due to their resistances. The full-bridge configuration shown has the advantage that no voltage is established between electrodes 402 and 404 as long as the ratio of the resistances of the passive converter 200 to the active converter 220 of test cantilever 2 is equal to the ratio of the resistances of the passive converter 300 to the active converter 320 of reference cantilever 3. Therefore, a deviation in resistance is particularly sufficient to change the resistance ratio, thereby establishing a voltage between electrodes 402 and 404.

[0288] If the reference cantilever 3 and the test cantilever 2 interact with the sample 9 and the analyte 90, the two deformable portions 22 and 32 undergo, for example, a change in surface stress, which is greater for the deformable portion 22 of the test cantilever 2 than for the deformable portion 32 of the reference cantilever 3. Therefore, the resistance of the active test converter for the deformable portion 22 of the test cantilever 2 changes to a greater extent than that of the active reference converter 320 for the deformable portion 32 of the reference cantilever 3. As long as the resistance of the passive converters 200 and 300 does not change or changes at least equally, a change in the resistance ratio is derived from the deformation of the deformable portion 22 of the test cantilever 2 due to its interaction with the analyte 90 of the sample 9, which specifically interacts with the reference layer 24 of the test cantilever 2. In the case of this interaction, a voltage is correspondingly established between the electrodes 402 and 404 such that the force applied to the active test converter 220 can be expressed as a bridge transverse voltage VB relative to the active reference converter 320. The transverse voltage VB of the bridge is preferably scaled with the presence of analyte 90 in sample 9, so that quantitative evaluation of the measurement signal can be achieved.

[0289] The bridge lateral voltage detector 44 can display or forward the bridge lateral voltage VB, making its presence visible to the user of sensor 1. Specifically, this bridge lateral voltage detector 44 can also be obtained via an AD converter, which converts the bridge lateral voltage VB into a digital signal that can be forwarded to an external measuring device. The AD converter can operate in two different measurement modes. The first measurement mode is a differential measurement mode, in which the bridge lateral voltage VB is measured to produce a relative measurement value for the deformation of both the reference cantilever and the test cantilever 3, 2. In this differential measurement mode, the measurement signals of all converters 200, 220, 300, 320 are considered to a certain extent, making the output signal of the AD converter a measurement signal that is free from environmental influences. The relative deformation of the deformable portions 32, 22 can be inferred from this measurement signal, thereby inferring the presence of the analyte 90.

[0290] The second measurement mode is the so-called absolute measurement mode. In this absolute measurement mode, instead of detecting the transverse voltage of the bridge, more precisely, signals are intercepted at electrodes 402 or 404 in isolation, allowing conclusions to be drawn regarding the corresponding deflections of the deformable portions 32, 22. This information is not available to the user in the differential measurement mode.

[0291] exist Figure 6 Another embodiment of sensor 1 is shown. Here, sensor 1 includes multiple cantilever pairs, wherein each cantilever pair includes a reference cantilever 3' and a test cantilever 2'. The reference cantilever 3' and the test cantilever 2', or the corresponding transducer, are as shown in... Figures 5A to 5C The cantilever arms are electrically connected to each other via electrode circuits, allowing the bridge transverse voltage VB' to be captured for each cantilever pair. The bridge transverse voltage VB' can be captured from each cantilever pair by the AD converter 440 or by the bridge transverse voltage detector 44. Specifically, the AD converter 440 can output, for example, the measurement signal of a specific cantilever pair or the integrated measurement signal of all cantilever pairs, or a combination thereof, via AD converter logic. Therefore, it is particularly feasible to average the measurement signals across different cantilever pairs, resulting in a higher statistical significance of the indication of the presence of analyte 90. However, it is also possible to apply different reference layers and receptor layers 34, 24 to different cantilever pairs, allowing the sensor 1 to simultaneously examine the sample 9 for different analytes 90. Alternatively, it is also feasible, for example, to use a single reference cantilever 3 as a reference for multiple test cantilever arms 2.

