CN117813484A

CN117813484A - Sensor, sensor system and method for detecting thermodynamic parameters of a sample, and use of a sensor or sensor system

Info

Publication number: CN117813484A
Application number: CN202280055581.1A
Authority: CN
Inventors: F·林赛斯; 文森特·林赛斯; F·沃尔克莱恩
Original assignee: Linseis Mebgerate GmbH
Current assignee: Linseis Mebgerate GmbH
Priority date: 2021-06-18
Filing date: 2022-06-16
Publication date: 2024-04-02

Abstract

The sensor comprises a support structure (1,1.1,2) having at least one substrate (1) and at least one self-supporting membrane (2), the edge region of the membrane (2) being arranged on the substrate (1). The at least one heating element (3) is formed by at least one conductive track on a first portion of the first surface of the film (2). The at least one thermopile (4.1, 4.2, 4.3) is formed by a plurality of thermocouples connected in series, and the electrically conductive track of the heating element (3) and/or the at least one heating element (3) at least partially encloses the membrane (2) on the first surface. The electronic evaluation and control unit is electrically connected to the thermopile (4.1, 4.2, 4.3) and is configured to detect at least one temperature gradient formed in the membrane (2) due to a thermodynamic process occurring in the sample (6) and a heat release or heat absorption associated with the thermodynamic process, based on a calibration by means of the heating element (3) and on the sample (6) on the membrane (2).

Description

Sensor, sensor system and method for detecting thermodynamic parameters of a sample, and use of a sensor or sensor system

Technical Field

The present invention relates to a sensor, a sensor system and a method for detecting a thermodynamic parameter of a sample and to the use of a sensor or a sensor system.

Background

When determining thermodynamic parameters, in particular of small samples, a critical problem is that there is only a small amount of heat release or heat absorption in such samples, as compared to the thermal noise caused by the measuring device. Therefore, when measuring very small amounts of heat, stringent requirements are required in terms of insulation of the sample. Furthermore, disturbances in the measurement process, which may be caused, for example, by thermodynamic processes occurring in the vicinity of the sample or by uncontrolled influences of the measurement device on the sample itself, may lead to impaired measurement results.

Therefore, high sensitivity thermal sensors, such as nano calorimeters, have a complex structure and are only envisaged for specific applications. Furthermore, nano calorimeters generally only work effectively in a narrow spectral range, thus requiring complex calibration in this regard.

Disclosure of Invention

It is therefore an object of the present invention to propose a sensor, a sensor system and a method for determining thermodynamic parameters with a high degree of measurement accuracy but only with low complexity.

This object is achieved by a sensor according to claim 1, a sensor system according to claim 11, a method according to claim 15 and a use of a sensor or a sensor system according to claim 18. Advantageous embodiments are described in the dependent claims.

The present invention relates to a sensor for detecting a thermodynamic parameter of a sample. The sensor includes a support structure, at least one heating element, at least one thermopile, and at least one electronic evaluation and control unit.

The support structure includes at least one substrate and at least one self-supporting film. The outer edge region of the at least one self-supporting film is disposed on the at least one substrate.

The at least one heating element is formed with at least one conductive track disposed on a first portion of the first surface of the self-supporting film.

The at least one thermopile is formed with a plurality of thermocouples electrically interconnected in series and at least partially surrounding the at least one conductive track and/or the at least one heating element on the first surface of the self-supporting film.

The at least one electronic evaluation and control unit is electrically connected to the thermopile and configured for detecting at least one temperature gradient formed in the self-supporting film due to a thermodynamic process occurring in the sample and a related heat release or heat absorption based on a calibration by means of the at least one heating element and a sample arranged at or on the self-supporting film.

By arranging the at least one heating element, the at least one thermopile and/or the sample at least partially at or on the self-supporting membrane, the sensitive components of the measuring device and the sample are thermally insulated in a particularly efficient manner. In this case, the thermal conductivity of the self-supporting film is preferably smaller than the thermal conductivity of the substrate. Particularly preferably, the substrate forms together with the self-supporting film a support structure in the form of a nanobridge or microbridge.

The proposed sensor also allows to calibrate the at least one thermopile by means of the at least one heating element in a particularly simple and accurate manner. To this end, a calibration curve, which may indicate a functional relationship between the heat output of the at least one heating element and the voltage applied at the end of the at least one thermopile, may be detected, for example by means of the at least one electronic evaluation and control unit, when the sample is not present. To this end, the at least one conductive track of the at least one heating element may also be formed or arranged in a meandering shape in the first portion of the first surface of the self-supporting film.

