Abstract:
A system for the integrated and automated analysis of DNA or protein, including a single-use cartridge, with an analysis device having a control device, and devices for capturing and processing signals, the control device carrying out a completely automatic process and evaluation of molecular diagnostic analysis via single-use cartridges (Lab-on-a-Chip). Controlling of an analysis process, which occurs in the cartridge, involves the subsequent displacement and thermostatisation of liquids with a first device, and with a second device the signals which are obtained during the analysis are processed. The first and the second devices are synchronized in such a manner that the analysis process of the sample can be carried out in a totally integrated manner thus producing an immediate result.

Description:
CROSS REFERENCE TO RELATED APPLICATION 
       [0001]    This application is a continuation of commonly owned, co-pending U.S. patent application No. 11/920,978, filed Jul. 23, 2009, which is a §371 of PCT/EP2006/062499 filed May 22, 2006 and claims 35 USC §119 priority of German Patent Application DE 10 2008 059 536.7 filed Dec. 17, 2005. 
       BACKGROUND OF THE INVENTION 
       [0002]    1. Field of the Invention 
         [0003]    At least one embodiment generally relates to a system for the integrated and automated analysis of DNA or protein, for example one comprising a single-use cartridge (card), an evaluation device and a device for signal recording and processing. In particular, at least one embodiment of the invention generally relates to a control device as part of the evaluation device for the fully automatic processing and evaluation of molecular diagnostic analyses with disposable cartridges (“lab-on-a-chip”) and also known as a biochip; see, commonly owned U.S. Patent Application Publication 2007/01411553). In addition, at least one embodiment of the invention also generally relates to a method for operating the type of system. 
         [0004]    2. Description of Related Art 
         [0005]    The significance of decentralized analysis devices (“point of care”, “near patient testing”) in molecular diagnostics or general medical technology is increasing. In addition, fast tests are becoming more and more important in the areas of foodstuff monitoring and environmental protection. 
         [0006]    The general literature, but also especially the patent literature includes a large number of publications on the aforementioned topic: International Patent Application Publications WO 02/072 262 A1 and WO 02/073 153 A1 (which corresponds to U.S. Patent Application Publication 2005/0031490) disclose systems for application in biomedical technology in which samples taken in a decentralized manner are evaluated in a decentralized manner by means of an optionally mobile read-out device. The samples, in particular, are in this case collected in a single-use cartridge formed like a check card (“card”). 
         [0007]    Such a cartridge for application in the DNA analysis of whole blood samples is disclosed in detail in International Patent Application Publication WO 2006/042 838 A1 and corresponding U.S. Pat. No. 7,851,227, not previously published. In this case, the following features of the cartridge are regarded as essential for automatically carrying out all the measures required for process analysis from individual partial processes in the cartridge:
       the cartridge contains a system of microchannels and/or microcavities for a microfluidic process technology,   the microchannels or the microcavities have predetermined geometrical structures for receiving reagents, wherein   the reagents are stored in a storage-stable form at specific locations in the microchannels or the microcavities of the cartridge,   means are present for providing the dry-stored reagents for the respective partial process in a suitable form, in particular as a liquid reagent.
 
Reference is expressly made to the disclosure of these features in the above earlier application.
       
 
         [0012]    Furthermore, U.S. Patent Application Publications 2002/0179444 A1 and 2003/0148530 A1 disclose individual solutions for a blood diagnosis method and the associated signal processing. Specific problem solutions for the realization of the system of the type mentioned in the introduction comprising the previously described card and associated suitable means for evaluation are described in earlier applications in the name of the applicant that have not yet been published. 
       SUMMARY OF THE INVENTION 
       [0013]    At least one embodiment of the invention is directed to a system which meets practical requirements in particular with regard to the evaluation device. At least one embodiment is directed to an associated control method for evaluation in the case of a system comprising cartridge and evaluation device. In the case of at least one embodiment, the following requirements are made of the evaluation device:
       low price   small structural design   simple operating control (“one button” operation)   rapid performance of the analysis   integrated microfluidics   safety against contamination, i.e., avoidance of instances of soiling and infections-high operational reliability   capability of communication with data processing systems.       
 
         [0021]    No practically suitable solution has been disclosed hitherto for the fully automatic nucleic acid analysis from taking the sample (e.g., blood) to displaying the result, in particular including cell disruption, PCR and detection. Since the equipment currently proposed for biochemical analysis does not yet meet all the practical requirements, at least one embodiment of the invention improves the system so as to allow a maximally automated and reproducible evaluation. In particular, the intention here is to ensure that the result is displayed directly on a display or the data are forwarded into a computer system. The intention is to specify, in at least one embodiment, a suitable operating method for this purpose. 
