EP1642648A1 - Apparatus and method for regulating the temperature of a liquid - Google Patents

Abstract

Liquid samples (11-20) which need to be raised to a set temperature within a fixed short interval are moved through e.g. an infrared radiation zone (2). Inert beads of material of thermal conductivity greater than 0.6W/mK are added to the samples in order to accelerate the heating rate. The temperature of each sample is monitored (3) and may be used to control the heater. Independent claims are included for the method of increasing sample heating rate by addition of heat absorption material, and for the use of infrared heating.

Description

The present invention relates to a device for adjusting a temperature of a liquid according to the preamble of claim 1 and a corresponding method.

It is well known that chemical analyzes of samples and chemical / physical processes must be carried out at a predetermined temperature in order to obtain correct results. In particular, in a large number of chemical analyzes within a relatively short period of time or in processes in which a temperature or different temperatures must be set, require powerful and costly temperature control units, so that these requirements can be met.

Various devices and methods for adjusting the temperature are known. By way of example, reference is made to the following publications: DE-42 03 202 A1, EP-0 160 282 B1, EP-0 318 255 A2, WO 98/38487, US Pat. No. 6,210,882 and EP-0-345 882 A1.

• Grosse thermische Massen müssen bei einer Temperaturänderung mitgeheizt oder mitgekühlt werden;
• Es treten Diffusionslimitationen zwischen einer geheizten Probengefässwandung und der Flüssigkeit auf (Grenzschichtbildung);
• ein direkter Kontakt zwischen der Wärmequelle bzw. Wärmesenke und dem zu beheizenden Probengefäss ist erforderlich; eine schlechte Kontaktierung zwischen Temperiereinheit und Probengefäss führt zu einer erheblichen Verzögerung in der Temperatureinstellung;
• Kontaktierungen durch Sensorkabel wirken als Wärmesenken und führen zu zusätzlichen Verlusten.

The known teachings can basically be divided into two groups. The first group includes the so-called solid-state incubators, in which the samples are heated or cooled by the solid, whichever is appropriate Heat capacity takes a lot of time. If liquid samples have to be tempered, one or more of the following problems arise:

• Large thermal masses must be co-heated or co-cooled with a change in temperature;
• Diffusion limitations occur between a heated sample vessel wall and the liquid (boundary layer formation);
• direct contact between the heat source or heat sink and the sample vessel to be heated is required; poor contact between tempering unit and sample vessel leads to a considerable delay in the temperature setting;
• Contacts through sensor cables act as heat sinks and lead to additional losses.

• nicht optimierte Absorptionsspektren der zu erwärmenden Reaktionsgemische;
• nicht optimierte Transmissionsspektren der Probengefässe;
• anderen Systemelemente werden ungewollt durch die IR-Strahlung erwärmt.

The second group includes tempering units which are based on irradiation, in particular IR (infrared) irradiation. Although, in principle, an improved behavior compared to the first group can be ascertained, there are also a number of disadvantages to be considered in this second group, which lead to a sub-optimal heating behavior for liquids:

• non-optimized absorption spectra of the reaction mixtures to be heated;
• non-optimized transmission spectra of the sample vessels;
• other system elements are inadvertently heated by the IR radiation.

The present invention is therefore based on the object of specifying a device for adjusting a temperature of a liquid, wherein the device does not have one or more of the disadvantages mentioned above.

This object is achieved by the measures indicated in the characterizing part of patent claim 1. advantageous embodiments of the invention and a method are given in further claims.

The invention has the following advantages: Since the liquid to be examined contains absorption elements which have a thermal conductivity greater than 0.6 W / m K, the temperature setting in the liquid to be examined is considerably accelerated. Thus, the throughput of samples per unit time can be increased accordingly.

Fig. 1,

in schematischer Darstellung, eine erfindungsgemässe Vorrichtung als so genannter Linear-IR-Inkubator,

Fig. 2,

wiederum in schematischer Darstellung, eine weitere Ausführungsform einer erfindungsgemässen Vorrichtung als Linear-IR-Inkubator,

Fig. 3,

wiederum in schematischer Darstellung, eine weitere Ausführungsform der erfindungsgemässen Vorrichtung als so genannter Rotor-IR-Inkubator und

Fig. 4,

wiederum in schematischer Darstellung, eine noch weitere Ausführungsform der erfindungsgemässen Vorrichtung als Rotor-IR-Inkubator.