[0292] In particular, the sensor 1, having multiple cantilever pairs, is configured on the chip 100. Here, "chip" can mean that the sensor 1 is manufactured from a single substrate, such that the different cantilever pairs 2, 3 are mechanically connected to each other. However, it is also possible that the chip 100 includes another electronic circuit, such as a CMOS circuit, i.e., a semiconductor circuit that intercepts the transverse voltage VB of the bridge and performs further processing directly. Such a semiconductor circuit combined with the sensor is also called a system-on-a-chip.

[0293] exist Figure 7 The diagram schematically illustrates the construction of different deformable portions 22 and 32 of the reference or test cantilever 3, 2. Apart from the acceptor or reference layer, the cantilever construction is identical, ensuring that the interaction with the sample or surrounding medium and the mechanical design of the cantilever are as similar as possible.

[0294] A reference converter layer 340 or a test converter layer 240 is applied to the deformable portions 32 and 22 of the reference cantilever or test cantilever 3, 2, which on one side constitutes electrodes for the reference converter and the test converter (in Figure 7(not shown in the figure), and alternatively, an attachment may be made between the surface of the deformable portions 32, 22 and the reference functional layer 390 or the test functional layer 290.

[0295] Monolayers 341 and 241 may be applied to the surface of the reference functional layer 390 or the test functional layer 290, and a receptor layer 242 or a reference layer 342 may be applied to the monolayers 341 and 241.

[0296] Functional layers 390 and 290 have the following function: to induce an asymmetric layer structure in cantilevers 3 and 2 such that there is as large a difference as possible in the extension of the upper and lower surfaces of the cantilevers. Converter layers 340 and 240 may, in particular, comprise or be made of gold, wherein the converter is correspondingly contacted via electrodes disposed in converter layers 340 and 240.

[0297] Electrical insulation can also be applied to the transition layers 340 and 240 by means of the functional layers 390 and 290, especially to the transition layers 340 and 240 having gold or being made of gold, in order to provide insulation relative to the environment.

[0298] Functional layers 390 and 290 can also be used to compensate for surface unevenness or trenches caused by the structuring of electrodes through converter layers 340 and 240 and / or the configuration of the converter.

[0299] So-called self-organizing monolayers 341 and 241 may be applied to the functional layers 390 and 290. These self-organizing monolayers 341 and 241 can compensate for the unevenness of the remaining surfaces of the functional layers 390 and 290 below them and at the same time provide reinforcement for other layers, namely reference layers or receptor layers 34 and 24.

[0300] The reference layer or acceptor layer 34 and 24 can have different structures and can be adapted to the corresponding requirements of the analyte.

[0301] In a preferred embodiment, however, both layers are based on a layer that may include so-called protein A 242, which on one hand binds to the self-organized monolayers 241, 341, but may also have and bind antibody 243 or isotype control antibody 343 on its surface.

[0302] Antibody 243 is a protein that reacts to or binds to antigen 5 to label viral cells, for example, in the human immune system, so that the immune system can correspondingly eliminate the labeled virus, thereby, for example, suppressing or preventing a viral outbreak. Antibody 243 is as specific as possible to antigen 5, however it can also interact with other similar antigens 50. Figure 7 As shown, antibody 243 can interact to some extent with antigen 5 and similar antigen 50.

[0303] In contrast to antibody 243, isotype control antibody 343 is a protein that preferably does not interact with antigen 5 with ultra-high specificity. This virtually eliminates interaction with specific antigen 5. This is in Figure 7 As shown in the diagram, isotype control antibody 343 can only interact with two similar antigens 50, but cannot interact with antigen 5, which is schematically shown in a square here.

[0304] By having test cantilever 2 contain antibody 243 and reference cantilever 3 contain isotype control antibody 343, it is ensured that in sample 9, analyte 90 can only interact with test cantilever 2 if it is antigen 5. This ensures that the relative deformation of test cantilever 2 caused by the analyte, compared to the deformation of reference cantilever 3, is based solely on the presence of analyte 90 or antigen 5. Therefore, antigen 5 can be reliably and rapidly detected using the sensor 1.