         [0022]    The operating method of at least one embodiment for carrying out an evaluation of a sample in a single-use cartridge with the aid of the control device in a system. Especially the realizations for carrying out a DNA analysis, and also in particular an SNP analysis, or alternatively a protein analysis, are contained in further embodiments of the method. 
         [0023]    The basis of at least one embodiment of the invention, therefore, is an improved concept by comparison with the prior art: a device construction realized in accordance with this concept is designed according to at least one embodiment of the invention for the fully automatic processing and evaluation of molecular diagnostic analyses with disposable cartridges (lab-on-a-chip), in particular for the control and read-out of analysis processes within cartridges in the form of modified check cards. 
         [0024]    In the case of at least one embodiment of the invention, the control device has the following features, in particular:
       a cartridge receptacle for receiving, locking, unlocking and releasing the cartridge,   a device for correctly positioning the cartridge in the reader,   sensors for identifying the cartridge, in particular a correct cartridge, e.g., limit switches, barcode,   a water reservoir for diluting the sample, dissolving dry reagents of the cartridge, carrying out flushing operations, wherein fluidic contact can be made with the water reservoir by way of a septum being pierced by a pointed hollow needle,   a sterile filter ventilation valve for ventilating the water reservoir when water is drawn,   a power supply unit,   a pump for conveying extremely small quantities of liquid, for example in the microliters range,   means for distributing water via valves, e.g., water-carrying solenoid valves,   a pressure sensor in the water feed for monitoring fluidic operations,   at least one interface for feeding water into the cartridge,   sensors for identifying the filling of throughflow channels on the cartridge, e.g., capacitive sensors with electrodes above and below the cartridge,   a device for closing off and opening venting openings of the cartridge, e.g., air-carrying solenoid valves,   a device for closing off and opening chambers, in particular the PCR chamber, on the cartridge, e.g., plungers pressing onto a film,   a combination comprising a magnetic bead collector and a thermostatic regulation device for capturing magnetic beads and for carrying out thermocycling processes for the PCR,   a sandwich arrangement of two abovementioned devices for rapid thermocycling,   a device for ensuring optimum heat transfer between the thermostatic regulation device and cartridge, e.g., by way of a contact pressure defined by way of springs,   a device for making electrical contact with an electrical detection module, e.g., contact pins,   an integrated thermostatic regulation for the detection module,   control, measuring and regulating electronics for all the functions,   a microcontroller for control and data acquisition, and   a display for representing the analysis results.       
 
         [0046]    In the associated method for operating the control and read-out device for the evaluation of a cartridge filled with a sample, the following method steps are carried out specifically for a DNA analysis:
       the cartridge receptacle is opened and the pump draws water from the reservoir given a suitable valve position,   the control device indicates readiness for operation,   a user inserts the cartridge with a sample, e.g., blood,   the analysis is started by a “one button” action or automatically, e.g., by way of a cartridge limit switch,   given a suitable valve position, water is pumped into the cartridge via a water port in order to wash out excess sample material,   the venting valves are actuated in a suitable manner in order to allow or prevent the filling of cartridge channels by way of permitting or avoiding venting,   as a result of the inflow of water, the sample is diluted and pumped into the cell disruption channel, wherein dry reagents are dissolved,   a residence time ensues for cell disruption, wherein liberated DNA binds to magnetic beads,   nearly at the same time two ELISA reagent channels are filled, wherein dry ELISA reagents (enzyme label and substrate) are dissolved,   the content of the cell disruption channel is flushed by further pumping of water through the PCR chamber, wherein the magnetic beads with DNA are held back by a magnetic field, the remainder is flushed into a waste channel,   the valves of the PCR chamber are closed off,   the thermocycling is started, wherein dry PCR reagents are dissolved,   a predetermined number of thermocycles are carried out at defined temperatures (PCR),   the valves of the PCR chamber are opened after conclusion of the PCR,   given a suitable valve position, water is pumped into the cartridge via a further water port and the PCR product is flushed from the PCR chamber into a detection chamber,   the detection chamber is thermostatically regulated, wherein hybridization of the DNA with catcher molecules takes place,   air possibly present between the PCR product and the dissolved ELISA reagents is pumped into a waste channel by suitable setting of water port and venting valves,   the dissolved enzyme label is pumped via the detection chamber into a further waste channel by suitable setting of water port and venting valves,   the dissolved substrate is pumped via the detection chamber into a further waste channel by suitable setting of water port and venting valves,   the electrical detection is started,   e.g., an SNP analysis is carried out by recording melting curves.       
