Patent Abstract:
The present invention is directed to a cartridge device for a measuring system for measuring viscoelastic characteristics of a sample liquid. In particular a blood sample, comprising a cartridge body having at least one measurement cavity formed therein and having at least one probe element arranged in said at least one measurement cavity for performing a test on said sample liquid; and a cover being attachable on said cartridge body; wherein said cover covers at least partially said at least one measurement cavity and forms a retaining element for retaining said probe element in a predetermined position within said at least one measurement cavity. The invention is directed to a measurement system and a method for measuring viscoelastic characteristics of a sample liquid.

Full Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application is a continuation of and claims priority to U.S. Ser. No. 13/895,034 filed May 15, 2013, which is a continuation of U.S. Ser. No. 12/640,376 filed Dec. 17, 2009, which claims the benefit of U.S. Provisional Application No. 61/140,344, filed Dec. 23, 2008, the entire disclosures of which are herein incorporated by reference. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention relates to a cartridge device for a measuring system for measuring viscoelastic characteristics of a sample liquid, in particular of a blood sample liquid. The present invention also relates to a corresponding measuring system and method. 
         [0003]    It is essential for survival that a wound stops bleeding, i.e. that the body possesses an adequate mechanism for haemostasis. The process of blood clotting can be activated in the case of injuries or inflammations by either extrinsic or intrinsic factors, e.g. tissue factor (TF) or Hagemann factor (F XII), respectively. Both activation channels are continued in a common branch of the cascade resulting in thrombin formation. The thrombin itself finally initiates the formation of fibrin fibres which represent the protein backbone of blood clots. 
         [0004]    The other main constituent of the find blood clot are the thrombocytes which are interconnected by the fibrin fibres and undergo a number of physiological changes during the process of coagulation. Within limits a lack of thrombocytes can be substituted by an increased amount of fibrin or vice versa. This is reflected in the observation that the thrombocyte counts as well as the fibrinogen concentration varies even within a healthy population. 
         [0005]    Various methods have been introduced to assess the potential of blood to form an adequate clot and to determine the blood clots stability. Common laboratory tests such as thrombocyte counts or the determination of fibrin concentration provide information on whether the tested component is available in sufficient amount but lack in answering the question whether the tested component works properly under physiological conditions (e.g. the polymerisation activity of fibrinogen under physiological conditions can not be assessed by common optical methods). Besides that, most laboratory tests work on blood-plasma and therefore require an additional step for preparation and additional time which is unfavourable especially under POC (point of care) conditions. 
         [0006]    Another group of tests which overcomes these problems is summarized by the term “viscoelastic methods”. The common feature of these methods is that the blood clot firmness (or other parameters dependent thereon) is continuously determined, from the formation of the first fibrin fibres until the dissolution of the blood clot by fibrinolysis. Blood clot firmness is a functional parameter, which is important for haemostasis in vivo, as a clot must resist blood pressure and shear stress at the site of vascular injury. Clot firmness results from multiple interlinked processes: coagulation activation, thrombin formation, fibrin formation and polymerization, platelet activation and fibrin-platelet interaction and can be compromised by fibrinolysis. Thus, by the use of viscoelastic monitoring all these mechanisms of the coagulation system can be assessed. 
         [0007]    A common feature of all these methods used for coagulation diagnosis is that the blood clot is placed in the space between a cylindrical pin and an axially symmetric cup and the ability of the blood dot to couple those two bodies is determined. 
         [0008]    The first viscoelastometric method was called “thrombelastography” (Harlert H: Blutgerinnungsstudien mit der Thrombelastographie, einem neuen Untersuchungsverfahren. Klin Wochenschrift 26:577-583, 1948). As illustrated in  FIG. 1 , in the thromboelastography, the sample as a sample liquid  1  is placed in a cup  2  that is periodically rotated to the left and to the right by about 5°, respectively. A probe pin  3  is freely suspended by a torsion wire  4 . When a clot is formed it starts to transfer the movement of the cup  2  to the probe pin  3  against the reverse momentum of the torsion wire  4 . The movement of the probe pin  3  as a measure for the clot firmness is continuously recorded and plotted against time. For historical reasons the firmness is measured in millimetres. 
         [0009]    The result of a typical measurement of this kind is illustrated in  FIG. 2 . One of the most important parameters is the time between the activator induced start of the coagulation cascade and the time until the first long fibrin fibres have been build up which is indicated by the firmness signal exceeding a defined value. This parameter will be called clotting time or just CT in the following. Another important parameter is the clot formation time (CFT) which gives a measure for the velocity of the development of a clot. The CFT is defined as the time it takes for the clot firmness to increase from 2 to 20 mm. The maximum firmness a clot reaches during a measurement, further on referred to as maximum clot firmness or just MCF, is also of great diagnostic importance. 
