Abstract:
Tempering of sample ( 58 ) in test strip ( 37 ) is carried out by temperature regulating unit ( 40 ) and heating/cooling unit ( 92 ). The sample is fed to the test strip by a developer fluid ( 57 ) and a metering unit ( 55 ). The result of the detection reaction becomes visible by a change in color ( 36 ), which is detected optically and analyzed. The data of a control chart ( 52 ) with the measured values of first and second temperature sensors ( 41, 42 ) are used to set the control parameters for tempering. Code ( 86 ) on the test sample holder ( 35 ) is read in a sequence of steps. Parameters for phases of the measurement are determined from measured values of first and second temperature sensors, values of the control chart and the code of the test sample holder. These parameters are used by the temperature regulating unit during the measurement.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application claims the benefit of priority under 35 U.S.C. §119 of German Patent Application DE 10 2008 017 196.4 filed Apr. 4, 2008, the entire contents of which are incorporated herein by reference. 
     FIELD OF THE INVENTION 
     The present invention pertains to a measuring device for the analysis of biological material and to a process for putting into operation and for operating the measuring device. 
     BACKGROUND OF THE INVENTION 
     A device for the analysis of biological material, in which a test sample holder is inserted into a measuring device, is known from DE 69915481 T2. The analysis of biological material, for example, human saliva, is described in DE 19751363 B3. It is necessary here, in a sequence of process steps, to collect a sample of the biological material in a suitable tank, to meter a defined quantity of an aqueous developer solution, and to insert the mixture of aqueous solution and biological material into a test sample holder, into which a test strip is placed. The test strip contains a collection matrix and a detection matrix. The presence or absence of an analyte in the collected biological material is demonstrated by an immunochemical detection reaction. The presence of the analyte to be detected in the sample of the biological material causes a color change on the test strip in the detection reaction. 
     The device known from DE 69915481 T2 uses an optical analysis unit for the analysis of the color change. A combination of immunochemical detection reaction and chromatographic analysis is thus obtained. The course of the immunochemical reaction depends essentially on the processing times and ambient conditions, the rate of the reaction process and hence the reproducibility of the detection of an analyte in a sample of biological material being affected especially by the temperature. 
     A test sample holder for collecting a quantity of biological material is known from DE 19546565 A1, and another embodiment of a test sample holder is known from US 20010034068 A1. 
     Parts of the analytical process step, e.g., the collection of the sampler and the metering with the developing fluid onto the sample take place outside the device in the device specified in DE 69915481 T2. It is disadvantageous in such an embodiment that the effects of the ambient conditions, especially of the temperature, cannot be controlled for the duration of the detection reaction. This limits the temperature range in which the measuring device can be used without affecting the reproducibility. 
     Furthermore, it is disadvantageous that the time period between the metering of the developer fluid onto the sample and the chromatographic analysis continues to be at the discretion of the user and thus also affects the subsequent measurement. The consequence of this is a fluctuation of the measurement results due to the process and, as a result, a greater measuring uncertainty over the entire measuring chain. 
     SUMMARY OF THE INVENTION 
     An object of the present invention is therefore to propose a measuring device and a process for actuating same in such a way that the reproducibility of the measurement process is improved and the effect of the ambient conditions is reduced. 
     According to the invention, a measuring device is provided with an electronic unit comprising a central control unit, a sequential control and a control chart. An optical analysis unit is provided with an optical reading element. A metering unit, a holder for a fluid tank containing a developer fluid, a temperature regulating unit and a heating/cooling element for generating a tempered zone of a test sample holder are also provided. First and second temperature sensors are provided for detecting the ambient temperature and the temperature of the tempering block. At least one contact means is provided for controlling the measuring operation. 
     The advantage of the present invention is essentially that all processing steps of the detection reaction take place in the interior of the measuring device and no preparatory preparation of the sample with a developer fluid by the user must be performed outside the measuring device. 
