Sensor and measurement method for converting chemical and / or biochemical information from at least one analyte
Patent Information
- Authority / Receiving Office
- EP · EP
- Patent Type
- Applications
- Current Assignee / Owner
- DIGID GMBH
- Filing Date
- 2024-08-08
- Publication Date
- 2026-06-17
Smart Images
Figure EP2024072476_13022025_PF_FP_ABST
Abstract
Description
[0001] Sensor and measuring method for converting chemical and / or biochemical information of at least one analyte
[0002] Technical area
[0003] The present invention relates to a sensor and a method for converting chemical and / or biochemical information of at least one analyte in a sample into a measurement signal, as well as a method for producing a sensor.
[0004] State of the art
[0005] The use of spring elements or cantilevers for the detection of analytes in samples is well known. This method utilizes the interaction of the cantilever with a sample fluid and the binding of the analyte in the sample to a coating of the cantilever to induce a deformation of the cantilever. The presence of the analyte can then be determined from this deformation using a strain gauge.
[0006] The deformation of cantilevers due to different 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.
[0007] WO 2007 / 088018 A1 further proposes spring elements for use in biosensors such as DNA analysis.
[0008] DE 10 2021 107 255 A1 discloses 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 and / or quantitative statement about the presence of the analyte in the sample based on the generated electrical signal.
[0009] However, if a sample is to be analyzed for multiple analytes, the current state of the art requires a number of different sensors, each of which must be brought into contact with the sample one after the other. However, this current approach is time-consuming, sample-intensive, and costly, since each sample can only be analyzed for one analyte.
[0010] Description of the invention
[0011] Based on the known prior art, it is therefore an object of the present invention to provide an improved sensor, its production, and a corresponding measuring method.
[0012] The problem is solved by a sensor having the features of claim 1. Advantageous further developments emerge from the subclaims, the description, and the figures.
[0013] Accordingly, a sensor for converting chemical and / or biochemical information of at least one analyte in a sample into a measurement signal is proposed, comprising at least three cantilevers, each of the cantilevers having a base and a deformable part and a first and a second transducer being arranged on each of the cantilevers, at least two of the at least three cantilevers forming a measurement tuple with the associated transducers, a multiplexer configured to receive a control signal from a control signal transmitter in order to contact the transducers of the cantilevers of the measurement tuple corresponding to the control signal, and an evaluation unit that converts the chemical and / or biochemical information of the analyte into a measurement signal and outputs it on the basis of the detected electrical signals of the contacted measurement tuple.
[0014] A sample refers to a limited amount of a substance that was taken from a larger amount 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 the substance occurrence and composition of the sample can be used to infer the corresponding occurrence in the reservoir.
[0015] For example, a sample can be a saliva sample, a blood sample, a swab, in particular a throat swab, a nasal swab or a sinus swab, or it can be removed tissue. A sample includes, in particular, any type of biological sample, and in particular also samples from animals. A sample can also be a non-biological sample, for example a sample of a chemical substance. In particular, one sample form can be converted into another sample form so that the analyte, or its presence, can be detected in a simple and reliable manner. For example, a swab can be dissolved in a liquid so that the swab dissolved in the liquid then becomes the actual sample. For example, the sample can be or contain lymph fluid or lymph.
[0016] 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 with the sensor. The analyte can be present directly in the sample, dissolved in the sample, or adhere to the sample or a part of the sample, in particular a sample particle. The analyte can also enter into a chemical, biological, and / or physical interaction with the sample, so that the analyte can only be detected indirectly via a corresponding interaction.
[0017] Chemical information can include, for example, the type of analyte, the concentration of the analyte, the occurrence of the analyte, the weight of the analyte, the reactivity of the analyte, the density of the analyte, etc. Biochemical information includes the same properties as chemical information, but these substances can arise, for example, through biological processes. In particular, biochemical information is referred to when the analyte has a particular influence on the biological cycle, for example, metabolism or the immune system.
[0018] To convert the chemical and / or biochemical information of the analyte into an electrical signal, the sensor includes a cantilever. A cantilever is a spring element with a base and a deformable part.
[0019] The base is a stationary part of the cantilever, which is, in particular, fixedly connected to a substrate and / or supported and / or machined from the substrate. The base of the cantilever is designed as a rigid base, so that only the deformable part of the cantilever is deformable.
[0020] The deformable part of the cantilever extends longitudinally beyond the substrate on which the base is mounted. In other words, the deformable part of the cantilever is suspended from the base at one end and is not supported by the substrate. By extending beyond the substrate, the deformable part of the cantilever can be bent, deflected, and stretched. The spatial boundary at which the cantilever is bendable, or where the cantilever transitions from the base to the deformable part, is called the bending edge. The bending edge is usually an edge of the substrate if the cantilever extends beyond the substrate.
[0021] If the cantilever is deformed, material stresses and forces arise in or on the cantilever material, which can be measured. If such material stress and / or force can be measured, it can be inferred that the cantilever is deforming. A deformation can be a lifting or lowering deformation. However, the cantilever can also deform itself, for example, by bulging, undulating, or distorting.
[0022] The purpose of the transducers is to determine or measure the deformation of the cantilevers. The transducers can be arranged on the base and the deformable parts of the cantilevers, or only on the deformable parts of the cantilevers.
[0023] For example, a deformation of the cantilever can cause the resistance of a transducer to increase or decrease, while a lack of deformation of the cantilever also causes no change in the resistance of the transducer. This can be achieved, for example, by designing the transducer according to the principle of a strain gauge, whereby a deformation of the respective cantilever is expressed in a change in the length of the strain gauge of the transducer applied to it. Thus, a deformation of the cantilever can be detected directly by a change in the resistance of the strain gauge.
[0024] Thus, the chemical and / or biochemical information of the analyte becomes detectable via a deformation of the cantilever, a subsequent registration via a transducer, and finally via a change in an electrical property of the transducer.
[0025] The transducers of the cantilevers of the measuring tuple can be designed and configured to output an electrical signal corresponding to the occurrence and / or concentration and / or amount of the analyte in the sample.
[0026] A receptor layer for selectively absorbing the analyte can be applied at least to the deformable part of at least one of the cantilevers, thereby forming a test cantilever, and / or a reference layer for selectively not absorbing the analyte can be applied at least to the deformable part of at least one of the cantilevers, thereby forming a reference cantilever. A test cantilever can have a coating so that the test cantilever bends or its surface tension changes upon interaction with a specific analyte. A reference cantilever can have a further coating so that the reference cantilever bends or its surface tension changes upon interaction with another analyte. In this case, the test cantilever can also serve as a reference for the bending of the reference cantilever.In other words, both the reference cantilever and the test cantilever can each act as a test cantilever for different analytes.