[0305] In contrast to the upper surface of the cantilever, the lower surface of the cantilever is passivated. This passivation can cause and prevent the interaction, binding, adsorption, or absorption of analyte 90 of sample 9 within or on the cantilever. However, in particular, this passivation layer also helps to increase the asymmetry of the layer structure in order to induce the largest possible stretching effect at the upper surfaces of cantilevers 3, 2. Specifically, the passivation layer may comprise trimethoxysilane and / or blocking substances.

[0306] The sensor shown can be used in particular to detect antigen 5 of the Sars-CoV-2 virus or other viruses. For this purpose, the receptor layer 24 of the test cantilever 2 includes, for example, a Sars-CoV-2 antibody, while the reference layer 34 includes a Sars-CoV-2-specific isotype control antibody. Correspondingly, when the Sars-CoV-2 virus antigen 5 is present in the sample 9 and said antigen is deposited on the test cantilever 2 or the receptor layer 24, a measurement signal is generated by the sensor 1.

[0307] exist Figure 8 The reference cantilever 3 or test cantilever 2 is schematically shown. The cantilever 3, 2 is divided into bases 30, 20 and deformable portions 32, 22, wherein the boundary between the bases 30, 20 and the deformable portions 32, 22 is located at the curved edges 31, 21.

[0308] In the illustrated embodiment, the reference cantilever 3 or the test cantilever 2 comprises or is constructed from multiple layers. Here, the cantilever 3, 2 includes a substrate 301, 201, which is, for example, made of silicon or silicon. A first carrier layer 321, 221, for example made of SiN, is applied to the substrate 301, 201. The first carrier layer 321, 221 extends beyond the edge of the substrate 301, 201, thereby extending not only on the base 30, 20 but also on the deformable portions 32, 22, and thus structurally also constitutes the deformable portions 32, 22 of the cantilever 3, 2.

[0309] Furthermore, cantilever 3, 2 includes a test converter layer 240 or a reference converter layer 340, which is configured as a conductive layer and forms electrical contacts for passive reference converters or test converters 300, 200 on substrate 30, 20, and for active reference converters and test converters 320, 220 on deformable portions 32, 22. Corresponding structured conductor tracks may be provided in the test converter layer 240 or reference converter layer 340, forming conductor structures for contacting the corresponding converters.

[0310] The corresponding converters 300, 320, 200, and 220 can be housed in the corresponding converter layers 340 and 240. In other words, the conductor tracks of the converter layers can be configured such that the converters 300, 320, 200, and 220 are in direct contact with or applied to the first carrier layers 321 and 221, and the conductor tracks are laterally connected thereto.

[0311] In the illustrated embodiment, the converter layers 340 and 240, which are configured as conductive layers, can also be used as activation layers to improve surface stretching in the converter layers, thereby increasing the sensitivity of the active reference converter or test converter 320 and 220 during cantilever deformation.

[0312] As shown in the figure, the gaps in the converter layers 340, 240 at the locations of the active and passive reference converters or test converters 300, 200 and 320, 220 indicate that the converter layers 340, 240, which are configured as conductive layers, are structured as electrodes for suitable electrical contact with the reference converters or test converters 320, 220, 300, 200.

[0313] The cantilever 3, 2 also includes a test functional layer or reference functional layer 390, 290 disposed between the converter layer 340, 240 and the receptor layer or reference layer 34, 24. In the illustrated embodiment, the functional layers 390, 290 cover the entire surface of the converter layers 340, 240 and include active and passive reference transducers or test transducers 320, 220 and 300, 200. The receptor layer or reference layer 32, 22 is applied to the outer surface of the functional layers 390, 290 to ensure direct contact with the sample to be inspected.

[0314] The test functional layer 290 or the reference functional layer 390 can thereby, for example, compensate for or at least reduce surface unevenness caused by the structuring of electrodes in the converter layers 340, 240.

[0315] The test functional layer 290 or reference functional layer 390 can thereby, for example, achieve electrical insulation of the electrodes in the converter layers 340, 240 and converters 200, 220, 300, 320 relative to the acceptor layer or reference layer 32, 22.

