SENSOR, SENSOR SYSTEM AND METHOD FOR DETECTING THERMODYNAMIC PARAMETERS OF A SAMPLE, AND USE OF THE SENSOR OR SENSOR SYSTEM

Abstract

The sensor may have a support structure having at least one substrate and at least one self-supporting membrane. At least one heating element has at least one electrical conducting track arranged on a first surface of the membrane. At least one thermopile, and the electrical conducting track of the heating element and/or the at least one heating element at least partly encloses the membrane on the first surface. An electronic evaluation and control unit is configured for detecting, on the basis of a calibration carried out by the heating element and a sample arranged at or on the membrane, at least one temperature gradient that has formed in the membrane owing to a thermodynamic process taking place in the sample and an associated release of heat or absorption of heat.

Claims

1-20 (canceled)

21. A sensor for detecting thermodynamic parameters of a sample, comprising: a support structure having at least one substrate and at least one self-supporting membrane, wherein edge regions of the at least one self-supporting membrane are arranged on the at least one substrate, at least one heating element, which is formed having at least one electrical conducting track arranged on a first portion of a first surface of the self-supporting membrane, at least one thermopile, which is formed having a plurality of thermocouples that are electrically interconnected in series, and at least partly encloses the at least one electrical conducting track of the at least one heating element and/or the at least one heating element on the first surface of the self-supporting membrane, at least one electronic evaluation and control unit, which is electrically connected to the thermopile and is configured for detecting, on the basis of a calibration carried out by the at least one heating element and a sample arranged at or on the self-supporting membrane, at least one temperature gradient that has formed in the self-supporting membrane owing to a thermodynamic process taking place in the sample and an associated release of heat or absorption of heat.

22. The sensor according to claim 21, wherein during the detection of the at least one temperature gradient by the electronic evaluation and control unit, the sample is arranged at or on a second surface, opposite the first portion of the first surface, of the self-supporting membrane and/or on a second surface, pointing away from the at least one electrical conducting track of the at least one heating element, of the self-supporting membrane and so as to be directly opposite the at least one electrical conducting track of the at least one heating element.

23. The sensor according to claim 21, wherein a reservoir is arranged around the region in which the particular sample is arranged.

24. The sensor according to claim 21, wherein a heat-conducting layer is arranged on the at least one electrical conducting track of the at least one heating element or on a layer in which the at least one electrical conducting track of the at least one heating element and/or the at least one heating element is/are integrated, the surface of the heat-conducting layer that faces the at least one electrical conducting track of the at least one heating element and/or faces the at least one heating element being arranged so as to correspond to the first portion of the first surface of the self-supporting membrane, and/or the heat-conducting layer being formed of gold.

25. The sensor according to claim 21, wherein starting from the outer edge of the self-supporting membrane, the electrical conductors of the thermocouples are led on the first surface of the self-supporting membrane as far as the outer edge of the first portion of the first surface of the self-supporting membrane.

26. The sensor according to claim 21, wherein a plurality of first connection points and a plurality of second connection points of the thermocouples are arranged in alternation along the at least one thermopile, the first connection points and the second connection points each electrically interconnecting two electrical conductors formed of different materials, and the first connection points being arranged at the outer edge of the first portion of the first surface and/or the second connection points being arranged at a distance from the outer edge of the first portion of the first surface and/or being arranged on the substrate of the support structure.

27. The sensor according to claim 21, wherein the at least one heating element comprises at least two electrical contact elements, which are electrically connected to the outer ends of the at least one electrical conducting track of the at least one heating element and/or are arranged on the substrate, and/or the at least one thermopile comprises at least two further electrical contact elements, which are each electrically connected to an outer end of the thermopile and/or are arranged on the substrate.

28. The sensor according to claim 21, wherein the support structure, the at least one heating element and the at least one thermopile are arranged in a housing, the housing being formed of copper and/or the housing comprising thermally conductive supporting or retaining structures and/or the housing being connected to the support structure by thermally conductive supporting or retaining structures and/or by a thermal paste, and/or electrical contacts being led from the support structure through an outer frame of the housing into a region located outside the housing, and/or the housing being arranged in a thermostatic chamber.

29. The sensor according to claim 21, wherein the first surface of the self-supporting membrane measures at least 10 mm2 and/or the thickness of the self-supporting membrane is at most 1 um and/or a distance between the second surface, facing away from the at least one heating element, of the self-supporting membrane and the housing and/or an outer frame of the housing is at least 5 mm.