 
         [0068]    As an alternative to the above method sequence, a protein analysis is also possible, wherein no cell disruption and no PCR are necessary. In this case, the proteins sought are isolated from the sample by way of magnetic beads and detected in the detection chamber. Haptens can be detected analogously. 
         [0069]    An analysis process integrated throughout is carried out, then, by the method according to an embodiment of the invention. This is understood to be a fully automated method sequence without manual intervention. After the introduction of the cartridge with the sample into the control device, the sample treatment and analysis process proceeds automatically until the actual detection of the substances sought. This has the advantage, in particular, of high reproducibility and a low error rate. 
         [0070]    What is particularly advantageous in the system according to at least one embodiment of the invention is that the control device can be embodied in compact fashion and has both internal fluidic interfaces and electrical interfaces. Interfaces for linking to external computer systems are additionally present. These may be serial and/or wireless interfaces, for example. In an example embodiment, the control device comprises a connection possibility for a commercially available PDA. This enables a display to be integrated into the control device in a simple manner. In a particularly preferred example embodiment, a display and operating unit is fixedly integrated into the control device. 
         [0071]    With the system according to at least one embodiment of the invention, a considerable advance is achieved compared with the previously proposed devices. It is now possible, for example, for the measured data to be directly displayed or forwarded for evaluation. 
         [0072]    Further details and advantages of the application are explained on the basis of the example embodiment described below in association with the accompanying drawings, in which: 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0073]      FIG. 1  shows a schematic overview diagram of an analysis device, 
           [0074]      FIG. 2  shows a schematic overview diagram of a cartridge, 
           [0075]      FIG. 3  shows a schematic flowchart of an analysis method, 
           [0076]      FIG. 4  shows a schematic overview diagram of the functional units of the control device, 
           [0077]      FIG. 5  shows a schematic overview diagram of the fluidic components of the control device, 
           [0078]      FIG. 6  and  FIG. 7  show schematic illustrations of a measuring device for a filling level, 
           [0079]      FIG. 8  shows a schematic illustration of a fluidic interface between the cartridge and the control device, 
           [0080]      FIG. 9  shows a schematic illustration of a venting interface between the cartridge and the control device, 
           [0081]      FIG. 10  shows a schematic illustration of a PCR chamber of the cartridge, and 
           [0082]      FIG. 11  shows a schematic illustration of a detection chamber of the cartridge. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0083]    An analysis device is described below as one example embodiment of the invention. The analysis device is divided into a control device and a cartridge. Whereas the cartridge is, for example, present as a disposable article on which the actual analysis process proceeds, the control device is reusable and serves for controlling the analysis process. The cartridge contains only passive components; the entire control proceeds from the control device. 
         [0084]      FIG. 1  shows the construction of the analysis device. It includes a cartridge  101 , which can be inserted into a cartridge receptacle  103  of a control device  105 . The cartridge receptacle  103  is connected to a power supply unit  107 , which supplies the receptacle with power. For the transmission of data of the analysis process, the cartridge receptacle  103  is additionally connected to an electronic unit  109 . The data can be output from the electronic unit  109  via an interface  111 . 
         [0085]    The interface  111  is formed as an RS232 interface, for example. The electronic unit  109  is connected to the power supply unit  107  for its power supply. 
         [0086]    In order to carry out the analysis process, water is required in the cartridge. This water is stored in a supply container  113 . The supply container  113  is a commercially available bottle containing sterile, distilled water, for example, which is closed off by a septum. A corresponding receptacle for the bottle in the control device is provided with a cannula which pierces the septum when the bottle is inserted. As a result, the water becomes accessible and it can be drawn from the bottle via a connected pump  115 . The pump  115  can take up a defined quantity of water and pump it into the cartridge receptacle  103  via a connection. The water passes into the cartridge  101  via the cartridge receptacle  103  and is available in the analysis process. The pump  115  is connected to the power supply unit  107  for its power supply. 
         [0087]      FIG. 2  schematically illustrates the cartridge  101 , which has already been disclosed in detail in International Patent Application Publication WO 2006/042 838 A1 and corresponding U.S. Pat. No. 7,851,227, not previously published, which disclosure is also subject matter of the present patent application, wherein the entire contents thereof is hereby incorporated herein by reference. 
