SENSOR FOR CONVERSION OF CHEMICAL AND / OR BIOCHEMICAL INFORMATION OF AN ANALYTE

Description

Technical field

[0001] The present invention relates to a sensor for converting chemical and / or biochemical information of an analyte in a sample into an electrical signal in order to derive a qualitative statement about the presence of the analyte in the sample and / or a quantitative statement about the analyte in the sample based on the generated electrical signal. State of the art

[0002] The use of spring elements or cantilevers for the detection of analytes in samples is known. This method utilizes the interaction of the cantilever with a sample liquid and the binding of the analyte in the sample to a coating of the cantilever to cause deformation of the cantilever. The presence of the analyte can then be determined from this deformation using a strain gauge.

[0003] The deformation of cantilevers due to differing surface tensions is described, 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

[0004] WO 2007 / 088018 A1 further proposes spring elements for use in biosensors such as DNA analysis.

[0005] However, detecting an analyte in a sample can prove difficult due to the significant mechanical and thermal interferences of the sample liquid, as well as the presence of other chemical substances. Therefore, it is necessary to filter out from the actual measurement signal those components that are solely attributable to the interaction of the analyte with the cantilever.

[0006] Sensors with a microscopic, flexible, mechanical structure are known from DE 600 23 917 T2. Cantilevers with strain sensor elements for converting mechanical movements of the cantilever into electrical signals are known from WO 97 / 09584 A. Polymer cantilevers for applications in biosensors are known from WO 2005 / 100965 A1. Cantilevers with a surface tension sensor are known from WO 2005 / 100965 A1. Description of the invention

[0007] Starting from the known state of the art, it is an object of the present invention to provide an improved sensor for the conversion of chemical and / or biochemical information.

[0008] The problem is solved by a sensor for converting chemical and / or biochemical information with the features of claim 1. Advantageous further developments are described in the dependent claims, the description, and the figures.

[0009] Accordingly, a sensor for converting chemical and / or biochemical information of an analyte in a sample into an electrical signal is proposed, comprising a test cantilever having a base and a deformable part, wherein at least on the deformable part a receptor layer for selective uptake of an analyte from the sample is applied, wherein a first and a second test transducer are arranged on the test cantilever, and a reference cantilever having a base and a deformable part, wherein at least on the deformable part a reference layer for selective non-uptake of the analyte is applied, wherein a first and a second reference transducer are arranged on the reference cantilever, the transducers being designed and configured to output an electrical signal corresponding to the occurrence and / or concentration of the analyte in the sample.wherein, due to the selective non-uptake of the analyte by the reference layer, the interaction of the reference cantilever with the sample containing the analyte corresponds to the interaction of the test cantilever with the sample without analyte. According to the invention, the test transducers are arranged on the deformable part of the test cantilever and the reference transducers are arranged on the deformable part of the reference cantilever.

[0010] In this context, a sample refers to a limited quantity of a substance that has been taken from a larger quantity of the substance, for example from a reservoir, whereby the composition of the sample is representative of the composition of the substance in the reservoir and accordingly, conclusions can be drawn about the corresponding occurrence in the reservoir from the substance occurrence and composition of the sample.

[0011] For example, a sample can be a saliva sample, a blood sample, a urine sample, a swab (especially a throat swab, a nasal swab, or a sinus swab), or a tissue sample. A sample includes, in particular, any type of biological sample, including samples from animals. A sample can also be a non-biological sample, such as a sample of a chemical substance.

[0012] In particular, one sample form can be converted into another sample form, allowing the analyte, or its presence, to be detected in a simple and reliable manner. For example, a swab can be dissolved in a liquid, so that the dissolved swab then becomes the actual sample. For instance, the sample could be or contain lymph fluid.

[0013] The sample then contains the chemical and / or biochemical information about the analyte. An analyte is the substance whose presence in the sample is to be qualitatively and / or quantitatively detected, or detected by the sensor. The analyte can be directly present in the sample, dissolved in the sample, or adhering to the sample or a part of the sample, especially a sample particle. The analyte can also undergo a chemical, biological, and / or physical interaction with the sample, meaning that the analyte can only be detected indirectly via such an interaction.

[0014] Chemical information can include, for example, the type of analyte, its concentration, its occurrence, its weight, its reactivity, its density, and so on. Biochemical information encompasses the same properties as chemical information; however, these substances can also be produced through biological processes. In particular, the term biochemical information is used when the analyte has a special influence on biological processes, such as metabolism or the immune system.

[0015] To convert the chemical and / or biochemical information of the analyte into an electrical signal, the sensor comprises a reference cantilever and a test cantilever. A cantilever is a spring element consisting of a base and a deformable section.

[0016] The base is an immobile part of the cantilever, which is either fixed to a substrate, supported by it, or machined from the substrate. The cantilever base is designed as a rigid structure, so that only the deformable part of the cantilever is deformable.

[0017] The deformable portion of the cantilever extends longitudinally beyond the substrate on which the base is mounted. In other words, the deformable portion of the cantilever is suspended at one end from the base and is not supported by the substrate. Because the deformable portion extends beyond the substrate, it can be bent, deflected, and stretched. The spatial boundary at which the cantilever becomes bendable, or where the cantilever transitions from the base to the deformable portion, is called the bending edge. The bending edge is typically an edge of the substrate if the cantilever extends beyond it.

[0018] When a cantilever is deformed, material stresses and forces arise within or on the cantilever material, which can be measured. If such material stress and / or force can be measured, it indicates deformation of the cantilever. This deformation can be upward or downward. The cantilever can also deform itself, for example, by bulging, wrinkling, or distorting.

[0019] The deformation of the cantilever can be induced by a suitable coating specific to the material. For this reason, the reference cantilever has a reference layer for the selective non-uptake of the analyte, while the test cantilever has a receptor layer for analyte uptake.

[0020] A receptor layer is a substance that can interact with the analyte. This means that the receptor layer is specifically chosen for each analyte. Similarly, a reference layer is a substance that cannot interact with the analyte. The reference layer is also therefore specifically chosen for the analyte.

[0021] In this context, interaction means that the analyte is in chemical, biochemical, and / or physical interaction with the receptor layer. In particular, the interaction can consist of the analyte binding to the receptor layer. An interaction can also consist of the absorption, adsorption, or non-specific adhesion of the analyte to the receptor layer.

[0022] The receptor and reference layers are preferably chemically identical with respect to potential interfering influences and preferably differ only in their interaction with the analyte. A substance that is not the analyte therefore interacts with the receptor layer with the same strength or weakness as with the reference layer.

[0023] The selective uptake of the analyte by the test cantilever causes a force to act upon it, making the test cantilever highly sensitive to the analyte. Consequently, other substances in the sample, excluding the analyte, contribute only to background noise in the form of a baseline deflection of the test cantilever. The force on the test cantilever increases, for example, more rapidly with increasing analyte concentration in the sample or with the rapid accumulation of analyte on the cantilever surface. The maximum force achievable for a given configuration is reached when the cantilever is completely covered.

[0024] The selective non-uptake of the analyte at the reference cantilever, on the other hand, means that no force is exerted by the analyte on the reference cantilever, so that only the substances that are not the analyte contribute to background noise in the form of a basic bending of the reference cantilever.

[0025] This force can cause deformation in the deformable part of the test cantilever, while the deformable part of the reference cantilever remains unchanged. The deflection of the cantilever is based on a change in surface tension due to interaction with the analyte. This change in surface tension leads to elongation or compression of the upper (or lower) surface of the cantilever. The differential elongation or compression on the upper and lower surfaces induces an internal force or stress in the material, resulting in deformation.