Preferably, the electronic evaluation and control unit and the at least one thermopile are configured for detecting at least one temperature gradient forming a vector orthogonal to a normal of the first surface of the self-supporting film. Due to the low thickness of the self-supporting film of at most 1 μm, the component of the at least one temperature gradient extending parallel to the normal of the first surface can be ignored.

During the detection of the at least one temperature gradient by means of the electronic evaluation and control unit, the sample may advantageously be arranged at or on a second surface of the self-supporting film opposite to the first portion of the first surface. For example, the second surface may comprise a second portion, which may be arranged to correspond to the first portion of the first surface. Particularly preferably, the sample is arranged at or on the second portion of the second surface of the self-supporting film. Particularly preferably, the sample is arranged on the second surface of the self-supporting film facing away from the at least one conductive track of the at least one heating element so as to be directly opposite the at least one conductive track.

Preferably, the thermally conductive layer is arranged on the at least one electrically conductive track of the at least one heating element or on a layer in which the at least one electrically conductive track and/or the at least one heating element is integrated. Particularly preferably, a surface of the thermally conductive layer facing the at least one electrically conductive track and/or the at least one heating element is arranged to correspond to the first portion of the first surface. In particular, the outer edge of the thermally conductive layer may extend parallel to the outer edge of the first portion of the first surface of the self-supporting film.

A reservoir may be formed around the area where the particular sample is arranged, with which reservoir the liquid sample may remain in shape and in the sensitive area, and also a sufficiently large volume of sample may be kept available.

For example, the layer in which the at least one electrically conductive track and/or the at least one heating element are integrated may be formed with an electrically passivated or insulated portion, which may be arranged between the at least one heating element and the thermally conductive layer. The electrical passivation may be formed of, for example, silicon dioxide.

Preferably, the thermally conductive layer has a thermal conductivity of at least 200W/(m K). For example, the thermally conductive layer may be formed of gold or made of gold. Advantageously, a particularly uniform temperature distribution can be ensured in the first portion of the first surface of the self-supporting film due to the thermally conductive layer. In addition, the heat emission loss or the undesired heat radiation loss in and around the region can be reduced, thereby further improving the sensitivity of the sensor.

Preferably, the electrical conductor of the thermocouple is guided on the first surface of the self-supporting film, starting from an outer edge of the self-supporting film, to an outer edge of the first portion of the first surface of the self-supporting film.

The first and second plurality of connection points of the thermocouple may be alternately formed along the thermopile. The first connection point and the second connection point may each electrically interconnect two electrical conductors formed of different materials. Preferably, the first connection point is arranged on an outer edge of the first portion of the first surface. The second connection point may be arranged at a distance from an outer edge of the first portion of the first surface. Particularly preferably, the second connection point is arranged on the substrate of the support structure or on an outer edge region of the self-supporting film.

Preferably, the thermopile at least partially surrounds the at least one conductive track, the at least one heating element or the first portion of the first surface in a meandering manner. To this end, the thermopile may be formed with at least ten thermocouples interconnected in series, preferably with at least twenty thermocouples interconnected in series, particularly preferably with at least forty or even more thermocouples interconnected in series.

Thus, by means of the temperature difference detected by the at least one thermopile, for example the magnitude of the at least one temperature gradient, may correspond to a temperature difference between the temperature of the self-supporting film at or on the first portion of the first surface of the self-supporting film and the temperature of the substrate or the temperature of the self-supporting film at or on an edge region of the first surface of the self-supporting film.

Preferably, the at least one heating element comprises at least two electrical contact elements, which may be electrically connected to the outer ends of the conductive tracks of the at least one heating element. The at least two electrical contact elements of the at least one heating element may be arranged on the substrate or on an outer edge region of the self-supporting film.

Additionally or alternatively, the at least one thermopile may further comprise at least two further electrical contact elements, which may each be electrically connected to an outer end of the at least one thermopile. The at least two further electrical contact elements may be arranged on the substrate or on an outer edge region of the self-supporting film.

For calibration purposes, for example, the at least one electronic evaluation and control unit may be electrically connected to the at least one heating element by means of the at least two electrical contact elements of the at least one heating element and/or to the at least one thermopile by means of the at least two further electrical contact elements of the at least one thermopile.

Preferably, the sensor comprises a housing in order to obtain the highest possible signal stability and further reduce thermal noise. The support structure, the at least one heating element, and the at least one thermopile may be disposed in the housing with a sample. It is particularly advantageous if the housing is arranged in a thermostatic chamber, by means of which the surroundings and the housing itself can be kept at a constant predetermined temperature. In this case, the housing may advantageously be formed of an electrically insulating and thermally conductive material, such as copper.