The invention will be explained below with reference to drawings, for example. Show

Fig. 1,

in a schematic representation, a device according to the invention as a so-called linear IR incubator,

2,

again in a schematic representation, a further embodiment of a device according to the invention as a linear IR incubator,

3,

in turn, in a schematic representation, another embodiment of the inventive device as a so-called rotor IR incubator and

4,

in turn, in a schematic representation, a still further embodiment of the inventive device as a rotor-IR incubator.

Fig. 1 shows a schematic representation of an embodiment of the invention, in which eight sample vessels 11 to 18 are arranged substantially on a straight line, wherein a transport unit 20 is provided to hold one hand, the sample vessels 11 to 18 in position and on the other hand, to a to ensure easy transport of the sample vessels 11 to 18. A temperature control unit 2 is provided laterally along the sample vessels 11 to 18 or the transport unit 20, by means of which the temperature of the liquid present in the sample vessels 11 to 18 can be adjusted. For this purpose, a control unit 1 is provided, which is operatively connected to the temperature control unit 2, ie in the control unit 1, a control signal is generated, which leads to a corresponding temperature radiation through the temperature control unit 2.

Basically, a first embodiment of the present invention is that the control unit 1 receives no feedback on the temperature generated in the sample vessels 11 to 18.

A further embodiment of the present invention, however, as shown in Fig. 1, is that sensor elements 3 are provided in the region of the sample vessels 11 to 18, by means of which the respective temperature of the existing in the sample vessels 11 to 18 fluids can be determined. On the one hand there is the possibility that for each sample vessel 11 to 18 a sensor element 3 is present, on the other hand the possibility that the temperature is measured only in one of the sample vessels 11 to 18, in which case it is assumed that the measured temperature value in all other sample vessels 11 to 18 is the same.

The embodiments of the present invention with sensor elements 3 enables the regulation of the temperature radiation of the temperature control unit 2, whereby a desired temperature of the liquids present in the sample vessels can be adjusted quickly and precisely.

In FIG. 1, denoted by 5 is a system bus, via which the device according to the invention can be coupled, for example, to a higher-level system which, for example, assumes all the controls of a process It has been found that the tempering unit 2 is particularly suitable for an IR (infrared) radiation unit. An IR radiation unit irradiates the liquid in the sample vessels 11 to 18 in the infrared wavelength range. However, other wavelength ranges are also conceivable.

The tempering unit 2 used is realized, for example, as a surface radiator (two-dimensional) in thick-film or thin-film technology.

So that the adjustment of the temperature of the liquids contained in the sample vessels 11 to 18 can be carried out faster and more efficiently, it is proposed according to the invention to admix absorption elements to the liquids contained in the sample vessels. The absorption elements have the task to absorb the radiation energy emitted by the temperature control unit 2 and deliver it as heat to the liquids contained in the sample vessels 11 to 18. The choice for an absorption element is therefore dependent on the temperature control unit 2 used or on the wavelength range of the radiation used.

• hohe Wärmeleitfähigkeit, vorzugsweise grösser als 0.6 w/m K;
• geringe Wärmekapazität, vorzugsweise kleiner als 4000 J/kg K;
• magnetisiert bzw. magnetisierbar;
• geringe spezifische Dichte, vorzugsweise kleiner als 6 g/cm³.

The absorption elements should not chemically influence the liquid to be investigated or processed, ie be inert with respect to the liquid, and additionally have, for example, one or more of the following properties:

• high thermal conductivity, preferably greater than 0.6 w / m K;
• low heat capacity, preferably less than 4000 J / kg K;
• magnetized or magnetizable;
• low specific gravity, preferably less than 6 g / cm ³ .

• Höherer Wirkungsgrad;
• Höhere Aufheizgeschwindigkeit der in den Probengefässen 11 bis 18 enthaltnen Flüssigkeiten;
• Stärkere Konvektionseffekte innerhalb der Probengefässe 11 bis 18 aufgrund des lokalen Wärmeeintrages an den Absorptionselementen;
• Bessere Homogenität innerhalb der zu erwärmenden Flüssigkeit infolge des verstärkten Konvektionseffektes innerhalb der Probengefässe 11 bis 18 (ein zusätzliches Mischen der Flüssigkeiten ist nicht notwendig).