30. The sensor according to claim 21, wherein the substrate is formed of silicon and/or the self-supporting membrane is formed of silicon nitride and/or p-type thermocouple legs of the thermocouples are formed of antimony and/or n-type thermocouple legs of the thermocouples are formed of bismuth.

31. The sensor according to claim 21, wherein, in a surface region on which the sample is arranged, there is arranged a biosensor which is formed by at least two electrodes, which are arranged at a distance from one another and are connected to an electrical voltage source having a constant electrical voltage and to the at least one electronic evaluation and control unit, and the electrical current flow between the at least two electrodes is measured by the at least one electronic evaluation and control unit, and a measured variable that is characteristic of the metabolism of the sample can be detected and evaluated by the at least one electronic evaluation and control unit.

32. The sensor according to claim 21, wherein at least one measurement instrument is connected to or arranged in the housing, and the proportion of oxygen and/or carbon dioxide contained in the atmosphere inside the housing can be determined using said measurement instrument.

33. The sensor according to claim 21, wherein the at least two sensors are arranged in a shared housing.

34. The sensor according to claim 21, wherein the thermopiles of the two sensors are electrically wired in series.

35. A method for detecting thermodynamic parameters of the sample using the sensor according claim 21, in which in a first step, a calibration is carried out by the at least one heating element, in which calibration the electrical voltage applied at the ends of the at least one thermopile is detected as a function of the heat output of the at least one heating element, and in a second step, on the basis of the calibration carried out in the first step, at least one temperature gradient that has formed in the self-supporting membrane owing to a thermodynamic process taking place in the sample and an associated release of heat or absorption of heat is detected.

36. The method according to claim 35, wherein the sample is arranged in the housing and/or at or on the first surface of the self-supporting membrane chronologically before the second step and/or before the first step, and/or the sample is not heated by the at least one heating element during the second step.

37. The method according to claim 35, wherein the temperature of the substrate is kept constant during the first and/or the second step.

38. The method according to claim 35, wherein a temperature gradient is increased in the range of 0.05 k to 5 K within 5 s by at least one pulse in which the temperature in the region of the sample is increased by a predeterminable temperature within a predetermined time period, and then the drop in the temperature in the region of the sample is detected in a time-resolved manner, and the temperature drop curve of said pulse, detected in a time-resolved manner, is compared, by the at least one electronic evaluation and control unit, with temperature drop curves detected in a time-resolved manner beforehand on similar samples having a known metabolic functionality.

39. The method according to claim 36, wherein the sample is arranged in an encapsulation at least while the second step is being carried out.

40. The method according to claim 35, further comprising determining thermodynamic parameters of metabolic processes in biological cells.

Description

[0059] The invention will be explained in more detail below on the basis of embodiment examples.

[0060] In the drawings:

[0061] FIG. 1a is a schematic view of a front of an example sensor according to the invention,

[0062] FIG. 1b is a sectional view of the example sensor according to the invention shown in FIG. 1,

[0063] FIG. 1c is a sectional view of the example sensor according to the invention shown in FIG. 1 comprising an additional reservoir,

[0064] FIG. 2a shows an example sensor according to the invention comprising a housing,

[0065] FIG. 2b shows an example sensor according to the invention comprising a housing in which vacuum conditions can be maintained, and

[0066] FIG. 3 shows two interconnected sensors for improved compensation of errors.

[0067] FIG. 1a shows the example sensor for detecting thermodynamic parameters of biological cells as a sample 6.

[0068] The sensor comprises a support structure, which is formed having a substrate 1 and a self-supporting membrane 2. Additionally, the support structure can be formed having an outer layer 1.1. The substrate 1 is formed of silicon, the thickness of the substrate 1 being approximately 300 ?m. The self-supporting membrane 2 is formed of silicon nitride and has a thickness of 300 ?m. The self-supporting membrane is square, having a surface area of 36 mm.sup.2. The substrate 1 has a cavity, which is closed on one side by the self-supporting membrane 2. In this case, the outer edge regions of the self-supporting membrane 2 are arranged on the substrate 1 such that the support structure forms a microbridge. For this purpose, the substrate 1 has a frame-like shape. This is where the new reservoir is now located, which takes on the function of the sample holder.

