EP2186565A1 - Measuring device and method for determining fluid parameters specified by a laboratory - Google Patents

Abstract

The device has a measuring unit (5) integrally formed in a laboratory system (1). The measuring unit comprises a measuring block without a reaction chamber, and a sensor (17). The measuring block comprises cavities (16) for receiving and guiding fluid provided by the laboratory system. The cavities are completely arranged within the measuring block. The sensor determines physical and/or chemical parameters e.g. velocity and pressure, of fluid provided in the cavities, and is arranged at or in fluidic operative connection with the cavities of the measuring block. Independent claims are also included for the following: (1) a hybridizing system (2) a method for determining fluid parameters using a measuring device.

Description

According to the preamble of independent claim 1, the invention relates to a measuring device with a measuring unit and a processing unit for determining fluid parameters provided by a laboratory system. This measuring unit is integrally formed in this laboratory system. The invention also relates, according to the preamble of independent claim 20, to a method for determining fluid parameters provided by a laboratory system. For carrying out this method, the measuring device quoted above is used.

Automation of laboratory processes in life science areas, such as pharmacological research, clinical diagnostics or genomics, is an important step to increase the efficiency, quality and reliability of biochemical reactions and investigations. Automated laboratory systems are known for performing a variety of processes, such as handling larger volumes of liquids (such as fermenters or automated pipetting machines) or smaller volumes of liquid (such as spotting / immobilizing biological samples on supports), nucleic acid amplifications (such as the polymerase chain reaction). PCR, or sequencing reactions) or else for carrying out hybridization reactions.

The problem which may arise in automated laboratory processes is explained below by way of example by carrying out hybridization reactions. Such hybridization reactions are preferably carried out in gap-shaped, small spaces. There are binding reactions between two various chemical or biological binding partners. In this case, typically one of the partners, the sample to be hybridized, is immobilized on a solid substrate surface. These samples to be hybridized are then contacted with a suspension containing the desired binding partner, the pattern. Hybridization reactions form the basis for various investigation techniques in molecular biology laboratories. Immobilized samples may include, for example, amino acid-containing (eg, proteins, peptides) or nucleic acid-containing (eg, DNA, cDNA, RNA) samples. Samples added to the immobilized samples can be any molecules or chemical compounds (eg, DNA, cDNA, and / or proteins or polypeptides) that hybridize or otherwise bind to the immobilized samples. Devices or systems for the automated implementation of such hybridization reactions are already available.

In particular, the DNA microarray technique has become established for hybridizing DNA. This is based on a hybridization reaction in which simultaneously or simultaneously thousands of genes are detected and / or analyzed. This technique involves the immobilization of DNA samples from many genes on a substrate, e.g. on a glass slide for a light microscope. The DNA samples are preferably stored in a defined array of sample spots or "spots", i. in a two-dimensional grid arrangement, applied to the substrate. Later, starting from a specific position within such an array, it is possible to deduce the origin of the corresponding DNA sample and thus its identity. The technique further includes contacting the DNA sample array with RNA pattern suspensions to detect specific nucleotide sequences in the DNA samples. RNA patterns may be labeled with a so-called "tag" or "label", i. be provided with a molecule which is e.g. emits a fluorescent light having a specific wavelength.

Under good experimental conditions, for example, RNA samples hybridize or bind to immobilized DNA samples and together with them form hybrid DNA-RNA strands. The better an RNA pattern matches a spotted DNA sample - the more perfect the corresponding base pairs are complementary - the stronger the bond between them. The differences in binding / hybridization of RNA patterns to the various DNA samples of an array can be determined by measuring the intensity and wavelength dependence of the fluorescence of each individual microarray element. Thus, it can then be found out whether and to what extent the degree of gene expression in the examined DNA samples varies. With the use of DNA microarrays comprehensive statements can thus be made about the expression of large quantities of genes and their expression patterns, although only small amounts of biological material must be used.

DNA microarrays have established themselves as successful tools. The laboratory systems for carrying out hybridizations have been continually improved (cf., for example, US Pat US 6,238,910 or the document EP 1 260 265 B1 the applicant of the current patent application). These documents disclose systems with devices for providing a hybridization space for the hybridization of nucleic acid samples, proteins or tissues on a microscope slide. Such a known standard device forms a gap-shaped hybridization space with the slide. she is in FIG. 1 and is described in more detail in the following section.

It may happen that a laboratory process automated with a laboratory system, such as such a hybridization reaction, provides results that are unclear or not analyzable. In such cases, however, it is not possible, or only possible to some extent, to determine which problems have led to such a poor result and where the problems are caused (for example, by the user or the laboratory system). However, to achieve an acceptable result, the problem must be identified and remedied. Quality, efficiency and reliability of laboratory processes or biochemical reactions depend on a wide variety of parameters influencing the experimental conditions. In the case of a hybridization reaction, for example, such parameters are chemical parameters of the reagents specially adapted for the reaction (for example salinity of the wash buffer, and also the pH to which a hybridization medium is exposed / "application parameter"). and physical parameters such as the temperature or pressure of the fluids in the hybridization system. To recognize an existing problem in a reaction, individual parameters would have to be changed specifically. Due to the large number of parameters, however, there are very many different operating conditions, all of which would require extensive testing. With such detailed problem identification and problem solving a lot of time has to be invested. In addition, incorrect manipulation of the laboratory system can cause additional sources of error, which increases the effort considerably.

In order to detect a specific problem, for example in hybridization reactions, biological / biochemical and physical approaches have been proposed. For example, the application document discloses DE 100 18 036 A1 a method of using a biological control system for the parameters that have been applied to increase the efficiency of a hybridization reaction. As parameters to be changed in particular temperature and time are disclosed here.

Furthermore, it is known in the art that externally applied parameters, such as temperature and pressure, can be controlled. Typically, these parameters are controlled by means of sensors typically mounted in or directly on the devices that generate these parameters, such as heaters or pumps. So was in the patent US 6,238,910 proposed that in an automated hybridization device temperature sensors are integrated directly into a temperature plate. The temperature of this plate is transferred to a slide by means of various pads. Thus, the temperature is measured directly in the device generating it.

Out WO 03/106033 An automated hybridization device is known in which an externally applied temperature is measured in or at a hybridization space of a test unit. For this purpose, a thermocouple can be integrated in a cover part of this experimental unit.

The object of the present invention is to propose alternative ways to detect and analyze problems that occur in automated laboratory processes and can result in poor process results.

1. (a) die Messeinheit einen Messblock ohne Reaktionsraum und zumindest einen Sensor umfasst;
2. (b) der Messblock Hohlräume zur Aufnahme von durch das Laborsystem bereitgestellten Fluiden umfasst, wobei die Hohlräume im Wesentlichen vollständig innerhalb des Messblocks angeordnet sind; und dass
3. (c) der zumindest eine Sensor, zum Bestimmen von physikalischen und/oder chemischen Parametern von sich in den Hohlräumen befindlichen Fluiden, an oder in fluidischer Wirkverbindung mit diesen Hohlräumen des Messblocks angeordnet ist.

This object is achieved according to a first aspect and the features of independent claim 1 by a measuring device which is designed to be integrated into this laboratory system for determining fluid parameters provided by a laboratory system with a measuring unit and a processing unit. The inventive measuring device is characterized in that

1. (A) the measuring unit comprises a measuring block without reaction space and at least one sensor;
2. (b) the measuring block comprises cavities for receiving fluids provided by the laboratory system, the cavities being disposed substantially entirely within the measuring block; and that
3. (c) the at least one sensor, for determining physical and / or chemical parameters of fluids located in the cavities, is arranged on or in fluidically active connection with these cavities of the measuring block.

1. (a) die Messeinheit einen Messblock ohne Reaktionsraum und zumindest einen Sensor umfasst;
2. (b) der Messblock Hohlräume umfasst, die Fluide, welche von dem Laborsystem bereitgestellt werden, aufnehmen, und die im Wesentlichen vollständig innerhalb des Messblocks angeordnet sind; und
3. (c) physikalische und/oder chemische Parameter von den sich in den Hohlräumen befindlichen Fluiden von dem zumindest einen Sensor bestimmt werden, der an oder in fluidischer Wirkverbindung mit diesen Hohlräumen des Messblocks angeordnet ist.

This object is achieved according to a second aspect and the features of independent claim 20 in that a method is provided which uses a corresponding measuring device with a measuring unit and a processing unit for determining fluid parameters provided by a laboratory system. The measuring unit of this measuring device is integrated into the laboratory system. This inventive method is characterized in that

1. (A) the measuring unit comprises a measuring block without reaction space and at least one sensor;
2. (b) the gauge block includes cavities that receive fluids provided by the laboratory system and that are disposed substantially entirely within the gauge block; and
3. (c) physical and / or chemical parameters of the fluids in the cavities are determined by the at least one sensor, which is arranged on or in fluidic connection with these cavities of the measuring block.