[0027] However, it may also be the case that the reference cantilever has a coating that does not indicate any interaction with an analyte, so that the bending of the reference cantilever is only due to the physical environmental conditions,
[0028] For example, the first transducer of the reference cantilever can induce a first electrical reference state through the influence of the ambient conditions and interaction with the sample, while the interaction of the test cantilever with the ambient conditions of the sample induces a first electrical test state of the first transducer of the test cantilever.
[0029] For example, the reference cantilever can be bent by a first amount due to the influence of the ambient conditions, so that the deflection causes a first reference state in the first transducer and causes a second electrical reference state in the second transducer.
[0030] In turn, the test cantilever can be bent by a second amount due to the influence of the ambient conditions and by a third amount due to the additional interaction with the analyte in the sample, which induces a first electrical test state in the first transducer and a second electrical test state in the second transducer.
[0031] Comparing the electrical states of the first and second transducers provides a measure of the cantilever deformation. At the same time, comparing the first transducer and / or the second transducer provides a measure of the difference in cantilever deformation. This makes it possible to determine the specific influence of an analyte on the test cantilever. The four-transducer design has the advantage of allowing such local calibration of the sensor at the point of influence of the sample and analyte.
[0032] A measurement tuple is a set of cantilevers with associated transducers. For example, a measurement tuple can comprise two cantilevers with their associated transducers. However, a measurement tuple can also comprise neighboring cantilevers with their associated transducers. A measurement tuple can also comprise any number of cantilevers with their associated transducers. In particular, cantilevers with their associated transducers can belong to different measurement tuples. In particular, the transducers of the cantilevers of a measurement tuple can communicate with each other via an electrical connection.
[0033] For example, a measurement tuple combines all cantilevers and transducers that are sensitive to a specific analyte or can serve as a reference cantilever for that analyte. The measurement tuple can then be used to detect whether the corresponding analyte is present in the sample.
[0034] A measurement tuple is preferably composed of cantilevers that have essentially the same resistance of their transducers and / or other characteristic physical or chemical properties. In other words, the cantilevers and transducers in a measurement tuple have similar physical and chemical properties or different but previously known properties, such as the homogeneity and coverage density of functional coatings. Accordingly, a measurement tuple is not limited to a geometric arrangement of the cantilevers on the sensor chip. Rather, a logical assignment between different cantilevers of the sensor can be achieved, which is independent of the geometry and spatial arrangement of the cantilevers.
[0035] For example, 100 cantilevers can be divided into 5 x 20 measurement tuples, or into 2 x 50 measurement tuples, or into 50 x 2 measurement tuples, or into 100 x 1 measurement tuples. The cantilevers can be distributed arbitrarily across the sensor. Statistical evaluations can be performed from the different signals of the measurement tuples for an analyte. In particular, statistical evaluations can also be performed from the combination of different signals of the measurement tuples for an analyte.
[0036] By using measurement tuples, it is possible, for example, to compensate for substrate inhomogeneities that would interfere with the measurement if neighboring cantilevers were used as test and reference cantilevers on a single wafer substrate. The quality of the cantilevers and transducers then only meets the required quality criteria with a certain statistical probability. With a large number of cantilevers and transducers, the probability that neighboring cantilevers will exhibit varying quality increases. However, the proposed use of measurement tuples makes it possible, for example, to find the ideal reference cantilever for a test cantilever regardless of location. In other words, the respective reference cantilevers and test cantilevers can be combined into measurement tuples, regardless of their original production.
[0037] A multiplexer of the sensor is configured to receive a control signal from a control signal generator and to contact the measuring tuples corresponding to the control signal.
[0038] A multiplexer is a device that, in response to an electrical signal, can establish an electrical connection to a plurality of transducers and can connect the plurality of transducers to one another. A multiplexer thus enables alternating contact between different transducers on the sensor. This allows the multiplexer to contact a plurality of measurement tuples sequentially or simultaneously.
[0039] For example, a first measurement tuple can examine a first analyte and output the electrical signal. For example, a second measurement tuple can examine a second analyte and output the electrical signal. It is also possible for there to be multiple measurement tuples for a specific analyte.
[0040] For example, a first measurement tuple can be sensitive to a first analyte, and a second measurement tuple can be sensitive to a second analyte that differs from the first analyte. Preferably, a plurality of measurement tuples is provided, with at least one measurement tuple being sensitive to a specific analyte. Accordingly, different analytes can be measured with the sensor; particularly preferably, a plurality of analytes is measured.
[0041] The cantilevers of different measuring tuples can have different geometries and / or different materials.
[0042] For example, a first measurement tuple can have a first cantilever geometry, and a second measurement tuple can have a second cantilever geometry, whereby the first and second measurement tuple are sensitive to the same analyte. Both cantilever geometries can have specific advantages for detection, so that weighting and processing of the electrical signals leads to greater significance of the measurement signals.
[0043] In particular, different cantilever geometries and / or different materials can result in different cantilever bending in the same sample. For example, the cantilever geometries of the first and second measurement tuple can be adjusted so that the first measurement tuple outputs a measurement signal that is twice as large or three times as large, etc., compared to the measured value of the second measurement tuple. For example, the known or predictable bending properties can be used to verify the detection of an analyte, since the measured values of the measurement tuples are in a certain numerical ratio to each other.
[0044] The same applies to different materials, which, due to their different elastic moduli, also influence the bending properties of the cantilevers. Different physical influences such as flow or temperature would, in any case, produce different ratios of the measured values.
[0045] The sensor has an evaluation unit which, based on the electrical signals of the contacted measuring tuples, converts and outputs the chemical and / or biochemical information of the at least one analyte into a measurement signal.
[0046] The transducers in the measurement tuple can, for example, send electrical signals to the evaluation unit. The evaluation unit can bundle, process, and / or enhance the signals and output a corresponding measurement signal. For example, the evaluation unit can combine the electrical signals or consider the shape, form, and geometry of the cantilevers when generating the measurement signal. For example, the evaluation unit can also consider the physical and / or chemical properties.
[0047] One advantage of the invention is that different analytes can be analyzed using different measurement tuples. By contacting the individual measurement tuples, meaning that the transducers of the cantilevers of the measurement tuples are contacted, a significantly faster, more automated, and more reliable, or stable, and / or safer, detection of the analytes in the sample can be achieved.