     The process according to the present invention for putting into operation and for operating a measuring device is characterized by a sequence of the following steps such that:
     a) In a first step, a section of the process control is transferred by the central control unit to the process control and to the temperature regulating unit,   b) in a second step, the first and second temperature sensors are polled and the temperature regulating unit is prepared,   c) the test sample holder is inserted into the measuring device in a third step,   d) the fluid tank with the developer fluid is inserted into the holder in a fourth step,   e) the door of the device is closed in a fifth step,   f) the at least first contact element is polled in a sixth step,   g) the at least second contact element is polled in a seventh step,   h) the at least third contact element is polled in an eighth step,   I) the code on the test sample holder is polled in a ninth step,   j) the control chart, code and measured values of the first and second temperature sensors are used to determine the control parameters for the tempering in a tenth step,   k) tempering of the tempering block is brought about in an eleventh step and the temperature of the tempering block is regulated by the temperature regulating unit,   l) the metering of the developer fluid onto the sample is brought about by means of the metering unit in a twelfth step,   m) tempering of the tempering block is brought about and the temperature of the tempering block is regulated by the temperature regulating unit in a thirteenth step,   n) tempering is ended in a fourteenth step, and   o) the process control is again taken over by the central control unit in a fifteenth step.   

     Provisions are made in a special embodiment of the process for the insertion of the fluid tank provided in the third step to be omitted and for feeding a defined quantity of developer fluid from a storage tank in the interior space of the measuring device into a metering tank to be brought about, instead. 
     In an alternative course of the process, pretempering of the tempering block is performed already in the second step, which makes possible a short time for establishing the readiness to operate after starting up the device. This is a meaningful variant when, for example, the measuring device is operated with an external supply voltage and the operating time is not shortened in a disadvantageous manner as a consequence of the energy consumption by a continual tempering. 
     The analysis taking place in the measuring device is started in the manner according to the present invention by a sequential control by means of a switching means. 
     This switching means may be a button actuated by the user, which is arranged on the operating unit of the measuring device. This button is, for example, part of a unit for operating and outputting user instructions and measured values and is labeled “START.” As an alternative, a switching contact is present as an additional switching means, which detects the insertion of the test sample holder into the interior space of the measuring device. The opening or closing of a door of the device after insertion of the test sample holder can be detected by means of other switching means in an alternative embodiment, and the insertion of the fluid tank with the developer fluid into a holder can be additionally detected in another preferred embodiment. 
     The test sample holder is provided with a code, which can be detected by means of optical reading and subsequently analyzed. Mechanical switches, magnetically actuated switches and a device in the form of a photoelectric cell are conceivable as switching means in respective alternative embodiments. 
     The switching means and the code of the test sample holder are polled after the insertion of the test sample holder into the measuring device and of the fluid tank with the developer fluid into the holder, and the first phase of measurement will subsequently begin. 
     The phases of the measurement with tempering of the test sample holder are given by preset time intervals of a defined duration with at least one preset first tempering temperature. The tempering of the test sample holder brings about indirectly a tempering of the test strip via a tempering block. The tempering block is brought to the first tempering temperature at the beginning, the developer fluid is metered onto the sample in the next step, and the mixture of developer fluid and sample of the biological material is tempered indirectly in the test strip in a next step according to a preset, second tempering temperature. The tempering temperature is detected by a first temperature sensor, which is rigidly connected to the tempering block with a good temperature coupling. To determine the ambient conditions, a second temperature sensor, which has a design suitable for detecting the air temperature in the interior space of the measuring device, is arranged in the interior space of the measuring device. The fluid tank with the developer fluid is not placed by the user into the holder during each analysis operation in an alternative embodiment, but a quantity of developer fluid is made available for the metering unit from an internal storage tank of the device. The tempering block is made of a metallic material in a preferred embodiment. 
     The duration of the phases of measurement for tempering and metering, as well as the first and second tempering temperatures are determined on the basis of the ambient conditions, the codes of the test sample holder, as well as preset data of a control chart. 
     At least one control chart, which contains the tabular values for the tempering temperatures and the time intervals of the phases of measurement, is present for this in a data storage unit. 