The present invention thus provides a method and a measuring device for carrying out the method with which, in particular, fluid parameters that are provided by a laboratory system can be determined. This allows for an effective result analysis by processing the signals provided by the respective sensors, which are indirect information about instrument parameters of laboratory systems. In the context of the present invention, gases, liquids and gas / liquid mixtures are considered as fluids.

Additional inventive features and preferred embodiments will be apparent from the dependent claims.

• ■ Laborgeräte, die zum automatisierten Durchführen solcher Laborprozesse befähigt sind, können mittels des vorgeschlagenen Gerätes und Verfahrens nach ihrer Fertigung auf bevorzugte Werksparameter eingestellt werden.
• ■ Es wird ein Gerät und ein Verfahren vorgeschlagen, das erlaubt, Probleme bei automatisiert durchgeführten Laborprozessen festzustellen.
• ■ Festgestellte Probleme können in Bezug auf ihren Ursprung, zum Beispiel im Laborgerät selbst oder in der Applikation, analysiert werden.
• ■ Eine Fehlerfeststellung und Fehleranalyse mittels des vorgeschlagenen Gerätes oder Verfahrens erlaubt eine frühzeitige und damit zeitsparende und kostenreduzierte Fehlerzuordnung.

Advantages of the present invention include:

• ■ Laboratory equipment capable of performing such laboratory processes automatically can be set to preferred factory parameters using the proposed apparatus and method after fabrication.
• ■ A device and method is proposed which allows problems to be detected in automated laboratory processes.
• ■ Identified problems can be analyzed with regard to their origin, for example in the laboratory device itself or in the application.
• ■ Error detection and error analysis by means of the proposed device or method allows an early and thus time-saving and cost-reduced error assignment.

Fig. 1

einen senkrechten Längsschnitt durch eine aus dem Stand der Technik bekannte Hybridisierungseinheit eines Hybridisierungssystems mit einer Standard-Vorrichtung, an deren Stelle eine erfindungsgemässe Messeinheit in die Hybridisierungseinheit einsetzbar ist;

Fig. 2

einen senkrechten Längsschnitt durch eine Messeinheit, die in die Hybridisierungseinheit eines Hybridisierungssystems eingesetzt und damit in dieses Hybridisierungssystem integriert ist;

Fig. 3

eine beispielhafte Messung eines Fluidflusses in einer Messstrecke zwischen zwei Flusssensoren 19 einer erfindungsgemässen Messeinheit;

Fig. 4

stark vereinfachte Messkonzepte eines Messgerätes mit einer Messeinheit und einer Verarbeitungseinheit, wobei:
Fig. 4A eine erste Variante des Messkonzeptes,
Fig. 4B eine zweite Variante des Messkonzeptes, und
Fig. 4C eine dritte Variante des Messkonzeptes zeigt;

Fig. 5

beispielhafte Gruppen aus Hybridisierungseinheiten, bei denen eine Messeinheit an Stelle einer Standard-Vorrichtung integriert ist, wobei:
Fig. 5A eine erste Variante einer Gruppe aus vier Hybridisierungseinheiten zeigt, bei der eine Messeinheit an Stelle einer ersten Standard-Vorrichtung integriert ist,
Fig. 5B eine zweite Variante einer Gruppe aus vier Hybridisierungseinheiten zeigt, bei eine Messeinheit an Stelle einer zweiten Standard-Vorrichtung integriert ist,
Fig. 5C eine dritte Variante einer Gruppe aus zwei Hybridisierungseinheiten zeigt, bei der eine Messeinheit an Stelle einer dritten Standard-Vorrichtung integriert ist, und
Fig. 5D eine vierte Variante einer Gruppe aus zwei Hybridisierungseinheiten zeigt, bei der eine Messeinheit an Stelle einer dritten Standard-Vorrichtung integriert ist.

The invention will now be explained in more detail with reference to exemplary embodiments and schematic drawings. The drawings and description are not intended to limit the scope of the invention. It shows:

Fig. 1

a vertical longitudinal section through a known from the prior art hybridization of a hybridization system with a standard device, in place of which a measuring unit according to the invention can be inserted into the hybridization unit;

Fig. 2

a vertical longitudinal section through a measuring unit which is inserted into the hybridization unit of a hybridization system and thus integrated into this hybridization system;

Fig. 3

an exemplary measurement of a fluid flow in a measuring section between two flow sensors 19 of a measuring unit according to the invention;

Fig. 4

greatly simplified measuring concepts of a measuring device with a measuring unit and a processing unit, wherein:
Fig. 4A a first variant of the measurement concept,
Fig. 4B a second variant of the measurement concept, and
Fig. 4C shows a third variant of the measurement concept;

Fig. 5

exemplary groups of hybridization units in which a measurement unit is integrated instead of a standard device, wherein:
Fig. 5A shows a first variant of a group of four hybridization units, in which a measuring unit is integrated instead of a first standard device,
Fig. 5B shows a second variant of a group of four hybridization units, integrated in a measuring unit instead of a second standard device,
Fig. 5C shows a third variant of a group of two hybridization units, in which a measuring unit is integrated instead of a third standard device, and
Fig. 5D shows a fourth variant of a group of two hybridization units, in which a measuring unit is integrated instead of a third standard device.

A measuring device 4 according to the invention comprises a measuring unit 5 and a processing unit 6 (cf. Fig. 4 ). The measuring unit 5 is designed so that it can be integrated into a laboratory system 1 in order to determine there the fluid parameters provided by the laboratory system 1. As laboratory systems 1, such systems should be understood here, which make it possible to run a variety of laboratory processes. It is preferred that the laboratory processes can be carried out automatically by means of these laboratory systems 1. Exemplary laboratory systems 1 can be designed to handle larger or smaller volumes of liquid. These are known as fermenters or pipetting machines (larger volumes), or as systems for spotting / immobilizing eg biological samples on laboratory-typical carriers. Other conceivable laboratory systems 1 are systems for carrying out PCR or sequencing reactions or, in a particularly preferred embodiment, systems for carrying out hybridization reactions. By the example of hybridization systems 2, the present invention will be described in more detail, but its scope is not limited.

FIG. 1 shows a vertical longitudinal section through an already known from the prior art hybridization unit 3 of such a hybridization system 2. The hybridization unit 3 comprises a standard device 33 and is from the document EP 1 260 265 B1 or from the document EP 1 614 466 A2 known. Both documents are patents or patent applications of the applicant of the current application. This standard device 33 is designed as a lid movable relative to a slide 35. Typically, such a slide comprises 35 nucleic acid probes, proteins or tissue slices that are to be contacted (hybridized) with a pattern. They are immobilized on a surface 36 of the slide 35. Typical slides 35 may be glass slides 35 suitable for light microscopy or at least have approximate dimensions to such glass slides, even if they are made of a different material (eg

Plastic). Also known are slides on glass or plastic base, on which, for example, a cellulose membrane is attached. For the movement, the standard device 33 can be inserted into a holder 26. This holder 26 is then - with inserted standard device 33 - moved via an axis 29 relative to the slide 35.

The standard device 33 defines with the slide 35 a gap-shaped hybridization space 34. The slide 35 can be positioned on a frame 28. The frame 28 can serve both for positioning slides 35 within a hybridization unit 3 and for transporting or storing the slides 35. It is itself positioned on a base plate 51 of the hybridization unit 3. For sealing the hybridization space 34, the standard device 33 comprises a sealing surface 50, which is preferably designed as an annular seal, for example as an O-ring. It seals the hybridization space 34 from the environment by applying a sealing surface 50 to a surface 36 of the slide 35.

The standard device 33 also includes lines 39 for feeding and discharging media into the hybridization space 34 or out of the hybridization space 34. The standard device 33 further comprises a pattern supply line 41 adapted for supplying sample liquids into the hybridization space 34 and an agitation device 42 for moving liquids in the hybridization space 34. Possible embodiments are described in detail in the above-mentioned documents EP 1 260 265 B1 and EP 1 614 466 A2 so that reference is made expressly to these documents for details. This agitation device 42 comprises for moving liquids a pressure chamber 44 in which an agitation pressure is generated. The pressure chamber 44 is separated by a membrane 43 from an agitation chamber 45. The agitation chamber 45 is in turn connected via an agitation line 46 to the hybridization space 34. After establishing a thermal equilibrium in the hybridization space 34 and after closure of the pattern supply line 41, a fluid is introduced into the pressure chamber 44 via a pressure line or discharged from it. Depending on the over- or under-pressure, the membrane 43 bends through, reduced or enlarged accordingly the agitation chamber 45 and moves the liquid through the Agitationsleitung 46 in the hybridization space 34. A variant of a standard device may include a second agitator 42 'with a pressure chamber 44', a membrane 43 ', an agitation chamber 45' and an agitation line 46 ', so that both devices can generate a pendulum motion of liquids in the hybridization space.