[0316] Figure 9A An exemplary layered structure of the cantilever is shown, including carrier layers 321, 221 and converter layers 340, 240, as well as passive converters 300, 200 and active converters 320, 220.

[0317] Additionally, the neutral axes 35 and 25 of the cantilever 3 and 2 are drawn as dashed lines.

[0318] The neutral axes 35 and 25 are characterized in that no change in length occurs when the cantilever bends along the axis. As exemplarily shown in the figures, the tension of the neutral axis is significantly affected by the layered structure. For homogeneous materials, especially those with a uniform elastic modulus, the neutral axis is stretched along the geometric center of the material (considering the bending / deformation of the material transverse to the neutral axis).

[0319] In the case of multiple layers, and where the elastic modulus and thickness of the participating layers differ as necessary, the neutral axis can also be far from the geometric center of the layered structure, as shown by the corresponding equation in the general description section.

[0320] Preferably, the neutral axes 35, 25 should be as far away from the active converter as possible to maximize the sensitivity of the sensor. In other words, the neutral axes 35, 25 are preferably positioned such that the change in surface stress or length at the location of the active converter is as large as possible.

[0321] However, Figure 9AThe neutral axes 35 and 25 in the diagram indicate deviations at the locations where transducers 300, 200 and 320, 220 are positioned. Typically, the material of the transducer causes a shift in the neutral axis, which points towards the transducer. Consequently, in the event of bending or changes in surface stress, a reduced length variation occurs at the transducer location compared to the rest of the layered structure, thus decreasing the sensor's sensitivity.

[0322] In order to control the aforementioned undesirable effects, Figure 9B According to a preferred embodiment, functional layers 390 and 290 are applied to converter layers 340 and 240. By applying functional layers 390 and 290, neutral axes 35 and 25 can be moved within the layer structure.

[0323] This is Figure 9B As shown in the image. (and) Figure 9A Compared to the neutral axis of 35 and 25, Figure 9B The neutral axes move downwards. In order for the neutral axes 36, 25 to move downwards through the additional functional layers 340, 240, according to the embodiment, the elastic modulus of the functional layers 340, 240 must be significantly smaller than the elastic modulus of the underlying layer structure. Furthermore, the thickness of the functional layers 340, 240 must be sufficiently small to induce displacement of the neutral axes 35, 25, away from the transducer's orientation.

[0324] Figure 10 Basically shown as Figure 9B The same setup is used, however, the structured height profile of functional layers 390, 290 is schematically shown here, exemplarily illustrated as empty spaces 391, 291 at the locations of active reference converters or test converters 320, 220. For example... Figure 10 As shown, the stretching of the neutral axes 35 and 25 can be affected by changing the height profile of the functional layers 390 and 290, so that the neutral axes are located away from the converter at the converter location.

[0325] The open spaces 391 and 291 are used to achieve a targeted influence on the stress distribution of the cantilever 3 and 2. The stress distribution is preferably designed so that the stress is maximized at the location of the active reference converter or test converter 320 and 220 when the deformable parts 32 and 22 of the cantilever 3 and 2 are deformed.

[0326] It should be noted that it is also feasible to apply receptor layers 34 and 24 onto the structured functional layers 390 and 290.

[0327] Figure 11AA top view is shown of the cantilever, particularly the carrier layers 321, 221 and the converter layers 340, 240 above them, in which passive converters 300, 200 and active converters 320, 220 are embedded.

[0328] For example, converter layers 340 and 240 may be made of gold or include gold and include electrodes, i.e., electrical contacts for the converter. As shown in Figure 11, the converter is structured in a non-typical shape. Here, a typical shape usually corresponds to a rectangular shape. This structuring allows for a non-uniform stress distribution in the converter.

