WO2009065241A1

WO2009065241A1 - Calorimeter for receiving small quantities of fluid

Info

Publication number: WO2009065241A1
Application number: PCT/CH2008/000486
Authority: WO
Inventors: Rudolf Buser; Jürg Gentsch; Cosmas Malin
Original assignee: Liconic Ag
Priority date: 2007-11-19
Filing date: 2008-11-18
Publication date: 2009-05-28

Abstract

A calorimeter for the calorimetric measurement of quantities of fluid in the nanoliter range comprises a reaction chamber (3), the temperature of which is to be measured. To this end, a thermopile (2) comprising a plurality of thermal elements disposed in a star shape is disposed beneath the reaction chamber (3). Said elements allow very precise temperature measurement, without the measuring current influencing the temperature in the reaction chamber (3). In order to improve the signal/noise behavior, the conductive tracks (5, 6) of the thermal elements are configured wider toward the outside, whereby the internal resistance thereof decreases.

Description

Calorimeter for taking small amounts of liquid

Reference to related applications

This application claims the priority of

Swiss Patent Application 1782/07, filed Oct. 19, 2007, the entire disclosure of which is hereby incorporated by reference.

background

The invention relates to a calorimeter for receiving small amounts of liquid according to the preamble of claim 1. "Small amounts of liquid" in this context amounts in the range of 200 to 1000 nanoliters to understand.

Such calorimeters are used in particular in the field of drug discovery and in the study of chemical reactions. They have a reaction chamber for receiving a substance or mixture of substances and measure, for example, the enthalpy of a reaction in the chamber. The enthalpy leads to a change in temperature, which may only be fractions of 1 itiK.

Known calorimeters of this type have a substrate on which the reaction chamber is arranged. In addition, a measuring resistor is provided as a temperature sensor. The resistance value of the measuring resistor is measured with a measuring current. From a change in the resistance value, the temperature change in the reaction chamber can be determined.

Presentation of the invention

Object of the present invention is the resolution or sensitivity of a calorimeter this Kind of improving. This object is fulfilled by the calorimeter according to claim 1.

Accordingly, a thermopile is used as the temperature sensor. The use of a thermopile as a temperature sensor has the advantage that the measurement can be carried out without having to send a measuring current through the temperature sensor. This has the advantage that heating up of the temperature sensor by the measuring flow does not occur and the associated thermal

Disturbance of the system is avoided, whereby an increase in the measurement accuracy is achieved.

Preferably, the thermopile has a plurality of first interconnects of a first material and a plurality of second interconnects of a second material. The tracks extend between inner and outer contact points. At each contact point, a first and a second conductor track are connected to each other. In order to improve the signal-to-noise ratio, the width of the first and / or the second conductor tracks may increase from the inner contact points towards the outer contact points. As a result, the available space is used optimally to achieve the lowest possible internal resistance of the thermopile.

In particular, those tracks, which consist of the material of lower conductivity, should increase towards the outside in their width more than those tracks, which consist of the material of higher conductivity. As a result, the available space is used optimally.

Advantageously, the thermopile is covered by a protective layer which protects it from the liquid in the reaction chamber. In a particularly easy to manufacture variant, the protective layer of a photoresist. Furthermore, an evaporation chamber, which can be filled with a reference liquid, can be arranged around the reaction chamber. The evaporation of reference liquid increases the saturation of the surrounding gas and thus reduces the evaporation of liquid from the reaction chamber interfering with the measurement.

The calorimeter according to the invention is particularly suitable for the thermal analysis of chemical and / or biological reactions or physical processes, e.g. Phase transitions.

For this purpose, a plurality of reaction chambers and thermopiles are advantageously arranged in a two-dimensional matrix on the substrate.

Brief description of the drawings

Further preferred embodiments of the invention will become apparent from the dependent claims and from the following description with reference to FIGS. Show:

1 shows a first embodiment of a Kalorime ^¬ ters from above,

2 shows a section through the calorimeter along line II-II of FIG. 1, FIG. 3 shows a section through a second embodiment of the calorimeter,

4 shows the useful signal as a function of the thermopile geometry,

5 shows the useful signal as a function of the measuring diameter for a minimum width of the thermocouples of 16 μm,

6 shows a detail from FIG. 5,

Fig. 7 shows the useful signal depending on the length of the thermocouples, Fig. 8 shows a third embodiment of the calorimeter from above and 9 shows a fourth embodiment of the calorimeter from above.