Furthermore, the housing may comprise a highly thermally conductive support or holding structure, which may likewise be formed, for example, from copper. The support or holding structure may be arranged inside the housing and configured for receiving, supporting or holding the support structure with the self-supporting membrane, the at least one heating element and the at least one thermopile such that the self-supporting membrane may be arranged at a distance from an outer edge of a frame of the housing or an inner surface of an outer frame of the housing. To this end, the support or retaining structures may for example be configured in the form of support columns or retaining ridges, and each support column or retaining ridge is connected at one end to the outer frame of the housing and at the other end to the support structure. The housing may also be sealed from the surrounding environment, at least during each measurement. Thus, the determination may be made while maintaining vacuum conditions, at least near vacuum, so that the sensor can be operated in a packaged manner in vacuum. In this process, the entire sensor may be placed under vacuum. Only the "sample side" of the sensor may be provided with microfluidics in order to be able to deposit a specific sample on the membrane of the sensor. By operating the sensor in vacuum, high sensitivity (about 6 times) can be obtained again, since heat loss and thermal noise can be significantly reduced. In this case, the vacuum condition may be dominant on both sides of the membrane. Only the area of the sample carrying surface may be outside of the conditions. An encapsulated microfluidic system can thus be presented.

The atmosphere over the sensitive area on which the sample may be arranged may be changed in a defined manner. If the sensor is operated in open air, the evaporation enthalpy of the aqueous solution, possibly containing the sample therein, will mask the actual measurement signal a number of times. Thus, the atmosphere in the actual measurement chamber around a particular sample should be controlled. In the simplest case, the sample volume may be sealed and the user may wait until an equilibrium vapor pressure is established. The evaporation of the liquid can thus be stopped.

Atmospheric conditions, in particular the pressure in particular in the region where the particular sample is arranged, can also be set in a defined manner. In addition, the atmospheric pressure, which is also dominant in the area around the sensor and the housing, can be maintained on both sides of the membrane.

Preferably, only the outer edge region of the self-supporting film or the substrate of the support structure is connected to the support or holding structure. Particularly preferably, the support structure is connected to the housing or to an outer frame of the housing by means of the support or holding structure. In order to ensure as good a thermal contact as possible between the housing and the support or holding structure, the support structure may be connected to the support or holding mechanism by means of a thermal paste, which may be arranged between the support structure and the support or holding structure.

The housing may further comprise electrical contacts that are guided from the support structure through the outer frame of the housing into a region located outside the housing. In this case, the electrical contacts may each electrically connect the at least one heating element and/or the electrical contact element of the at least one thermopile to the at least one electronic evaluation and control unit.

In this case, the sample may be arranged at or on a second surface of the self-supporting film facing away from the support and holding structure. Here, the sensitivity of the sensor may also depend on the distance between the sample or the self-supporting membrane and the inner surface of the housing or the outer frame of the housing. It may therefore prove to be advantageous if the distance between the inner surface of the housing or the outer frame of the housing and the self-supporting membrane or the sample is at least 2.5mm, preferably at least 5mm.

In this case, the first surface of the self-supporting film may have a size of at least 20mm ² Preferably at least 30mm ² . The first portion of the first surface may be at least 10mm in size ² Preferably at least 15mm ² . Preferably, the thickness of the self-supporting film is at most 1000 μm, preferably less than 500nm, particularly preferably less than 350nm. By selecting a large first surface of the membrane with a low membrane thickness at the same time, the signal-to-noise ratio and thus the measurement accuracy of the sensor can be improved in particular. The current size of reservoirs for holding samples (active surfaces) is about 1mm by 0.3mm, or 5mm by 0.3mm in large reservoirs. The active area should be selected in a range between 0.1mm by 0.3mm and 5mm by 0.3mm. The thickness may be selected in a range between 0.3mm and 0.8 mm.

The thermal, chemical and mechanical properties of the sensor may advantageously be affected by suitable material selection or material combination and the geometry of the various components. For example, the substrate may be formed of silicon. The self-supporting film may be formed of a material having a lower thermal conductivity than the substrate and/or the thermally conductive layer. For example, the self-supporting film may be formed of silicon nitride. Additionally or alternatively, the substrate may comprise a further layer, which may form an outer surface of the substrate on a side or surface facing away from the self-supporting film. The further layer may also be formed of a material that is thermally and/or electrically insulating with respect to the substrate, for example, formed of silicon nitride.

It is also advantageous if the materials of the thermocouple legs of the thermocouple each have a different seebeck coefficient, while ensuring good compatibility or adhesion of the two thermocouple legs with at least one material of the self-supporting film. For example, at least a first thermocouple leg of the thermocouple of the at least one thermopile, preferably a p-type thermocouple leg, may be formed of or made of antimony. At least a second thermocouple leg, preferably an n-type thermocouple leg, of the thermocouple of the at least one thermopile may be formed of bismuth or made of bismuth.