[0026] State-of-the-art reference cantilevers lack a receptor layer that is sensitive to the analyte. While this allows for the determination of effects such as sample turbulence and the thermal drift of the sensor system, the analyte can bind to the reference layer of such a cantilever through non-specific binding. This means the analyte itself contributes to background noise. Therefore, with a state-of-the-art sensor, reference measurements in a reference sample—that is, a sample without analyte—are necessary. Only in this way can the effect of non-analyte binding be detected.

[0027] In the proposed sensor, the selective non-uptake of the analyte by the reference cantilever drastically simplifies the measurement procedure, since the reference cantilever is not sensitive to the analyte and therefore the analyte does not contribute to the background noise. Only substances other than the analyte contribute to the background noise of the reference cantilever. In a sense, the selective non-uptake of the analyte by the reference cantilever ensures that the reference cantilever is exposed to the same turbulence, thermal drift, and the same influence of all non-analyte substances as in a reference sample. However, the difference is that the reference signal is determined directly in the sample liquid.

[0028] In particular, a reference cantilever with a reference layer and a test cantilever with a receptor layer results in a significantly more specific analysis of the analyte than a reference cantilever without a receptor layer, since both the reference layer and the receptor layer exhibit a specific interaction or non-interaction with the analyte.

[0029] The sensor design with a reference cantilever and a test cantilever offers the advantage of allowing two measurements to be taken simultaneously in the sample, with the measurement from the reference cantilever calibrating the measurement from the test cantilever. This reduces the influence of environmental factors, such as chemical, thermal, mechanical, electrical, and fluidic disturbances, on the respective measurement, enabling the presence of the analyte to be determined by comparing the measurements at the test cantilever and the reference cantilever.

[0030] These forces or material stresses, such as strains or compressions acting on the cantilevers, can ultimately be detected by the transducers, whereby different strains or compressions result in different stresses being detected by the transducers.

[0031] The purpose of the transducers is therefore to determine or measure the deformation of the cantilevers. According to the invention, the transducers are arranged on the deformable parts of the cantilevers. For example, deformation of the cantilever can cause the resistance of a transducer to increase or decrease, while no deformation of the cantilever causes no change in the transducer's resistance. This can be achieved, for example, by designing the transducers according to the principle of a strain gauge, whereby a deformation of the respective cantilever manifests itself as a change in length of the strain gauge applied to it, and thus a deformation of the cantilever can be detected directly by a change in the resistance of the strain gauge.

[0032] Thus, the chemical and / or biochemical information of the analyte can be detected via a deformation of the cantilever, a subsequent registration via a transducer, and finally via a change in an electrical property of the transducer.

[0033] By placing the first and second test transducers on the deformable parts of the test cantilever and the first and second reference transducers on the deformable part of the reference cantilever, a measure of the strain of the test transducer can be found which corresponds to the strength of the interaction of the analyte with the deformable part of the test cantilever.

[0034] For example, the first reference transducer of the reference cantilever can, through the influence of the environmental conditions and interaction with the sample, bring about a first electrical reference state of the first reference transducer, while the interaction of the test cantilever with the environmental conditions of the sample brings about a first electrical test state of the first test transducer.

[0035] For example, the reference cantilever can be deflected by a first amount due to environmental conditions, such that the deflection creates a first electrical reference state in the first reference transducer and a second electrical reference state in the second reference transducer. The test cantilever is deflected by a second amount due to environmental conditions and by a third amount due to the additional interaction with the analyte in the sample, creating a first electrical test state in the first test transducer and a second electrical test state in the second test transducer.

[0036] Comparing the electrical states of the first and second transducers provides a measure of the cantilever deformation. Simultaneously, comparing the first and / or second transducers individually yields a measure of the difference in cantilever deformation. This makes it possible to infer a specific influence of an analyte on the test cantilever.

[0037] The design with four transducers has the advantage that such local calibration of the sensor at the point of influence of the sample and the analyte is possible.

[0038] The force to be detected can be a bending force and / or a tensile force and / or a shear force and / or a compression force and / or can be based on the bending stiffness of the reference cantilever and test cantilever.

[0039] A bending force can cause a change in the geometry of the cantilever, in particular imparting a curvature to the cantilever that differs from the unstressed cantilever.

[0040] A stretching or compressive force can, in particular, cause a change in the length of the cantilever. The specific change in length can vary depending on the orientation of the cantilever's crystal lattice.

[0041] The strain (or compression) can differ, particularly between the upper and lower surfaces of the cantilever. Surface strain can occur parallel to the base of the cantilever (transverse strain) or perpendicular to the base (longitudinal strain). The magnitude of the strain depends strongly on the geometry and crystal structure of the cantilever, as well as on any additional layers applied to the surface, such as electrodes. Therefore, optimal analyte detection can be achieved by optimizing the orientation and geometry of the cantilever.

[0042] If the tensile force differs between the upper and lower surfaces, the acting force is also referred to as shear force.

[0043] A bending cantilever is subjected to a bending force because it is curved. This stretches the upper surface of the cantilever, and this stretching is particularly greater than on the lower surface, resulting in a shear force acting on the cantilever overall.

[0044] 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. By selecting the material or material composition, or by processing the material, the elastic modulus can be adjusted within a certain range, thus optimizing the effect to be measured for the respective transducer. Conversely, it is also possible to adapt the transducers to the given elastic modulus of the material and optimize their sensitivity.

[0045] Preferably, the cantilevers can be so-called bimaterial cantilevers, for example, cantilevers made of a gold and a silicon nitride layer. A bimaterial cantilever consists of material layers that together exhibit a defined stress state. For example, the state can be stress-free, so that the intrinsic mechanical stresses are minimal. However, a bimaterial cantilever can also be prestressed, so that the cantilever is particularly sensitive to changes in surface tension. Alternatively, a homogeneous cantilever can be coated differently on its top and bottom surfaces to mimic the described bimaterial effect. In particular, isotropic and anisotropic materials can be used for the cantilevers to optimize longitudinal and transverse strain. For example, an isotropic metal can be used on an anisotropic substrate.

[0046] The deformable parts of the reference and test cantilevers can have identical geometric dimensions, wherein preferably the width of the deformable part of the reference and test cantilevers corresponds to the length of the deformable part of the reference and test cantilevers, wherein particularly preferably the deformable parts of the reference and test cantilevers are less than 200µm wide, less than 200µm long and less than 1µm thick, in particular 50µm wide, 50µm long and 0.3µm thick or 125µm wide, 20µm long and 0.1µm thick.

[0047] This allows a particularly large force to be generated on the transducers through the deformation of the cantilevers.

[0048] The deformable parts of the cantilever can, for example, have a different geometry than a rectangular one. For instance, the cantilever can have a V-shaped or triangular geometry. In particular, it is also possible that the cantilever is not a closed body, but has, for example, holes or cutouts.

[0049] The reference and test cantilevers can comprise Si3N4 and / or SiO2 and / or Si3N4 / SiO2 and / or SiC and / or Si and / or aluminum oxide, or consist entirely of Si, or comprise at least one polymer. Similarly, the bases or the overall base can also comprise the aforementioned materials. The bases and the reference and test cantilevers can also be fabricated as a single unit from the aforementioned materials using conventional manufacturing processes, such as those known from wafer processing.

[0050] The silicon-based reference and test cantilevers allow the use of manufacturing processes familiar from the semiconductor industry, thus enabling the production of the proposed sensors on a large industrial scale. Polymers can also be produced on a large industrial scale and offer the advantage that their material properties can be largely predetermined.