As in the document EP 1 614 466 A2 described, the standard device 33 in addition to the agitator 42,42 'includes a completely separate from this printing device 47, with which a space pressure in the hybridization space 34 is generated. This volume pressure is increased in relation to the surrounding atmospheric pressure and is superimposed by the agitation pressure in the hybridization space. The room pressure serves to prevent or suppress the formation of air bubbles in the hybridization space 34.

In essence, all lines 39 of the standard device for feeding or discharging media open into a common connection plane 38 of the standard device 33. This connection plane 38 preferably runs substantially parallel to the hybridization space 34. By means of a connection plate 37 of the hybridization unit 3 tight connection of the lines 39 of the standard device 33 with the lines 39 'of the hybridization system 1 allows.

In the following, the measuring device 4 according to the invention and its connection to a laboratory system 1 will now be described and explained in more detail using the example of a prior art hybridization system 2 introduced above:

FIG. 2 shows a vertical longitudinal section through an exemplary measuring unit 5 of an inventive measuring device 4 in a highly simplified and schematic representation. An inventive measuring device 4 serves to determine fluid parameters provided by a laboratory system 1. The measuring device 4 according to the invention is also suitable for carrying out a method according to the invention. For this purpose, the measuring unit 5 of the measuring device 4th integrated into a laboratory system 1. As already mentioned above, the measuring device 4 is to be explained in more detail in connection with hybridization systems 2, but it is not limited to the use in such systems.

In the FIG. 2 according to the invention comprises a measuring block 15 and at least one sensor 17. In this case, the measuring block 15 is designed such that it does not provide any space for carrying out a laboratory process or a reaction or can form part of such a space. As such a reaction space 34 is referred to in the context of this invention, a space in which a biological or chemical process (reaction) can proceed. Such processes are already described in more detail above, by way of example hybridization reactions or else PCR reactions may be mentioned at this point.

The at least one sensor 17 is arranged on or in fluidic connection with cavities 16 of the measuring block 15. These cavities 16 serve to receive fluids 13 provided by the laboratory system 1 and the hybridization system 2. By virtue of this arrangement, the sensors 17 are capable of determining the physical and / or chemical parameters of the fluids contained in the cavities 16.

These cavities 16 may be formed as fluid lines and / or as fluid chambers, which are arranged substantially completely within the measuring block 15. The arrangement of the orifices of fluid lines and fluid chambers in this connection plane 38 'corresponds essentially to an arrangement of supply and / or discharge lines in a common connection plane 38 of a laboratory system 1. By means of the connection plate 37 of the hybridization system 2, in which its lines 39 'also open into a plane, the cavities 16 of the measuring unit 5 are tightly connected to the line system of the hybridization system 2 and thus functionally integrated into the hybridization system 2. In fact, the measuring units 5 according to the invention can simply be used at the location of a standard device 33 in a hybridization system 2.

For determining parameters of the fluids 13 located in the measuring block 15, the at least one sensor 17 is arranged on or in fluidically active connection with the cavities 16 of the measuring block 15. In this case, the at least one sensor 17 is preferably positioned either on or in the cavities 16 so that it is in direct contact with the fluid 13 to be measured, without influencing the parameters of the fluids 13 themselves. Alternatively, the at least one sensor 17 is arranged in fluidic connection with the cavities 16 of the measuring block 15. In this case, the sensor 17 is not necessarily in direct contact with the fluid 13 of the cavities 16, but it may for example be separated from the cavities 16 by a membrane or other layer. The fluid parameters are then detected by the at least one sensor 17 via the fluidically active connection. Such an arrangement is in FIG. 2 for a sensor 17 designed as a pressure sensor 20 for gases. Fluid parameters, such as flow or fluid pressure, can then be detected by the sensor 17 via the fluidic connection.

The fluids 13 of the hybridization system 2 received by the cavities 16 can be liquids, gases or mixtures of liquids and gases. Liquids may include, for example, media, buffers or reagents for carrying out reactions. Liquids used may also include other reactants or reaction catalysts, such as enzymes or other proteins. Gases include air or inert gases such as noble gases or nitrogen (N ₂ ). In a preferred embodiment, N _{2 is used} as the drying fluid and pumped or blown through the cavities 16. In particular, in hybridization reactions N ₂ is preferably used for drying hybridization products on slides 35 or for blowing out the cavities 16 and other lines 39, 39 '.

According to this embodiment of a measuring device 4 according to the invention, when it is integrated in a laboratory system 1, the current parameters of fluids 13 provided by the laboratory system 1 are determined under at least approximately practical conditions within the measuring block 15: the parameters which are not measured are not measured of the measuring block 15 from external Devices, such as pressure pumps or heating / cooling systems, were generated on the fluid (target values). The measuring device 4 thus provides substantially comparable cavities with similar volumes or flow resistances as a standard device 33 has. This determines those fluid parameters which prevail within the laboratory system at the destination (actual values). The fluid parameters provided by external devices may differ more or less strongly from the parameters prevailing in the measuring block 15 after passage through various lines and valves. Crucial for the factually reliable assessment of a reaction quality, however, is the determination of the actual value. On the basis of this actual value, one can then make sound conclusions about the reaction process that has taken place in the laboratory system. On the other hand, for example, an experimenter, a service technician or the producer can use the actual value determination for calibrating and adjusting the external devices.

Sensors 17 are well known in the art. In particular, in the context of this invention, the term sensor 17 should be understood as meaning those technical components which are capable of recording physical and / or chemical properties of its environment or of measured objects as measured values. This measured value recording can be carried out qualitatively (for example as a yes / no answer) or quantitatively. The acquired measured values can then be converted by the sensor 17 itself or by downstream further components into processable quantities, e.g. electrical or electronic signals are converted. At least one sensor 17 is preferably included by the measuring unit 5. Depending on requirements, however, a plurality of sensors 17 may also be included in the measuring unit 5.

Parameters to be recorded are, for example, pressure, flow velocity, mass flow or volume flow, temperature, sound conductance or density, optical properties (eg coloration or turbidity), or else substance concentrations or pH values. In principle, all the physical and / or chemical properties of a fluid known to the person skilled in the art, which can be determined by means of sensors 17, can be measured within the scope of this invention. Prefers measured fluid parameters are the pressure, the volume flow (determined on the basis of the flow velocity or the flow) and the temperature of a fluid.

The operation of sensors 17 is well known in the art, and therefore should not be further elaborated at this point. By way of example, the principle of semiconductor technology or resistance measurement may be mentioned here. In a measuring device 4 according to the invention, sensors 17 of very different modes of operation can be integrated. The prerequisite is only the detection of the physical and / or chemical parameters of the fluids 13, which are located in the cavities 16, and their conversion into processable quantities or signals. It is not critical to the feasibility of the invention whether a type of sensor 17 is used only for a particular parameter or for multiple parameters. For example, a sensor can be used both for determining a flow velocity of a liquid or for determining a flow velocity of a gas, if it is designed accordingly. In general, commercially available sensors 17 can be used.

The measurement signal output by the at least one sensor 17 is processed by a processing unit 6 of the measuring device 4 into a desired size or response for evaluation. The processing unit 6 comprises at least one microcontroller 11, which transmits the digital data received by the at least one sensor 17 to a computer 12 of the processing unit 6. Furthermore, the processing unit 6 comprises data control systems 8, 9, 10, which process and forward the signals emitted by the sensor for the microcontroller 11. Such data control systems 8, 9, 10 include analog / digital converters 10, serial or parallel data buses 8 and direct digital input / output connections 9. It is also conceivable to use other elements or methods known from the prior art in the processing unit 6 which are necessary for a controlled data forwarding and processing.

In a first preferred embodiment, the at least one sensor is for determining a flow velocity of a fluid or for determining a Fluid pressure formed. In this case, the at least one sensor 17 for determining a flow velocity of a fluid can be designed as a flow sensor 19 for liquids or gases. Furthermore, the at least one sensor 17 for determining a fluid pressure may be designed as a pressure sensor 20 for liquids or gases.

For example, sensors 17 used in this and the following embodiments are:

Pressure sensors:

• ■ SenSpecial™ Drucksensor SCPB-B0/3.5G50i2C32717R5 und/oder
• ■ SenSpecial™ Drucksensor SCPB-B0/1.5G50i2C32717R5

Diese beispielhaften Drucksensoren basieren auf der Halbleitertechnologie und funktionieren nach dem piezoresistiven Prinzip.The company SensDev LTD. (47 Station Street, Birkirkara - BKR 12, Malta / Kressnerstrasse 12, 09217 Burgstaedt, Germany):

• ■ SenSpecial ™ Pressure Sensor SCPB-B0 / 3.5G50i2C32717R5 and / or
• ■ SenSpecial ™ Pressure Sensor SCPB-B0 / 1.5G50i2C32717R5

These exemplary pressure sensors are based on semiconductor technology and operate on the piezoresistive principle.

Fluid flow sensors:

The company IST AG (Industriestr. 2, 9630 Wattwil, Switzerland):
■ FS1.A.1L.195
The measuring principle of this sensor is based on resistance measurement by means of a high-ohm resistor and a low-ohm resistor.