         [0088]    The cartridge  101  is present in the form of a plastic card  201  of the size of a check card and comprises a number of channels. Via a sample port  203 , a sample can be pipetted into the cartridge  101 . Water can be introduced into the cartridge  101  via four water ports  205 ,  205 ′,  205 ″ and  205 ″′. The cartridge  101  is additionally provided with four venting ports  207 ,  207 ′,  207 ″ and  207 ″′, through which air can escape when the channels are filled. A metering section  209  comprises a volume of 11 and services for tapping of this quantity from the sample that has been pipetted in. A sample waste channel  211  serves for receiving the rest of the sample. The venting port  207 ″′ lies at the end of the sample waste channel  211 . The metering section  209  is adjoined by a cell disruption channel  213 , in which reagents for the cell disruption are stored in dry form. It is only as a result of the introduction of the sample in diluted form that the reagents are dissolved and cell disruption takes place. As a result of the cell disruption, DNA contained in the cells is liberated, said DNA binding to magnetic beads likewise present in the cell disruption channel  213 . 
         [0089]    The cell disruption channel  213  is connected to a PCR chamber  215 , in which a PCR can be carried out. The PCR chamber  215  can be closed off by way of two valves  217 . The required reagents are situated in the PCR chamber  215  likewise in dry form. Arranged downstream of the PCR chamber  215  is a PCR waste channel  219  connected to the venting port  207 ″. A water channel  221  connected to the water port  205 ″ leads in at one end of the cell disruption channel  213 . The PCR chamber  215  is connected to a detection chamber  223 , in which the DNA can be detected by means of a sensor array. The detection chamber  223  is connected to two waste channels  225  and  227  ending in the ventilation ports  207 ′ and  207 , respectively. In addition, the detection chamber  223  is connected to two ELISA reagent channels  229  and  231  (ELISA: enzyme linked immuno sorbent assay), which, for their part, are connected to the water ports  205 ′ and  205 , respectively. ELISA reagents  232  are stored in dry form in the ELISA reagent channels  229  and  231 , and after being dissolved in water can be flushed into the detection chamber  223 . 
         [0090]      FIG. 3  shows a schematic flowchart of an analysis process. In a first method step S 1 , the cartridge is prepared. This involves pipetting the sample into the cartridge and possibly providing water in the control device. As it is pipetted in, the sample accumulates in the sample waste channel  211  of the cartridge (referring to  FIG. 2 ), the metering section  209  likewise filling up in the process. In a second method step S 3 , the cartridge is introduced into the control device. As a result of the introduction of the cartridge, valves situated in the read-out device are connected to the water ports  205  to  205 ′″ and the venting ports  207  to  207 ′″, such that water can be introduced into the cartridge and air can escape. Moreover, a switch in the read-out device is actuated, whereupon the analysis process starts automatically. 
         [0091]    In this case it is ensured by way of functional elements known per se that the cartridge is in the correct position and has the correct orientation. Moreover, the fact of whether the cartridge is one which is suitable for the control device is identified. At the beginning of the analysis process within the cartridge  101 , the water channel  221  is filled with water, the water channel  221  likewise being vented via the PCR waste channel  219 . This simplifies the method sequence since the air present in the water channel  221  could not escape in the further sequence. 
         [0092]    In a third method step S 5 , water is pumped into the water port  205 ″′, such that that portion of the sample which is situated in the metering section  209  is isolated. The venting port  207 ′, which is otherwise closed off by the valve, is opened for this purpose. As soon as the sample waste channel  211  has been filled, the venting port  207 ′ is closed off again in a fourth method step S 7 . The filling level of the sample waste channel  211  is measured by way of filling level sensors arranged in the control device. The functioning is explained with reference to  FIGS. 6 and 7 . 
         [0093]    As a result of the venting port  207 ′ being closed off, pressure starts to build up as water continues to be pumped in, such that that portion of the sample which is situated in the metering section  209  is flushed into the cell disruption channel  213 . The valve assigned to the venting port  207 ″ in the control device is opened for this purpose. The sample is diluted with water. As a result of the introduction of the diluted sample, the dry reagents in the cell disruption channel  213  are dissolved whereupon cell disruption takes place in a fifth method step S 9 . DNA situated in the cells of the sample is liberated in this case. The liberated DNA binds to magnetic beads stored in the cell disruption channel  213 . 
         [0094]    At the same time as the cell disruption, in a sixth method step S 11 , the ELISA reagent channels  229  and  231  are filled with water. The valves assigned to the venting ports  207 ′ and  207  in the control device are opened for this purpose. The filling level of the ELISA reagent channels  229  and  231  is measured by filling level sensors arranged in the control device. 
         [0095]    After the cell disruption has been concluded, in a seventh method step S 13 , the diluted sample with the magnetic bead-DNA complexes is flushed through the PCR chamber  215 . For this purpose, as already previously, water is pumped through the water port  205 ′ and the venting port  207 ″ is opened. In the control device, there is a magnet arranged above the PCR chamber  215 , the magnetic bead-DNA complexes being held back in the PCR chamber  215  by said magnet. The remainder of the diluted sample is flushed into the PCR waste channel  219 . In an eighth method step S 15 , water is again pumped through the PCR chamber  215 , thereby cleaning the magnetic bead-DNA complexes. 