[0048] A receptor layer for selectively absorbing the analyte can be applied at least to the deformable part of the test cantilever, and a reference layer for selectively not absorbing the analyte can be applied at least to the deformable part of the reference cantilever,
[0049] A receptor layer is a substance that can interact with the analyte. This means that the receptor layer is selected specifically for each analyte. Similarly, a reference layer is a substance that cannot interact with the analyte. The reference layer is therefore also selected specifically for the analyte.
[0050] In this case, interaction means that the analyte interacts chemically, biochemically, and / or physically with the receptor layer. In particular, the interaction can consist of binding of the analyte to the receptor layer. Interaction can also consist of absorption, adsorption, or chemisorption of the analyte to the receptor layer.
[0051] The receptor and reference layers are preferably chemically identical with respect to potential interference and differ only in their interaction with the analyte. A substance other than the analyte will therefore interact just as strongly or just as weakly with the receptor layer as with the reference layer.
[0052] The selective uptake of the analyte by the test cantilever causes a force to act on the test cantilever through the analyte, causing the test cantilever to react sensitively to the analyte. Accordingly, the other substances in the sample that are not the analyte only contribute to a background noise in the form of a basic deflection of the test cantilever. For example, the force acting on the test cantilever increases more rapidly, the higher the concentration of the analyte in the sample or the faster the surface of the cantilever is covered with the analyte. The maximum force possible for the respective configuration is reached when the cantilever is completely covered.
[0053] 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 a background noise in the form of a basic bending of the reference cantilever.
[0054] This acting force can cause deformation in the deformable part of the test cantilever, while the deformable part of the reference cantilever remains unchanged. The basis for the deflection of the cantilever is the change in surface tension due to the interaction with the analyte. The change in surface tension leads to a stretching or contraction of the upper (or lower) surface of the cantilever. The different stretching or contraction on the upper and lower surfaces creates an internal force or material stress in the material, which leads to deformation.
[0055] State-of-the-art reference cantilevers simply lack a receptor layer that reacts sensitively to the analyte. This allows effects such as turbulence in the sample and the thermal drift of the sensor system to be determined. However, with such a reference cantilever, the analyte can bind, for example, through nonspecific binding to the reference layer of the reference cantilever. This causes the analyte itself to contribute to the background noise. Therefore, with a state-of-the-art sensor, reference measurements in a reference sample, i.e., a sample without analyte, are necessary. Only in this way can the effect of nonspecific binding of substances that are not the analyte be determined.
[0056] In the sensor according to the invention, the measurement process is drastically simplified by the selective non-uptake of the analyte by the reference cantilever, 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 can cause the reference cantilever to be exposed to the same turbulence, the same thermal drift, and the same influence of all substances other than the analyte as in a reference liquid. However, the difference is that the reference signal is determined directly in the sample liquid.
[0057] In particular, a reference cantilever with a reference layer and a test cantilever with a receptor layer result in a significantly more specific analysis of the analyte than just 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.
[0058] The sensor's design, with a measurement tuple comprising a reference cantilever and a test cantilever, has the advantage that two measurements can be taken simultaneously in the sample, with the measurement of the reference cantilever calibrating the measurement of the test cantilever. This reduces environmental influences, such as chemical, thermal, mechanical, electrical, fluidic, and gas flow interference, on the respective measurement, allowing the presence of the analyte to be determined by comparing the measurement of the test cantilever and the reference cantilever.
[0059] These forces or material stresses, such as strains or contractions, which act on the cantilevers can ultimately be detected by the transducers, whereby different strengths of strain or contraction are detected by the transducers.
[0060] At least one measurement tuple can comprise at least one test cantilever and at least two reference cantilevers.
[0061] This means that, for example, two reference cantilevers are available for a single test cantilever. Such multiple referencing can increase the specificity of the sensor.
[0062] At least one measurement tuple can comprise at least two test cantilevers and at least one reference cantilever.
[0063] This means, for example, that two test cantilevers are referenced by a single reference cantilever. Accordingly, a single reference cantilever can be used to reference multiple test cantilevers, allowing multiple test sensors to be arranged on the sensor.
[0064] At least one measurement tuple can comprise at least two test cantilevers and at least two reference cantilevers.
[0065] For example, the sensor can have a first and a second test cantilever that are chemically and physically very similar, as well as a first and a second reference cantilever that are also chemically and physically very similar. For example, the first test cantilever could be referenced to the first or the second reference cantilever. However, it is also possible for both test cantilevers to be referenced to both reference cantilevers.
[0066] By using combined test and / or reference cantilevers, a particularly meaningful measurement signal can be generated. Based on a first measurement tuple, an analyte-specific measurement signal can be output, and based on a second measurement tuple, an interfering analyte-specific measurement signal can be output.
[0067] For example, an interfering analyte may interact with the analyte bound to the test layer, but not with the test layer or the analyte itself.
[0068] However, it is also possible that the interfering analyte binds to the receptor layer, thus leading to a false-positive test result. It is also possible that the interfering analyte binds to the analyte, preventing it from binding to the receptor layer, thus leading to a false-negative test result. It is also possible that the interfering analyte binds to the receptor layer, thereby preventing the analyte from binding to the receptor layer.
[0069] Such a so-called cross-reaction can be detected by a second measurement tuple that is sensitive to the interfering analyte.
[0070] At least two measurement tuples of the sensor can be sensitive to two different analytes.
[0071] For example, a first measurement tuple can be used to detect a first analyte, while a second measurement tuple can be used to detect a second analyte.
[0072] In particular, the detection can be the time-resolved measurement of the bending state of the cantilever in order to obtain information about the reaction kinematics of the analyte in the sample.
[0073] This allows different analytes to be detected with a single sensor, increasing the cost-effectiveness of such a sensor. In particular, this design allows the sensor to be used for different analytes, allowing for rapid analysis of the different analytes.
[0074] The cantilevers of different measuring tuples can have different geometries.
[0075] For example, a first measurement tuple may have rectangular cantilevers, while a second measurement tuple may have triangular cantilevers. Triangular and rectangular cantilevers, for example, have different natural frequencies. These different natural frequencies make it possible to better filter out mechanical disturbances, such as airborne sound or sound in the sample liquid.
[0076] For example, a first measurement tuple may have a first rectangular shape and a second measurement tuple may have a second rectangular shape.
[0077] Cantilevers of different sizes exhibit different bending behavior than identical cantilevers. Furthermore, the temporal response of the cantilevers to an analyte strongly depends on the size of the interaction surface.
[0078] Accordingly, further parasitic effects can also be identified.