Ways to carry out the invention

definitions:

Within the scope of the specification and claims, the following definitions are used: The directions "bottom" and "top" are defined by the relative arrangement of reaction chambers and substrate such that the reaction chambers are defined as above and the substrate as below.

The term "vertical" is understood as the connection direction between top and bottom.

A thermopile ( "thermopile") is a Se ^¬ rieanordnung a plurality of thermocouples. A thermocouple is a component of two different and at one end interconnected conductors, through which an electrical clamping ^¬ voltage produced due to the Seeback-effect.

Calorimeter Construction:

The embodiment of the calorimeter according to FIGS. 1 and 2 has a substrate 1 made of quartz glass. On the substrate 1, a thermopile 2 is arranged, as well as a Re ^¬ action chamber 3 for receiving a sample liquid. 4

The use of quartz glass as a material for the substrate 1 is advantageous, since quartz glass has a low thermal conductivity and, in addition, can be subjected to processes with very high temperatures. These high process temperatures are particularly advantageous in the production of polysilicon. It is also suitable for coating with polysilicon. In addition, the quartz glass can also be polished down to a very small thickness in order to allow a visual inspection of the reaction by means of a microscope also from below. It is also conceivable, however, instead of

Quartz glass to use another material, such as silicon. However, since silicon has approximately 100 times higher conductivity than quartz glass, the silicon in the region of the reaction chamber in this case should be e.g. be recessed and spanned by a thin membrane on which the reaction chamber is arranged. Corresponding arrangements and production techniques based on anisotropic etching processes are known to the person skilled in the art. Further, instead of the quartz glass substrate and plastic can be used. In this case, the manufacturing process for the thermopile are adjusted accordingly.

The thermopile 2 consists of an electrical series connection of several thermocouples. Each thermocouple comprises a first interconnect 5 of a first material and a second interconnect 6 of a second material. The first and second traces extend between inner contact points 7 and sweet contact points 8, a portion of which are provided with the corresponding reference numerals 7 and 8, respectively, in FIG. At each contact point in each case a first and a second conductor track 5 and 6 are connected to each other. The term contact point also encompasses a non-point-shaped, extended contact area, such as e.g. illustrated by the elongated sweeter contact points 8.

The inner contact points 7 are arranged on a circle. They are located vertically below the reaction chamber 3 so that they are in good thermal contact therewith. The circle is coaxial with the vertical center line M of the rotationally symmetrical, circular reaction chamber 3.

The outer contact points 8 are arranged on a circle, namely offset laterally to

Reaction chamber 3, ie not directly below it vertically, so that it is thermally insulated from the reaction chamber. are lier. This circle is also coaxial with the vertical center line M of the reaction chamber 3.

The reaction chamber 3 is surrounded by a side wall 9. This is formed by a wall layer 10, which is arranged above the substrate 1 and recessed in the region of the reaction chamber 3. Preferably, the wall layer 10 is covered by a photoresist, e.g. SU8, as such can be easily structured. However, it can also be made of another organic or inorganic material.

In the embodiment according to FIG. 2, the outer contact points 8 are arranged vertically below or (viewed from the center axis M) radially outside and below the wall layer 10 in order to achieve good thermal insulation from the reaction chamber 3.

As can be seen from FIG. 2, a protective layer 12 is arranged between the thermopile 2 or the printed conductors 6, 7 and the reaction chamber 3. This has the task to isolate the thermopile chemically and electrically from the liquid 4. It can e.g. of an organic material, e.g. Photoresist (SU8) or a dielectric such as e.g. SiN, insist.

As shown particularly in Fig. 1 seen running the first and second conductive lines 5, 6 in substantially straight and radially relative to the vertical center line M of the reaction chamber, since there is in this direction the largest temperature gradient, and because too long way vermie ^¬ should be as these would increase the internal resistance of the thermopile and thus impair the signal / noise ratio.