[0329] Figure 11B The diagram illustrates a cantilever layer structure comprising carrier layers 321, 221 and converter layers 340, 240, wherein the passive converters 300, 200 and the active converters 320, 220 have unconventional shapes in their height profiles. Here, the unconventional shape corresponds to a flat height profile of the converter. This structuring of the converter's height profile can cause targeted effects on stress distribution and on the neutral axis at locations within the converter itself. The structuring can be designed such that stress distribution at corresponding locations within the converter is optimized, i.e., the length change of the cantilever is maximized, particularly when the cantilever bends at the location of the converter.

[0330] Where applicable, all individual features shown in the embodiments may be combined and / or interchanged with each other without departing from the scope of the invention.

[0331] List of reference numerals

[0332] 1. Sensor

[0333] 10. Curved edges

[0334] 2. Test cantilever

[0335] 20 base

[0336] 201 matrix

[0337] 21. Curved edge

[0338] 200 Passive Test Converter

[0339] 22 Deformable parts

[0340] 221 Carrier Layer

[0341] 220 Active Test Converter

[0342] 24 Receptor layer

[0343] 25. Test the neutral axis of the cantilever.

[0344] 240 Test converter layer

[0345] 241 Self-organizing single layer

[0346] 242 Protein A

[0347] 243 Antibody

[0348] 244 Passivation layer

[0349] 26 Surface

[0350] 260 Top surface

[0351] 262 Lower surface

[0352] 290 Test Functional Layer

[0353] 291. Empty Section

[0354] 3. Reference cantilever

[0355] 30 base

[0356] 301 matrix

[0357] 31. Curved edge

[0358] 300 Passive Reference Converter

[0359] 32 Deformable parts

[0360] 321 Carrier Layer

[0361] 320 Active Reference Converter

[0362] 34 Reference Layer

[0363] 35. Reference cantilever neutral axis

[0364] 340 Reference Converter Layer

[0365] 341 Self-organizing single layer

[0366] 342 Protein A

[0367] 343 isotype control antibody

[0368] 344 passivation layer

[0369] 36 Surface

[0370] 360° top surface

[0371] 362 Lower surface

[0372] 390 Reference Functional Layer

[0373] 391. Empty Section

[0374] 4 Electronic devices

[0375] 40 electrodes

[0376] Electrodes 400, 401, 402, and 403

[0377] 42 Bridge transverse voltage detector

[0378] 44AD converter

[0379] 440AD converter logic

[0380] 5 antigens

[0381] 50 Other antigens

[0382] F force

[0383] L deflection

[0384] D stretching

[0385] Spacing between AT active and passive converters

[0386] Spacing between AE electrodes

[0387] S symmetry axis

[0388] VB bridge transverse voltage

Claims

1. A sensor (1) for converting chemical and / or biochemical information of at least one analyte (90) in a sample (9) into an electrical signal, comprising: A test cantilever (2) having a base (20) and a deformable portion (22), wherein at least on the deformable portion (22) of the test cantilever (2) a receptor layer (24) for selectively receiving the analyte (90) is applied, wherein the test cantilever (2) has a test converter layer (240) comprising a passive test converter (200) on the base (20) of the test cantilever (2) and an active test converter (220) on the deformable portion (22) of the test cantilever (2), and wherein a test function layer (290) is disposed between the test converter layer (240) and the receptor layer (24). A reference cantilever (3) having a base (30) and a deformable portion (32), wherein a reference layer (34) for selectively not receiving the analyte (90) is applied to the deformable portion (32) of the reference cantilever (3), wherein the reference cantilever (3) has a reference converter layer (340), the reference converter layer including a passive reference converter (300) on the base (30) of the reference cantilever (3) and an active reference converter on the deformable portion (32) of the reference cantilever (3). The active test converter (220) and / or the active reference converter (340) are configured with a reference function layer (390) between the reference converter layer (34) and the reference layer (34), wherein the test function layer (290) and / or the reference function layer (390) are geometrically structured such that the deformation induced by the deformation of the deformable portion (22) of the test cantilever (2) and / or the deformable portion (32) of the reference cantilever (3) is maximized.

2. The sensor (1) according to claim 1, characterized in that, The active and passive reference converters (320, 300) and the active and passive test converters (220, 200) are configured to output electrical signals corresponding to the presence and / or concentration and / or amount of the analyte (90) in the sample (9).