Temperature sensors:

The company IST AG (Industriestr. 2, 9630 Wattwil, Switzerland):
■ TSic-306F
This exemplary temperature sensor is based on measurement of a voltage linear to the temperature. This voltage is then digitized by an analogue / digital converter.

In a second preferred embodiment, the measuring unit 5 comprises at least two sensors 17. According to this second preferred embodiment, at least one pressure and a flow rate of fluids 13 provided by a laboratory system 1 are measured with the measuring unit 5. There is one for that Sensor is designed as a flow sensor 19 and the second sensor as a pressure sensor 20. Depending on the tolerance of the sensors 19, 20 used, the two regions of the cavities 16, on which the sensors 19, 20 are arranged, are separated from one another by means of valves. This is desirable in particular when, for example, a gas pressure sensor 20 used is impaired in its function during liquid contact. Such an embodiment is exemplary in the Figures 4B and 4C shown. Various variants of measuring concepts with a measuring unit 5 and a processing unit 6 are shown here. A separation of cavities 16 has been achieved, for example, by using the valve NEX 212S from Parker Hannifin Corporation (sold by Sensortechnics GmbH, Boschstrasse 10, 82178 Puchheim, Germany). In the embodiments shown here was the pressure sensor SCPB-BO / 3.5G50i2C32717R5 the company SensDev LTD. used to determine the gas pressure of a drying fluid (eg N ₂ ). This sensor 17 is designed as a high-pressure sensor 20 and is therefore particularly suitable for determining the N ₂ pressure. To protect the sensor from liquid pressure surges, the use of a valve has been introduced in these variants.

A particularly preferred variant is the use of separate pressure sensors 20 for different pressure ranges, as indicated above. It is preferred when the measuring unit 5 is integrated, for example, in a hybridization system 2 of the prior art described above. In this case, a high pressure sensor and a low pressure sensor are used to determine an N ₂ pressure and to determine agitation and / or chamber pressure. High-pressure and low-pressure sensors are characterized by different measuring ranges. Such a sensor arrangement with two pressure sensors 20 is in the FIGS. 4A, 4B and 4C shown.

For determining the pressure of a drying fluid, such as N ₂ , a pressure sensor 20 designed as a high-pressure sensor (with a measuring range of up to 3.5 bar) is preferably used (for example the SenSpecial ™ pressure sensor SCPB-BO / 3.5G50i2C32717R5 from SensDev LTD.). The pressure to be measured of the drying fluid in a preferred embodiment is between 1.5 and 3.5 bar, in a particularly preferred embodiment between 2 and 3 bar and in a most preferred embodiment, between 2.5 and 2.9 bar above ambient atmospheric pressure.

On the other hand, a pressure sensor 20 designed as a low-pressure sensor (with a measuring range of up to 1.5 bar) is used to determine an agitation pressure and / or a chamber pressure. The room pressure is generated by the pressure device 47 and is preferably between 10 mbar and 1.5 bar above the ambient normal atmospheric pressure. Particularly preferred is an agitation pressure of 0.9 to 1 bar above the ambient normal atmospheric pressure. The agitation pressure is, as described above, formed by the agitation device 42 independently of the room pressure. It is superimposed on the room pressure in the hybridization space 34. The agitation pressure is preferably between 0.5 and 1.4 bar, and more preferably between 1.2 and 1.3 bar. Thus, the pressure to be determined by the low-pressure sensor, which is composed in particular of chamber pressure and agitation pressure, is between 10 mbar and 1.5 bar above the ambient normal pressure. A preferably used, designed as a low pressure sensor pressure sensor 20 is the SenSpecial ™ pressure sensor SCPB-B0 / 1.5G50i2C32717R5 SensDev LTD.

This use of two separate sensors 20 for low pressure and high pressure of gases makes it possible, for example, to detect structural defects in a hybridization system 2 according to the invention. For example, if a membrane 43, 43 'of the agitator 42, 42' is defective, the pressure drop can be detected specifically by the low pressure sensor become. The error detection is thus sensor-specific.

In an alternative embodiment, the measuring unit 5 for determining a flow speed of a fluid 13 comprises at least two identically constructed sensors 19, 20, which are arranged at a distance from one another or in fluidic connection with a cavity 16. Preferably, this cavity 16 is designed as a fluid line which corresponds in its dimension to a fluid line of a laboratory system 1, for example a standard device 33 of a hybridization system 2 described here. This alternative embodiment is particularly preferred for the determination of a liquid flow. The flow speed is measured on a measuring section. This measuring section is that section of the fluid line which lies between the two flow sensors 19. The principle of such a flow measurement is that each of the two preferably identical sensors 19 provides a signal when a liquid front passes the sensor. In order to determine the flow velocity, the amplitude of the signal is then not used, but the time t (the time signal) which the liquid needs to flow through the measuring section between the two identically constructed sensors 19 is determined. By incorporating the length of the measuring section and the diameter of the fluid line, the volume flow is then calculated.

An exemplary measurement of the fluid flow in the measuring section between the two flow sensors 19 was carried out by means of a prototype of the measuring block 15 of the measuring unit 5 according to the invention (cf. Fig. 2 ) and is in FIG. 3 shown. The abscissa is the time axis, which is divided into steps of 5'000 ms and 5 s, respectively. The ordinate shows the intensity or the amplitude of the flow sensor signal in [mV]. On the basis of this representation, it is clear that the time t required for the liquid to flow through the measuring path between the two sensors 19 corresponds to or is calculated from the time difference (Δt) represented in this figure.

The sensors FS1.A.1L.195 from IST AG were used for this signal measurement. These are identical flow sensors for gases or liquids. Very good is the signal that the sensor I and the sensor II delivers when passing through a liquid front. Because of the clear signals, the time (δt) required by the liquid front to travel the measuring distance between the two sensors I, II can be accurately determined and calculated back to the flow rate. Flow rates of liquids between 5 ml / min and 20 ml / min, more preferably between 8 ml / min and 14 ml / min are preferred for this hybridization system. Although specifically suitable for such a flow measurement flow sensor 19 may directly determine the flow velocity of a liquid. In experiments, it has been found that the measurement is more accurate when two identical flow sensors 19 of this type are arranged on a measuring section, and closed by means of a measured time signal on the flow rate becomes. In this way, possible disturbing influences of changing environmental conditions (eg changes in the room or fluid temperature) can be reduced. In a variant of this embodiment, however, it is also possible to use sensors 17, which are designed as light barriers and emit the optical signals for further processing. Such a sensor may be a commercially available forked light barrier.

Such an alternative embodiment of a measuring unit 5 with two identical sensors for determining a flow rate of a liquid is in the FIG. 2 shown. Here, the measuring section is formed tubular, and the two identical sensors 19 are arranged on or in fluid communication with the tubular fluid line 16 ', one at the beginning and one at the end of the hose. One side of the measuring section is shown with a solid line, the other side with a dashed line. Start and end are substantially horizontal, the central part of the tube is shown as vertically extending fluid lines. However, any other arrangement outside and / or within the measuring unit 5 is conceivable in which the two sensors 19 define a signal path. If the measuring unit 5 is integrated into a hybridization system 2 described above, the dimension of the measuring section within the measuring block is preferably selected such that it corresponds at least approximately to the dimension of a line with the fluid to be characterized within the standard device 33.

As mentioned above, in a particularly preferred embodiment of this alternative arrangement, the sensors 17 of identical construction for measuring a flow velocity of a fluid are designed as flow sensors 19. Likewise preferred is the use of two light barriers 21 as two identical sensors 17. A flow sensor 19 can emit an acoustic or electrically capacitive signal, while the sensors designed as light barriers 21 emit optical signals for further processing. The signals emitted by the sensors are then used by the processing unit 6 of the measuring device 4 to calculate a flow velocity of the fluid 13.

If the measuring device 4 according to the invention is integrated into a laboratory system 1 via its measuring unit 5, it can determine "on site" the fluid parameters provided by the laboratory system 1 (actual values). Preferably, the measuring unit 5 of the measuring device 4 is inserted into a hybridization system 2. Within the scope of the present invention, a hybridization system 2 is to be understood as meaning a laboratory system 1 which is suitable for carrying out hybridization reactions. Typically, such hybridization systems 2 provide at least one reaction space 34 in which the hybridization reaction can proceed. It further comprises vessels for storing fluids 13, conduits, pumps, valves, seals, devices for generating fluid parameters, and the like. Such an exemplary hybridization system is the one mentioned above and from the documents EP 1 260 265 B1 or EP 1 614 466 A2 known from the prior art. Preferably, the measuring unit 5 is integrated into a hybridization unit 3 of this hybridization system 2.