         [0010]    Modifications of the original thromboelastography technique (Hartert et al. (U.S. Pat. No. 3,714,815) have been described by Cavallari et al. (U.S. Pat. No. 4,193,293), by Do et al. (U.S. Pat. No. 4,148,216), by Cohen (U.S. Pat. No. 6,537,819). A further modification by Calatzis at al. (U.S. Pat. No. 5,777,215) illustrated in  FIG. 3  is known under the term thromboelastometry. 
         [0011]    Contrary to the modifications mentioned above, thromboelastometry is based on a cup  2  fixed in a cup holder  12  while the probe bin  3  is actively rotated. For this purpose the probe pin  3  is attached to a shaft  6  which is suspended by a ball bearing  7  in a base plate  11  and has a spring  9  connected to it. An oscillating motion perpendicular to the drawing plane induced at the opposite end of the spring is transformed into a periodically rotation of the shaft  6  and the connected cup  2  around a rotation axis  5  by about 5° in each direction. As the sample liquid  1  begins to coagulate the motion amplitude of the shaft  6  which is detected by the deflection of a light beam from detecting means  10  and a mirror  9  starts to decrease. 
         [0012]    During coagulation the fibrin backbone creates a mechanical elastic linkage between the surfaces of the blood-containing cup  2  and a probe pin  3  plunged therein. A proceeding coagulation process induced by adding one or more activating factor(s) can thus be observed. In this way, various deficiencies of a patient&#39;s haemostatic status can be revealed and can be interpreted for proper medical intervention. 
         [0013]    A general advantage of viscoelastometric, e.g. thromboelastometric, techniques compared to other laboratory methods in this field therefore is that the coagulation process and the change of mechanical properties of the sample are monitored as a whole. This means that—in contrary to other laboratory methods mentioned above—thromboelastometry does not only indicate if all components of the coagulation pathways are available sufficient amounts but also if each component works properly. 
         [0014]    To obtain detailed information on the correct amount and function of the thrombocytes as well as the fibrinogen and certain factors nowadays there is an increasing amount of compounds available which activate or inhibit certain components of the coagulation system. This allows determining at which point of the coagulation system a problem is located. 
         [0015]    For practical reasons theses compounds are usually injected into the disposable plastic cup which later on is used for the measurement by using a pipette (either a manual or an automatic one). In the last preparation step, after the blood or plasma sample has been added, the whole amount of sample (blood/plasma and the additional chemicals) is mixed by drawing it into the pipette tip and dispensing it into the cup again. 
         [0016]    The possibility to activate or to inhibit certain components of the coagulation system is especially useful in conjunction with state-of-the-art thromboelastometers such as the ROTEM (Pentapharm GmbH, Munich, Germany) which allows conducting four measurements in parallel. This allows detailed information on the current status of the coagulation-situation of a patient to be achieved and therefore allows an appropriate therapy within several minutes. 
         [0017]    This is of particular importance in case of patients struck by massive blood loss as it often occurs in context with multiple traumata or major surgery. The blood of such patients often is diluted due to infusions which are administered to replace the loss in volume. This leads to a decrease of the concentration of thrombocytes as well as coagulation factors including fibrinogen. 
         [0018]    Main advantages of thromboelastometry and thromboelastography are the possibility to perform several differential tests in parallel in order to precisely determine which kinds of blood products are the appropriate medication, the possibility to perform the measurement at or close to the point of care (POC) and—compared to other methods—the relatively small amount of time until valid results are available. 
         [0019]    On the other hand the operator has to perform a significant number of steps in order to start the measurement (preparation of the reagents, attachment of the probe pin and the cup to the instrument, pipetting and mixing the blood sample and the reagents, adjustment of computer settings, etc.) on which the time spent is considerable, especially in the case of surgery being performed. 
         [0020]    Furthermore this rather complex preparation also increases the risk of operating errors. There have been several approaches to simplify the usage of thromboelastometers. The Rotem-System (Pentapharm GmbH, Munich, Germany) e.g. is supplied with an automatic pipette which simplifies the handling to a large degree and thereby decreases the risk of operating errors. 