[0079] However, it is also possible to use cantilevers of different thicknesses for the same analyte. This allows a very wide dynamic range to be covered, in which the sensor delivers reliable signals for the analyte. For example, thick cantilevers can be used for the detection of a large amount of analyte, while thin cantilevers are used for the detection of small amounts of analyte.
[0080] The sensor may comprise a control signal generator having a database with the measurement tuples and configured to send a control signal to the multiplexer.
[0081] For example, the shape and form of the cantilevers can be stored in the database. Likewise, the resistances of the individual transducers and / or the location of the cantilevers on the sensor and / or the analyte type or the analyte that can be measured with a particular cantilever can be stored. Furthermore, a list of compatible cantilevers can be stored for each cantilever. In this sense, the cantilever can be assigned to a measurement tuple. In particular, a single cantilever and its transducers can also be assigned to different measurement tuples.
[0082] The control signal transmitter can send a control signal to the multiplexer, contacting at least one measurement tuple. The control signal ultimately determines which measurement tuple should be used for measurement, which in turn determines which analyte should be determined. The control signal transmitter allows for flexible adjustment of the sensor.
[0083] For example, different analytes can be measured in a sequence of measurements.
[0084] For example, the measurement signals of the different analytes can also be sampled differently. For example, a first analyte can interact quickly with the first receptor layer, while a second analyte can interact slowly with the second receptor layer. In the former case, more measurement points can be recorded per minute, second, or millisecond to determine the reaction kinematics.
[0085] The above-mentioned object is further achieved by a method for converting chemical and / or biochemical information of at least one analyte in a sample into a measurement signal using a sensor according to the invention having the features of claim 9. Advantageous developments of the method emerge from the subclaims as well as the present description and the figures.
[0086] Accordingly, a method for converting chemical and / or biochemical information of an analyte in a sample into a measurement signal using one of the sensors described above is provided, comprising the following steps of selecting at least one measurement tuple specific for the analyte using the signal generator, contacting the cantilevers of the measurement tuple with the multiplexer, detecting the electrical signals of the transducers of the contacted measurement tuple with the evaluation unit, converting the chemical and / or biochemical information of the analyte using the measurement tuple specific for the respective analyte into a measurement signal using the evaluation unit, and outputting a measurement signal using the evaluation unit.
[0087] In other words, the sensor can measure a large number of analytes, whereby, for example, one or more measurement tuples can be available for each analyte.
[0088] In a first step, a measurement tuple suitable for the desired analyte is selected. This selection step can involve the control signal generator or the localization of a desired analyte in the corresponding database.
[0089] In a further step, the desired measurement tuple(s) is / are contacted by the multiplexer via a control signal. The individual transducers of the cantilevers can be contacted, but can also be interconnected. For example, it is possible to measure the resistance values of the individual transducers directly or using a compensation circuit that includes the typical characteristics of the transducers, such as the temperature-dependent resistance. It is also possible, however, for the transducers to be connected in a bridge circuit via the multiplexer, so that only relative changes in the resistance values are output.
[0090] In a third step, the detected electrical signals from the measurement tuple can be received by the evaluation unit. The evaluation unit receives, for example, the individual resistance values or resistance changes in the measurement tuple.
[0091] In a fourth step, a measurement signal can be output using the evaluation unit.
[0092] This has the advantage that the data processing already takes place in the evaluation unit, so that a signal connection between the evaluation unit and, for example, an external computer is not burdened.
[0093] The procedure can be performed for all measurement tuples or only for specific measurement tuples.
[0094] For example, the sensor can have a first plurality of measurement tuples with which a first analyte can be measured and a second plurality of measurement tuples with which a second analyte can be measured. For example, only the measurement tuples for the first analyte can be selected for measurement, resulting in a faster measurement. However, it is also possible for all measurement tuples of the first plurality of measurement tuples to be selected for measurement, followed by the second plurality of measurement tuples.
[0095] Preferably, the method can be carried out sequentially, with the measurement tuples being selected and measured successively. Furthermore, this sequence also allows the measurement tuples of the first plurality to be measured first, followed by the measurement tuples of the second plurality of measurement tuples.
[0096] In particular, a measurement tuple can comprise only a single cantilever with its associated transducers. In this sense, measurement values for each individual cantilever can be acquired by sequentially measuring the measurement tuples.
[0097] For example, the measured value of each such measurement tuple can be routinely recorded and the measured values subsequently processed. For example, this can be used to synthesize any combination of measurement tuples. However, it is also possible that such a measurement of all cantilevers can be used to obtain an initial selection for a specific measurement tuple, for example, in the case where an unknown substance is to be investigated with the sensor. For example, the presence of a specific nucleotide sequence can be deduced during DNA sequencing.
[0098] The measurement signals can be output integrally for an analyte based on several measurement tuples, or the individual measurement signals of the individual measurement tuples can be output.
[0099] Since different measurement tuples can be used for a single analyte, the electrical signals of the transducers associated with the measurement tuples can be combined to obtain better statistical significance and accuracy.
[0100] For example, a first measurement tuple can provide a first measurement signal, and a second measurement tuple can provide a second measurement signal. However, it is also possible for the evaluation unit to first receive the electrical signals from the first measurement tuple and then receive the electrical signals from the second measurement tuple, weighting the electrical signals, and calculating them against each other.
[0101] The output of the measurement signal may include a statistical analysis.
[0102] This allows the measurement signal to exhibit greater statistical relevance. For example, a large number of test cantilevers can be calculated with a large number of reference cantilevers of a measurement tuple, so that a separate measurement signal can be output for each test cantilever. However, it is also possible for only a single measurement signal to be output for each measurement tuple. Likewise, only a single measurement signal can be output for each analyte, even if this signal is determined by a large number of measurement tuples.
[0103] The evaluation unit can output the measurement signals, for example, via an interface, such as a wireless interface or via a cable. A computer, a smartphone, or another mobile device can connect to the sensor via such an interface. The above-mentioned object is further achieved by a method for producing a sensor having the features of claim 13. Advantageous developments of the method emerge from the subclaims as well as the present description and the figures.
[0104] Accordingly, a method for manufacturing a sensor is proposed, which comprises the following steps: manufacturing the cantilevers, manufacturing the transducers on the cantilevers, characterizing the cantilevers and the associated transducers, assigning the cantilevers with the transducers to a measuring tuple based on the characterization, and coating the cantilevers of a measuring tuple with reference or test layers for a specific analyte.
[0105] The method is based on the idea that, due to production-technical fluctuations in the manufacture of the cantilevers, it is sensible to detect an analyte only with cantilevers that interact similarly with an analyte.
[0106] Accordingly, a large number of cantilevers are initially manufactured.