In the embodiment shown, the first interconnects 5 are made of aluminum and the second interconnects 6 of doped polysilicon. Information on doping will be given below. However, it is also conceivable that both interconnects 5 and 6 are made of differently doped polysilicon or another semiconductor material, in particular of p- and n-doped polysilicon, consist. Also suitable are NiCr and Ni as first and second material for the tracks, or Cr and Ni, for which materials the Seeback coefficient is less than for aluminum and doped polysilicon. As a further measure to reduce the signal / noise ratio, the width of the. Tracks 6 and / or 7 towards the outside to. This is based on the consideration that in order to reduce the signal noise, the lowest possible internal resistance of the thermopile is desired. Thus, the space available for the material of the tracks should be well used - and as there is more space to the outside, the tracks can be wider there.

In the embodiment of Fig. 1, only the second conductor tracks 6 are wider towards the outside. This is useful because the second interconnects 6, which consist of the doped polysilicon, have a substantially lower conductivity than the first interconnects 5 made of aluminum. In the embodiment according to FIG. 1, the first and the second conductor tracks overlap only in the area of the contact points 7, 8, and are otherwise arranged next to one another. This arrangement makes it possible to shift to an insulating intermediate layer between the conductor tracks. However, it is also conceivable to use the interconnects with an intermediate insulating layer, e.g. of SiC> 2 or SiN, one above the other, whereby windows are provided in the intermediate layer to form the contact points. As a result, more space is available for the individual interconnects and the internal resistance of the thermopile can be further reduced or the number of thermocouples can be increased.

Optimization criteria The component described can be optimized in various aspects. For example, the number of thermocouples and their size within certain These limits can be selected or the doping of the polysilicon can be determined in a suitable manner. The following are some criteria that allow to optimize the parameters of the calorimeter.

endowment

Boron ions are used for the doping of the polysilicon since p-doped silicon has a lower thermal conductivity than n-doped silicon. The doping concentration changes the specific electrical resistance. In order to obtain a conductivity significantly better than 10 ^~ 2 Q _cm and thus to keep the noise low, the doping concentration should be at least 10 ^ 0 cm ^~ 3, for example.

Dimensioning of the thermopile In order to choose the dimensioning of the thermopile, one can assume a given size of the reaction chamber. Typical diameters of the reaction chamber are between 1000 and 2000 μm.

Based on the given size, the temperature distribution within the calorimeter can be calculated. On the one hand, the width of the individual thermocouples should be as low as possible, since in this case more thermocouples can be accommodated and the measuring signal increases with the number of thermocouples. At the same time, the noise increases because with increasing number of thermal elements ^¬ the conductor tracks have to be designed thinner and thinner, to raise its resistance. The longer the thermocouples are, that is, the farther the contact points 7 and 8 are apart, the greater the fundamental difference in temperature and therefore the measured voltage, but at the same time the noise increases as the internal resistance increases.

The diameter of the circle on which the inner contact points 7 lie is also an important factor. ger design parameters. If the diameter is very small, the voltage per thermocouple increases, but the maximum number of thermocouples decreases because the inner contacts can not be arbitrarily small. Based on these considerations, as

Payload signal, for example, the product of measurement signal multiplied by signal / noise ratio depending on the diameter of the circle of the inner contact points 7 and the length of the thermocouples are calculated. A corresponding graphic for a reaction chamber with 1500 μm

Diameter being designated for illustration in Fig. 4, is provided 5 and 6 ^¬, "gage diameter" of the diameter of the circle of the inner contact points. In this case, it was assumed that the thermal elements must have a width of at least 16 microns.

It is found that the optimum measuring diameter and the optimum length of the thermocouples from the minimum width of the traces are substantially un ^¬ dependent. Advantageously, the number of Thermoelemen ^¬ te should be at least about 10, however, so that a reasonably strong signal is generated when klei ^¬ nen temperature differences still.