[0051] The transducers can have identical intrinsic physical properties, wherein the transducers are configured to adapt their electrical properties, preferably the electrical resistance or another value proportional to the k-value, according to the forces acting on the reference and test cantilevers.

[0052] The k-value, also called gauge factor, is the constant of proportionality between the strain of the transducer and its change in resistance: Δ R R = k Δ L L , where Δ RThe change in resistance of the transducer is R, the resistance of the transducer with the cantilever straight, Δ L the change in length of the transducer and L The length of the transducer with the cantilever straight is measured. In particular, all other measured quantities proportional to the k-value or resistance, such as conductivity, can also be measured.

[0053] Identical intrinsic physical properties encompass those properties responsible for the measurement characteristics of the transducer on a cantilever. This particularly concerns the resistance or conductivity of the transducer. The resistance depends primarily on the geometry of the transducer, so for the conductivity of different transducers to be uniform, their geometry must be identical. Specifically, each transducer should react identically to the same force or deformation of the cantilever.

[0054] The intrinsic physical properties are determined primarily by the nanostructure of the transducers. A reliable manufacturing process ensures that all transducers respond identically to a force, so that deviations in the various measured forces are solely due to the external influence on the cantilevers and do not depend on the intrinsic physical properties.

[0055] The reference and test cantilevers, as well as the first and second reference and test transducers, can be arranged in a mirror-symmetrical manner relative to each other.

[0056] A mirror-symmetrical design makes it possible to reduce external interference affecting the transducers, or at least to direct it symmetrically to each other. This improves measurement accuracy and reduces susceptibility to interference.

[0057] The sensor can have electrodes, preferably four electrodes, which are configured to electrically contact the transducers.

[0058] An electrode, in this context, is a conductive layer, for example made of gold, or a wire or cable, which establishes an electrically conductive connection from one end of the transducer to an external device, such as a current or voltage source or a corresponding measuring instrument. In principle, any conductive connection between the transducer and the external device can be considered an electrode. However, here the term "electrode" specifically refers to the part of the electrical connection that is implemented on the sensor.

[0059] Typically, an electrical connection from the sensor to an external source or measuring device is established via an electrical connector. Here, an electrical connector with a cable or wire is connected to a so-called bond pad, for example, by ultrasonically welding the wire to it. An electrical connection then leads directly from the bond pad to the transducer. The electrically isopotential surface between the transducer and the bond pad is referred to as the electrode.

[0060] The electrode serves to electrically contact the transducers and, in particular, to create the possibility of transmitting the electrical signals from the sensor to a measuring device.

[0061] In particular, the electrodes can be at different electrical potentials and interact with each other through these potentials. To minimize this mutual influence of the electrical currents and voltages in the electrodes, it is therefore advantageous if the electrodes also have a symmetrical shape, so that the respective disturbance is at least uniformly distributed across the entire system. This can be achieved, in particular, by using an even number of electrodes, or by using only four electrodes in the case of four transducers.

[0062] The design of the electrode geometry allows the underlying signal level resulting from potential differences at the electrodes to be less than 1.1V, thus eliminating the need for electrical encapsulation of the electrodes. Electrical encapsulation, in this context, can refer to, for example, electrical insulation, covering, or shielding of the electrodes and bond wires. This simplifies the manufacturing process and improves measurement accuracy.

[0063] The transducers can be electrically connected in a full bridge, the full bridge being designed to generate a bridge cross-voltage due to the electrical properties of the transducers, especially in the case of an asymmetric change in the electrical properties of the transducers.

[0064] A full bridge is a measuring device used to measure electrical resistances or small changes in resistance. A full bridge is also known as a Wheatstone bridge, H-bridge, symmetrical full bridge, or thermally symmetrical full bridge.

[0065] In the sensor's full bridge state, the bridge cross-voltage is ideally zero, since all participating transducers detect the same force. This ground state is preferably set during the manufacturing process, resulting in only a small offset voltage between the electrodes, which can be compensated for by a measurement setup.

[0066] From this initial state of the full bridge, asymmetrical force changes can then be preferentially detected. For example, if the first test transducer of the test cantilever reacts to a force application with a change in its electrical properties, i.e., a change in its electrical resistance, then the ratio of resistances in the full bridge is no longer balanced, resulting in a bridge cross-voltage. This bridge cross-voltage can then be detected with a measuring device.

[0067] By implementing it as a full bridge, a calibration of the test transducers of the test cantilever is achieved via the reference transducers of the reference cantilever.

[0068] The sensor can include a bridge cross-voltage detector configured to detect the bridge cross-voltage of the full bridge, wherein the detected bridge cross-voltage allows conclusions to be drawn about the presence of the analyte selectively absorbed by the receptor layer, preferably about the size or concentration of the occurrence.

[0069] A bridge voltage detector can be any detector capable of detecting a voltage. For example, it could be a measuring resistor, a signal generator, a measuring device that displays the voltage, or any other type of detector that generates an output signal by detecting a voltage. In particular, the bridge voltage detector can be configured as an analog-to-digital converter (ADC) and convert the bridge voltage into a digital value.

[0070] Ideally, the change in bridge voltage is expressed as a ratiometric change relative to a defined, i.e., measured, supply voltage. For example, a drift in the supply voltage then does not affect the measurement signal.

[0071] The first and second test transducers can each be arranged in a recess or a common recess of the test cantilever, and the first and second reference transducers can each be arranged in a recess or a common recess of the reference cantilever.

[0072] For example, a recess can have a rectangular cross-section in the thickness direction of the cantilever and / or a rectangular cross-section in the longitudinal direction of the cross-section. However, it is also possible that the recess has a partially elliptical or circular cross-section.

[0073] A recess can accommodate a transducer, so that the transducer is positioned within the recess. In particular, the transducer can fill the entire recess, so that its volume is completely filled by the transducer. However, it is also possible for the transducer to fill only a portion of the volume or to be positioned only on one side of the recess, for example, on the bottom side. The bottom side is the side that is recessed from the surface of the cantilever.

[0074] The indentations in the test cantilever and the reference cantilever can increase the elasticity of the test cantilever and the reference cantilever locally at the location of the transducers.

[0075] This is due to the fact that the material of the cantilevers becomes thinner.

[0076] The test transducers in the recesses of the test cantilever can reduce the extensibility of the test cantilever, and the reference transducers in the recesses of the reference cantilever can reduce the extensibility of the reference cantilever.

[0077] In a sense, the transducers are the antagonists of the depressions and cause a reduction in elasticity. For this reason, transducers that are only applied to the surface of a cantilever reduce elasticity and thus reduce measurement sensitivity.

[0078] The transducers, which are arranged in the recesses of the cantilevers, detect the strain of a cantilever that exhibits high elasticity, thus enabling high measurement sensitivity. However, to achieve any measurement sensitivity at all, the transducer must be positioned at a distance from the neutral axis. Preferably, the neutral axis does not intersect the transducer but lies outside of it.

[0079] The increased measurement sensitivity can be explained mathematically as follows. For thin and wide cantilevers, the mechanical stress is σ of the cantilever defined by σ = My I , where M is the bending moment generated by, for example, chemical interaction, and y is the distance to the neutral axis of the cantilever. The neutral axis is the axis along which the stresses present in the material exactly cancel each other out. This takes into account all layers of the cantilever, including activation and passivation layers. For thin and wide cantilevers, the second moment of area I is given, for example, by I = bh 3 12 , where b is the width of the cantilever and h is the thickness of the cantilever. The extension of the cantilever is given by: ϵ = σ E , where E is Young's modulus. Substituting the above equations yields the cantilever extension as a function of the distance to the neutral axis: ϵ = 12 My Ebh 3 .