One or more of the following effects can be achieved with the absorption elements according to the invention:

• Higher efficiency;
• Higher heating rate of the liquids contained in sample vessels 11 to 18;
• Greater convection effects within the sample vessels 11 to 18 due to the local heat input at the absorption elements;
• Better homogeneity within the liquid to be heated due to the increased convection effect within the sample vessels 11 to 18 (additional mixing of the liquids is not necessary).

As absorption elements are, for example, spherical particles in the size of 0.1 to 100 .mu.m, in particular from 0.5 to 5 microns. These are glass beads with enclosed magnetic pigments, for example iron oxide. Such absorption elements are also referred to as MGPs (Magnetic Glass Particles). Furthermore, the absorption can be increased by the use of polymers (PS) for the production of absorbent elements. Finally, can the thermal conductivity and thus a heat input into the liquids can be increased by adding absorption elements of other inert particles (for example of aluminum, ceramic or carbon fibers).

Particularly suitable absorption elements are particulate solids, as described, for example, in the known teachings according to WO 96/41 811 or US Pat. No. 6,255,477 B1 or WO 00/32 762 or US Pat. No. 6,545,143 B1 or WO 01/37 291 or US Pat US 2003/224 366 A1 of the same Applicant have been described. The disclosure of the above-mentioned international patent applications is therefore fully an integral part of the present patent application.

As has already been pointed out, the absorption elements primarily have the task of converting radiation into heat and delivering it to the liquid to be heated in the sample vessel in order to be able to achieve a desired temperature of the liquid as quickly as possible. Furthermore, embodiments are conceivable and desirable in which particles are used as absorption elements, to which nucleic acid can be reversibly bound, as has also been described in the aforementioned international patent application with the publication number WO 96/41 811. In this case, the method consists of binding nucleic acids to the particles for cleaning. Through the connection, an extremely efficient heat transfer can be obtained. The liquid to be examined is included preferably aqueous, in particular a nucleic acid-containing sample, for example a body fluid or a fluid derived therefrom.

A further improvement of the efficiency and the heat input into the liquid of the sample vessels 11 to 18 is achieved in the inventive device in that the sample vessels 11 to 18 are made of a material with low heat capacity and / or reduced absorption. For example, the use of COC (cycloolefin copolymer) is useful instead of the PP (polypropylene) commonly used for sample vessels.

In addition to the choice of suitable material for the sample vessels to obtain the above properties further optimization by suitable properties of the selected temperature control is possible. Thus, when using an IR radiation unit, its radiation spectrum must be matched to the material used for the sample vessels 11 to 18. This will result in an optimized overall system.

In the embodiment shown in FIG. 1, the introduction of heat into the sample vessels 11 to 18 via the laterally arranged temperature control unit 2. The measurement of the instantaneous temperature by means of the sensor elements 3 is preferably, but not necessarily, from above, that is on the Opening in the sample vessels 11 to 18. This can be a direct measurement the temperature can be made, and there are no Messverfälschungen due to lying between the sensor element 3 and the liquid vessel walls to be expected.

Alternatively, the liquid in the sample vessels 11 to 18 can be heated from below or from above. In this case, a temperature measurement from the side is preferred.

FIG. 2 shows a further embodiment of the device according to the invention with a linear IR incubator. Instead of a laterally arranged tempering unit, as in the embodiment according to FIG. 1, the embodiment according to FIG. 2 comprises a rake-shaped tempering unit, which consists of the essentially parallel tempering elements 2a to 2f. The tempering elements 2a to 2f can also be produced with the mentioned thin-film or thick-film technologies. In this embodiment, it is possible to individually regulate the temperature of the liquids contained in the individual sample vessels 11 to 15. For this purpose, the control unit 1 is individually connected to the temperature control 2a to 2f.

The temperature measurement takes place, as in the embodiment according to FIG. 1, via sensor elements 3, which are connected to the control unit 1 (shown in dashed lines in FIG. 2). Preferably, the sensor elements 3 arranged above or below the sample vessels 11 to 15.