The invention also relates to a sensor system.

In this regard, the biosensor may be disposed in a surface region on which the sample is disposed. The biosensor may be formed by at least two electrodes arranged at a distance from each other and connected to a voltage source with a preferably constant voltage and the at least one electronic evaluation and control unit. The electrodes are connected to the at least one electronic evaluation and control unit. The current between the at least two electrodes is measured by the electronic evaluation and control unit and the measured variable as the metabolic characteristic of the sample is detected and evaluated by the at least one electronic evaluation and control unit. The measured variable may preferably be pH, which may be characteristic of a metabolic change of the biological sample.

Like the conductive tracks leading to the electronic evaluation and control unit, the electrodes may also be formed on the surface of the self-supporting film by means of thin-film or thick-film technology.

In this case, the electrodes should be arranged directly at the specific sample. Preferably, the electrodes are made of titanium, but may also be made of platinum, gold or other suitable metals.

The electrodes are electrically isolated from the substrate, which may typically be formed of silicon. This can be achieved, for example, by means of a dielectric passivation layer or by locally modifying the silicon so that it is practically non-conductive.

The electrodes may be applied by means of thin or thick film techniques.

Independently or in addition thereto, the sensor system may also be formed with at least one measuring instrument connected to or arranged in the housing. The measuring instrument may then be used to determine the proportion of oxygen and/or carbon dioxide contained in the atmosphere within the housing. Instead of the measuring device, at least one suitable sensor may also be arranged in the housing. In this case, the housing should be sealed off from the surrounding atmosphere in an airtight manner, or can be sealed off from it. Depending on the metabolism that takes place in the biological sample at this time, the proportion of oxygen decreases while the proportion of carbon dioxide increases and vice versa, so that the conclusion of the current state of a particular sample can also be drawn.

The sensor system may also be formed with at least two sensors as described above, arranged in a shared housing. In this case, a first one of the at least two sensors may be used to detect a thermodynamic parameter of the sample under investigation, and a second one of the at least two sensors may be used as a reference sensor.

Preferably, the reference sensor may also be used to determine and/or compensate for undesired temperature gradients, which may be formed even in the absence of a sample due to, for example, non-controllable heat sources or production induced asymmetries in the first sensor. To this end, the at least two sensors may further comprise a common support structure and/or a common substrate. The support structure and/or the base plate of each sensor of the sensor system may also be integrally joined together or frictionally interconnected in order to be able to exchange heat or compensate for undesired temperature gradients at least temporarily, for example by means of at least one heating element of the reference sensor. To this end, the sensor system may comprise, in addition to the first sensor, a plurality of second sensors formed as reference sensors. Preferably, the sensor system is formed with at least four sensors as described above, which may be arranged in one housing.

Advantageously, two sensors may be arranged directly adjacent to each other on a wafer as substrate, resulting in a virtually integrated dual sensor. In this process, the thermocouples of the two sensors may be directly interconnected. To this end, the conductive tracks on the sensor forming the thermopile may already be directly interconnected in an electrically conductive manner. Alternatively, however, this may also be implemented electronically outside the sensor using a correspondingly configured electronic evaluation unit connected to the two sensors.

In the case of differential evaluation, the heat flow between the two reservoirs of the two sensors can be measured. In this way, the temperature difference between the two measurement locations on the two sensors can be measured.

The invention also relates to a method for detecting a thermodynamic parameter of a sample using the above-mentioned sensor or sensor system.

In the method, in a first step, a calibration is performed by means of the at least one heating element, in which calibration the voltage applied at the end of the at least one thermopile is detected from the heat output of the at least one heating element.

In a second step, at least one temperature gradient formed in the self-supporting film due to thermodynamic processes occurring in the sample and associated heat release or heat absorption is detected based on the calibration performed in the first step.

In this process, the sample may be arranged in the housing and/or at or on the first surface of the self-supporting film in a time sequence before the second step and/or before the first step. During the second step, the heat output of the at least one heating element may be kept constant and/or reduced to zero, such that the sample cannot be heated by means of the at least one heating element during the second step. In particular, the at least one heating element may be configured in particular for calibrating the sensor or the at least one thermopile.

Preferably, the temperature of the substrate of the support structure and/or the outer edge region of the self-supporting film is kept constant during the first step and/or the second step. This may be achieved, for example, by arranging the housing together with the support structure, the at least one thermopile and the at least one heating element in a thermostatic chamber and by ensuring good heat conduction between the housing, the support or retaining structure and the substrate of the support structure or the outer edge region of the self-supporting film. Alternatively or additionally, the housing itself may also be formed as a thermostatic chamber.