[0080] By reducing the distance y of the transducer to the neutral axis while maintaining a constant Young's modulus E, the strain and thus the sensitivity of the cantilever decrease. However, the reduced stiffness of the cantilever due to its thinner profile more than compensates for this reduced strain, resulting in exceptionally high sensitivity.

[0081] At least one recess can be deeper than 5%, preferably deeper than 20%, particularly preferably deeper than 50% of the thickness of the cantilever.

[0082] The deeper the recess, the more elastic the cantilever becomes. For example, the cantilever can be 500 nm thick, so the recess can be deeper than 25 nm, preferably deeper than 100 nm, and most preferably deeper than 250 nm.

[0083] The distance of at least one transducer to the neutral axis can be less than 20%, preferably less than 10%, and most preferably less than 5% of the cantilever thickness. The smaller the distance, the greater the measurement sensitivity.

[0084] The height of at least one transducer can be at least equal to the depth of the recess.

[0085] In particular, the top surface of the transducer can be flush with the surface of the cantilever. However, it is also possible that the top surface of the transducer lies above the surface of the cantilever. In this case, however, contact must be made via the cantilever edge.

[0086] The stiffness of the cantilever can be adjusted, in particular, by choosing the thickness of the transducer.

[0087] The indentations can be located on the upper and / or lower surfaces of the cantilever.

[0088] Indentations on the upper and / or lower surface allow for the detection of various bending moments, resulting in a particularly large measurement signal being generated by the transducers.

[0089] In contrast to the prior art, the transducer is not thinned to maintain or reduce the elasticity of the cantilever despite its presence, in order to obtain the largest possible measurement signal. Rather, the cantilever is thinned here to minimize the distance to the original neutral axis in order to obtain the largest possible measurement signal.

[0090] According to the invention, the first and second transducers are configured to detect different force components.

[0091] Depending on the orientation of the transducers relative to the axes of the cantilever, i.e., in particular relative to the longitudinal axis, the width axis and the thickness axis of the cantilever, different forces act.

[0092] In particular, the detection of different force components can be used to increase the signal spread between the first and second transducers of a cantilever. This allows for the generation of a particularly large measurement signal.

[0093] According to the invention, the first transducer is aligned along the longitudinal axis of the cantilever and the second transducer is aligned perpendicular to the longitudinal axis of the cantilever.

[0094] The first transducer can be located at the location of maximum surface tension of the cantilever, and the second transducer can be located at the location of minimum surface tension of the cantilever.

[0095] The location of minimum surface tension can, in particular, be the location of the most negative surface tension.

[0096] This also allows for the generation of a particularly large measurement signal.

[0097] By comparing both measurement signals between the reference cantilever and the test cantilever, a particularly large measurement signal can be generated.

[0098] The upper surfaces of the reference and test cantilevers can be activated by an activation layer. This activation layer is designed to provide a greater surface strain in the event of a force being applied to the reference and test cantilevers compared to the non-activated lower surface. The activation layer may comprise gold or other chemically inert materials. However, it is also possible to activate the lower surface, which simply reverses the description of the upper and lower surfaces.

[0099] Activating the upper surface can mean that applying an activation layer provides an adhesion promoter for a further layer. This may be because the base material of the cantilever, for example, does not bond with the subsequent layer, especially the reference layer.

[0100] In particular, the activation layer can include gold, or consist entirely of gold.

[0101] Preferably, the entire surface of the cantilever is covered with gold, as the receptor layer is preferentially built upon the gold layer. Accordingly, a large area of ​​the activation layer allows for a larger area to be covered by the receptor layer, resulting in a large detector area for the analyte. This large detector area, in turn, leads to a particularly large deformation of the cantilever, enabling sensitive detection of the analyte's presence.

[0102] However, it is also possible that only the deformable part of the cantilever is covered with gold, especially up to the bending edge.

[0103] Because the upper surface has an activation layer, the cantilever's structure is not homogeneous or asymmetrical in height, but rather consists of layers. This significantly influences the cantilever's elasticity, resulting in greater surface strain on the upper surface when the cantilever is deformed, which in turn leads to a stronger measurement signal.

[0104] Due to its high conductivity, the gold coating on the cantilever can also be used to form electrodes for the transducers. This allows the distance between the electrodes to be minimized, as it leaves as little of the cantilever's surface area uncoated with gold as possible. Consequently, the detector area can be made larger.

[0105] The activation layer can also consist of, or comprise, a chromium-gold alloy, as this has less impact on the mechanical properties of the cantilever. In particular, the addition of chromium ensures homogeneity of the crystallites in the gold layer, thus avoiding potentially disruptive anisotropy effects caused by the crystal lattice of a hypothetical crystalline layer.

[0106] However, it is also possible that the activation layer consists of or comprises a titanium-gold alloy.

[0107] The lower surfaces of the reference and test cantilevers may be passivated by a passivation layer, wherein the passivation layer is designed to minimize non-specific protein adhesion to the reference and test cantilevers, and wherein the passivation layer comprises trimethoxisilan and / or a blocking substance.

[0108] Unlike an activation layer, a passivation layer is designed to minimize or prevent interaction between the cantilever and another material. Consequently, during the fabrication of the receptor layer, it binds only to the upper surface of the cantilever and not to the lower surface. This allows for greater surface tension at the upper surface when the receptor layer binds to an analyte. Furthermore, this enhances the asymmetry of the layer structure, which can lead to improved strain properties for signal detection.

[0109] Particularly suitable for passivating the lower surface are materials such as trimethoxisilan and so-called blocking layers. This passivation layer minimizes non-specific protein adhesion. Protein adhesion is the adhesion of a protein to the surface. Non-specific adhesion of a protein, or any substance in general, to the cantilever can distort the measurement result, as these non-specific substances also interact with the cantilever. By preventing this non-specific adhesion, the relative influence of the desired specific adhesion or interaction of the analyte with the cantilever is increased compared to the cantilever's ground state.

[0110] However, it is also possible that a passivation layer binds the analyte, but in such a way that the resulting surface tension on the underside is opposite to the surface tension of the activation layer on the top side. This can lead to greater deformation of the cantilever.

[0111] The so-called blocking layer can be tailored to the specific analyte being analyzed and, preferably, to the solution in which the analyte is present, in order to define a measurement window for the analyte. The blocking layer is applied using a process called spotting or washing.

[0112] During the washing process, a so-called "sealer" protects the hydration shell of the detector proteins as they dry, thus making them storable, especially at room temperature without refrigeration. The sealer is soluble in a matrix, making it soluble in a sample liquid such as water. Furthermore, the sealer has a certain thickness, which mechanically stabilizes the cantilevers, thus increasing their protection during storage. A sealer can, for example, contain sugar. The sugar crystals are hydrophilic and therefore protect the hydration shell of the proteins. This allows for a process called protein reconstitution, in which the dried proteins are reactivated in the sample liquid.

[0113] When spotting receptor proteins, so-called "buffers" are used to enable reconstitution of the proteins in the sample liquid. Here too, drying increases the shelf life of the sensors.

[0114] The reference cantilever and the test cantilever can have an identical chemical structure.

[0115] This ensures that the measurement signal, especially in the case of a differential measurement of the bridge cross-sectional voltage, is based solely on the influence of the analyte on the cantilever and is not caused by other properties of the cantilever.