[0107] The sensor's cantilevers can be manufactured as a single piece from a single substrate. This has the advantage that the manufacturing step only needs to be performed once, ensuring a time-efficient manufacturing process.
[0108] The sensor can be assembled from cantilevers made from the same substrate. For example, all cantilevers can be manufactured from a single silicon substrate made from different wafers. The individual cantilevers can be separated from the different wafers in a subsequent pick-and-place process and assembled into a sensor.
[0109] For example, some processes, such as wet chemical processes, can also be performed at the wafer scale. If, for example, multiple analytes are to be detected, the cantilevers can be taken from different wafers.
[0110] This has the advantage that only cantilevers of a predetermined quality can be used for the sensor. Furthermore, the individually coated cantilevers from a single wafer can be installed in various test systems.
[0111] The sensor can be assembled from cantilevers made of different substrates. This has the advantage that the cantilever can be selected for each specific analyte. For example, an analyte may strongly interact with a first substrate, which could, however, distort the measurement signal. Accordingly, a chemically inert substrate can be selected for this specific analyte. In particular, the cantilevers of one measuring tuple can be arranged side by side, for example, or nested with the cantilevers of another measuring tuple. For example, such an arrangement can optimize the installation space.
[0112] The characterization of the cantilevers and the associated transducers may include quality parameters and / or performance parameters of the cantilevers and / or the associated transducers.
[0113] A performance parameter can include the sensitivity and / or specificity and / or yield of a cantilever and / or transducer. It is of great importance for the user of a sensor that the respective analytical results are consistent and reliable, or that the user receives an indication of the probability or certainty associated with the respective analytical results.
[0114] A quality parameter can be, for example, the cantilever's natural frequency, which provides information about its mechanical integrity. However, such a parameter can also be the actual surface area after the manufacturing process or the stiffness. For example, different cantilevers can have the same stiffness if different substrates and surface geometries are used. The quality parameter can be the self-similarity of the transducers' electrical resistances. If the transducers have the same resistance, they are self-similar.
[0115] It has been found that the self-similarity of the resistances of the resistance bridge is a good indicator of the quality of the transducers and can therefore be used as at least one of the quality parameters that can be used to select the respective transducer.
[0116] Based on the measured parameters, each cantilever and its transducers can be assigned to a measurement tuple. This measurement tuple then contains, for example, all cantilevers with similar physical and / or chemical properties.
[0117] However, artificial intelligence can also assign the quality parameters and / or performance parameters of the cantilevers and / or the associated transducers to specific measurement tuples. For this purpose, a threshold value can be determined for quality parameters and / or performance parameters, whereby the threshold value corresponds to a probability based on which the correctness of the measurement result from a measurement with the cantilever and / or transducer is determined. Based on the measured quality parameters, an appropriately trained artificial intelligence can assign the cantilevers and / or transducers to a specific performance class, for example, which have similar performance parameters. Cantilevers and / or transducers with similar performance parameters can ultimately be assigned to the same measurement tuples, thus ensuring, for example, a certain specificity of the measurements.
[0118] If a list of quality parameters and / or performance parameters is available, a selection of cantilevers and / or transducers for a measurement tuple can be made, whereby the selection takes into account the application scenario.
[0119] The cantilevers in such a measurement tuple can then be coated with a test layer or a reference layer. For example, a first portion of the cantilevers of the measurement tuple can be coated with a first test layer, a second portion of the cantilevers of the measurement tuple can be coated with a second test layer, a third portion of the cantilevers of the measurement tuple can be coated with a first reference layer, and a fourth portion of the cantilevers of the measurement tuple can be coated with a second reference layer. This can, for example, ensure that the measurement tuple contains the same number of cantilevers with a reference coating as cantilevers with a test coating.
[0120] The location parameters of the cantilevers, i.e. the location of the cantilevers on the sensor, as well as the type of applied layer and the performance parameters determined during characterization, can be stored in a database, so that a selection of appropriate measuring devices for a specific analyte is possible.
[0121] The measurement tuples and the corresponding analytes can be stored in a database on a control signal generator. This allows the control signal generator to select the appropriate measurement tuples for the detection of a specific analyte particularly easily and without user intervention.
[0122] However, it is also possible for the database to be stored in the cloud, as long as the control signal generator has access to it. For example, the database can also be stored in the EEPROM, the cryptochip on the biosensor, or in control software stored on a terminal device.
[0123] Storage can preferably be done in encrypted form.
[0124] Encryption is particularly important for data integrity. Since the output measurement signal contains health-related data, for example, data encryption is essential. Encryption prevents a sensor from delivering false-negative results to a computer, for example. Brief description of the figures
[0125] Preferred further embodiments of the invention are explained in more detail in the following description of the figures. In the figures:
[0126] Figure 1 shows a schematic structure of a sensor according to the prior art;
[0127] Figure 2 shows a schematic structure of the sensor according to the invention;
[0128] Figure 3 shows a schematic structure of an embodiment of the sensor according to the invention;
[0129] Figure 4 shows a schematic flow diagram of the measuring procedure;
[0130] Figure 5 shows a schematic device and method for measuring erythrocyte sedimentation rate; and
[0131] Figure 6 is a schematic flow diagram of the manufacturing process.
[0132] Detailed description of preferred embodiments
[0133] Preferred embodiments are described below with reference to the figures. Identical, similar, or equivalent elements in the different figures are provided with identical reference numerals, and a repeated description of these elements is partially omitted to avoid redundancies.
[0134] Figure 1 schematically shows an embodiment of a sensor 1 for converting chemical and / or biochemical information according to the prior art. The sensor 1 comprises a test cantilever 2, which has a base and a deformable part. A first transducer 200 and a second transducer 220 are arranged on the test cantilever 2. Analogously, the sensor 1 also has a reference cantilever 3, which in turn has a base and a deformable part. A first transducer 300 and a second transducer 320 are arranged on the reference cantilever 3.
[0135] The transducers 200, 220, 300, 320 are each connected via electrodes 40 to an electronics unit 4 capable of recording or transmitting the measurement signals from 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. The sensor 1 has the task of indicating the presence and preferably the amount of an analyte 90 in a sample 9. In Figure 1, the sample 9 is a liquid, for example lymph or a diluted lymph fluid. However, the sample 9 can also be saliva, blood, or another body fluid. The sample 9 can also originate from a tissue sample or be obtained and / or synthesized from another sampled substance. The analyte 90 can be dissolved in the sample or present in an undissolved manner as a suspension, dispersion or emulsion.