In particular, the temperature of the housing, the temperature of the substrate of the support structure and/or the temperature of the outer edge region of the self-supporting film may remain the same during the first step and/or the second step. Thus, a particularly accurate detection of the temperature gradient formed from the central region of the self-supporting film (e.g. from the first portion of the first surface) may be achieved.

At least in the second step, the sample may be arranged in an encapsulation. The encapsulation may be formed by a membrane, a liquid, and/or one or more droplets at least partially surrounding the sample. Preferably, the support structure is arranged at or on the support or holding structure of the housing such that the sample may be placed or arranged on the second surface of the self-supporting film together with the encapsulation.

In performing the method, a temperature gradient may be obtained by at least one pulse. In the pulse, the temperature in the sample region may be increased by a predetermined temperature over a predetermined period of time; preferably, the temperature may be raised in the range between 0.05K and 5K within 5 seconds. Next, a temperature drop in the sample region is detected in a time-resolved manner, and the respective detected temperature drop curve is compared with a temperature drop curve that has been detected in a time-resolved manner in advance on a similar sample with a known metabolic function by means of the at least one electronic evaluation and control unit. In this way, the conclusion can also be drawn on the current metabolic function of the biological sample. The time-resolved detection of the pulse-like temperature increase and the temperature drop profile and the comparison with the previously detected temperature drop profile can be repeated cyclically, preferably at identical intervals but also at different intervals.

In this case, the heating is carried out periodically, the current flowing through the heating element at a current in the range of 50 μa and 5mA corresponding to a function I (t) =i at a frequency ω ₀ cos (ωt). In this case, the voltage drop across the heating element is detected.

The temperature oscillation of the heating element can be according to the equationCalculated from the third harmonic component of the voltage, this can typically be done using known 3-omega methods.

Information about the state of the sample, such as ingrowth behavior, growth, specific cell counts, etc., can then be obtained from the characteristic temperature response.

The sensor according to the invention, the sensor system according to the invention and/or the method according to the invention can be used for detecting and determining thermodynamic parameters of different samples, for example medical or biological samples. The thermodynamic parameter may be, for example, temperature, heat of condensation or heat capacity. In this case, the chemical reactions occurring in the sample can be determined more fully by means of the sensor. The sensor according to the invention, the sensor system according to the invention and/or the method according to the invention can be used to determine thermodynamic parameters of metabolic processes in biological cells and/or condensation processes on surfaces or in films.

The invention will be explained in more detail based on the following embodiments.

Drawings

In the figure:

figure 1a is a schematic diagram of the front face of an exemplary sensor according to the present invention,

figure 1b is a cross-sectional view of an exemplary sensor according to the invention shown in figure 1,

fig. 1c is a cross-sectional view of an example sensor according to the invention shown in fig. 1, the example sensor including an additional reservoir,

fig. 2a shows an example sensor according to the invention, which example sensor comprises a housing,

FIG. 2b shows an example sensor according to the present invention, including a housing in which a vacuum condition may be maintained, an

Fig. 3 shows two interconnected sensors for improved error compensation.

Detailed Description

Fig. 1a shows an example sensor for detecting a thermodynamic parameter of a biological cell as sample 6.

The sensor comprises a support structure formed with a substrate 1 and a self-supporting membrane 2. Furthermore, the support structure may be formed with an outer layer 1.1. The substrate 1 is formed of silicon, and the thickness of the substrate 1 is about 300 μm. The self-supporting film 2 is formed of silicon nitride and has a thickness of 300 nm. The self-supporting film was square with 36mm ² Is a surface area of the substrate. The substrate 1 has a cavity which is closed on one side by a self-supporting film 2. In this case, the outer edge region of the self-supporting film 2 is arranged on the substrate 1 such that the supporting structure forms a microbridge. For this purpose, the base plate 1 has a frame-like shape. This is the location where the new reservoir is now located, which assumes the function of the sample holder.

The sensor further comprises a heating element 3. The heating element 3 has at least one conductive track formed of antimony and arranged in a meandering manner on a central region that is a first portion of the first surface of the self-supporting film 2. Furthermore, the heating element 3 has an electrical contact element 3.1, which is electrically connected to the electrically conductive track, which electrical contact element 3.1 is arranged on the substrate 1. In this case, the conductive track is arranged in a passivation layer formed of silicon dioxide.

A thermally conductive layer 5 formed of gold is arranged on the passivation layer, in which the electrically conductive tracks of the heating element 3 are integrated. The surface of the heat conducting layer 5 facing the heating element 3 is arranged to correspond to a first portion of the first surface of the self-supporting film 2. In particular, the heat-conducting layer 5 has a thickness of 300nm and 16mm ² Is a square surface area of (c). Thus, the first portion of the first surface of the self-supporting film is square and formed to 16mm ² Is a size of (c) a.