In an alternative embodiment, sensor elements 3 'are provided directly on the temperature control elements 2a to 2f, as is indicated by way of example in the case of the first temperature control element 2a.

In Fig. 3 shows a further embodiment of the inventive device is shown. In this embodiment, a so-called rotor-IR incubator is used, in which the sample vessels 11 to 1B are arranged on a circle. Accordingly, the sample vessels 11 to 18 are held in position by a circular transport unit 20. The tempering unit 2 is arranged in the center of the circular transport unit 20, so that the heat rays run radially, thus impinging laterally on the sample vessels 11 to 18. As in the embodiments according to FIGS. 1 and 2, a single or multiple sensor elements 3 are also provided in that according to FIG. 3 in order to measure the temperature of the liquids contained in the sample vessels 11 to 18 and optionally to the control unit 1 for regulating the temperature to pass over the temperature control unit 2.

So that no direct influence of the sensor unit 3 or of the sensor units by the tempering unit 2 can occur, the sensor unit or the sensor units are to be suitably placed. In the just explained Embodiment with centrally arranged tempering 2 is particularly suitable an arrangement of the sensor unit 3 on the sample vessels 11 to 18, whereby a direct influence by the temperature control unit 2 is excluded.

FIG. 4 shows a further embodiment of the device according to the invention with a rotor-IR-incubator. In contrast to the embodiment according to FIG. 3, the embodiment according to FIG. 4 consists in that the temperature control unit 2 is arranged below one of the sample vessels 11 to 18. Conceivable and in a modification of the embodiment according to FIG. 4, a further embodiment variant is that a temperature control unit 2 is arranged under a plurality of or among all sample vessels 11 to 18.

In an arrangement, for example, with a single sample vessel containing 100μl of water and 6 mg of MGPs, using a 90 watt halogen lamp as a tempering, starting from room temperature, a water temperature of 80 ° Celsius was reached after about 40 seconds. The sample vessel is placed concentrically over a halogen lamp as a tempering unit, wherein the halogen lamp is arranged in a rotationally symmetrical mirror. In order to reduce the proportion of visible rays, a wavelength filter is further provided between the tempering unit and the sample vessel. In order to obtain an accurate and fast temperature setting, a sensor element is non-contact Temperature sensor provided, with which the control unit and the temperature control unit are operatively connected.

It is expressly pointed out that a tempering unit 2, which generates beams in the infrared range, is particularly suitable for all of the described embodiments according to the invention. Nevertheless, tempering units are also conceivable which generate beams in other wavelength ranges. Decisive is a vote of the used rays in connection with the used materials for the absorption elements and for the sample vessels 11 to 18.

Suitable sample vessels are conventional so-called tubes, which consist of a cylindrical section and leak towards the closed end, for example, in a tip.

Alternatively, so-called flat cells are suitable, which consist essentially of one or more chambers with a small depth (a few hundred microns) in a carrier material, wherein the outer dimensions of the chamber and its geometry may be arbitrary.

It has been found that so-called Eppendorf tubes or other tubes with a capacity of, for example, 300 .mu.l to 2.5 ml are suitable. Furthermore, hollow cylinders and capillary tubes are also suitable as sample vessels.

In principle, the capacity of the sample vessels, however they are designed, may be up to about 5 ml, in particular in the range from 0.1 to 5 ml or in particular in the range from 0.3 to 2.5 ml.

In an alternative embodiment of the sample vessels as flat cells, a depth of, for example, 0.1 to 1.0 mm, in particular from 0.3 to 0.7 mm, is selected. The capacity is selected in a range of 0.1 to 100 ul, preferably in the range between 0.3 and 50 ul, preferably in the range between 0.5 and 0.9 ul or in the range between 30 and 40 ul.

In a further embodiment of the invention with flat cells as sample vessels, the cells have an olive shape, i. the cross-sectional area of a cell is oval with a maximum width of 6 mm and a maximum length of 14 mm, the cell depth being about 0.65 mm. In addition to an oval cross-sectional area but also a circular cross-sectional area is conceivable. In this case, the cell corresponds to a cylindrical cavity, for example, has a diameter of 1.5 mm and a height of also 1.5 mm. For these embodiments of a flat cell, the information on the capacities with respect to the above-mentioned flat cells apply accordingly.