[0136] In any case, the sensor 1 is intended to examine the sample 9 with regard to the presence and / or concentration and / or amount of the analyte 90. For this purpose, a receptor layer with which an analyte 90 can interact, or a receptor layer that can adsorb or absorb the analyte 90, is applied to the test cantilever 2.
[0137] Due to the interaction, the surface tension of the section of the deformable part of the test cantilever 2 covered with the receptor layer changes, resulting in a deformation of the deformable part of the test cantilever 2. The transducers 200, 220 therefore register a deformation of the deformable part of the test cantilever 2, which is in turn interpreted as a measurement signal in the electronics 4.
[0138] However, the interaction with the sample liquid 9 itself can already cause a deformation to be registered by the 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. Therefore, the presence of an analyte 90 is not responsible for such a deformation, but solely the sample liquid 9.
[0139] In order to determine or equalize or compensate for the magnitude of this basic effect of sample 9 on test cantilever 2, reference cantilever 3 is brought into contact with sample 9 at the same time as test cantilever 2. For this purpose, reference cantilever 3 has a reference layer with which analyte 90, which explicitly interacts with the receptor layer of test cantilever 2, cannot interact. This selective non-uptake of analyte 90 in the reference layer enables differentiation from the measurement signal of test cantilever 2. Accordingly, the measurement signals of transducers 200, 220, 300, and 320 differ, provided an analyte 90 is present in sample 9. The measurement signals between test cantilever 2 and reference cantilever 3 thus differ by exactly the effect caused by analyte 90.
[0140] 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., influence the measurement accuracy. These different environmental conditions can, however, be corrected by comparing the measured values of the transducers 200, 220, 300, 320. Accordingly, the presence of an analyte 90 in a sample 9 can be analyzed in isolation via the sensor 1 by reducing and isolating the influence of interactions that cannot be attributed to the analyte 90 through a large number of measuring points on the reference and test cantilevers 3, 2. This enables a high measurement accuracy of the presence of the analyte 90 in the sample 9.In the simplest case, the amount of analyte 90 present in sample 9 can be directly determined from the magnitude of the difference between the measurement signals of transducers 200, 220, 300, 320 of test cantilever 2 and reference cantilever 3.
[0141] The transducers 200, 220, 300, 320 are connected via electrodes 401, 402, 403, 404. In particular, the second transducer 220 is connected to the second transducer 320 via electrode 401. Furthermore, the first transducer 200 is connected to the first transducer 300 via electrode 403. The second transducer 220 is also connected to the first transducer 200 via electrode 402, whereas the second transducer 320 is connected to the first transducer 300 via electrode 404. This results in a total of four electrodes via which the transducers 200, 220, 300, 320 are electrically connected to one another. The transducers 200, 220, 300, 320 are electrically connected in a so-called full bridge.
[0142] The sensor 1 proposed here is schematically shown in Figure 2. The sensor 1 here has, for example, at least one test cantilever 2 and one reference cantilever 3, whose transducers can each be contacted with a multiplexer 10.
[0143] In Figure 2, the sensor has three test cantilevers 2, 2', which are sensitive to different analytes 90 and 90', respectively. Sensor 1 also has two reference cantilevers 3, 3', each of which, for example, allows for selective non-reception of analytes 90 and 90', respectively. The multiplexer 10 allows contact with different cantilevers 2, 2', 3, 3' virtually simultaneously or in quick succession.
[0144] In this way, the associated cantilevers of a measuring tuple can be contacted specifically.
[0145] A measurement tuple is a predetermined set of cantilevers with associated transducers. In the case outlined above, a first measurement tuple for measuring a first analyte 90 comprises at least one test cantilever 2 and at least one reference cantilever 3, and a second measurement tuple for measuring a second analyte 90' also comprises at least one test cantilever 2' and at least one reference cantilever 3'. A measurement tuple can also have at least two test cantilevers 2 and exactly one reference cantilever 3, or exactly one test cantilever 2 and at least two reference cantilevers 3.
[0146] For example, the multiplexer 10 can contact the test cantilever 2 and the reference cantilever 3. The test cantilever 2 and the reference cantilever 3 then form a first measurement tuple.
[0147] For example, the multiplexer can contact the two test cantilevers 2' and the reference cantilever 3' simultaneously, so that both test cantilevers are referenced to the same reference cantilever 3'. The two test cantilevers 2' and the reference cantilever 3' then form a second measurement tuple.
[0148] For example, test cantilever 2 and test cantilever 2' can also be interconnected so that test cantilever 2' can serve as a reference for the measured values of test cantilever 2. Test cantilever 2' and test cantilever 2 then form a third measurement tuple.
[0149] The electrical signals of the transducers of the various measuring tuples can be received by the evaluation unit 12 and evaluated to form a measuring signal.
[0150] The various measurement tuples can be selected by a signal generator 8 of the multiplexer 10. The signal generator 8 can, for example, access a database in which the various measurement tuples are stored. The various measurement tuples are suitable, for example, for the detection of a specific analyte 90. With the multiplexer 10, the individual cantilevers and / or the measurement tuples can be contacted in rapid succession, for example, so that the evaluation unit 12 can detect the electrical signals of the measurement tuple. The electrical signals can then be processed in the evaluation unit. For example, the evaluation unit 12 can synthesize a full-bridge signal from the individual resistances of the transducers. However, it is also possible for the signals from different test cantilevers 2' to be averaged first and then calculated with the reference cantilever 3'.
[0151] Figure 3 shows another embodiment of the sensor 1. Here, the test cantilevers may be sensitive to the same analyte 90, but the test cantilevers 2 and 2' differ in their geometry or another performance and / or quality parameter.
[0152] Cantilevers 2' and 3' can therefore be assigned to a first measurement tuple. Cantilevers 2 and 3 can also be assigned to a second measurement tuple.
[0153] The electrical signals of the measurement tuples can, for example, be read out sequentially by the evaluation unit 12. The evaluation unit 12 can then, for example, output the measurement signals of the individual measurement tuples or output a single integral value. The integral value can, for example, include further data processing by taking into account the different geometries and / or the different performance and / or quality parameters.
[0154] For example, in a further embodiment, 20 individual test cantilevers 2 and 20 individual reference cantilevers 3 can detect a single analyte 90. In a first variant, the electrical signals of the test cantilevers 2 can be averaged, and the electrical signals of the reference cantilevers 3 can be averaged, with the measurement signal being the difference between the averaged signals. In a second variant, each of the test cantilevers 2 can be synthesized with each reference cantilever 3 into a full bridge, with the measurement signal being the mean of the full-bridge measurement values.