As can be seen from FIGS. 5 and 6, with a measuring chamber diameter of 1500 .mu.m, the inner contact points 7 should lie on a circle with a diameter between 400 and 800 .mu.m.

As far as the length of the thermocouples is concerned, an optimum range between approximately 800 and 2000 .mu.m is evident from the useful signal according to FIG. 7 calculated for a reaction chamber with a diameter of 1500 .mu.m.

Production The calorimeter is produced, for example, starting from a quartz glass substrate, which is coated with known processes using a polysilicon coating. will see. The polysilicon is doped with boron, eg by ion implantation. Then it is structured, for example, by means of photolithographic and etching techniques in a known manner to form the second interconnects 6. Then, an annealing step may follow to distribute the boron evenly in ^{"polysilicon.}

In a next step, the structured polysilicon is covered with a layer of aluminum, which is then in turn structured and thus forms the first conductor tracks 5. Now, the protective layer 12 may be applied and, if desired, patterned. Finally, the wall layer 10 is applied and also structured to form the reaction chambers 3. Preferably, a plurality of calorimeters are created on a common substrate 1. Depending on the application, these can then remain on the same substrate or be separated by sawing.

Reference chamber, evaporation chamber

If more or less volatile liquids are introduced into the reaction chamber 3, their evaporation can lead to a strong temperature signal, which under certain circumstances is able to cover the enthalpy of the reaction. In order to reduce the evaporation of the liquid, the investigations can take place in a suitably saturated ambient atmosphere.

Further or additionally thereto, a reference chamber may be provided in the vicinity of the reaction chamber 3. A corresponding embodiment is shown in Fig. 3. In this embodiment, the reference chamber 15 is arranged rotationally symmetrical and annular around the reaction chamber 3 and separated from it by an annular portion 16 of the wall layer 10. The thermopile 2 or its thermocouples extend between the reaction chamber 3 and the reference chamber 15. The inner contact points 7 are in the reaction chamber 3 and the outer contact points 8 arranged at the reference chamber 15, so that the temperature difference between the two chambers can be measured with the thermocouple. In operation, the reference chamber 15 is filled with a reference liquid having approximately the same rate of evaporation and evaporation energy as the liquid in the reaction chamber 3. A remaining temperature difference between the two chambers in this case is primarily due to the enthalpy of the reaction taking place in the reaction chamber 3 ,

In the embodiment according to FIG. 3, the reference chamber 15 is arranged around the reaction chamber 3. An alternative, advantageous execution is shown in Fig. 8, where the reference chamber 15 is arranged laterally next to the reac ^¬ tion chamber 3 and the two chambers have the same shape. As a result, the evaporation rates are better symmetrized. In the embodiment according to FIG. 8, two thermaulauls 2a, 2b are provided, one for the reaction chamber 3 and a second one for the reference chamber 15. The thermocouples 2a, 2b are connected in series in opposite directions, so that their voltages subtract and the output signal corresponds to the temperature difference between the two chambers 3, 15. It is also conceivable, analogous to the embodiment according to FIG. 3, to use only one thermopile, whose one row of contact points 7 are arranged below the reaction chamber 3 and whose other row of contact points 8 are below the reference chamber 15.

A further embodiment is shown in FIG. 9. This combines the advantages of the embodiments according to FIGS. 3 and 8. As in the embodiment of FIG. 8, two identically constructed chambers 3, 15 are provided, one of which serves as a reaction chamber 3 and the other as a reference chamber 15. However, in addition to the chambers 3, 15 are each provided two further chambers 20, hereinafter referred to as evaporation chambers. These chambers are filled during operation with a reference liquid, which has approximately the same evaporation rate and evaporation energy as the liquid in the reaction chamber 3 and reference chamber 15. The evaporating from the evaporation chambers liquid increases the partial pressure of the vaporized substance in the ambient air, resulting in in that the evaporation from the chambers 3, 15 decreases, as a result of which undesired evaporation effects in the reaction chamber 3 and in the reference chamber 15 are reduced.