[0116] In particular, chemical identity refers to the fact that the cantilevers are modified and adapted in such a way that they differ only in their binding or interaction properties with the analyte being measured. For all other substances, the aim is to achieve the most identical interaction possible, or at least the least possible interaction.

[0117] For this purpose, the reference cantilever and the test cantilever have an identical layer structure, differing only in that the test cantilever has a receptor layer and the reference cantilever has a reference layer. In particular, chemical identity means that the two cantilevers differ only in the reference and test layers, respectively.

[0118] The entire layer structure of the cantilever described above can also be inverted. This means that the reference and receptor layers can be applied to the lower surface of the cantilever instead of the upper surface. For example, the receptor layer can also be located on the underside of the cantilever.

[0119] For the cantilever to deform, ideally all chemical binding to the cantilever should occur unilaterally, or the signs of the chemical bonding on the top and bottom surfaces should differ. If the analyte binds on the top surface, no non-specific binding should occur on the bottom surface of the cantilever, as otherwise the surface tension resulting from the analyte's chemical bonding could be compensated by the non-specific chemical bonding on the bottom surface of the cantilever.

[0120] In other words, the chemical bond on the top and bottom surfaces must be at least asymmetrical to cause deformation. A stronger bond on the top surface than on the bottom surface, or vice versa, will accordingly lead to a measurable deformation of the test cantilever.

[0121] The reference and test cantilever may have an additional layer comprising a self-organizing monolayer.

[0122] A self-organizing monolayer can, in particular, reduce irregularities on the gold surface, thus enabling a uniform coating of the cantilever with the receptor or reference layer. The homogeneous surface properties of the cantilever can then ultimately improve the binding properties of the receptor layer and the analytes.

[0123] The receptor layer can include antibodies for an antigen, and the reference layer can include an antigen-specific isotype control antibody directed toward the antibody of the reference layer.

[0124] Antibodies are proteins produced by body cells as a reaction product to antigens. Antibodies are typically used by the human immune system to bind to viral antigens, thus marking the viruses and preventing an outbreak of viral infection. However, there are also antibodies that bind to non-immunological substances such as THC. In particular, an antibody may bind to multiple antigens, thereby reducing its specificity.

[0125] In contrast, an isotype control antibody does not bind to the antigen of a virus, so that if both the antibody binds to the antigen and the isotype control antibody does not bind to the antigen, the presence of a specific virus or an antigen of a virus can be concluded with high specificity.

[0126] The antibody of an antigen can be part of the receptor layer of the test cantilever, while the isotype control antibody of the antigen can be part of the reference layer. This has the advantage that a deflection of the test cantilever can be simultaneously confirmed by a lack of deflection of the reference cantilever.

[0127] The reference and receptor layer of the cantilever may also contain the so-called protein A, which binds covalently to the self-organizing monolayer, for better adhesion of the antibodies.

[0128] The layers can be produced using a dipping / spotting process, with spotting preferably being carried out using commercially available machines. In this process, droplets of the respective layer are deposited onto the cantilever, thus spatially limiting the functionalization. This enables, in particular, cost-effective and independent coating of the cantilevers. The very small droplets are prevented from drying by appropriate control of environmental parameters such as temperature, humidity, and dew point. The undersides of the cantilevers are not activated, so the antibodies used only come into contact with the upper surface of the cantilever. The layers are then dried, so that elevated or lowered temperatures have little or preferably no effect on the antibodies. This allows for long-term storage, especially in an inert gas.The protein layers are applied particularly after the transducers have been applied but before the sensors or chips are separated from the wafer.

[0129] The receptor layer can generally provide molecule-specific binding forces, while the reference layer does not provide molecule-specific binding forces. This makes it possible to detect a specific molecule species.

[0130] The receptor layer can comprise single-stranded DNA (ssDNA) and / or other DNA fragments that can bind specifically to DNA fragments in the sample. The reference layer can comprise single-stranded DNA and / or other DNA fragments that do not bind to any chemical, biochemical, and / or physical species in the sample, but match the receptor layer in characteristic parameters (e.g., chain length, chemical structure).

[0131] The receptor layer can comprise single-stranded RNA and / or other RNA fragments that can bind specifically to RNA fragments in the sample. The reference layer can comprise single-stranded RNA and / or other RNA fragments that do not bind to any chemical, biochemical, and / or physical species in the sample, but match the receptor layer in characteristic parameters (e.g., chain length, chemical structure). This makes it possible to detect a specific DNA or RNA, as well as its fragments and / or other oligonucleotides.

[0132] The receptor layer may include antibodies and / or other proteins that can specifically bind target proteins, and the reference layer may include correspondingly specific isotype control antibodies and / or other proteins that do not bind to any chemical, biochemical, and / or physical species in the sample.

[0133] The receptor layer can contain scFv antibodies, and the reference layer can contain scFv antibody-specific isotype control antibodies. An scFv antibody is an artificially produced antibody fragment. By dividing an antibody into multiple fragments, the sensor's reactivity can be increased to low sample concentrations. For example, the scFv antibody can be in an F(ab), F(ab')2, or F(ab') configuration.

[0134] The receptor layer and / or the reference layer may include hydrogels.

[0135] Hydrogels are molecular matrices that bind water very well and swell considerably upon contact with water. Through chemical modification of the hydrogels, particularly the matrix, a strong reaction of the hydrogel to the presence of antibodies can be achieved, thus multiplying the mechanical deformation of the cantilever. In particular, this also makes it possible to perform a pH-sensitive measurement of the analyte. Brief description of the characters

[0136] Embodiments of the invention are explained in more detail by the following description of the figures. These show: Figure 1 is a schematic representation of a sensor not according to the invention; Figures 2A, B, C, D, E, F are schematic representations of the sensor with various recesses; Figures 3A, B, C, D are schematic representations of the cantilever with longitudinal and transverse strains; Figures 4A, B are schematic representations of a sensor according to the invention and configurations of the transducers; Figures 5A, B are a further schematic representation of a sensor not according to the invention including sensor electrodes; and Figure 6 is a schematic representation of the binding of antigens to antibodies. Detailed description

[0137] The following are examples of embodiments described with reference to the figures. Identical, similar, or equivalent elements in the different figures are designated with identical reference numerals, and repeated descriptions of these elements are sometimes omitted to avoid redundancy.

[0138] In Figure 1A schematic representation of a sensor 1 (not according to the invention) for converting chemical and / or biochemical information is shown. The sensor 1 comprises a test cantilever 2, which has a base 20 and a deformable part 22. A first test transducer 200 and a second test transducer 220 are arranged on the deformable part 22. Similarly, the sensor 1 also has a reference cantilever 3, which in turn has a base 30 and a deformable part 32. A first reference transducer 300 and a second reference transducer 320 are arranged on the deformable part 32.

[0139] The transducers 200, 220, 300, 320 are each connected via electrodes 40 to an electronics unit 4, which is capable of recording or forwarding the measurement signals of the transducers 200, 220, 300, 320, while the electronics unit 4 is also capable of supplying the transducers 200, 220, 300, 320 with current and / or voltage.

[0140] Sensor 1 is designed to indicate the presence, and preferably the quantity, of analyte 90 in a sample 9. Figure 1 Sample 9 is a liquid, for example, lymph or diluted lymph fluid. However, it could also be saliva, blood, or another bodily fluid. Sample 9 may also be derived from a tissue sample or obtained and / or synthesized from another extracted substance. Analyte 90 may be dissolved in the sample or present in an undissolved form as a suspension, dispersion, or emulsion.