         [0096]    In a ninth method step S 17 , the valves  217  of the PCR chamber  215  are closed. In a tenth method step S 19 , the DNA of the magnetic bead-DNA complexes is replicated by a PCR. For this purpose, corresponding reagents are situated in the PCR chamber  215  in dry form, said reagents being dissolved by the addition of water. In order to manipulate the temperature in the PCR chamber  215 , two Peltier units are situated in the control device. After the conclusion of the PCR, in an eleventh method step S 21 , the valves  217  of the PCR chamber  215  are opened. In a twelfth method step S 23 , water is pumped into the channel  221  via the water port  205 ″, such that the water previously situated in the channel  221  is flushed into the PCR chamber  215 . The channel  221  contains dry stored salts which are thus added to the PCR product, that is to say the replicated DNA. At the same time, the replicated DNA is flushed from the PCR chamber  215  into the detection chamber  223 . In this case, the venting ports  207 ″ and  207 ′ are closed, and the venting port  207  is open. 
         [0097]    In a thirteenth method step S 25 , a hybridization between the PCR product and capture molecules arranged in the detection chamber  223  takes place in the detection chamber  223 . In order to support the hybridization, the temperature in the detection chamber  215  is set in a defined manner by way of a Peltier element arranged in the control device. In a fourteenth method step S 27 , a label enzyme (e.g., streptavidin alkaline phosphatase, streptavidin esterase or oligonucleotide-coupled esterase) linked to a coupling molecule is pumped from the ELISA reagent channel  231  through the detection chamber. For this purpose, water is pumped through the water port  205  and the venting port  207 ′ is opened. The DNA linked to the catcher molecules is marked by the label enzyme. In a fifteenth method step S 29 , a dissolved enzyme substrate is pumped from the ELISA reagent channel  229  through the detection chamber  215 . Both enzyme label and enzyme substrate channel are vented before the flooding of the detection chamber  231  via the channel  227  in order to prevent air from being entrained into the detection chamber  223 . By virtue of the substrate, a so-called redox cycling process occurs in the detection chamber, and the bound DNA can be detected by said process. Evaluation of the measurement data correspondingly takes place in a sixteenth method step S 31 . 
         [0098]      FIG. 4  illustrates the central components of the control device  105  in a block diagram. A microcontroller  401  serves as central controller of the entire analysis process, said microcontroller being connected to a computing unit  403  via a serial RS232 interface  402 . Said computing unit  403  is a commercially available PDA, for example, and serves for recording measurement data from the analysis process. The computing unit  403  is equipped with a radio module  404 , via which the measurement data can be transmitted to an evaluation unit  405 . The radio module  404  communicates with the evaluation server  405  for example by infrared, Bluetooth or WLAN. 
         [0099]    The microcontroller  401  controls all the components of the control device  105  which are involved in the analysis process. The cartridge receptacle  103  comprises a stepper motor  407 , which moves a part of the cartridge receptacle  103  upon insertion of the cartridge, such that the cartridge is correctly received. The Peltier elements are brought into position in this case. A limit switch  409  interrupts the process when the cartridge has been completely introduced. As a result of the introduction process, the water ports and the venting ports are connected to corresponding channels in the control device. Valves  413  controlled by the microcontroller  401  are arranged in the channels. A signal processing unit  415  serves for communicating the control signals. The arrangement and functioning of the channels and valves are explained with reference to  FIG. 5 . 
         [0100]    For the movement of the water in the channels, the pump  115  is controlled by the microcontroller  401 . Its piston is moved by a stepper motor  417 , which is in turn controlled by means of an output stage  419  and a limit switch  421 . The pressure in the pump  115  is measured by means of a pressure sensor  423  and read out by the microcontroller  401  via a signal processing unit  425 . 
         [0101]    The movement of the water in the cartridge is monitored by means of filling level sensors  427 , which are read by the microcontroller  401  via a signal processing unit  429 . 
         [0102]    The valves of the PCR chamber are controlled via a servomotor  431  and a signal processing unit  433 . Three Peltier elements  435  and temperature sensors  437 , which are controlled and read via a PID controller  439  and an output stage  441 , serve for the thermostatic regulation of the PCR chamber and the detection chamber. The PID controller  439  is controlled by the microcontroller  401  via a signal processing unit  443 . 