[0155] Through further statistical analysis, for example, outliers can be ignored in the output of the measured values, or incorrect calculations or incorrect measured values can be detected. This increases the significance of the measured values. Figure 4 schematically shows a method according to the invention for converting chemical and / or biochemical information.
[0156] In a first step U1, at least one measurement tuple with the signal generator s is selected. In a second step U2, the measurement tuples are contacted with the multiplexer 10. The cantilevers of the measurement tuples or the measurement tuples can be contacted simultaneously or sequentially. The electrical signals of the contacted measurement tuple are detected by the evaluation unit in a step U3 and converted into a measurement signal by the evaluation unit in a fourth step U4. In a fifth step U5, a measurement signal is output by the evaluation unit 12.
[0157] For example, a sequential measurement can be performed for a large number of selected measurement tuples (represented by the dashed line in Figure 4). After each detection of the electrical signal from the contacted measurement tuple, a new measurement tuple can be contacted. The measured values are temporarily stored in the evaluation unit after each detection process and then converted, for example, into a measurement signal.
[0158] However, it is also possible to measure different analytes simultaneously. For example, the sample fluid reaches all cantilevers at approximately the same time, which means that the interaction of the analytes with the test layers or reference layers also begins at the same time. It is therefore particularly advantageous to measure all cantilevers or their transducers simultaneously.
[0159] From a measurement technology perspective, this simultaneous measurement can be achieved by having the multiplexer cyclically switch through the individual transducers of the cantilevers – preferably the cantilevers forming a measurement tuple directly one after the other. In this sense, for example, a sequential measurement is performed even though all cantilevers are measured simultaneously within the period length of the measurement cycle.
[0160] Figure 5 shows a possible embodiment of the method. For example, the erythrocyte sedimentation rate is to be determined using sensor 1. The erythrocyte sedimentation rate (erythrocyte sedimentation rate) indicates how quickly the red blood cells sink in a blood sample that has been rendered incoagulable. It is influenced by the number, shape, and deformability of the red blood cells. For this purpose, a treated blood sample 9 is placed in a tube in which a sensor 1 according to the invention is also arranged. However, the blood sample 9 can also be untreated, with the interfering parameters being isolated by measurement using additional measuring tuples. For example, every second of the cantilevers 2 shown can be used to detect the red blood cells; accordingly, these two cantilevers 2 each form a measuring tuple.
[0161] In a first scenario, the specific measurement tuples suitable for detecting blood cells can be contacted successively. In particular, this can refer to measurement tuples that only have one cantilever with associated transducers. From the measurement of the chemical and / or biological information, the presence of blood cells at the respective cantilever can be determined as a function of the cantilever location.
[0162] However, it is also possible to combine neighboring cantilevers into a single measuring tuple and contact these cantilevers simultaneously. For example, the local gradient of the blood cell concentration can then be measured as a measured value, for example, as a resistance difference between the transducers, which is determined by a bridge circuit.
[0163] In this way, the measurement of the erythrocyte sedimentation rate can also be displayed dynamically and with time resolution.
[0164] In particular, it is possible to repeat the measurements after a certain time period. This makes it possible to link the temporal evolution of the gradient or the presence of blood cells with the location of the cantilevers. This directly results in the determination of the sedimentation rate of the blood cells.
[0165] For example, a marker for a specific disease can be measured in further measurement tuples, so that, for example, the sedimentation rate can be linked to a specific protein or inflammatory agent.
[0166] Figure 6 schematically shows a manufacturing method for a sensor 1 according to the invention. In a first step S1, a plurality of cantilevers can be manufactured. The cantilevers can be produced, for example, from a single substrate. However, it is also possible for the cantilevers to be manufactured from different substrates and / or in different geometries. In a second step S2, the transducers can be arranged on the cantilevers.
[0167] In a third step S3, the cantilevers and the transducers can be characterized.
[0168] For example, the natural frequencies of the cantilevers can be determined, with the natural frequencies then being used for characterization. Alternatively or additionally, the resistance values of the individual transducers can be determined, so that the resistance values can be used to characterize the cantilevers. Furthermore, information from optical images can be incorporated into the evaluation, characterizing cantilevers, for example, with regard to purity or pre-bending. For example, wafer properties measured using microindentation methods can also be incorporated into the characterization. In principle, all properties and measurement data generated during production, as well as all combinations thereof and the overall findings obtained, can also be incorporated into the characterization.
[0169] In step S4, the cantilevers and their associated transducers can then be assigned to a measurement tuple. For example, those cantilevers with similar geometries and / or similar natural frequencies and / or whose transducers have as similar resistance values as possible can be assigned to a measurement tuple.
[0170] By assigning individual cantilevers to a measurement tuple, the properties of the measurement tuple can be advantageously predetermined for the planned measurement of the respective analyte. For example, the electrical properties of a measurement tuple consisting of a test cantilever and a reference cantilever can be particularly advantageous if the determined resistances of all transducers are very similar. In other words, the measurement accuracy, for example, a sensitivity and / or specificity for a specific analyte, of a measurement tuple can be particularly high if the resistance values of the transducers are very similar and / or if other properties of the cantilevers are explicitly adapted to the respective analysis project.
[0171] By assigning the individual cantilevers to a measuring tuple, particularly advantageous measuring properties can be achieved for the respective analyte to be measured.
[0172] The assignment of the cantilevers comprising the measurement tuple does not have to be predetermined by their spatial arrangement; rather, the multiplexer allows the cantilevers to be connected to form measurement tuples regardless of their spatial arrangement. In other words, even non-adjacent or distantly arranged cantilevers can be connected to form a measurement tuple. In step S5, the cantilevers assigned to a measurement tuple can be assigned reference slices and test slices.
[0173] In a further step or during the respective previous steps, the measured values of the characterization and the occupancy of the cantilevers as well as the measurement tuples can be saved in a database of the control signal generator.
[0174] In particular, after the cantilevers have been covered with the respective test layers or reference layers, a new characterization can be carried out as part of a quality control, the results of which are taken into account in the decision-making process for the formation of the measurement tuples.
[0175] In a corresponding measurement method using the sensor according to the invention, for example, as shown in Figure 2, the sensor 1 shown can be connected to a computer (not shown) via an interface 40, for example, a cable 42. For example, the analysis of a specific analyte 90 can be specified via the computer. The desired analyte can be searched for and selected in the database of the signal generator 10 via a data communication connection.
[0176] At least one measurement tuple can be assigned to the corresponding analyte in the database of the signal generator 10. The measurement tuple also enables the geometric localization of the cantilevers and the corresponding electrical contacting of the associated transducers.