[0141] In any case, the sensor 1 is to be used to examine sample 9 with regard to the presence and / or concentration and / or quantity of analyte 90. For this purpose, a receptor layer 24 is applied to the test cantilever 2, with which analyte 90 can interact, or a receptor layer 24 that can adsorb or absorb analyte 90.

[0142] The interaction changes the surface tension of the section of the deformable part 22 of the test cantilever 2 covered with the receptor layer 24, leading to a deformation of the deformable part 22 of the test cantilever 2. The first and second test transducers 200, 220 therefore register a deformation of the deformable part of the test cantilever 2, which is then interpreted as a measurement signal in the electronics 4.

[0143] However, the interaction with the sample liquid 9 can already lead to the registration of a deformation by the test transducers 200, 220, for example, if only the surface tension of the liquid acts on the deformable part 22 of the test cantilever 2 and deforms it. The presence of an analyte 90 is therefore not responsible for such a deformation.

[0144] To determine the magnitude of the baseline effect of sample 9 on test cantilever 2, reference cantilever 3 is simultaneously brought into contact with sample 9. For this purpose, reference cantilever 3 has a reference layer 34 with which analyte 90 cannot interact. This allows differentiation from the measurement signal of test cantilever 2. Accordingly, the measurement signals of transducers 200, 220, 300, and 320 differ if analyte 90 is present in sample 9.

[0145] However, the test cantilever 2 and the reference cantilever 3 are located at different positions in the sample 9, so that different environmental conditions, such as temperature fluctuations or concentration gradients, etc., affect the measurement accuracy.

[0146] These differing environmental conditions can be compensated for by comparing the measured values ​​of transducers 200, 220, 300, and 320. Thus, the presence of analyte 90 in a sample 9 can be analyzed in isolation using sensor 1. This is achieved by using a large number of measurement points on the reference and test cantilevers 3 and 2 to reduce and isolate the influence of interactions not attributable to analyte 90. This enables a high degree of measurement accuracy for the presence of analyte 90 in the sample 9. In the simplest case, the magnitude of the difference between the measurement signals of transducers 200, 220, 300, and 320, the test cantilever 2, and the reference cantilever 3 can be used to directly determine the amount of analyte 90 present in the sample 9.

[0147] In Figure 2AThe comparison of the deformable parts 32, 22 of the reference and test cantilevers 3, 2 under deformation and longitudinal strain is shown. The deformable part 32 of the reference cantilever 3 has an upper surface 360 ​​and a lower surface 362. Likewise, the deformable part 22 of the test cantilever 2 has an upper surface 260 and a lower surface 262. If an analyte 90 of the sample 9 interacts with the test cantilever 2, or with the receptor layer 24, a deformation of the deformable part 22 occurs, moving from the stationary part (which transitions into the base of the test cantilever) to the freely movable part of the deformable part 22. The deflection L shown here is given by the relative deflection between the deformable part 32 of the reference cantilever 3 and the deformable part 22 of the test cantilever 2 due to the interaction with the analyte 90.

[0148] The deformation of the deformable part 22 of the test cantilever 2 is in Figure 2BThis is shown as an example for test cantilever 2. The description for reference cantilever 3 is analogous. The reason for this is that the upper surface 260 and the lower surface 262 of test cantilever 2 stretch to different degrees due to the interaction with analyte 90, resulting in deformation of test cantilever 2. Due to the large strain D on the upper surface 260, the first and second test transducers 200, 220 applied to it can register a strain force F. The registered strain force F can be converted into an electronic signal by the test transducers 200, 220, or it can influence an existing electronic signal, such as an applied voltage. This can occur, for example, if the test transducers 200, 220 change their resistance when subjected to a strain force F, which in turn results in strain of the test transducers 200, 220.

[0149] As in Figure 2B As shown, the first and second test transducers 200, 220 can be arranged in a recess of the test cantilever 2. The recess increases the elasticity of the test cantilever 2, while the first and second test transducers 200, 220 increase its stiffness. By combining these two effects, the first and second test transducers 200, 220 can measure the strain of a test cantilever with high elasticity, thus generating a particularly strong measurement signal. If the test transducers 200, 220 were arranged only on the surface of the cantilever 2, 3 and not in a recess, the test cantilever 2 would be stiffer, especially in the region of the respective transducers, resulting in a weaker measurement signal.

[0150] The depressions can be deeper than 5%, preferably deeper than 20%, and particularly preferably deeper than 50% of the thickness of the test cantilever 2. In the present case, in Figure 2B The depth is approximately 80% of the thickness of the cantilever 2, 3.

[0151] Additionally, the height of the first and second test transducers 200, 220 corresponds to the depth of their respective recesses, so that the upper surface of the test transducers 200, 220 is flush with the upper surface 260 of the cantilever 2. However, it is also possible for the test transducers 200, 220 to protrude beyond the upper surface 260, as shown in Figure 2C shown, or partially located below the upper surface 260, as shown in 2D Figure shown, or lie a total of 260 below the upper surface (not shown).

[0152] Furthermore, in the Figures 2C and 2DThe neutral axis N is drawn, along which no material stress exists in the ground state, taking into account the layer structure in particular. The neutral axis N can be determined, for example, via computer simulations of the layer system with the geometry of the cantilever.

[0153] The first and second test transducers 200, 220 of the test cantilever 2 can also be arranged in recesses located on the lower surface of the test cantilever 2, as shown in Figure 2E shown. In particular, it is also possible that the recess of the first test transducer 200 is located on the upper surface of the test cantilever 2, while the recess of the second test transducer is located on the lower surface (or vice versa), as shown in Figure 2F shown. In particular, the test transducers 200 and 220 can also have different thicknesses.

[0154] Using beam theory, it is possible, for example, to predict at which points on the deformable part 22 the strain D is greatest. It is possible to position the test transducers 200 and 220 at these points to achieve an optimal signal-to-noise ratio and to react as sensitively as possible to the strains. However, other conditions should also be considered when precisely positioning the test transducers. In particular, the test transducers 200 and 220 can also be positioned at the points on the test cantilever 2 where the changes in strain upon contact with a sample are greatest.

[0155] In particular, the orientation of the test transducers 200 and 220 relative to the orientation of the cantilevers plays an important role. Figure 3AFor example, a test cantilever in its ground state is shown. When the test cantilever 2 comes into contact with the analyte 90, the surface tension changes and the material deforms, as shown in Figure 3B shown. In Figure 3B The figure shows that the test cantilever undergoes deformation perpendicular to the base 20, or to the bending edge. This is accompanied by a longitudinal expansion DI of the upper surface. Simultaneously, a deformation occurs parallel to the base 20, or to the bending edge, which is accompanied by a transverse expansion Dq of the upper surface. The geometry of the test cantilever 2 determines the direction along which a greater expansion D is caused. In particular, the test transducers 200 and 220 can be aligned along these directions to generate a particularly strong measurement signal.

[0156] In Figure 3CIt is shown by way of example that a first test transducer 200 is arranged at the location of the greatest longitudinal strain of the test cantilever 2, while a second test transducer 220 is arranged at the location of the greatest transverse strain of the test cantilever 2. The test transducers 200, 220 are elliptical in shape, but they can also have a rectangular profile, as shown in Figure 2 As shown, the two test transducers 200 and 220 are oriented differently with respect to the longitudinal axis of the test cantilever 2. The orientation of the test transducers 200 and 220 can, for example, be aligned with the long axis of the elliptical test transducers 200 and 220. Accordingly, an isotropic transducer material can detect longitudinal or transverse strain, or even a mixed state, due to its geometric configuration.