In the embodiment according to Fig. 8, two Ver ^¬ dampfungskammern 20 are provided, each of which extends annularly around each one of the chambers 3 and 15 respectively. It is conceivable, however, only one evaporation chamber

20 to provide, which extends around both chambers 3 and 15 he ^¬ stretches. With other both chambers 3, 15 surrounded by at least one evaporation chamber 20, wherein the evaporation chamber 20 is common to both chambers 3, 15 or each of the chambers 3, 15 is associated with their own evaporation ^¬ chamber.

An evaporation chamber can also be provided for calorimeters without a reference chamber.

further explanation

Regardless of whether a reference chamber 15 is provided, preferably several calorimeters or more reaction chambers and thermopiles are arranged in a two-dimensional matrix on the same substrate 1, so that, similar to a microtiter plate, a plurality of experiments can be carried out simultaneously and automatically ,

As can be seen from FIG. 1, a heating may additionally be provided in the reaction chamber 3, for example consisting of an annular resistor 18 (polysilicon in the present embodiment) and Supply lines 19 (made of aluminum). This makes it possible to control the temperature in the reaction chamber or, using the signal from the thermopile 2, to control it.

Claims

claims

A calorimeter for receiving small amounts of liquid comprising a substrate (1), a reaction chamber (3) arranged on the substrate (1) and a temperature sensor arranged on the substrate (1) in the reaction chamber (3), characterized in that Temperature sensor is a thermopile (2).

2. calorimeter according to claim 1, wherein the thermopile (2) comprises a plurality of first conductor tracks (5) made of a first material and a plurality of second conductor tracks (6) made of a second material and wherein the conductor tracks (5, 6) between inner and outer contact points (7, 8) extend, where each one ne first and a second conductor track (5, 6) are interconnected.

3. calorimeter according to claim 2, wherein a width of the first and / or second conductor tracks (5, 6) increases from the inner contact points (7) against the outer contact points (8).

4. calorimeter according to claim 3, wherein a conductivity of the first material is greater than a conductivity of the second material, and wherein the width of the second conductor tracks (6) towards the outer contact points (8) toward more increases than the width of the first conductor tracks (5).

5. calorimeter according to one of claims 2 to 4, wherein at a measuring chamber diameter of about 1500 microns, the first contact points on a circle with a diameter between 400 and 800 microns and / or the thermocouples have a length between 800 and 2000 microns.

6. Calorimeter according to one of the preceding claims, wherein on the substrate (1) has a wall layer

(10), which is recessed in the region of the reaction chamber (3) and forms a side wall (9) for the reaction chamber (3), wherein the wall layer (10) is a photoresist.

7. Calorimeter according to one of the preceding claims, wherein the substrate (1) is made of quartz glass.

8. Calorimeter according to one of the preceding claims, wherein between the thermopile (2) and the reaction chamber (3) a protective layer (12) of photoresist is arranged.

9. Calorimeter according to one of the preceding claims, wherein in the reaction chamber (3) a reference chamber (15) is arranged and wherein the calorimeter means (2; 2a, 2b), to measure a temperature difference between the two chambers.

10. A calorimeter according to claim 9, wherein the thermopile (2) extends between the reaction chamber (3) and the reference chamber (15) to measure the temperature difference between the two chambers.

11. A calorimeter according to claim 10, wherein the inner contact points (7) in the reaction chamber (3) and the outer contact points (8) at the reference chamber (15) are arranged.

12. Calorimeter according to one of claims 9 to 11, wherein the reference chamber (15) is arranged annularly around the reaction chamber (3).

13. Calorimeter according to one of the preceding claims, wherein the reaction chamber (3) at least one evaporation chamber (15, 20) is arranged for receiving a liquid to be evaporated.

14. A calorimeter according to claim 13, wherein a reference chamber (15) is disposed in the reaction chamber (3), and wherein the calorimeter comprises means (2; 2a, 2b) for measuring a temperature difference between the two chambers, and both the reference chamber (15) and the reaction chamber (3) are surrounded by at least one evaporation chamber (20).

15. Calorimeter according to one of the preceding claims, wherein on the substrate (1) a plurality of

Reaction chambers (3) and thermopile (2) are arranged in a two-dimensional matrix.