         [0103]    The signals generated by the redox cycling on the sensor array are measured via a contact-making module  445  and forwarded to a signal processing unit  451  via read-out circuits  447  and a multiplexer  449 . The signal processing unit  451  is connected to the microcontroller. The necessary control voltages, such as e.g., a reference voltage and a counter-voltage of a potentiostat, are fed to the sensor array via the contact-making module  445 . The sensor array is embodied as a CMOS sensor chip, for example. In this case, the contact-making module  445  advantageously has the arrangement as in a commercially available smart card reader. 
         [0104]      FIG. 5  illustrates a schematic overview diagram of the fluidic components of the control device. The cartridge receptacle  103  includes four water ports  503 ,  503 ′,  503 ″ and  503 ″′, which are connected to the water ports of the cartridge when the latter has been inserted. Four venting ports  505 ,  505 ′,  505 ″ and  505 ′ are likewise provided, which are connected to the corresponding venting ports of the cartridge. The cartridge receptacle  103  furthermore includes three filling level sensors  507 ,  507 ′ and  507 ″, the functioning of which is explained with reference to  FIGS. 6 and 7 . They operate capacitively and comprise two capacitor plates. In order to ensure a simple construction of the cartridge receptacle  103 , one capacitor plate  509  is formed in large-area fashion and is used jointly for all the filling level sensors  507 ,  507 ′ and  507 ″. The other capacitor plates  511 ,  511 ′ and  511 ″ are correspondingly embodied separately. 
         [0105]    The filling level sensors  507  and  507 ′ are designed in each case for monitoring two channels of the cartridge and are arranged at corresponding locations of the cartridge receptacle  103 . The filling level sensor  507  serves for monitoring the two ELISA reagent channels  229  and  231 , while the filling level sensor  507 ′ monitors the sample waste channel  211  and the PCR waste channel  219 . The filling level sensor  507 ″ serves for monitoring the waste channel  227 . 
         [0106]    Two motors  503  for controlling two actuators  515  are additionally arranged in the cartridge receptacle  103 . The actuators  515  serve for opening and closing the valves of the PCR chamber on the cartridge. 
         [0107]    The water required for the analysis process comes from a commercially available bottle  517 , which is closed off by a septum  519 . The bottle  517  is held by a receptacle  521  of the control device, two cannulas  523  and  525  being arranged in said receptacle. When the bottle  517  is introduced into the receptacle  521 , the septum  519  is pierced by the two cannulas  523  and  525  and the water in the bottle  517  is made accessible. The cannula  523  is connected to a pump  115  via a line  527  and a three-way valve  529 . By means of the pump  115 , a volume of water that can be set in a defined manner can be drawn from the bottle  517 . The pump  115  comprises a hollow cylinder  533  with a movable piston  535 . The piston  535  can be moved in a defined manner by means of a stepper motor  537 . A pressure sensor  539  is arranged in the line  527 , and the pressure in the line  527  can be determined by way of the pressure sensor. 
         [0108]    The cannula  525  serves for ventilating the bottle, since a negative pressure would otherwise arise when water is drawn. The cannula is connected to a sterile filter  541 , via which air can pass into the bottle. 
         [0109]    The three-way valve  529  can be connected to the four water ports  503 ,  503 ′,  503 ″ and  503 ″′ via a line system  543 . A plurality of lines  527 ′ and three further three-way valves  529 ′, by which the three-way valve  529  can be selectively connected to each of the water ports  503 ,  503 ′,  503 ″ and  503 ″′, are provided for this purpose. Through suitable switching of the three-way valves  529 ′, the water can thus be pumped from the hollow cylinder  533  into one of the water ports  503 ,  503 ′,  503 ″ or  503 ″. The pressure occurring in the line system  543  and the line  527  is detected by the pressure sensor  539  in this case. 
         [0110]    The air present in the channels of the cartridge before the start of the analysis process must be able to pass out of the cartridge as the latter is filled with water. The four ventilating ports  505 ,  505 ′,  505 ″ and  505 ″′ are provided for this purpose in the cartridge receptacle. They are connected via lines  545  to two-way valves  547 , which can be optionally closed or open. When water is introduced into one of the channels, the corresponding one of the valves  547  is opened, such that air can escape from the cartridge. 
         [0111]      FIGS. 6 and 7  show the functioning of the filling level sensors.  FIG. 6  illustrates the control device  105  in a sectional view. A cartridge  101  has been introduced into the cartridge receptacle  103 . In the cartridge receptacle  103 , two capacitor plates  607  and  609  are arranged above and below the cartridge  101 . The capacitor plates  607  and  609  are connected to a measuring unit  611 , by which the capacitance of the capacitor formed by the capacitor plates  607  and  609  can be determined. 