     The values for the tempering temperatures and the time intervals for tempering and metering have been determined empirically on the basis of measuring experiments for different detection reactions. Different codes are preferably placed on the test sample holders for different detection reactions, and the specific control chart can be identified on the basis of these codes and used to determine the specific tempering parameters. A subsequent refreshing and complementation of the control chart by means of data transmission via a data interface is provided in an advantageous embodiment in order to make it possible to adapt the process parameters of the measuring device to the further development of the biological analytical procedures. 
     The temperature of the heating element is regulated with the use of the tabular values in the data storage medium, the code of the test sample holder and the measured signals of the first and second temperature sensors, and regulation is preferably performed according to a proportional-integral control characteristic. The tempering of the tempering block is carried out by means of a heating element and a cooling element, and a combination of heating function and cooling function can be selected in a special embodiment by the use of a Peltier element. The opposite side of the Peltier element is coupled here by a cooling body to the ambient air. 
     A special embodiment contains, in addition to the heating/cooling element designed as a Peltier element, an additional element, which may be designed, for example, as an electric resistance heating element or as a semiconductor heating element in the form of a transistor, in order to shorten the heat-up time of the tempering block. 
     An additional energy storage unit with low internal resistance, preferably a rechargeable battery, which can supply the electric current necessary for a rapid temperature change in a short time, is provided in an advantageous embodiment to shorten the measuring time. Pretempering of the tempering block may also be carried out already before the insertion of the test sample holder in an advantageous embodiment. 
     This is a meaningful variant when, for example, the measuring device is operated by means of an external supply voltage and therefore the operating time is not shortened as a consequence of discharge of the battery due to continual tempering. 
     An exemplary embodiment of the present invention is shown in the drawings and will be explained in more detail below. The various features of novelty which characterize the invention are pointed out with particularity in the claims annexed to and forming a part of this disclosure. For a better understanding of the invention, its operating advantages and specific objects attained by its uses, reference is made to the accompanying drawings and descriptive matter in which preferred embodiments of the invention are illustrated. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       In the drawings: 
         FIG. 1  is a schematic view showing the design of a measuring device for the analysis of a sample of biological material; 
         FIG. 2  is a schematic view showing the course of the putting into operation and tempering of the measuring device; 
         FIG. 3  shows the exemplary design of a control chart; 
         FIG. 4  is an external view of the measuring device for the analysis of a sample of biological material; and 
         FIG. 5  is an external view of the measuring device in connection with the test sample holder and the insertion thereof into the measuring device. 
     
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     Referring to the drawings in particular,  FIG. 1  schematically shows a measuring device  30  for the analysis of saliva samples, in which a test sample holder  35  is inserted into the interior space  33  via an access opening  34 . 
     A collector tube  85 , which contains a collector element  84  with a sample  58  of the analyte, is arranged at the test sample holder  35 . This measuring device  30  comprises a housing  31  with an operating and output unit  80 , with an electronic unit  50 , which is divided into the components central control unit  49 , sequential control  51  and a data storage unit with a control chart  52 ; a metering unit  48  with an optical reading element  47 ; a metering unit  55 , and a temperature regulating unit  53 . 
     The line connections of the individual components are shown in  FIG. 1 , partly with a crossed line routing, and will now be specifically described. 
     The sequential control  51  is connected to a control chart  52  via a first data line  64 , to a first contact element  44  via a first contact line  66 , to a second contact element  46  via a second contact line  68 , to a third contact element  78  via a third contact line  59 , and to the temperature regulating unit  53  via a first control line  63 . 
     The central control unit  49  is connected to the optical analysis unit  48  via a second data line  65  and to the operating and analysis unit  80  via a third data line  70  and to the sequential control  51  via a fourth data line  72 . 
     A fifth data line  73  connects the control chart  52  to a data interface  87 . 
     The control chart  52  according to  FIG. 3  contains a first set of temperature values  103  and time period values  104  and a second set of temperature values  105  and time period values  106 . 
     The temperature regulating unit  53  is connected to a first temperature sensor  41  via a first measuring line  61  and to a second temperature sensor  42  via a second measuring line  62 . 