[0069] The sensor further comprises a heating element 3. The heating element 3 has at least one electrical conducting track, which is formed of antimony and arranged in a meandering manner on a central region as the first portion of the first surface of the self-supporting membrane 2. In addition, the heating element 3 has electrical contact elements 3.1, which are electrically connected to the electrical conducting track, the electrical contact elements 3.1 being arranged on the substrate 1. In this case, the electrical conducting track is arranged in a passivation layer formed of silicon dioxide.

[0070] A heat-conducting layer 5 formed of gold is arranged on the passivation layer in which the electrical conducting track of the heating element 3 is integrated. The surface, facing the heating element 3, of the heat-conducting layer 5 is arranged so as to correspond to the first portion of the first surface of the self-supporting membrane 2. In particular, the heat-conducting layer 5 has a thickness of 300 nm and a square surface area of 16 mm.sup.2. Accordingly, the first portion of the first surface of the self-supporting membrane is square and is formed measuring 16 mm.sup.2.

[0071] The sensor further comprises a thermopile. The thermopile is formed having a plurality of thermocouples, which are electrically interconnected in series and in turn each have two different thermocouple legs 4.1, 4.2, and encloses the electrical conducting track of the heating element 3 on the first surface of the self-supporting membrane 2 in a meandering manner. Further electrical contact elements 4.3 are arranged respectively on the two outer ends of the thermopile, which is formed having the thermocouple legs 4.1, 4.2, and are electrically connected to the thermocouples, which are in turn formed having thermocouple legs 4.1, 4.2.

[0072] The sensor also comprises an electronic evaluation and control unit (not shown), which is electrically connected to the thermopile and is configured for detecting, on the basis of a calibration carried out by means of the heating element 3 and on the basis of the biological cells as the sample 6, a temperature gradient that has formed in the self-supporting membrane 2 owing to thermodynamic processes taking place in the biological cells as the sample 6 and an associated release of heat.

[0073] For this purpose, starting from the outer edge of the self-supporting membrane 2, the electrical conductors of the thermocouple legs 4.1, 4.2 are led on the first surface of the self-supporting membrane 2 as far as the outer edge of the first portion of the first surface of the self-supporting membrane 2.

[0074] A plurality of first, cold connection points 4.4 and a plurality of second, hot connection points 4.5 are formed in alternation along the thermopile in the thermopile on the thermocouple legs 4.1, 4.2. The first, cold connection points 4.4 are arranged at the outer edge of the first portion of the first surface, which runs in parallel with the outer edge of the heat-conducting layer 5. The second, hot connection points 4.5 are arranged at a distance from the outer edge of the first portion of the first surface and arranged on the substrate 1 of the support structure.

[0075] By arranging the thermocouples oriented in this manner, temperature gradients that form vertically in relation to the normal of the first surface in the self-supporting membrane 2 in the direction of the outer edge regions of the self-supporting membrane 2 can be detected efficiently by way of the further contact elements 4.3 of the thermopile by means of the electronic evaluation and control unit.

[0076] In the example shown in FIG. 1a, the p-type thermocouple legs 4.1 of the thermocouples are made of antimony and the n-type thermocouple legs 4.2 of the thermocouples are made of bismuth. The thickness of the p-type thermocouple legs 4.1, the n-type thermocouple legs 4.2 and the further layer 1.1 is 200 nm.

[0077] Recurring features are provided with the same reference numerals as in FIG. 1a in the subsequent figures.

[0078] FIG. 1b shows a schematic layered construction of the example sensor according to the invention shown in FIG. 1a. Specifically, FIG. 1b is a cross section along the section line A-B shown in FIG. 1a.

[0079] A further outer layer 1.1 of the support structure, which is formed of silicon nitride, is arranged on a surface of the substrate 1 pointing away from the self-supporting membrane 2. The biological cells as the sample 6 are arranged in a plurality of liquid droplets as an encapsulation on the second surface of the self-supporting membrane 2 pointing away from the heating element 3.

[0080] The configuration shown in FIG. 1c differs merely in that a reservoir 11 in the form of a chamber in which the sample 6 is received is arranged around the sample 6 on the side of the membrane 2 on which the particular biological sample 6 is also arranged.

[0081] FIG. 2a shows an example sensor according to the invention as shown in FIGS. 1a and 1b, the sensor additionally having a housing 7 formed of copper. The housing 7 is formed having a plurality of pillars as supporting structures 7.1 for receiving or securing the support structure, and having an outer frame 7.2. Both the supporting structures 7.1 and the outer frame 7.2 are formed of copper.