         [0021]    WO 2008093216 describes the approach to provide the adequate amount of each of the reagents needed for one specific test in a ready-to-use mixture. In order to prevent the reaction of the reagents prior to the measurement, they are supplied in a lyophilisate state. This is additionally advantageous as the reagents can be stored at room temperature. Using this approach the preparation is reduced to the steps of adding the blood sample into the reagent container, mixing of blood with the reagent and transferring the mixture to the instrument. 
         [0022]    US 2007/0059840 A1 describes a hemostasis analysis device and method. The device includes a container for holding a sample to be tested and a bobber configured to be buoyantly suspended on the sample. A magnet is secured to the bobber. The container can be driven in an oscillating motion. An external magnetic field is generated adjacent to the bobber. A magnetic field strength detector detects changes in the magnetic field as a result of movement of the bobber and magnet responsive to the oscillating motion of the container and clotting of the sample. 
         [0023]    Such a new measuring system entails acceptability problems and uncertainties for a user. Moreover, that analysis device does not fit in existing measuring systems. Therefore new systems have to be completely designed. 
         [0024]    All these modifications lead to a significant improvement of handling of modern thromboelastometers and thromboelastographs, however, no successful approach to develop a widely automated technique has been made since Hartert&#39;s invention 60 years ago. One of the two main reasons of that is the fact that the measurement requires two disposable parts (cup and pin) being moved in relation to each other and thus have to be reversibly attached to different parts of the measurement device. E.g. in  FIG. 3 , the probe pin  3  is attached to the shaft  6  and the cup  2  to the cup holder  12 , respectively. The other main reason is that different tests are required to get comprehensive information of a current bleeding status of a patient. These different tests require different reagents which have to be mixed with the blood sample. 
       SUMMARY OF THE INVENTION 
       [0025]    It is a problem underlying the presented invention to provide a cartridge device for a measuring system for measuring viscoelastic characteristics of a sample liquid, in particular a blood sample. 
         [0026]    Directly connected to this invention is the problem to provide a corresponding measuring system for measuring viscoelastic characteristics of a sample liquid, in particular the coagulation characteristics of a blood sample liquid. 
         [0027]    It is a further problem underlying the invention to provide a method for measuring viscoelastic characteristics of a sample liquid using said measuring system. 
         [0028]    These problems are solved by the subject-matter of the independent claims. Preferred embodiments are set forth in the dependent claims. 
         [0029]    In a first aspect, the present invention provides a cartridge device for a measuring system for measuring viscoelastic characteristics of a sample liquid, in particular a blood sample, comprising 
         [0030]    a cartridge body having at least one measurement cavity formed therein and having at least one probe element arranged in said at least one measurement cavity for performing a test on said sample liquid; and 
         [0031]    a cover being attachable on said cartridge body; 
         [0032]    wherein said cover covers at least partially said at least one measurement cavity and forms a retaining element for retaining said probe element in a predetermined position within said at least one measurement cavity. 
         [0033]    In a second aspect, the present invention provides a measuring system for measuring viscoelastic characteristics of a sample liquid, in particular a blood sample, comprising: at least one interface element; at least one shaft rotatably supported by the interface element to be rotated by drive means; at least one cartridge device fixed to the interface element for holding the sample liquid, the at least one cartridge device comprising a cartridge body with a cover and at least one probe element arranged in a measurement cavity formed in said cartridge body for cooperating with the at least one shaft; at least one detecting means cooperating with the shaft for measuring viscoelastic characteristics of the sample liquid; and 
         [0034]    control means to control the measuring system. 
         [0035]    In a third aspect, the present invention provides a method for measuring viscoelastic characteristics of a sample liquid by means of said measuring system, comprising the following steps: 
         [0036]    a) providing the cartridge device having at least one measurement cavity with at least one probe element arranged therein; 
         [0037]    b) attaching the cartridge device to said interface element, said shaft being inserted into said probe element; 
         [0038]    c) filling said measurement cavity of said cartridge device with sample liquid; 
         [0039]    d) rotating said shaft in an oscillating motion around said rotation axis; and 
         [0040]    e) measuring viscoelastic characteristics of said sample liquid by detecting the rotation of said shaft by said detecting means. 
         [0041]    In a preferred embodiment the probe element comprises a probe pin to cooperate with the sample liquid and a connector section for a connection to the measuring system. The connector section is formed e.g. as a bore extending within the probe element and comprises frictional connection means which can be e.g. clip means or a thread. An insertion guide facilitates an insertion of a part, in particular a shaft, of a measuring system. Thereby the shaft can be connected securely to the probe element. 
         [0042]    The at least one measurement cavity can comprise bearing or supporting means for the probe element to align or hold the probe element prior to insertion of the shaft. 