The sensor also includes a thermopile. The thermopile is formed with a plurality of thermocouples electrically interconnected in series and each having in turn two different thermocouple legs 4.1,4.2 and surrounding the conductive track of the heating element 3 on the first surface of the self-supporting film 2 in a meandering manner. Further electrical contact elements 4.3 are arranged on both outer ends of the thermopile formed with thermocouple legs 4.1,4.2, respectively, and are electrically connected to thermocouples, which in turn are formed with thermocouple legs 4.1 and 4.2.

The sensor further comprises an electronic evaluation and control unit (not shown) electrically connected to the thermopile and configured for detecting a temperature gradient formed in the self-supporting film 2 due to a thermodynamic process occurring in the biological cells as sample 6 and a related release of heat, based on a calibration performed by means of the heating element 3 and based on the biological cells as sample 6.

For this purpose, the electrical conductors of the thermocouple legs 4.1,4.2 are guided on the first surface of the self-supporting film to the outer edge of the first portion of the first surface of the self-supporting film 2, starting from the outer edge of the self-supporting film 2.

A plurality of first cold junction points 4.4 and a plurality of second hot junction points 4.5 are alternately formed on the thermocouple legs 4.1,4.2 along the thermocouples in the thermopile. The first cold junction 4.4 is arranged at an outer edge of the first portion of the first surface, which outer edge extends parallel to the outer edge of the heat conducting layer 5. The second thermal connection point 4.5 is arranged at a distance from the outer edge of the first portion of the first surface and on the substrate 1 of the support structure.

By arranging the thermocouples oriented in this way, the temperature gradient formed perpendicularly in the direction of the outer edge region of the self-supporting film 2 with respect to the normal of the first surface in the self-supporting film 2 can be effectively detected by means of the further contact elements 4.3 of the thermopile by means of the electronic evaluation and control unit.

In the example shown in fig. 1a, the p-type thermocouple leg 4.1 of the thermocouple is made of antimony and the n-type thermocouple leg 4.2 of the thermocouple is made of bismuth. The thickness of the p-type thermocouple leg 4.1, the n-type thermocouple leg 4.2 and the further layer 1.1 is 200nm.

In the following figures, the repeated features have the same reference numerals as in fig. 1 a.

Fig. 1b shows a schematic layered structure of an exemplary sensor according to the invention shown in fig. 1 a. Specifically, FIG. 1B is a section along section line A-B shown in FIG. 1 a.

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

The configuration shown in fig. 1c differs only in that on the side of the self-supporting film 2 where the specific biological sample 6 is also arranged, a reservoir 11 in the form of a chamber for receiving the sample 6 is arranged around the sample 6.

Fig. 2a shows an exemplary sensor according to the invention as shown in fig. 1a and 1b, which additionally has a housing 7 formed from copper. The housing 7 is formed with a plurality of struts as a support structure 7.1 for receiving or fixing the support structure and with an outer frame 7.2. Both the support structure 7.1 and the outer frame 7.2 are formed of copper.

The structure shown in fig. 2b differs from the structure shown in fig. 2a in that vacuum conditions can be maintained at least in the area arranged around the sample 6. For this purpose, a line with a supply 9 and a discharge 10 is led through the housing 7, through which a microfluidic can be led into the housing 7 and through the housing 7.

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

The electrical contacts 8 are each led from the electrical contact element 3.1 of the heating element 3 and the further electrical contact element 4.3 of the thermopile through the outer frame 7.2 of the housing 7 into a region outside the housing 7, in which region the electrical contacts 8 are electrically connected to the electronic evaluation and control unit. In this case, the transfer point is preferably on a solid copper block to prevent any heat emission.

Fig. 2a also shows the electrodes 12 of the biosensor.

Fig. 3 shows how two sensors can be combined with each other, which can be formed according to the above-described example and arranged together on one substrate 1. In this respect, at least two thermopiles of the two sensors, which are formed with thermocouple legs 4.1,4.2 and electrical contact elements 4.3, are electrically wired in series, so that the two sensors can operate in the manner explained in the summary of the invention section of the description.

The method for detecting a thermodynamic parameter of a biological cell as sample 6 using the sensor as shown in fig. 1a, 1b and 2 comprises at least a first step and a second step.

In a first step, a calibration is performed by means of the heating element 3, in which calibration the voltage applied to the ends of the thermopile is detected from 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 element 3.1 and the further electrical contact element 4.3. In particular, the electronic evaluation and control unit also comprises a controller by means of which the heat output of the heating element 3 is changed during the first step. In the first step, the biological cells as the sample 6 are not arranged in the housing 7.