     Via a second control line  67 , the temperature regulating unit  53  is connected to the heating and cooling elements, in this case in one embodiment as a combined heating/cooling element  92  in the form of a Peltier element. An additional heating element  93  is connected to the temperature regulating unit  53  via a fourth control line  71 . The temperature regulating unit  53  is connected to an energy storage unit  54  via a supply line  60 . The heating/cooling element  92  is attached to the tempering block  40  on one side and is provided on the other side with a cooling body  91 , via the surface of which good thermal coupling with the ambient temperature is ensured. The sequential control  51  is connected to a metering unit  55  via a third control line  69 . 
     The sample  58  in the test sample holder  35  and the test strip  36 , which is located on the test sample holder  35 , are inserted into the interior space  33  of housing  31  from the direction of access  83  via a push-in guide  39 . The fluid tank  56  with the developer fluid  57  is inserted into the interior space  33  and placed into the holder  96 . The access opening  34  is closed by a door  32  of the device after insertion of the test sample holder  35  and the insertion of the fluid tank  56 , and the interior space  33  is thus separated from ambient effects. The closing of the door  32  of the device is detected via the first contact element  44 , which is actuated by a first contact maker  43  located on the door  32  of the device. The position of the test sample holder  32  is detected by the second contact element  46 , which is actuated by a second contact maker  45 , which is arranged on the test sample holder  35  or is formed by the test sample holder  35  itself. The position of the fluid tank  56  is detected by the third contact element  78 , which is actuated by a third contact maker  77 , which is arranged on the fluid tank  56  or is formed by the fluid tank  56  itself. The metering unit  55  brings about the dispensing of a developer fluid  57  from a fluid tank  56  via the access opening  38  through the collector element  84  containing the sample  58  in the collector tube  85  onto an array of test strips  37  in the test sample holder  35 . 
     The course of the process according to the present invention is as follows: After a start button  81  and the first, second and third contact elements  44 ,  46 ,  78  have been polled and after a code  86  has been detected on the test sample holder  35  by the optical reading element  47  and after the code  86  has been analyzed by the optical analysis unit  48 , and after the subsequent detection of the first and second temperature sensors  41 ,  42 , the central control unit presets the temperature of the tempering zone  94  of the tempering block  40  (and the block tempering zone  94 ), which said temperature is to be controlled, for the temperature regulating unit  53  on the basis of the control chart  52 . 
     The tempering of the tempering zone  94  in the tempering block  40  brings about a tempering of the tempering zone  95  in the test sample holder  35 . The temperature regulating unit  53  actuates the heating/cooling element  92  and the additional heating element  93  and regulates the tempering zone  94  in tempering block  40  according to the control characteristics set, for example, according to a proportional-integral (PI) control characteristic. The first and second phases of the measurement and the metering of the developer fluid  57  onto the test strip  37  are controlled according to the contents of the control chart  52 . 
     The tempering temperatures for the first and second phases are determined by the code of the test sample holder  35  and by the data contents  103 ,  105  of the control chart  52 ; the overall duration of measurement is determined by the data contents  104 , and the duration of metering for the developer fluid  57  onto the test strip  37  is determined by the data contents  106  of the control chart  52 . After the end of the first phase, the developer fluid  57  is metered by means of the metering unit  55 , and the temperature is regulated to the second temperature during the second phase. 
     After the end of the second phase, the change in color  36  on the test strip  37  is detected via the optical reading element  47 , analyzed in the optical analysis unit  48 , transmitted to the central control unit  49 , and displayed on a display  82  of the operating and output unit  80 . 