In FIG. 2 is simplified, such a hybridization system 2 is shown, in which a measuring unit 5 of a measuring device 4 according to the invention is integrated. As described and from the FIG. 1 recognizable, the hybridization system 2 comprises a hybridization unit 3 with a standard device, wherein the standard device 33 with a slide 35 defines the hybridization space 34. In FIG. 2 Instead of the standard device 33, a measuring unit 5 of the measuring device 4 according to the invention is inserted into the holder 26, so that the measuring unit 5 can be moved by means of the holder 26 with respect to the slide 35 or the base plate 51. If the measuring unit 5 is to be used in another laboratory system 1, it can also be used in another way in this system 1. For example, simple slip-on or sliding mechanisms may be used, as well as other mechanisms known in the art which are well known to those skilled in the art and therefore will not be discussed further here.

If the measuring unit 5 of the measuring device 4 is corresponding FIG. 2 used in a hybridization system 2, no hybridization reactions are performed at this position, since the measuring unit 5 according to the embodiments described so far does not include or define a reaction space 34. If reactions are to be carried out parallel to the measurement, an arrangement of 2 or more hybridization units 3 is preferred, one of which is replaced by the measuring unit 5 (cf. Fig. 5A ). In this way, reactions can be carried out by means of the hybridization unit 3, and the parameters can be determined in parallel from the same fluids by means of the measuring instrument 4. This is made possible by the supply lines and leads 39 'of the hybridization system 2 via terminals of the measuring unit 5 with the cavities 16 of the measuring block 15 are connectable. In this case, substantially all the cavities 16 of the measuring block 15 open in a common connection plane 38 'of the measuring unit 5. By means of the connection plate 37 of the hybridization system 2, a tight connection of the cavities 16 of the measuring unit 5 with the lines 39' of the hybridization system 2 is made possible.

In particular for hybridization reactions, a wide variety of parameters are critical. In addition to the flow rate and pressure of fluids 13, which are necessary for adequate fluid supply and thus for providing certain reactants, temperature is also an important parameter. The temperature of a hybridization reaction is determined by the temperature of the fluids 13 provided and also by the temperature of the slide 35. It is usually influenced by temperature regulators and heating elements 49. Such temperature regulators correspond for example to the temperature control plate of the hybridization system 2 described here. Such a temperature control plate can be tempered via one or more heating elements 49. Peltier elements are preferred, but other heating elements well known to those skilled in the art are also usable in this connection. In particularly preferred variants of the embodiments described above, therefore, the measuring unit 5 of the measuring device 4 comprises a niche 25, in which at least one temperature sensor 24 is arranged. If such a measuring unit 5 is integrated in the hybridization system 2, it is preferably designed to be movable by means of the holder 26 against a surface 31 of the hybridization system 2, from which a temperature is to be determined. FIG. 2 shows such a measuring unit 5, in the example, two temperature sensors 24 are arranged in the niche 25. Surfaces 31 of the hybridization system are, for example The surface 36 of a slide 35 or the surface 52 of the base 51 of the hybridization unit 3. Preferably, the temperature sensor 24 or the two temperature sensors 24 are arranged on a circuit board 22 in the niche 25 that during a movement of the measuring unit 5, the surface 31 is acted upon by a metal plate 23. This metal plate 23 is preferably made of a metal with good thermal conductivity, such as aluminum or aluminum alloys and is in good thermal contact with the temperature sensors 24, which are connected via the circuit board 22 to the processing unit 6. In this case, the metal plate 23 may for example be dimensioned so that it substantially corresponds to the surface of the niche 25 and thus does not protrude laterally beyond this. In FIG. 2 For example, the metal plate 23 is dimensioned to be partially disposable within the niche 25 (with respect to its height). Alternatively, however, it may also be larger than the niche 25 and protrude beyond it, but preferably it is not larger than the surface 31 which acts on it.

In a particularly preferred variant of the at least one temperature sensor 24 of the measuring unit 5 is formed on a surface 31 of the hybridization system 2, of which a temperature is to be determined, resiliently acted upon. For this purpose, at least one spring element 32 is mounted in the niche 25, but depending on the shape of sensor 24 and niche 25, a plurality of spring elements 32 may also be used. This arrangement is particularly advantageous when the temperature sensor or the temperature sensors 24 are to be brought as close as possible to the surface 31 of the hybridization system 2, but without this surface 31, for example. damaged by too much imprint.

It is preferred that the surface 31 of the hybridization system 2 be formed as a temperature control plate. If the surface 31 is contacted directly by the temperature sensor 24, ie by its metal plate 23, then the temperature of the metal plate 23 equalizes in a very short time that of the surface 31, so that the measurement can be done simply by touch contact and heat conduction. Thus, by means of the temperature sensor 24 of the measuring unit 5, the actual prevailing temperature of the surface 31 can be determined. If the measurement, however, by means of detection of heat radiation, the Sensor 24 does not necessarily contact the surface 31, but could be arranged at a defined distance from this (not shown). A measurement of the temperature at the surface 31 by convection would be conceivable; However, this variant is inferior to the detection of heat radiation and the measurement by means of touch contact and heat conduction. Particularly preferred is the measurement by means of touch contact and heat conduction, because this method of measurement is technically simple and inexpensive executable and still provides reliable measurement results.
To determine the temperature of a surface 31 of the hybridization system 2, in a particularly preferred variant, a temperature sensor 24 is used which preferably has a large measuring range with the highest possible accuracy. A temperature sensor 24 used in this particularly preferred variant is, for example, the temperature sensor TSic-306F from IST AG (Industriestr. 2, 9630 Wattwil, Switzerland). By means of this sensor, a temperature-linear voltage is generated, which is digitized by an analog-to-digital converter. This sensor has a measuring range of 0 ° C to 100 ° C with an accuracy of +/- 0.1 ° C to 0.3 ° C. However, it is also possible to use two or more temperature sensors 24 for determining the temperature, wherein each of these temperature sensors 24 used has a different measuring range, each with high accuracy. A shortening of the measuring section facilitates the necessary offset calibration.

Depending on requirements and fluids used by the laboratory system 1, one or more sensors with specificity for a wide variety of fluid parameters can be used for the measuring device 4 according to the invention. Particularly preferred embodiments and variants of sensors and their arrangement within the measuring device have already been discussed in this document and can also be the FIGS. 4A to 4C be removed. These figures show different variants of measuring concepts of a measuring device 4 according to the invention. These measuring concepts illustrate the networking of the sensors and the computer for evaluating the sensor signals by means of various data management systems 8, 9, 10 and at least one microcontroller 11. Typically, the microcontroller 11 is part of the computer 12. The sensor data are first transported via connections 7 to the data management systems 8,9,10 and processed so that they of the microcontroller 11 and the computer 12 are evaluated. These data management systems 8, 9, 10 are preferably structurally encompassed by the computer 12, as in FIG FIG. 4A shown. Alternatively, the data management systems 8, 9, 10 are combined separately into a structural unit, which is independent of the computer 12 ( Fig. 4C ), or that is encompassed by a second computer 12 ( Fig. 4B ).

A =

Agitationsdruck zum Bewegen der Flüssigkeiten gegenüber von auf den Objektträgern 35 immobilisierten Proben und Kammerdruck zum Vermeiden von Gasblasen; mit einen Einlassventil und offenem Auslass;

B =

Trocknungsgasfluss (vorzugsweise N₂) mit Einlassventil;

C =

Flüssigkeitszufluss mit Einlassventil;

D =

Flüssigkeitsabfluss mit Auslassventil.

The FIG. 4 shows three preferred variants of the inventive measurement concept. In each case, the connections or the supply and discharge lines 39 'are shown on the left side, which are provided by the hybridization system 2. This provision is preferably carried out in a common connection plane 38 (cf. Fig. 2 ) and is for all variants in the FIGS. 4A, 4B and 4C identical. A measuring device 4 according to the invention comprises in each case a measuring unit 5 and a processing unit 6. At the measuring unit 5 according to the invention, the cavities 16 correspond to the inlets and outlets 39 of a standard device 33 and preferably all open in a common connecting plane 38 '. Preferably, all these media connections are arranged in a straight line (cf., for example EP 1 260 265 B1 ). By way of example, the following connections or fluid sources are shown here in each case (in the order from top to bottom):

A =

Agitation pressure for moving the liquids against samples immobilized on the slides 35 and chamber pressure to avoid gas bubbles; with an inlet valve and open outlet;

B =

Drying gas flow (preferably N ₂ ) with inlet valve;

C =

Fluid inlet with inlet valve;

D =

Liquid drain with outlet valve.

Basically, the processing units 6 are similar to these three measurement concepts and comprise a serial / parallel data bus 8; a direct digital input / output line 9, an analog / digital (A / D) converter 10 and a microcontroller 11, which communicate with each other via connecting lines 7 or exchange data or signals.

The FIGS. 4A, 4B and 4C each show a first pressure sensor 20, which is designed for measuring lower pressures (eg 10 mbar to 1500 mbar), which are provided by the fluid source A. The pressure measuring signals are passed on via the A / D converter 10 to the microcontroller 11 for evaluation.