After calibration, the biological cells as sample 6 are arranged in the droplet as an encapsulation on a second surface of the self-supporting film 2 opposite to the first portion of the first surface, in particular so as to be opposite to the conductive tracks of the heating element 3.

In a second step, the temperature gradient formed in the self-supporting film 2 due to metabolic processes occurring in biological cells as sample 6 and the associated heat release is detected based on the calibration performed in the first step. In the second step, no control is performed and the sample 6 is heated without the aid of the heating element 3. In the second step, the heat output of the heating element 3 is 0W.

In the first and second steps, the housing 7 is arranged in a thermostatic chamber such that the housing 7 with the outer frame 7.2 and the support structure 7.1, and the substrate 1 of the support structure, are constantly kept at the same temperature T in the first and second steps of the above-described method ₀ 。

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

Features of the various embodiments disclosed separately in the embodiment examples may be combined with each other and claimed separately.

List of reference numerals

1 substrate

1.1 layer

2 self-supporting film

3 heating element

3.1 electric contact element

4.1 thermocouple landing leg

4.2 thermocouple landing leg

4.3 electrical contact elements

4.4 first connection point (Cold)

4.5 second connection point (Heat)

5 heat conductive layer

6 sample

7 shell body

7.1 thermally conductive support or retaining Structure

7.2 frame

8 electrical contacts

9 supply part

10 discharge part

11 storage device

12 electrode

Claims

1. A sensor for detecting a thermodynamic parameter of a sample (6), comprising:

a support structure (1,1.1,2) having at least one substrate (1) and at least one self-supporting film (2), wherein an edge region of the at least one self-supporting film (2) is arranged on the at least one substrate (1),

at least one heating element (3) formed with at least one conductive track arranged on a first portion of the first surface of the self-supporting film (2),

at least one thermopile (4.1, 4.2, 4.3) formed with a plurality of thermocouples (4.1, 4.2) electrically interconnected in series and at least partially surrounding the at least one electrically conductive track of the at least one heating element (3) and/or the at least one heating element (3) on the first surface of the self-supporting film,

at least one electronic evaluation and control unit electrically connected to the thermopile (4.1, 4.2, 4.3) and configured for detecting at least one temperature gradient formed in the self-supporting film (2) due to a thermodynamic process occurring in the sample (6) and a related heat release or heat absorption, based on a calibration by means of the at least one heating element (3) and a sample (6) arranged at or on the self-supporting film (2).

2. Sensor according to the preceding claim, characterized in that, during the detection of the at least one temperature gradient by means of the electronic evaluation and control unit, the sample (6) is arranged at or on a second surface of the self-supporting film (2) opposite the first portion of the first surface and/or on a second surface of the self-supporting film (2) facing away from the at least one conductive track of the at least one heating element (3) so as to be directly opposite the at least one conductive track of the at least one heating element (3).

3. The sensor according to any of the preceding claims, characterized in that the reservoir (9) is arranged around the area where the specific sample (6) is arranged.

4. Sensor according to any one of the preceding claims, characterized in that a thermally conductive layer (5) is arranged on the at least one electrically conductive track of the at least one heating element (3) or on a layer in which the at least one electrically conductive track of the at least one heating element (3) and/or the at least one heating element (3) is integrated, a surface of the thermally conductive layer (5) facing the at least one electrically conductive track of the at least one heating element (3) and/or the at least one heating element (3) being arranged to correspond to the first part of the first surface of the self-supporting film (2), and/or the thermally conductive layer (5) is formed of metal, in particular gold.

5. The sensor according to any of the preceding claims, characterized in that, starting from the outer edge of the self-supporting film (2), the electrical conductors of the thermocouple (4.1, 4.2) are guided over the first surface of the self-supporting film (2) to the outer edge of the first portion of the first surface of the self-supporting film (2).

6. The sensor according to any of the preceding claims, characterized in that a plurality of first connection points (4.4) and a plurality of second connection points (4.5) of the thermocouple (4.1, 4.2) are alternately formed along the at least one thermopile (4.1, 4.2, 4.3), the first connection points (4.4) and the second connection points (4.5) each electrically interconnecting two electrical conductors (4.1, 4.2) formed of different materials, the first connection points (4.4) being arranged on an outer edge of the first portion of the first surface and/or the second connection points (4.5) being arranged at a distance from an outer edge of the first portion of the first surface and/or on the substrate (1) of the support structure (1,1.1,2).