[0177] The multiplexer contacts the measuring tuple and accordingly establishes an electrical connection to the transducers of the cantilevers.
[0178] The transducers of the measuring tuple generate electrical signals which are finally received by the evaluation unit 12 and wherein the chemical and / or biochemical information of the analyte is converted into a measurement signal by the evaluation unit.
[0179] The measurement signal is then output back to the computer.
[0180] Communication with the computer can be encrypted. The database and communication on the sensor can also be encrypted. Such encryption can be accomplished, for example, by an encryption control unit. Such encryption serves two purposes. First, the precise location of the cantilevers of a measurement tuple should be encrypted to prevent deliberate manipulation of the cantilevers. Second, encryption should also be present at interface 40 so that no manipulated false-positive or false-negative measurement signals can be output to the computer.
[0181] Where applicable, all individual features presented in the embodiments may be combined and / or exchanged without departing from the scope of the invention.
[0182] List of reference symbols
[0183] 1 sensor
[0184] 2 test cantilevers
[0185] 200 Transducers 220 Transducers
[0186] 3 reference cantilevers
[0187] 300 transducers
[0188] 320 transducers
[0189] 4 Electronics 401 , 402, 403, 404 Electrodes
[0190] 8 signal generators
[0191] 9 Sample
[0192] 90 analytes
[0193] 10 Multiplexer 12 Evaluation unit
[0194] 14 Signal encryption unit
[0195] 40 Interface
[0196] 42 cables
Claims
Claims 1 . Sensor (1) for converting chemical and / or biochemical information of at least one analyte (90) in a sample (9) into a measurement signal, comprising at least three cantilevers (2, 3), each of the cantilevers (2, 3) having a base and a deformable part, and a first and a second transducer (200, 220, 300, 320) being arranged on each of the cantilevers (2, 3), at least two of the at least three cantilevers (2, 3) forming a measurement tuple with the associated transducers (200, 220, 300, 320), a multiplexer (10) configured to receive a control signal from a control signal transmitter (8) in order to contact the transducers (200, 220, 300, 320) of the cantilevers (2, 3) of the measurement tuple corresponding to the control signal, and an evaluation unit (12) which, on the basis of the detected electrical signals of the contacted measuring tuple, converts and outputs the chemical and / or biochemical information of the analyte (90) into a measuring signal.
2. Sensor (1) according to claim 1, characterized in that the cantilevers (2, 3) of different measuring tuples have different geometries and / or different materials.
3. Sensor according to claim 1 or 2, characterized by a control signal transmitter (8) which has a database with the measurement tuples and is configured to send a control signal to the multiplexer (10), wherein preferably the database and / or the control signal is encrypted.
4. Sensor (1) according to one of the preceding claims, characterized in that the transducers (200, 220, 300, 320) of the cantilevers (2, 3) of the measuring tuple 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).
5. Sensor (1) according to one of the preceding claims, characterized in that a receptor layer for selectively absorbing the analyte is applied at least on the deformable part of at least one of the cantilevers (2), thereby forming a test cantilever (2), and / or a reference layer for selectively not absorbing the analyte is applied at least on the deformable part of at least one of the cantilevers (3), thereby forming a reference cantilever (3).
6. Sensor (1) according to claim 5, characterized in that at least one test cantilever (2) and at least one reference cantilever (3) with the associated transducers (200, 220, 300, 320) form a measurement tuple specific for the analyte.
7. Sensor (1) according to claim 6, characterized in that a measuring tuple comprises at least one test cantilever (2) and at least two reference cantilevers (3) with the respectively associated transducers, and / or a measuring tuple comprises at least two test cantilevers (2) and at least one reference cantilever (3) with the respectively associated transducers, and / or a measuring tuple comprises at least two test cantilevers (2) and at least two reference cantilevers (3) with the respectively associated transducers.
8. Sensor (1) according to one of the preceding claims, characterized in that a first measuring tuple is sensitive to a first analyte (90) and a second measuring tuple is sensitive to a second analyte (90') different from the first analyte (90), wherein preferably a plurality of measuring tuples is provided, wherein in each case at least one measuring tuple is sensitive to a specific analyte.
9. A method for converting chemical and / or biochemical information of an analyte (90) in a sample (9) into a measurement signal using a sensor (1) according to one of the preceding claims, comprising the following steps: Selecting at least one measurement tuple specific for the analyte with the signal generator (8), Contacting the cantilevers (2, 3) of the measuring tuple with the multiplexer (10), Detecting the electrical signals of the transducers (200, 220, 300, 320) of the contacted measuring tuple with the evaluation unit (12), Converting the chemical and / or biochemical information of the analyte with the measurement tuple specific for the respective analyte into a measurement signal with the evaluation unit (12), and Outputting a measurement signal with the evaluation unit (12).
10. The method according to claim 9, characterized in that the method is carried out for at least two different analytes with at least two measuring tuples specific for the different analytes, wherein the contacting of the different measuring tuples is preferably carried out sequentially or simultaneously.
11. Method according to claim 9 or 10, characterized in that the measurement signals for an analyte are output integrally on the basis of several measurement tuples, or that the individual measurement signals of the individual measurement tuples are output.
12. The method according to any one of claims 9 to 11, wherein the output of the measurement signal comprises a statistical analysis.
13. A method for producing a sensor according to any one of claims 1 to 8 comprising the following steps Manufacturing of the cantilevers (2, 3), Manufacturing of the transducers (200, 220, 300, 320) on the cantilevers (2, 3), Characterization of the cantilevers (2, 3) and the associated transducers (200, 220, 300, 320), Assigning the cantilevers (2, 3) with the transducers (200, 220, 300, 320) to a measurement tuple based on the characterization, Covering the cantilevers (2, 3) of a measuring tuple with reference or test layers for a specific analyte (90).
14. Method according to claim 13, characterized in that the cantilevers (2, 3) of the sensor (1) are manufactured in one piece from a substrate, or the sensor (1) is assembled from cantilevers (2, 3) made of the same substrates, or the sensor (1) is assembled from cantilevers (2, 3) made of different substrates.
15. The method according to claim 13 or 14, characterized in that the characterization comprises determining the natural frequencies of the cantilevers (2, 3) and / or determining the resistances of the transducers (200, 220, 300, 320) and / or determining the geometry of the cantilevers (2, 3).
16. Method according to one of claims 13 to 15, comprising the step: - storing the measurement tuples and the associated analytes in a database to which the Control signal transmitter (8) has access, preferably to the control signal transmitter (8), wherein the storage is preferably carried out in encrypted form.