[0157] The orientation of the transducers is determined by a preferred direction in which they exhibit the greatest sensitivity. This is typically highest in the direction of the transducer's greatest extent. For transducers with a rectangular base, the preferred direction extends along the longer side of the rectangle. For the elliptical base of the transducer indicated here, the preferred direction extends along the principal axis.

[0158] The first test transducer 200 is aligned parallel to the longitudinal axis of the test cantilever 2, while the second test transducer 220 is aligned perpendicular to the longitudinal axis of the test cantilever 2. In particular, the two test transducers 200 and 220 are thus oriented perpendicular to each other and form an angle of 90°.

[0159] In 3D figure schematically depicts the course of the test cantilever's elongation in Figure 3Cshown along the x-axis. The strain vanishes along the base 20 and increases in magnitude from the bending edge in the deformable part 22. In particular, the longitudinal strain along the x-axis and the transverse strain along the y-axis are of different magnitudes.

[0160] The above description of Figures 2 and 3 The same applies analogously to the functioning of the reference cantilever 3 with the first and second reference transducers 300, 320.

[0161] In Figure 4AFigure 1 shows an embodiment of the sensor 1 according to the invention, in which the reference cantilever 3 and the test cantilever 2 have identical geometric dimensions and are designed to be mirror images of each other. In particular, the height, width, and thickness of the reference cantilever 3 correspond to the height, width, and thickness of the test cantilever 2. This results in the same strain D on the upper surfaces 260, 360. Since the geometric dimensions of the cantilevers 2, 3 are identical, an identical dependence of the measurement signal on the strain is expected.

[0162] For example, the width B of the cantilever is equal to the height H of the cantilever 2, 3, which allows for a particularly large elongation D on the upper surface 260, 360 of the cantilever 2, 3. For example, the cantilevers are less than 150 µm wide, less than 150 µm long and less than 1 µm thick, in particular 50 µm wide, 50 µm long and 0.5 µm thick.

[0163] In the embodiment of sensor 1 in Figure 4A Furthermore, the bases 30, 20 of the reference and test cantilevers 3, 2 are arranged on the same overall base, which allows the cantilevers 2, 3 to be positioned closer together to reduce differences in environmental conditions.

[0164] In Figure 4B Another embodiment of the invention is shown, in which the first transducers 200, 300 are aligned perpendicular to the longitudinal axis of the cantilevers 2, 3 and the second transducers 220, 320 are aligned parallel to the longitudinal axis of the cantilevers 2, 3. For comparison, in Figure 4A The first transducers 200, 300 are aligned parallel to the longitudinal axis of the cantilevers 2, 3, while the second transducers are aligned perpendicular to the longitudinal axis of the cantilevers 2, 3.

[0165] Since the first transducers 200, 300 measure, for example, a transverse dimension of the cantilevers 2, 3 and the second transducers 220, 320 measure a longitudinal dimension, the difference in the measurement signals of the first transducers 200, 300 and the second transducers 220, 320 is solely due to the interaction or non-interaction of the analyte with the cantilevers.

[0166] In particular, the transducers 200, 220, 300, 320 shown can not only be arranged and aligned on the surface of the cantilevers 2, 3, but can also be arranged in a corresponding recess.

[0167] In Figure 5AAnother embodiment of sensor 1, not according to the invention, is shown. The transducers 200, 220, 300, 320 are contacted via electrodes 401, 402, 403, 404. In particular, the second test transducer 220 is connected to the second reference transducer 320 via electrode 401. Furthermore, the first test transducer 200 is connected to the first reference transducer 300 via electrode 403. The second test transducer 220 is also connected to the first test transducer 200 via electrode 402, whereas the second reference transducer 320 is connected to the first reference transducer 300 via electrode 404. Thus, a total of four electrodes are used to electrically contact the transducers 200, 220, 300, 320.

[0168] The transducers 200, 220, 300, and 320 are electrically connected in a so-called full bridge configuration. The full bridge circuit is shown in Figure 5BAs shown, in the full bridge configuration, a DC or AC voltage is applied between electrodes 403 and 401. Between these electrodes, the first and second transducers act as voltage dividers due to their electrical resistances. A full bridge in the form shown has the advantage that no voltage is generated between electrodes 402 and 404, provided that the ratio of the resistances of the first test transducer 200 to the second test transducer 220 of the test cantilever 2 is equal to the ratio of the resistances of the first reference transducer 300 to the second reference transducer 320 of the reference cantilever 3. Thus, a deviation of just one resistance is sufficient to change the resistance ratios and thereby generate a voltage between electrodes 402 and 404.

[0169] When the reference cantilever 3 and the test cantilever 2 interact with the sample 9 and the analyte 90, both deformable parts 22, 32, for example, experience a change in surface tension, which is greater for the deformable part 22 of the test cantilever 2 than for the deformable part 32 of the reference cantilever 3.

[0170] Since the resistances of the first and second transducers change differently due to, for example, their different orientations, a particularly large change in the resistance ratios results from the deformation of the deformable part 22 of the test cantilever 2 due to the interaction with the analyte 90 of the sample 9, which interacts specifically with the reference layer 24 of the test cantilever 2. Accordingly, such an interaction generates a voltage between the electrodes 402, 404, so that a force acting on the first and second test transducers 200, 220 relative to the first and second reference transducers 300, 320 can be indicated as the bridge cross-voltage VB. Preferably, the bridge cross-voltage VB scales with the abundance of analyte 90 in the sample 9, thus enabling a quantitative evaluation of the measurement signal.

[0171] A bridge cross-voltage detector 44 can display or transmit the bridge cross-voltage VB externally, so that the user of the sensor 1 can see that a bridge cross-voltage VB is present. In particular, such a bridge cross-voltage detector 44 can also be an analog-to-digital converter (ADC), whereby the ADC converts the bridge cross-voltage VB into a digital signal that can be transmitted to the external measuring device. Alternatively, the detector 44 can detect the signals at electrodes 402 and 404 independently of each other, so that a statement can be made about the respective deflections of the deformable parts 32, 22.

[0172] In Figure 6The schematic diagram shows the structure of the various deformable parts 22, 32 of the reference and test cantilevers 3, 2, respectively. The structure of the cantilevers is identical except for the receptor layer and the reference layer, so that the interaction with the sample and the surrounding medium, as well as the mechanical design of the cantilever, are largely the same.

[0173] An activation layer 34, 24 is applied to the deformable part 32, 22 of the reference or test cantilever 3, 2. An activation layer 240 is designed to create an adhesion mediator between the surface of the deformable part 32, 22 and another layer 241, 341. Furthermore, the activation layer 240 is intended to create an asymmetric layer structure of the cantilever 3, 2, such that there is the greatest possible difference in the extent of the upper surface of the cantilever and the lower surface of the cantilever.

[0174] A so-called self-organizing monolayer 241 can then be applied to the gold layer 240, which can compensate for the surface irregularities of the gold layer and at the same time provides an adhesion medium for a further layer, namely the reference or receptor layers 34, 24.

[0175] The structure of the reference and receptor layers 34 and 24 differs. However, both layers are based on a layer that can include the so-called protein A 242, which binds to the self-organizing monolayer 241 and 341, but can also have and bind antibody 243 or isotype control antibody 343 on its surface.

[0176] Antibodies 243 are proteins that react to, or bind to, antigen 5 and thus, for example, mark virus cells in the human immune system so that the immune system can destroy the marked virus, thereby containing or preventing a viral outbreak. Antibodies 243 are largely specific to antigen 5, but can also interact with other similar antigens 50. Figure 6It has been shown that antibody 243 can interact with antigen 5 and the similar antigens 50.