The FIGS. 4A, 4B and 4C each show a second pressure sensor 20, which is designed for measuring higher pressures (eg 1.5 to 3.5 bar), which are provided by the fluid source B. The pressure measurement signals are again passed via the A / D converter 10 to the microcontroller 11 for evaluation. The three measuring concepts differ here in that this second pressure sensor 20 in the Figures 4B and 4C can be separated by a valve from the source B, which is in the FIG. 4A not the case.

The FIG. 4C shows a first flow sensor 19, which is designed exclusively for measuring the gas flow, which is provided by the fluid source B. The gas flow measuring signals are transmitted via the serial / parallel data bus 8 to the microcontroller 11 for evaluation.

The FIG. 4C shows a second and third flow sensor 19, which are in direct fluid communication with each other and which are designed exclusively for measuring the liquid flow, which is provided by the fluid source C and leaves the measuring unit 5 via the liquid drain D. The fluid flow measurement signals are also passed on the serial / parallel data bus 8 to the microcontroller 11 for evaluation on. In contrast, the show FIGS. 4A and 4B a second and third flow sensor 19, which are also in direct fluid communication with each other, which are, however, designed to measure a liquid flow and a gas flow, wherein the liquid flow from the fluid source C, the gas flow but from the source B is provided. In any case, these media leave the measuring unit 5 via the liquid drain D.

All three variants according to the FIGS. 4A, 4B and 4C comprise at least one temperature sensor 24 arranged independently of all these fluid flows and is connected via separate connection lines 7 with the direct digital input / output line 9 and the microcontroller 11 of the computer 12.

In the following, further embodiments are presented and explained in more detail, in which the measuring unit 5 of the measuring device 4 is integrated into a hybridization system 2 from the prior art. As presented above and in the cited documents, such a hybridization system 2 comprises at least one hybridization unit 3. This hybridization unit 3 provides the reaction space 34 defined by at least one standard device 33 and one slide 35. The principle is that the measuring device 4, when it is integrated into the hybridization system 2 via its measuring unit 5, determines "on-site" the actual values of the fluid parameters provided by the hybridization system. In a preferred embodiment, the measuring unit 5 comprises substantially the same connections for the supply and discharge of fluids 13 provided by the hybridization system 2 as the standard device 33. Furthermore, the measuring unit 5 is designed in its essential dimensions so that it can be used instead of Standard device 33 can be inserted into a hybridization unit 3. Even in the dimensions of the cavities 16, a measuring unit 5 largely corresponds to those dimensions of the cavities of a standard device 33. In addition, the fluid parameters measured in the measuring unit can be mathematically corrected or adjusted so that they can be considered as measured under "real-time conditions" and with the ratios in a reaction space 34 of the standard device 33 can be compared. The measured in the measuring unit 5 fluid parameters are thus transferable to the fluid parameters of a hybridization reaction.

In a preferred variant of this embodiment, the measuring unit 5 of the measuring device 4 is designed so that it can be used in place of a first standard device 33 'in a hybridization system 2. In such a hybridization system 2, the standard device 33 of the hybridization unit is designed as this first standard device 33 '. It defines, in combination with a slide 35, a single hybridization space 34. Such a first standard device 33 'is shown in U.S. Pat FIG. 5A at position I in the holder 26 of the hybridization system shown used. The measuring unit 5 is designed such that it can be inserted into the hybridization system 2 at the location of a further first standard device 33 '. Such a situation is in FIG. 5A at position II in the holder 26 of the hybridization system 2. Thus, no hybridization reactions are carried out at this position II since the measuring unit 5 according to this variant does not include or define a reaction space 34. The further positions III and IV are also occupied by a further first standard device 33 '. Thus, up to three hybridization reactions can be carried out parallel to the determination of fluid parameters. Preferably, no slide 35 or a slide without immobilized samples is placed at position II. The hybridization spaces 34 at the positions I, III and IV are indicated by the sealing surfaces 50.

In a further preferred variant of this embodiment, the measuring unit 5 of the measuring device 4 can be used instead of a second standard device 33 "of a hybridization system 2. The standard device 33 of a hybridization unit 3 of the hybridization system 2 is designed as this second standard device 33" , This defines, in combination with a slide 35, at least two hybridization spaces 34. These two hybridization spaces 34 are sealed from the environment by means of two sealing surfaces of the second standard device 33 "Such a second standard device 33" is in the document EP 1 614 466 A2 described and in FIG. 5B shown inserted in position I in the holder 26 of the hybridization system. According to the document EP 1 614 466 A2 Such a second standard device 33 "either comprises a common agitation device 42 for both hybridization spaces 34 as well as common connections for the individual lines 39. Alternatively and for the use of a measuring unit 5 according to the invention, this second standard device 33" preferably has individual connections Hybridization space, which lie in a common connection plane 38. A measuring unit 5 of this variant is designed such that it can be inserted in the hybridization system 2 instead of a second standard device 33 " FIG. 5B shown at position II. In this case, the measuring unit 5 next to the measuring block 15 without reaction space 34 and at least a sensor 17 and a reaction block 40. This reaction block 40 defines with the slide 35 at least one hybridization space 34, which is preferably delimited by a sealing surface 50 from the environment. The reaction block 40 comprises substantially the same conduits 39 "as the second standard device 33" for a hybridization space 34 as well as substantially the same ports 38 "for the delivery and discharge of fluids 13 provided by the hybridization system 2 as the second standard device 33 ".

1. a) Fluide 13 des Hybridisierungssystems 2 in einen Reaktionsraum 34 des Reaktionsblockes 40 der Messeinheit 5 zum Durchführen einer Hybridisierungsreaktion geleitet werden; und gleichzeitig
2. b) Fluide 13 des Hybridisierungssystems 2 in einen Messblock 15 der Messeinheit 5 zum Bestimmen von durch das Hybridisierungssystem 2 bereitgestellten Fluidparametern geleitet werden.
   Sollen grössere Anzahlen an Hybridisierungsreaktionen neben einer Parametermessung zeitgleich in einem Hybridisierungssystem 2 durchgeführt werden, wird diese Ausführungsform eines Messgerätes bevorzugt in einem Hybridisierungssystem 2 verwendet, das zumindest eine Gruppe aus vier Hybridisierungseinheiten 3 mit je einer zweiten Standard-Vorrichtung 33" umfasst. Die Messeinheit 5 wird dann an Stelle einer zweiten Standard-Vorrichtung 33" in die Hybridisierungseinheit 3 eingesetzt. In Figur 5B ist eine solche Gruppe aus vier Hybridisierungseinheiten dargestellt, die in einen Halter 26 des Hybridisierungssystems 2 eingelegt sind. Die zweite Standard-Vorrichtung 33" der Hybridisierungseinheit 3 an Position II ist von einer Messeinheit 5 ersetzt. Soll eine Reaktion mittels des Reaktionsblockes 40 der Messeinheit 5 an dieser Position II durchgeführt werden, muss hier entsprechend ein Objektträger 35 mit immobilisierten Proben positioniert sein.

In this way, in parallel in a measuring unit 5:

1. a) fluids 13 of the hybridization system 2 are passed into a reaction space 34 of the reaction block 40 of the measuring unit 5 for carrying out a hybridization reaction; and at the same time
2. b) fluids 13 of the hybridization system 2 are conducted into a measuring block 15 of the measuring unit 5 for determining fluid parameters provided by the hybridization system 2.
   If a large number of hybridization reactions are to be carried out simultaneously in a hybridization system 2 in addition to a parameter measurement, this embodiment of a measuring device is preferably used in a hybridization system 2 which comprises at least one group of four hybridization units 3 each with a second standard device 33 " is then inserted into the hybridization unit 3 instead of a second standard device 33 ". In FIG. 5B is such a group of four hybridization units, which are inserted in a holder 26 of the hybridization system 2. The second standard device 33 "of the hybridization unit 3 at position II is replaced by a measuring unit 5. If a reaction is to be carried out by means of the reaction block 40 of the measuring unit 5 at this position II, a slide 35 with immobilized samples must be correspondingly positioned here.