     The process according to the present invention for putting into operation and for operating the measuring device is shown in  FIG. 2  and is characterized by a sequence of the following steps such that:
     a) In a first step  1 , a section of the process control is transferred by the central control unit to the process control and to the temperature regulating unit,   b) in a second step  2 , the first and second temperature sensors are polled and the temperature regulating unit is prepared,   c) the test sample holder is inserted into the measuring device in a third step  3 ,   d) the fluid tank with the developer fluid is inserted into the holder in a fourth step  4 ,   e) the door of the device is closed in a fifth step  5 ,   f) the at least first contact element is polled in a sixth step  6 ,   g) the at least second contact element is polled in a seventh step  7 ,   h) the at least third contact element is polled in an eighth step  8 ,   I) the code on the test sample holder is polled in a ninth step  9 ,   j) the control chart, code and measured values of the first and second temperature sensors are used to determine the control parameters for the tempering in a tenth step  10 ,   k) tempering of the tempering block is brought about in an eleventh step  11  and the temperature of the tempering block is regulated by the temperature regulating unit,   l) the metering of the developer fluid onto the sample is brought about by means of the metering unit in a twelfth step  12 ,   m) additional and different tempering of the tempering block is again brought about, and the temperature of the tempering block is regulated by the temperature regulating unit in a thirteenth step  13 ,   n) tempering is ended in a fourteenth step  14 , and   o) the process control is again taken over by the central control unit in a fifteenth step  15 .   

       FIG. 3  shows the structure of the control chart  52 . The chart is divided into a specification column  100 , in which the values of the ambient temperature are entered as a reference variable, and a first value block  101  and a second value block  102 . The time period values  104  for the overall duration of the measurement are entered in value block  101 . The temperature values  103  are entered there for the first phase of the measurement. The temperature values  105  for the second phase of the measurement and the time period values  106  for metering the developer fluid  57  onto the test strip  37  located in the test sample holder  35  are entered in a second value block  102 . 
     While specific embodiments of the invention have been shown and described in detail to illustrate the application of the principles of the invention, it will be understood that the invention may be embodied otherwise without departing from such principles. 
     Appendix 
     List of Reference Numbers 
     
         
           1  Step  1 , transfer of control from the central control unit 
           2  Step  2 , initialization, polling of the temperature sensors 
           3  Step  3 , insertion of the test sample holder 
           4  Step  4 , insertion of the fluid tank 
           5  Step  5 , closing of the device door 
           6  Step  6 , polling of the first contact element 
           7  Step  7 , polling of the second contact element 
           8  Step  8 , polling of the third contact element 
           9  Step  9 , reading of the code 
           10  Step  10 , determination of the control parameters 
           11  Step  11 , tempering 
           12  Step  12 , metering 
           13  Step  13 , tempering 
           14  Step  14 , ending of measurement 
           15  Step  15 , return of control to the central control unit 
           30  Measuring device 
           31  Housing 
           32  Device door 
           33  Interior space 
           34  Access opening 
           35  Test sample holder 
           36  Color change marking 
           37  Test strip 
           38  Access opening 
           39  Push-in guide 
           40  Tempering block 
           41  First temperature sensor 
           42  Second temperature sensor 
           43  First contact maker 
           44  First contact element 
           45  Second contact maker 
           46  Second contact element 
           47  Optical reading element 
           48  Optical analysis unit 
           49  Central control unit 
           50  Electronic unit 
           51  Sequential control 
           52  Control chart 
           53  Temperature regulating unit 
           54  Energy storage unit 
           55  Metering unit 
           56  Fluid tank 
           57  Developer fluid 
           58  Sample 
           59  Third contact line 
           60  Supply line 
           61  First measuring line 
           62  Second measuring line 
           63  First control line 
           64  First data line 
           65  Second data line 
           66  First contact line 
           67  Second control line 
           68  Second contact line 
           69  Third control line 
           70  Third data line 
           71  Fourth control line 
           72  Fourth data line 
           73  Fifth data line 
           77  Third contact maker 
           78  Third contact element 
           80  Operating and output unit 
           81  Button (start) 
           82  Display 
           83  Direction of access 
           84  Collector element 
           85  Collector tube 
           86  Code 
           87  Data interface 
           91  Cooling body 
           92  Heating/cooling element 
           93  Additional heating element 
           94  Tempering zone, block 
           95  Tempering zone, test sample 
           96  Holder 
           100  Specification column 
           101  First value block 
           102  Second value block 
           103  First set of temperature values 
           104  First set of time period values 
           105  Second set of temperature values 
           106  Second set of time period values