         [0043]    After the shaft has been inserted into the connector section, the shaft can be lifted to position the probe element at a working position. 
         [0044]    In an alternative preferred embodiment the probe element is formed as a detachably fixed component part of the cover. An operator only has to attach the cartridge device to the measuring system the shaft being inserted into the probe element will detach the probe element from the cover and hold it securely in a position ready to carry out a measurement. Therefore the probe element comprises a fixing section for detachably fixing the probe element at fixing means of the cover. 
         [0045]    After a measurement the cartridge device can be detached from the measuring system wherein the shaft is removed from the probe element. Then the probe element will seal the measurement cavity against the cover by means of e.g. a flange adapted to form a sealing. The cover retains the probe element within the measurement cavity. 
         [0046]    It is preferred that the fixing means of the cover comprises clip means cooperating with corresponding clip means of the fixing section of the probe element. 
         [0047]    In an alternative embodiment the fixing section of the probe element is integrally formed with the cover, the fixing means of the cover comprising a perforation. 
         [0048]    The cover can be fixed on the cartridge body either by bonding or welding. In an alternative embodiment the cover is integrally formed with the cartridge body, e.g. made of a plastic material. It is also possible that the cover is made of a material which is different from the cartridge body. That can be done for example by two- or more-component-moulding. 
         [0049]    In a further preferred embodiment the cartridge device further comprises at least one receiving cavity formed therein for receiving the sample liquid; at least one reagent cavity for holding at least one reagent; a ductwork connecting said cavities and the at least one measurement cavity; and at least one pump means connected to the ductwork for transporting the sample liquid from the at least one receiving cavity to the at least one measurement cavity by means of the ductwork, wherein the cover covers and at least partially forms said cavities and said ductwork and forms at least partially the pump means. 
         [0050]    In a further embodiment the at least one reagent cavity is integrally formed with the pump means or/and with the at least one measurement cavity or/and with one or more of the ductworks. The reagent cavity can be formed as a deep cavity or just a small place where reagent can be deposited. Thus the sample liquid being pumped through the ductwork end the pump means into the measurement cavity can be mixed with the reagent. 
         [0051]    The pump means comprise at least one valve for a directed flow of the sample liquid in order to direct the pumped liquid into the measurement cavity. 
         [0052]    In another embodiment the reagent or an additional reagent can be stored in at least one reagent receptacle which can be opened by external means. 
         [0053]    In a further embodiment the at least one reagent receptacle storing a reagent is integrated in the cover. 
         [0054]    In another embodiment the at least one reagent receptacle comprises a bottom part which can be opened by external means to discharge the reagent into the ductwork and/or into one of the cavities. The receptacle can be adapted as a blister receptacle, for example. 
         [0055]    The at least one reagent can be stored within the cartridge device in pulverized, solid or liquid form. 
         [0056]    The cartridge device can be further provided with at least one reagent stored therein. 
         [0057]    Filling in sample liquid can be done directly into the measurement cavity if no receiving cavity is provided. To this end the sample liquid can be injected through the cover via an opening or passage hole in the interface element or through a ductwork by an operator or by a control apparatus. 
         [0058]    In case of a receiving cavity the sample liquid can be filled into the receiving cavity and be pumped by the pump means to the measuring cavity. 
         [0059]    To fill in sample liquid, operate the pump means, add reagents and/or open the reagent receptacle the measuring system is equipped with a control apparatus. The control apparatus has means to access the pump means through a pump access formed as a passage of the interface element. Further the control apparatus can inject sample liquid through an inlet opening in the interface element into the receiving cavity. The control apparatus comprises also operating means to inject or to add reagents into the cartridge device as well as to open reagent receptacles. 
         [0060]    Further features and advantages of the present invention will be evident from a description of embodiments with reference to the figures. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0061]    The figures are showing the following: 
           [0062]      FIG. 1  is a schematic drawing of the principle of thromboelastography according to Hartert. 
           [0063]      FIG. 2  is an exemplary diagram showing a typical thromboelastometric measurement. 
           [0064]      FIG. 3  is a schematic drawing of the thromboelastometry. 
           [0065]      FIG. 4  is a schematic drawing of a first embodiment of a cartridge device according to the invention. 
           [0066]      FIG. 5  is a schematic drawing of a variation of the first embodiment of the cartridge device according to the invention. 
           [0067]      FIG. 6  is a schematic drawing of another variation of the first embodiment of the cartridge device according to the invention. 
           [0068]      FIG. 7 a    is a schematic drawing of a first embodiment of a probe element. 