         [0112]    In  FIG. 6 , a channel  613  shaped within the cartridge  101  is partly filled with water  615 . In the illustration in  FIG. 7 , the channel  613  is filled to an extent such that there is water  615 ′ between the capacitor plates  607  and  609 . As a result, the capacitance of the capacitor is altered in comparison with the state illustrated in  FIG. 6 . The change is determined by means of the measuring unit  611  and the liquid level in the channel is determined in this way. 
         [0113]      FIG. 8  shows a section through a part of the cartridge receptacle  103  with cartridge  101  inserted. The contact-making between the water ports of the control device  103  and the cartridge  101  is shown. A channel  707  is milled in a plastic body  705  of the cartridge  101 . The channel  707  is covered by way of an adhesive film  709 , the adhesive film  709  being adhesively bonded onto the plastic body  705 . The adhesive film  709  is commercially available and compatible with all the processes that proceed in the cartridge  101 . A further adhesive film  711  is fixed to the water port of the cartridge  101 . The further adhesive film can be pierced by a hollow needle  713  arranged in the cartridge receptacle  103  and the fluidic contact between the cartridge receptacle  103  and the cartridge  101  can thus be established. A seal  715  that prevents liquids from escaping is arranged in the cartridge receptacle  103 . the seal  715  is preferably composed of a biochemically compatible silicone material in order to avoid contamination of the water ports. 
         [0114]    Before the cartridge  101  is introduced into the cartridge receptacle  103 , an upper part  717  and a lower part  719  of the cartridge receptacle  103  are further away from one another than illustrated in  FIG. 8 . This enables the cartridge  101  to be introduced in a convenient manner. As soon as the cartridge  101  has been completely introduced, the two parts  717  and  719  are brought together and the cartridge  101  is locked in the cartridge receptacle  103 . At the same time, the adhesive film  711  is pierced by the hollow needle  713 . 
         [0115]      FIG. 9  shows a section through a part of the cartridge receptacle  103  with inserted cartridge  101  at one of the venting ports. In the cartridge  101 , analogously to the illustration in  FIG. 8 , a channel  707 ′ is milled into the plastic body  705 , said channel being covered by the adhesive film  709 . Around the venting port  721  of the cartridge  101 , a depression is milled into the plastic body  705 , an adhesive layer  723  being arranged in said depression. A Teflon membrane  725  is fixed on the adhesive layer  723 . A seal  715  is arranged in the lower part  719  of the cartridge receptacle  103 . A channel  727  is additionally provided, which runs through the seal  715  and is therefore in contact with the Teflon membrane  725 . A hose  729  connected to the venting valves of the control device is arranged in the channel  727 . 
         [0116]    The Teflon membrane  725  ensures that no liquid can escape from the cartridge. This serves to avoid contamination of the control device, which is intended to be able to be used for a multiplicity of analysis processes. The sample introduced into the cartridge  101  generally contains infectious biomaterial which would contaminate the control device upon contact, and the control device would therefore have to be cleaned or replaced for carrying out further analysis processes. The Teflon membrane  725  is permeable to vapor and gas, but impermeable to liquids. By way of the pressure sensor  533  of the control device it is ensured that the pressure in the cartridge  101  does not become excessively high and the Teflon membrane  725  or the adhesive film  709  is not damaged or torn. 
         [0117]      FIG. 10  illustrates a section through a part of the cartridge receptacle  103  with inserted cartridge  101 . Analogously to  FIGS. 8 and 9 , a channel  707 ″ is milled into the plastic body  705 . The channel  707 ″ has a widening serving as a PCR chamber  731 . The channel  707 ″ and the PCR chamber  731  are covered by the adhesive film  709 . 
         [0118]    In order to ensure rapid heat transfer for the thermocycling during the PCR, the PCR chamber  731  is kept as small as possible in a geometrical dimension (approximately 1 mm or volume &lt;20 μl) and the heat transfers are realized in a “sandwich” thermostatically regulating arrangement such that only small liquid layers (a few 100 μm) have to be brought to thermal equilibrium. The PCR chamber  731  is preferably situated in a housing with plane-parallel outer surfaces (plastic body  705  with cutout and adhesive film  709 ). 
         [0119]    In the cartridge receptacle  103 , two thermal coupling plates  733  and  733 ′, for example composed of aluminum, are arranged above and below the PCR chamber  731  of the cartridge  101 . The two thermal coupling plates  733  and  733 ′ are pressed against the adhesive film  709  and against the plastic body  705 , respectively, and serve for transmitting thermal energy of two Peltier units  735  and  735 ′ into the PCR chamber  731  when a PCR is carried out. The Peltier units  735  and  735 ′ are in thermal contact with two heat sinks  737  and  737 ′ which serve for dissipating heat during the cooling operations of the PCR cycles. They have a largest possible surface area in order to enable an efficient heat transfer to the ambient air, if appropriate with the aid of fans. 