The present invention is particularly suitable for the following applications: incubators, thermal cyclers and all applications related to energy input.

Claims (22)

Device for adjusting a temperature of a liquid which is contained in a sample vessel (11, ..., 18), wherein a control unit (1) and a temperature control unit (2) are provided, which are placed in the sample vessel (11, ... , 18), and wherein the control unit (1) is operatively connected to the temperature control unit (2), characterized in that the liquid to be examined contains absorption elements in order to accelerate the temperature adjustment in the liquid to be examined, the absorption elements having a thermal conductivity greater than 0.6 W / m K. Apparatus according to claim 1, characterized in that the absorption elements are substantially inert with respect to the liquid to be examined and also have one or more of the following properties: low heat capacity, preferably less than 4000 J / kg K; - Magnetized or magnetizable; low specific gravity, preferably less than 6 g / cm ³ . Apparatus according to claim 1 or 2, characterized in that the absorption elements consist of at least one of the following materials: - Glass; - ceramics; - aluminum; - Carbon fibers. Device according to one of claims 1 to 3, characterized in that the absorption elements contain a magnetic pigment, preferably of iron oxide. Device according to one of claims 1 to 4, characterized in that the material for the sample vessels (11, ..., 18) has a lower absorption capacity and / or a smaller heat capacity than the absorption elements. Device according to one of claims 1 to 5, characterized in that the sample vessels (11, ..., 18) have a capacity of less than 5 ml or in the range of 0.1 to 5 ml or in the range of 0.3 to 2.5 ml , Device according to one of claims 1 to 5, characterized in that the sample vessels (11, ..., 18) are formed as cells with a depth of 0.1 to 1 mm or 0-3 to 0-7 mm and that a cell has a capacity of 0.1 to 100 ul or 0.3 to 50 ul or 0.5 to 0.9 ul or 30 to 40 ul. Device according to one of claims 1 to 7, characterized in that the temperature control unit (2) acts on a plurality of sample vessels (11, ..., 18) with liquid to be examined. Device according to one of claims 1 to 8, characterized in that the sample vessels (11, ..., 18) by a transport unit (20) are held and transportable. Device according to one of claims 1 to 9, characterized in that a sensor element (3) is provided for determining the temperature of the liquid to be examined, wherein the sensor element (3) with the control unit (1) is operatively connected. Apparatus according to claim 10, characterized in that a sensor unit (3) is provided for each sample vessel (11, ..., 18). Device according to one of claims 1 to 11, characterized in that a plurality of sample vessels (11, ..., 18) are provided, which are arranged on a circle. Apparatus according to claim 12, characterized in that the temperature control unit (2) is arranged in the center of the circle. Apparatus according to claim 12, characterized in that the temperature control unit (2) below one of the sample vessels (11, ..., 18) is arranged. Device according to one of claims 12 to 14, characterized in that a sensor element (3) for determining the temperature of the liquid to be examined is provided, wherein the sensor element (3) with the control unit (1) is operatively connected and wherein the sensor element (3) with respect to a longitudinal axis of the sample vessels (11, ..., 18) is arranged laterally. Device according to one of claims 1 to 11, characterized in that a plurality of sample vessels (11, ..., 18) are provided, which are arranged on a straight line. Apparatus according to claim 16, characterized in that the temperature control unit (2) consists of at least one flat tempering (2a, ..., 2f). Device according to one of claims 16 to 17, characterized in that a sensor element (3) is provided for determining the temperature of the liquid to be examined, wherein the sensor element (3) is operatively connected to the control unit and wherein the sensor element (3) above a sample vessel (11, ..., 18) is arranged. Device according to one of claims 1 to 18, characterized in that as a temperature control unit (2) so-called IR (infrared) emitters are provided. Method for adjusting a temperature of a liquid contained in a sample vessel (11, ..., 18), the method being - That the liquid absorption elements are admixed and - That the sample vessel (11, ..., 18) is irradiated, wherein at least a portion of the radiation energy is converted into heat in the absorption elements. Method according to Claim 20, characterized in that the beams are in the infrared wavelength range. A method according to claim 20 or 21, characterized in that a temperature of the liquid contained in the sample vessels (11, ..., 18) is measured and that on the basis of the measured temperature, the radiation energy is adjusted.

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