3. The sensor (1) according to claim 1 or 2, characterized in that, The test function layer (290) covers the active test converter (220) and / or the passive test converter (200), and / or the reference function layer (390) covers the active reference converter (320) and / or the passive reference converter (300).

4. The sensor (1) according to claim 1 or 2, characterized in that, The test functional layer (290) forms a flat surface for accommodating the receptor layer (24) and / or the reference functional layer (390) forms a flat surface for accommodating the reference layer (34).

5. The sensor (1) according to claim 1 or 2, characterized in that, The test functional layer (290) and the reference functional layer (390) comprise the same material or are made of the same material.

6. The sensor (1) according to claim 1 or 2, characterized in that, The materials of the test functional layer (290) and / or the reference functional layer (390) are configured to adjust the surface energy in order to achieve or improve the bonding of the receptor layer (24) to the test functional layer (290) and / or the bonding of the reference layer (34) to the reference functional layer (390).

7. The sensor (1) according to claim 1 or 2, characterized in that, The test functional layer (290) and / or the reference functional layer (390) include an electrically insulating material with high insulation resistance or an electrically insulating material with high insulation resistance.

8. The sensor (1) according to claim 1 or 2, characterized in that, The test functional layer (290) and / or the reference functional layer (390) include a porous material that enables partial permeability for the selected substance and / or analyte.

9. The sensor (1) according to claim 1 or 2, characterized in that, The test converter layer (240) includes electrodes for contacting the passive test converter (200) and / or the active test converter (220), and / or the reference converter layer (340) includes electrodes for contacting the passive reference converter (300) and / or the active reference converter (320), and the electrodes for contacting the passive and / or active test converters and / or the passive and / or active reference converters are covered by the test function layer (290) and / or the reference function layer (390).

10. The sensor (1) according to claim 1 or 2, characterized in that, A passivation layer is provided on the lower surface of the test cantilever (2) and / or the lower surface of the reference cantilever (3), the passivation layer being configured to minimize the adhesion of the analyte to the lower side of the test cantilever (2) and / or the reference cantilever (3).

11. The sensor (1) according to claim 1 or 2, characterized in that, A receptor layer (24) and / or a reference layer (34) for selectively receiving analytes are provided on the underside of the test cantilever (2) and / or the reference cantilever (3).

12. The sensor (1) according to claim 11, characterized in that, The deformation caused by the change in upper surface stress due to the binding of the analyte to the receptor layer (24) and / or the reference layer (34) is the opposite of the deformation caused by the change in lower surface stress.

13. The sensor (1) according to claim 1 or 2, characterized in that, The material properties of the test functional layer (290) and / or the reference functional layer (390) are configured such that the deformation induced by the deformation of the deformable portion (22) of the test cantilever (2) and / or the deformable portion (32) of the reference cantilever (3) is maximized in the active test converter (220) and / or the active reference converter (320).

14. The sensor (1) according to claim 13, characterized in that, The material properties are thickness and / or elastic modulus.

15. The sensor (1) according to claim 1 or 2, characterized in that, By structuring the active and passive test converters (220, 200) and / or the active and passive reference converters (320, 300) in the horizontal plane of the test cantilever and / or reference cantilever, the sensitivity of the active and passive test converters and / or the active and passive reference converters is optimized by maximizing the deformation or length variation at the location of the active and passive test converters and / or the active and passive reference converters.

16. The sensor (1) according to any one of claims 1 or 2, characterized in that, The active and passive test converters (220, 200) and / or the active and passive reference converters (320, 300) are geometrically structured such that the sensitivity of the active and passive test converters and / or the active and passive reference converters is optimized by maximizing the deformation or length variation at the location of the active and passive test converters and / or the active and passive reference converters, wherein the long side in space of the active and passive test converters (220, 200) and / or the long side in space of the active and passive reference converters (320, 300) are parallel to the principal component orientation of the deformation of the deformable portion (22) of the test cantilever (2) and / or the deformable portion (32) of the reference cantilever (3).

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