         [0120]    A cutout  739  is shaped in the thermal coupling plate  733 . By virtue of the cutout  739 , the adhesive film  709  can bulge out in the event of possible excess pressure, for example during a temperature increase in a PCR cycle. 
         [0121]    Two permanent magnets  741  and  741 ′ are arranged centrally above and respectively below the heat sinks  737  and  737 ′. The magnetic field generated by the permanent magnets  737  and  737 ′ serves for holding back magnetic beads when the latter are flushed through the channel  707 ″ into the PCR chamber  731 . The DNA bound to the magnetic beads is thus held back for later replication by the PCR in the PCR chamber  731 . 
         [0122]    The field gradient generated by the two permanent magnets  741  and  741 ′ is too small, however, to efficiently hold back the magnetic beads. In order nevertheless to obtain a high field gradient in the PCR chamber  731  along the throughflow direction of the liquid containing the magnetic beads, the thermally conductive but magnetically neutral thermal coupling plates  733  and  733 ′ are equipped with small-volume bodies  743  and  743 ′ (approximately 5 mm 3 ) composed of a material having a high relative permeability μ(r), in conjunction with still good thermal conductivity, preferably permalloy (Ni—Fe) or Mumetal (Ni/Fe/Cu/Mo). 
         [0123]    The small-volume bodies  743  and  743 ′ respectively form a magnetic core directly at the surfaces of the PCR chamber  731 . The PCR chamber  731  is then situated directly between the magnetic cores. The magnetic cores are magnetized by the magnetic field of the permanent magnets  741  and  741 ′. The magnetic field lines are concentrated by way of the magnetic cores, whereby a high field gradient is generated. 
         [0124]    In the field gradient arranged parallel to the outer walls of the PCR chamber  731  and flow direction of the solution containing magnetic beads, the magnetic beads are drawn in, detained and therefore concentrated. 
         [0125]    The PCR chamber  731  can be closed up by way of two plungers  745  and  745 ′. The plungers  745  and  745 ′ can be pressed against the adhesive film  709  by way of springs and cams that are not illustrated here, such that the PCR chamber  731  is closed off. 
         [0126]    The heat sinks  737  and  737 ′ are connected to screws  761  via springs  759 . The screws  761  are screwed into the cartridge receptacle  103 . The thermal coupling plates  733  and  733 ′ connected to the heat sinks  737  and  737 ′, respectively, are pressed against the adhesive film  709  and the plastic body  705 , respectively, by the springs  759 , such that good thermal contact arises. At the same time, thermal contact between the thermal coupling plates  733  and  733 ′ and the cartridge receptacle  103  is avoided to the greatest possible extent. 
         [0127]      FIG. 11  illustrates a section through a part of the cartridge receptacle  103  with inserted cartridge  101 . A further channel  707 ″′ is milled into the plastic body  705 , said further channel being covered with the adhesive film  709 . A chip module  747 , by means of which the DNA contained in the sample can be detected, is arranged in the plastic body  705 . By way of example, a redox cycling process for detecting the DNA can take place on the chip module  747 . 
         [0128]    In order to support the hybridization between the DNA and corresponding capture molecules that takes place at the surface of the chip module  747 , the chip module  747  is thermally coupled to a Peltier element  753  via a thermal coupling plate  751 . The Peltier element  753  is thermally coupled to a cooling unit  755 . The temperature in the vicinity of the chip module  747  can be monitored by way of a temperature sensor  757  arranged in the thermal coupling plate  751 . SNP analyses, for example, can thus be carried out by means of determining melting curves. 
         [0129]    Outside the plane of the drawing, the unit formed from the thermal coupling plate  751 , the Peltier element  753  and the cooling unit  755  is connected to the lower part  719  of the cartridge receptacle. In this case, the unit is mounted in resilient fashion, such that it is pressed against the cartridge  101  and a good thermal contact between the thermal coupling plate  751  and the chip module  747  is established. 
         [0130]    Moreover, outside the plane of the drawing, sprung contact pins are provided within the lower part  719  of the cartridge receptacle  103 , and tap off electrical signals of the chip module  747  for evaluation. 
         [0131]    A practically suitable determination of DNA, proteins and also haptens is now possible with the described system including smart card for sample uptake and evaluation device with control device for sample processing and evaluation when the cartridge has been introduced into the evaluation device. 
         [0132]    Example embodiments being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the present invention, and all such modifications as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.