[0177] In contrast to antibody 243, the isotype control antibody 343 is a protein that preferentially exhibits ultra-high specificity and does not interact with antigen 5. This virtually eliminates the possibility of interaction with a specific antigen 5. This is evident in the Figure 6 This was demonstrated by showing that the isotype control antibody 343 can only interact with two similar antigens 50, but not with the antigen 5 shown schematically as a square here. Therefore, the relative change in the surface tension of the cantilevers 22, 32 is solely attributable to the specific antigen 5.

[0178] By having test cantilever 2 containing antibody 243 and reference cantilever 3 containing isotype control antibody 343, it is ensured that in sample 9, analyte 90, if analyte 90 is antigen 5, can only interact with test cantilever 2.

[0179] This ensures that the relative deformation of the test cantilever 2 caused by analyte 90, compared to the deformation of the reference cantilever 3, is solely due to the presence of analyte 90 or antigen 5. Therefore, this sensor 1 can reliably and quickly detect antigen 5.

[0180] In contrast to the upper surface of the cantilevers 2, 3, the lower surface of the cantilevers is passivated. Such passivation 244 and 344 can prevent the interaction, binding, or absorption of an analyte 90 of the sample 9 in or on the cantilever. In particular, such a passivation layer also contributes to increasing the asymmetry of the layer structure in order to produce the greatest possible strain effect on the upper surface of the cantilevers 3, 2. Specifically, the passivation layer can comprise trimethoxisilane and / or a blocking substance. Reference symbol list

[0181] 1 Sensor 10 Bending edge 2 Test cantilever 20 Base 200 First test transducer 22 Deformable part 220 Second test transducer 24 Receptor layer 240 Activation layer 241 Self-organizing monolayer 242 Protein A 243 Antibody 244 Passivation layer 26 Surface 260 Upper surface 262 Lower surface 3 Reference cantilever 30 Base 300 First reference transducer 32 Deformable part 320 Second reference transducer 34 Reference layer 340 Activation layer 341 Self-organizing monolayer 342 Protein A 343 Isotype control antibody 344 Passivation layer 36 Surface 360 ​​Upper surface 362 Lower surface 4 Electronics 40 Electrode 400, 401, 402, 403 Electrodes 42 Bridge transverse voltage detector 44 A / D converter 440 A / D converter logic 5 Antigen 50 Similar antigen 9 Sample 90 Analyte F Force L Deflection D Strain AT Distance between active and passive transducers A E Distance between electrodes S Axis of symmetry V B Bridge transverse voltage N Neutral axis

Claims

1. Sensor (1) for converting chemical and / or biochemical information of an analyte (90) in a sample (9) into an electrical signal, comprising a test cantilever (2) which has a base (20) and a deformable part (22), wherein a receptor layer (24) for selectively receiving the analyte (90) is applied at least on the deformable part, wherein a first and second test transducer (200, 220) are arranged on the test cantilever (2), a reference cantilever (3) which has a base (30) and a deformable part (32), wherein a reference layer (34) for selectively not-receiving the analyte (90) is applied at least on the deformable part (32), wherein a first and second reference transducer (320) are arranged on the reference cantilever (3), wherein the transducers (200, 220, 300, 320) are designed and configured to output an electrical signal corresponding to the occurrence and / or the concentration and / or the amount of the analyte (90) in the sample (9), wherein, as a result of the selective not-receiving of the analyte (90) by the reference layer (34), the interaction of the reference cantilever (3) with the sample (9) with analyte (90) corresponds to the interaction of the test cantilever (2) with the sample (9) without analyte (90), characterized in that the first and second test transducers (200, 220) are arranged on the deformable part (22) of the test cantilever (2) and the first and second reference transducers (300, 320) are arranged on the deformable part (32) of the reference cantilever (3), wherein the first and second transducers (200, 220, 300, 320) of the same cantilever (2, 3) are configured to detect different force components, wherein the first transducer (200, 300) is aligned along the longitudinal axis of the cantilever (2, 3) and the second transducer (220, 320) is aligned perpendicularly to the longitudinal axis of the cantilever (2, 3).

2. Sensor (1) according to claim 1, characterized in that the force to be detected is based on the bending stiffness of the reference and test cantilevers (3, 2).

3. Sensor (1) according to claim 1 or 2, characterized in that, by comparing the forces detected by the transducers (320, 300, 220, 200), an effect on the test cantilever (2) caused by the selective receiving of the analyte (90) and thus the occurrence thereof is concluded.

4. Sensor (1) according to one of the preceding claims, characterized in that the deformable parts (32, 22) of the reference and test cantilevers (3, 2) have identical geometric dimensions, wherein preferably the width of the deformable part of the reference and test cantilevers corresponds to the length of the deformable part of the reference and test cantilevers.

5. Sensor (1) according to one of the preceding claims, characterized in that the reference and test cantilevers (3, 2) comprise Si and / or aluminium oxide and / or at least one polymer.

6. Sensor (1) according to one of the preceding claims, characterized in that the transducers (320, 300, 220, 200) have identical intrinsic physical properties, wherein the transducers (320, 300, 220, 200) are configured to adapt their electrical properties corresponding to the forces acting on the reference and test cantilevers (3, 2).

7. Sensor (1) according to one of the preceding claims, characterized in that the reference and test cantilevers (3, 2) and the active and passive reference and test transducers (320, 300, 220, 200) are arranged mirror-symmetrically with respect to one another.

8. Sensor (1) according to one of the preceding claims, characterized in that the first and second test transducers (200, 220) are each arranged in a recess or a common recess of the test cantilever (2) and the first and second reference transducers (300, 320) are each arranged in a recess or a common recess of the reference cantilever (3).

9. Sensor (1) according to claim 8, characterized in that the recesses are arranged on the upper and / or the lower surfaces (260, 262, 360, 362) of the cantilever (2, 3).

10. Sensor (1) according to claim 9, characterized in that the at least one recess is deeper than 5% of the thickness of the cantilever (2, 3), and the distance of at least one transducer from the neutral axis of the cantilever is less than 20% of the thickness of the cantilever (2, 3).

11. Sensor (1) according to claim 9 or 10, characterized in that the height of at least one transducer (200, 220, 300, 320) corresponds at least to the depth of the recess.

12. Sensor (1) according to claim 11, characterized in that the first and the second transducer (200, 220, 300, 320) are arranged at the location of the maximum and the minimum surface tension of the cantilever (2, 3).

13. Sensor (1) according to one of the preceding claims, characterized in that the upper surfaces (360, 260) of the reference and test cantilevers (3, 2) are activated by an activation layer (340, 240), wherein the activation layer (340, 240) is configured to provide a greater surface tension compared to the non-activated lower surface (362, 262) of the reference and test cantilevers (3, 2), and wherein the activation layer (340, 240) comprises gold.

14. Sensor (1) according to one of the preceding claims, characterized in that the upper or lower surfaces (362, 262) of the reference and test cantilevers (3, 2) are passivated by a passivation layer (344, 244), wherein the passivation layer (344, 244) is configured to minimize non-specific protein adhesion on the reference and test cantilevers (3, 2), and wherein the passivation layer (344, 244) comprises trimethoxysilane and / or a blocking substance.

15. Sensor (1) according to one of the preceding claims, characterized in that the reference and test cantilevers (3, 2) have a further layer (341, 241) which comprises a self-organising monolayer.