The arrangement of four hybridization units into a group according to the FIGS. 5A and 5B is preferred insofar as that the temperature control plate of the hybridization system 2 has such dimensions that a frame 28 of the size of a microplate with four mutually parallel slides 35 just fits on the temperature control plate. All hybridization spaces 34 of such a hybridization unit 3 thus have identical temperature conditions. Depending on requirements, not only one of the first or second standard devices 33 ', 33 "is replaced by a measuring unit 5 according to the invention, but several. For example, if the hybridization system 2 is to be adjusted for the first time after production, all standard devices 33' are preferred. 33 "replaced by measuring units 5. In this way, the fluid parameters can be determined and optionally adjusted on each of the positions I-IV. In a further, preferred variant of this embodiment, the measuring unit 5 is designed so that it is used in place of a third standard device 33 "'in the hybridization unit 3 of a hybridization system 2. In such a hybridization system 2, the standard device 33 as a third standard device 33 "'formed. This, in combination with a slide 35, defines at least three or more hybridization spaces 34. Such a third standard device 33 "'is incorporated in the FIGS. 5C and 5D each shown on the position I / II. The individual reaction spaces are delimited by separate sealing surfaces 50 from the environment. The third standard devices 33 '' shown here each comprise four hybridization spaces 34. As in FIGS FIGS. 5C and 5D is indicated, a third standard device 33 "'is formed in its essential dimensions greater than a first or second standard device 33" (verg FIGS. 5A and 5B ). More specifically, a third standard device 33 "'substantially corresponds in dimension to two interconnected first or second standard devices 33', 33". This enlargement is preferred in order to take account of the increased number of connections required as well as supply and discharge lines of fluids 13 provided by the hybridization system 2 and their supply lines to or their derivatives from the four hybridization spaces 34. In this case, the third standard device 33 "'common connections for the supply and discharge of media, or for each of them defined hybridization space 34 may include a separate set of connections for the supply and discharge of fluids 13.

In this further variant, the measuring unit 5 is designed in such a way that it can be inserted into the hybridization system instead of the third standard device 33 " FIGS. 5C and 5D each shown at position III / IV in the holder 26 of the hybridization system 2. In this case, this measuring unit 5 comprises a measuring block 15 without reaction space 34 and with at least one sensor 17 and a reaction block 40. The reaction block 40 defines at least two or more hybridization spaces 34 with the slide 35. The number of hybridization spaces 34 defined by the reaction block 40 is variable. In FIG. 5C a measurement unit 5 is shown at position III / IV, whose reaction space defines three hybridization spaces 34. In FIG. 5D By contrast, a measuring unit 5 at position III / IV is shown, whose reaction block defines four hybridization spaces. In this case, all hybridization spaces 34 of a reaction block 40 are preferably defined with a single slide 35.
If larger numbers of hybridization reactions in addition to a parameter measurement at the same time in a hybridization system with a third standard device 33 '''are performed, the measuring device 4 is preferably used in a hybridization system 2, the at least one group of two hybridization units 3, each with a third standard The measuring unit 5 of the measuring device 4 is then inserted into the hybridization unit instead of a third standard device 33 "'. The FIGS. 5C and 5D show such a group of two hybridization units 3, which are inserted into a holder 26 of the hybridization system 2.

In a variant of these preferred embodiments, the reaction block 40 of the measuring unit 5 for replacing the second or third standard device 33 ", 33"'comprises further elements of these standard devices 33 for carrying out hybridization reactions. In this case, the reaction block 40 preferably comprises at least one pattern supply line 41 for feeding sample liquids into at least one hybridization space 34. More preferably, the reaction block 40 further comprises at least one agitation device 42, 42 'for generating an agitation pressure and for moving liquids 13 in a reaction space 34 This agitation device 42 of the reaction block 40 is substantially constructed like that of the standard device 33. Depending on the standard device 33 passing through the reaction block 40 of a measuring unit 5 is replaced, this may also include a number of agitators 42, which corresponds to the number of hybridization spaces 34.

The reaction block 40 particularly preferably comprises at least one pressure device 47 which is completely separate from the agitation device 42 for establishing a spatial pressure to be superimposed by the agitation pressure in at least one hybridization space 34. Pattern supply line 41, agitation device 42 and pressure device 47 are already associated with FIG FIG. 1 discussed and from the documents EP 1 260 265 B1 or EP 1 614 466 A2 known. These devices should therefore not be carried out again at this point. It is important that the principle of the standard device is transferred to a reaction block 40 of the measuring device 4 according to the invention. Because of the resulting complexity and the consequent complexity of the drawings, which a measuring unit 5 with measuring block 15, their cavities 16 and sensors 17 additionally with reaction block 40, sample supply line 41, agitation device 42 and printing device 47, is here only an example of a referenced principle arrangement and waived such a drawing. A measuring device 4 with at least one measuring unit 5, which comprises at least one sensor for determining a chamber pressure, is preferred. This chamber pressure serves to inhibit the formation of gas bubbles in the reaction space 34 and is generated by the pressure device 47 (see Source A in FIG Fig. 4 ). An exemplary sensor used is the low-pressure sensor described above, with which the chamber pressure and also this preferably cyclically superimposed agitation pressure are determined.

Particularly preferred variants of the described embodiments include a temperature control plate which is formed as a bottom plate. Such a temperature plate is thus capable of surface contact recording of up to four slides 35 capable. This may be desirable to avoid temperature loss between the temperature control plate and slide 35. In a further possible variant, the temperature control plate is formed as a cover plate (not shown), with which up to four slides 35 (compared to the Figures 1 and 2 ) inverted standard devices 33 or measuring units 5 can be lowered. Also, up to four slides 35 (as compared to the Figures 1 and 2 ) normally oriented standard devices 33 or measuring units 5 are raised (not shown).

It should be emphasized that with a measuring device 4 according to the invention both snapshots of the parameters prevailing in a laboratory system 1 can be determined, as well as the behavior of the parameters as a function of time. In the latter measurement, sensor data are continuously tracked and possibly recorded over a certain period of time. From this data can then be read, for example, the pressure curve or the temperature profile for a desired period. It is also conceivable that when using two or more sensors for a particular fluid parameters and gradients can be determined within the system. The advantage here is the determination of pressure gradients or temperature gradients.

The present invention also includes, in addition to a measuring device 4, a method for determining fluid parameters provided by a laboratory system 1. The implementation of such a method according to the invention comprises the use of a measuring device 4 with a measuring unit 5 and a processing unit 6, which has already been discussed in detail above. Particularly preferably, the measuring device 4 is installed in a hybridization system 2. The method according to the invention as well as the measuring device 4 according to the invention can be used at different usage levels of a laboratory system 1. For example, it can be used directly in production for setting and checking the newly manufactured laboratory system 1 to defined and standardized factory settings. For this application, it is preferred that the sensors 17 used are calibrated by means of calibration sensors (eg the sensors F-20 / CV-5k0-ABD-33-V and L23-ABD-33-K-70S from Bronkhorst, Nenzlingerweg 5, 4153 Reinach, Switzerland) are initially externally checked for their function. When the laboratory system 1 is in operation at a customer's premises, both customers and service technicians can use the meter 4 to self-control the actual fluid parameters provided by the laboratory system. Thus, it is now possible to circumvent protracted, mostly based on biological or chemical assays, test experiments, so that up to a third of the previously used test time can be saved. This can save a substantial part of the test costs. In addition, a check of the preset parameters can be performed before, for example, particularly costly experiments on the laboratory system 1 should be performed. For example, a slide costs about 1000 CHF, so if you use 4 to 40 slides per trial series, you can expect up to 40,000 CHF. Similarly, in diagnostic laboratories (eg clinics) misdiagnoses due to device deficiencies can be reduced by regularly checking the settings of the systems by means of a measuring device 4 according to the invention. In this way it is possible to identify and correct malfunctions or incorrect calibrations of the laboratory system 1 used in questionable or critical reaction results in a simple method. It is particularly advantageous to look at the possibility to limit the troubleshooting by means of the inventive measuring device 4 early in the error analysis in such questionable or critical reaction results. Thus, when using the measuring device 4, an error can already reliably be assigned to the device in a first step (in the case of a lack of devices) or, in the case of a detectable device error, to the application.

This method is preferably used for calibrating and / or adjusting the laboratory system 1 by means of the signals received by the at least one sensor 17 of the measuring unit 5 and processed by the processing unit 6. In this context, calibration should be understood to mean the acquisition of measured data and the comparison of these data with defined standards. Under Adjustment in this context is accordingly to understand the acquisition of data, comparing with standard and the adjustment.

Unless otherwise stated, the features and embodiments of the invention presented here can be combined with one another in a wide variety of variants. The resulting embodiments are within the scope of the present invention.