[0082] The construction shown in FIG. 2b differs from that shown in FIG. 2a in that vacuum conditions can be maintained at least in the region arranged around the sample 6. For this purpose, a line having a supply 9 and a drain 10 is led through the housing 7, by which line a microfluid can be conducted into and through the housing 7.

[0083] The pillars as the supporting structures 7.1 are connected to the outer frame 7.2 on a first side facing away from the support structure, and are connected to the self-supporting membrane 2 in the region of the outer edge regions of the first surface on a side facing the support structure. In this case, the substrate 1 and the further outer layer 1.1 are arranged on a side of the self-supporting membrane 2 pointing away from the supporting structures 7.1.

[0084] Electrical contacts 8 are each guided from the electrical contact elements 3.1 of the heating element 3 and the further electrical contact elements 4.3 of the thermopile, through the outer frame 7.2 of the housing 7, into a region outside the housing 7, where they are electrically connected to the electronic evaluation and control unit. In this case, the transfer point is preferably on the solid copper block, so as to prevent any discharge of heat.

[0085] FIG. 2a also shows the electrodes 12 for the biosensor.

[0086] FIG. 3 shows how two sensors, which may be formed in accordance with the above-described examples and arranged jointly on one substrate 1, can be combined with one another. In this regard, at least two thermopiles, which are formed having thermocouple legs 4.1, 4.2 and an electrical contact element 4.3, of the two sensors are electrically wired in series, as a result of which the two sensors can be operated in the manner explained in the general part of the description.

[0087] A method for detecting thermodynamic parameters of the biological cells as the sample 6 using a sensor as shown in FIGS. 1a, 1b and 2 comprises at least a first and a second step.

[0088] In the first step, a calibration is carried out by means of the heating element 3, in which calibration the electrical voltage applied at the ends of the thermopile is detected as a function of the heat output of the heating element 3. In the process, the electronic evaluation and control unit is electrically connected to the heating element 3 and the thermopile by means of the electrical contacts 8, the electrical contact elements 3.1 and the further electrical contact elements 4.3. In particular, the electronic evaluation and control unit also comprises a controller, by which the heat output of the heating element 3 is varied during the first step. The biological cells as the sample 6 are not arranged in the housing 7 during the first step.

[0089] After the calibration, the biological cells as the sample 6 are arranged in the liquid droplets as the encapsulation on a second surface, opposite the first portion of the first surface, of the self-supporting membrane 2, in particular so as to be opposite the electrical conducting track of the heating element 3.

[0090] In the second step, on the basis of the calibration carried out in the first step, temperature gradients that have formed in the self-supporting membrane 2 owing to metabolic processes taking place in the biological cells as the sample 6 and an associated release of heat are detected. During the second step, no control is carried out, nor is the sample 6 heated by means of the heating element 3. The heat output of the heating element 3 is 0 W during the second step.

[0091] During the first and the second step, the housing 7 is arranged in a thermostatic chamber such that both the housing 7, having the outer frame 7.2 and the supporting structures 7.1, and the substrate 1 of the support structure are kept constantly at one and the same temperature To during the first and the second step of the above-described method.

[0092] Using the above-described sensor and method, temperature gradients in the millikelvin range can be reliably and accurately determined while a thermal output of the sample is in the range from microwatts to a few nanowatts. In the process, the sensor can achieve a sensitivity of 100 V/W +25 V/W.

[0093] Features of the various embodiments disclosed solely in the embodiment examples can be combined with one another and claimed separately.

List of Reference Numerals

[0094] 1 Substrate [0095] 1.1 Layer [0096] 2 Membrane [0097] 3 Heating element [0098] 3.1 Electrical contact element [0099] 4.1 Thermocouple leg [0100] 4.2 Thermocouple leg [0101] 4.3 Electrical contact element [0102] 4.4 First connection point (cold) [0103] 4.5 Second connection point (hot) [0104] 5 Heat-conducting layer [0105] 6 Sample [0106] 7 Housing [0107] 7.1 Thermally conductive supporting or retaining structure [0108] 7.2 Frame [0109] 8 Electrical contact [0110] 9 Supply [0111] 10 Drain [0112] 11 Reservoir [0113] 12 Electrodes