7. The sensor according to any of the preceding claims, characterized in that the at least one heating element (3) comprises at least two electrical contact elements (3.1) which are electrically connected to the outer ends of the at least one electrically conductive track of the at least one heating element (3) and/or arranged on the substrate (1), and/or the at least one thermopile (4, 4.1, 4.2) comprises at least two further electrical contact elements (4.3) which are each electrically connected to the outer ends of the thermopiles (4.1, 4.2, 4.3) and/or arranged on the substrate (1).

8. The sensor according to any of the preceding claims, characterized in that the support structure (1,1.1,2), the at least one heating element (3) and the at least one thermopile (4.1, 4.2, 4.3) are arranged in a housing (7), the housing (7) is formed of copper and/or the housing (7) comprises a thermally conductive support or holding structure (7.1) and/or the housing (7) is connected to the support structure (1,1.1,2) by means of the thermally conductive support or holding structure (7.1) and/or by means of a thermal paste, and/or electrical contacts (8) are guided from the support structure (1,1.1,2) through an outer frame (7.2) of the housing (7) into an area located outside the housing (7), and/or the housing (7) is arranged in a constant temperature chamber.

9. The sensor according to any of the preceding claims, characterized in that the first surface of the self-supporting film (2) has a size of at least 10mm ² And/or the thickness of the self-supporting film (2) is at most 1 μm, and/or the distance between the second surface of the self-supporting film (2) facing away from the at least one heating element (3) and the housing (7) and/or the outer frame (7.2) of the housing (7) is at least 5mm.

10. Sensor according to any of the preceding claims, characterized in that the substrate (1) is formed of silicon and/or the self-supporting film (2) is formed of silicon nitride and/or the p-type thermocouple leg (4.1) of the thermocouple (4.1, 4.2) is formed of antimony and/or the n-type thermocouple leg (4.2) of the thermocouple (4.1, 4.2) is formed of bismuth.

11. Sensor system according to any one of claims 1 to 10, wherein in the surface area on which the sample (6) is arranged, a biosensor is arranged, which is formed by at least two electrodes (12), which at least two electrodes (12) are arranged at a distance from each other and are connected to a voltage source with preferably constant voltage and to the at least one electronic evaluation and control unit, and the current flow between the at least two electrodes (12) is measured by the at least one electronic evaluation and control unit, and

a measured variable being a metabolic characteristic of the sample (6) can be detected and evaluated by the at least one electronic evaluation and control unit.

12. Sensor system according to any of claims 1 to 10, characterized in that at least one measuring instrument is connected to the housing (7) or arranged in the housing (7) and can be used to determine the proportion of oxygen and/or carbon dioxide contained in the atmosphere within the housing (7).

13. Sensor system according to any of claims 1 to 12, characterized in that at least two of the sensors are arranged in a common housing (7).

14. Sensor system according to the preceding claim, characterized in that the thermopiles (4.1, 4.2, 4.3) of the two sensors are electrically wired in series.

15. Method for detecting a thermodynamic parameter of a sample (6) using a sensor according to any one of claims 1 to 10 or a sensor system according to any one of claims 11 to 14, wherein,

in a first step, a calibration is carried out by means of the at least one heating element (3), in which calibration the voltage applied to the ends of the at least one thermopile (4.1, 4.2, 4.3) is detected from the heat output of the at least one heating element (3, 3.1), and

in a second step, at least one temperature gradient formed in the self-supporting film (2) due to a thermodynamic process occurring in the sample (6) and a related heat release or heat absorption is detected based on the calibration performed in the first step.

16. Method according to claim 15, characterized in that the sample (6) is arranged in the housing (7) and/or at or on the first surface of the self-supporting film (2) before the second step and/or before the first step in chronological order and/or the sample (6) is heated during the second step without the aid of the at least one heating element (3).

17. The method according to claim 15 or 16, characterized in that the temperature of the substrate (2) is kept constant during the first step and/or the second step.

18. Method according to any one of claims 15 to 17, characterized in that the temperature gradient is increased by a range of 0.05K to 5K, preferably within 5s, by means of at least one pulse in which the temperature in the region of the sample (6) is increased by a predetermined temperature within a predetermined period of time, and then the temperature drop in the region of the sample (6) is detected in a time-resolved manner, and that the temperature drop profile of the pulse detected in a time-resolved manner is compared with a temperature drop profile detected in a time-resolved manner beforehand on a similar sample (6) with known metabolic functions by means of the at least one electronic evaluation and control unit.

19. Method according to claim 15, 16, 17 or 18, characterized in that the sample (6) is arranged in an encapsulation at least when the second step is performed.

20. Use of a sensor according to any one of claims 1 to 10 or a sensor system according to any one of claims 11 to 14 for determining thermodynamic parameters of a metabolic process in a biological cell.