LIST OF REFERENCE NUMBERS

1

laboratory system

2

hybridization system

3

hybridization unit

4

gauge

5

measuring unit

6

processing unit

7

Connection between 17 and 6

8th

serial / parallel data bus

9

direct digital input / output line

10

A / D converter

11

microcontrollers

12

computer

13

fluids

15

measuring block

16.16 '

cavities

17

sensor

19

Flow sensor for liquid / gas

20

Pressure sensor for liquid / gas

21

photocell

22

circuit board

23

metal plate

24

temperature sensor

25

niche

26

holder

28

frame

29

axis

30

connecting plate

31

Surface of 2

32

Spring / spring element

33

Standard Device

33 '

first standard device

33 "

second standard device

33 " '

third standard device

34

Hybridization chamber / reaction chamber

35

slides

36

Surface of the slide

37

Connection plate of 3

38

common connection level of the supply / discharge lines of 33

38 '

common connection plane of the cavities of FIG. 5

38 "

common connection level of the supply / discharge lines of 40

39

Inlets / outlets of 33

39 '

Inlets / outlets of 2

39 "

Inlets / outlets of 40

40

reaction block

41

Pattern feed

42

first agitation device

42 '

second agitation device

43

Membrane of 42

43 '

Membrane of 42 '

44

Pressure chamber of 42

44 '

Pressure chamber of 42 '

45

Agitation chamber of 42

45 '

Agitation chamber of 42 '

46

Agitation leadership of 42

46 '

Agitation leadership of 42

47

print Setup

49

heating element

50

sealing surface

51

Base plate of 3

52

Surface of 51

Claims (28)

Measuring device (4) having a measuring unit (5) and a processing unit (6) for determining fluid parameters provided by a laboratory system (1), the measuring unit (5) being designed to be integrated into this laboratory system (1),
characterized in that (A) the measuring unit (5) comprises a measuring block (15) without reaction space (34) and at least one sensor (17); (b) the metering block (15) includes cavities (16) for receiving or directing fluids (13) provided by the laboratory system (1), the cavities (16) being substantially entirely within the metering block (15); and (c) the at least one sensor (17) for determining physical and / or chemical parameters of fluids (13) located in the cavities (16), on or in fluidic communication with these cavities (16) of the measuring block (15). is arranged. Measuring device (4) according to claim 1, characterized in that the at least one sensor (17) is designed for determining a flow velocity of a fluid or for determining a fluid pressure. Measuring device (4) according to claim 1, characterized in that the measuring unit (5) comprises at least two sensors (17), of which the first sensor (19) for determining a flow velocity of a fluid and the second sensor (20) for determining a fluid -Drucks is formed. Measuring device (4) according to claim 1, characterized in that the measuring unit (5) for determining a flow velocity of a fluid comprises at least two identical sensors (17) which are arranged at a distance from each other on or in fluid communication with a fluid line. Measuring device (4) according to claim 4, characterized in that the at least two identically constructed sensors (17) are designed as flow sensors (19) or as light barriers (21). Measuring device (4) according to one of the preceding claims, characterized in that the measuring unit (5) of the measuring device (4) is designed to be insertable into a hybridization system (2). Measuring device (4) according to claim 6, characterized in that the measuring unit (5) of the measuring device (4) comprises a niche (25) in which at least one temperature sensor (24) is arranged, wherein the measuring unit (5) and a surface ( 31) of the hybridization system (2), of which a temperature is to be determined, are designed to be movable relative to one another. Measuring device (4) according to claim 7, characterized in that the at least one temperature sensor (24) of the measuring unit (5) on a surface (31) of the hybridization system (2), of which a temperature is to be determined, is resiliently acted upon. Hybridization system (2) with at least one hybridization unit (3), wherein said hybridization unit (3) comprises a standard device (33) which, in combination with a slide (35), defines at least one hybridization space (34), said standard device (3) 33) comprises connections for the supply and discharge of fluids (13) provided by the hybridization system (2), characterized in that the hybridization system (2) comprises at least one measurement unit (5) according to one of the preceding claims, wherein the measurement unit (5) essentially the same connections for the supply and discharge of fluids (13) provided by the hybridization system (2) as the standard device (33) and is designed in its essential dimensions so that the measuring unit (5) instead of the standard Device (33) is designed to be used in a hybridization unit (3). Hybridization system (2) according to claim 9, wherein the standard device (33) is designed as a first standard device (33 '), characterized in that the measuring unit (5) is used as a replacement for the first standard device (33'). is designed usable. Hybridization system (2) according to claim 9, wherein the standard device (33) as a second standard device (33 ") is formed, which defines at least two hybridization spaces (34) in combination with a slide (35), characterized in that the measuring unit (5) comprises a measuring block (15) without reaction space (34) and with at least one sensor (17) and a reaction block (40), wherein the reaction block (40) with the slide (35) defines at least one hybridization space (34) , and wherein the measuring unit (5) is designed to be usable instead of the second standard device (33 "). A hybridization system (2) according to claim 9, wherein the standard device is designed as a third standard device (33 "') which, in combination with a slide (35), defines at least three or more hybridization spaces, characterized in that the measurement unit ( 5) comprises a measuring block (15) without a reaction space (34) and with at least one sensor (17) and a reaction block (40), wherein the reaction block (40) with the slide (35) defines at least two or more hybridization spaces (34), and wherein the measuring unit (5) is designed as insertable in place of the third standard device (33 "'). Hybridization system (2) according to claim 10 or 11, characterized in that it comprises at least one group of four hybridization units (3), wherein at least one measuring unit (5) instead of a first or second standard device (33 ', 33 ") in a group of hybridization units (3) is used. Hybridization system (2) according to claim 11 or 12, characterized in that the reaction block (40) of the measuring unit (5) for replacing the second or third standard device (33 ", 33"') at least one pattern supply line (41) for Supplying sample liquids in at least one hybridization space (34). Hybridization system (2) according to one of claims 11 to 14, characterized in that the reaction block (40) of the measuring unit (5) for replacing the second or third standard device (33 ", 33"') at least one agitation device (42) for Moving liquids in at least one hybridization space (34), wherein the agitator (42) comprises at least one membrane (42) which separates a pressure chamber (44) in which an agitation pressure can be generated, from an agitation chamber (45) which an agitation conduit (46) is connected to at least one hybridization space (34). Hybridization system (2) according to claim 15, characterized in that the reaction block (40) of the measuring unit (5) for replacing the second or third standard device (33 ", 33"') at least one of the agitation device (42) completely separate printing device (47) for building up a room pressure in at least one hybridization space (34), wherein this room pressure (42) is superimposed by the agitation pressure. Hybridization system (2) according to one of claims 9 to 16, characterized in that the measuring unit (5) comprising at least one temperature sensor (24) and a surface (31) of the hybridization system (2) are designed to be movable relative to each other, wherein the Surface (31) is formed as a temperature control plate. Hybridization system (2) according to claim 17, characterized in that the temperature control plate is formed as a bottom plate or as a cover plate. Hybridization system (2) according to one of claims 15 or 16, characterized in that at least one sensor (17) is designed for determining a chamber pressure. Method for determining fluid parameters provided by a laboratory system (1) using a measuring device (4) according to claim 1 having a measuring unit (5) and a processing unit (6), wherein the measuring unit (5) is integrated into this laboratory system (1), characterized in that (A) the measuring unit (5) comprises a measuring block (15) without reaction space (34) and at least one sensor (17); (b) the metering block (15) includes cavities (16) which receive fluids (13) provided by the laboratory system (1) and which are disposed substantially entirely within the metering block (15); and (c) physical and / or chemical parameters of the fluids (13) located in the cavities (16) are determined by the at least one sensor (17) which is connected to or in fluid communication with these cavities (16) of the measuring block (15 ) is arranged. A method according to claim 20, characterized in that with the at least one sensor (17), a pressure and / or a flow velocity of a in the cavities (16) of the measuring block (15) located fluid (13) is measured. A method according to claim 20, characterized in that with at least two identical sensors (17), a flow velocity of a fluid (13) is measured, wherein the at least two identical sensors (17) are arranged at a distance to each other or in fluidic communication with a fluid line , Method according to claim 20 or 21, characterized in that signals received by the at least one sensor (17) of the measuring unit (5) and processed by the processing unit (6) are used for calibrating and / or adjusting the laboratory system (1). Method according to one of claims 20 to 23, characterized in that it is carried out for determining physical and / or chemical, provided by a hybridization system (2) fluid parameters. A method according to claim 24, characterized in that a temperature of a surface (31) of the hybridization system (2) is determined with a temperature sensor (24) arranged in a niche (25) of the measuring unit (5), wherein the measuring unit (5) and the Surface (31) of the hybridization system (2) are movable relative to each other. Method for determining fluid parameters provided by a hybridization system (2) using a measuring device (4) according to claim 1, wherein at least one hybridization unit (3) of the hybridization system (2) comprises a standard device (33) in combination with a slide (35) defines at least one hybridization space (34), wherein fluids (13) provided by the hybridization system (2) are supplied thereto via ports of the standard device and / or derived therefrom, characterized in that a Measuring unit (5) of the measuring device (4) is used instead of the standard device (33) in a hybridization unit (3), wherein the measuring unit (5) has a measuring block (15) without reaction space (34) and at least one sensor (17) and wherein the measuring unit (5) has substantially the same connections for the supply and discharge of fluids (13) provided by the hybridization system (2) e comprises the standard device (33) and is formed in its essential dimensions like this standard device (33). A method according to claim 26, characterized in that at least one measuring unit (5) instead of a first standard device (33 ') is used, wherein the first standard device (33') at least one hybridization space (34) in combination with a slide (35) defined. A method according to claim 26, characterized in that at least one measuring unit (5) is used instead of a second standard device (33 "), wherein the measuring unit (5) further comprises a reaction block (40), wherein the reaction block (40) at least one hybridization space (34) is defined with the slide (35) and wherein the at least one sensor (17) determines the physical and / or chemical fluid parameters spatially separated from but simultaneously to a hybridization reaction.

Images