           [0069]      FIG. 7 b    is a schematic drawing of the first embodiment of the probe element of  FIG. 7 a    within a measuring cavity of the first or a second embodiment of the cartridge device according to the invention before use. 
           [0070]      FIG. 7 c    is a schematic drawing of the first embodiment of the probe element of  FIG. 7 a    within a measuring cavity of the first or the second embodiment of the cartridge device according to the invention in use. 
           [0071]      FIGS. 8 a - c    are technical drawings of the preferred probe element of  FIG. 7   a.    
           [0072]      FIG. 9 a    is a side view of a third embodiment of a cartridge device according to the invention. 
           [0073]      FIG. 9 b    is a sectional view B-B of the cartridge device of  FIG. 9   a.    
           [0074]      FIG. 9 c    is a sectional view C-C of the cartridge device of  FIG. 9   a.    
           [0075]      FIG. 9 d    is a sectional view D-D of the cartridge device of  FIG. 9   a.    
           [0076]      FIG. 10 a    is a top view of the cartridge device of  FIG. 9   a.    
           [0077]      FIG. 10 b    is a sectional view E-E of the cartridge device of  FIG. 10   a.    
           [0078]      FIG. 11 a    is a sectional view of a pump means of the cartridge device of  FIG. 9   a.    
           [0079]      FIG. 11 b    is a sectional view of the pump means of  FIG. 11 a    in operated position. 
           [0080]      FIG. 12  is a schematic top view of the pump means of  FIG. 11   a.    
           [0081]      FIG. 13 a    is a side view of an embodiment of a measuring system according to the invention. 
           [0082]      FIG. 13 b    is a top view of the measuring system of  FIG. 13   a.    
           [0083]      FIG. 13 c    is a sectional view H-H of the measuring system of  FIG. 13   b.    
           [0084]      FIG. 14  is a sectional view of a reagent receptacle of a third embodiment of the cartridge device according to the invention. 
           [0085]      FIG. 15  is a schematic drawing of a second embodiment of the probe element. 
       
    
    
     DESCRIPTION OF EXEMPLARY EMBODIMENTS 
       [0086]    Parts and components having same functions are depicted with same references. 
         [0087]    Prior to a detailed description of the preferred embodiments the basic features and a basic practical implementation are summoned as follows. All embodiments refer to a cartridge device  50  (see  FIG. 13 c   ) which can be formed in a first embodiment (see  FIGS. 4, 5 and 6 ), in a second embodiment (see  FIGS. 7   b,    7   c  and  15 ) or in a third embodiment (see  FIGS. 9 to 10 ). The cartridge device  50  contains all parts coming into contact with a sample liquid  1  to be tested. These can be also reagents the sample liquid has to be mixed with for a measurement. The cartridge device  50  is part of a measuring system  40  (see  FIG. 13 c   ) to which the cartridge device  50  is attached before measurement. The measuring system  40  also comprises a control apparatus (not shown) which has been adapted to interact with the cartridge device  50  by electrical and/or mechanical means to control flow of sample liquid  1  (see  FIG. 7 c   ) and measurements as well as collect data. Furthermore this apparatus contains mechanical and electronic parts required for measurement, data analysis and user interaction. The present invention is not only suitable for thromboelastometry, thromboelastography and platelet aggregometry but also for other blood tests usually performed regarding surgery. 
         [0088]    A first embodiment of a cartridge device  50  of the invention will be described with reference to  FIGS. 4 and 5 . The cartridge device  50  for the measuring system  40  for measuring medical relevant, e.g. viscoelastic, characteristics like coagulation or platelet function of a sample liquid  1 , particularly a blood sample, comprises a receiving cavity  16  for receiving the sample liquid  1 , pump means  18  for pumping the sample liquid, a reagent cavity  19  for storing a reagent  21 , a measurement cavity  20  for measuring the sample liquid  1  and a ductwork connecting said cavities. The ductwork comprises an inlet duct  13  from the receiving cavity  16  to the pump means  18 , an intermediate duct from the pump means  18  to the reagent cavity  19  and an outlet duct  15  from the reagent cavity  19  to the measurement cavity  20 . In a variation said cavities and ducts can be arranged in different ways one of which is shown in  FIG. 5 , wherein pump means  18  and reagent cavity  19  are changed. 
         [0089]    In this embodiment the receiving cavity  16  consists of a cavity within the cartridge device  50 . The sample liquid  1  can be applied by means of a syringe, pipette etc, e.g. through a self sealing cap shown as a receiving cavity cover  33   a  in  FIG. 10   b.  By operating the pump means  18 , e.g. by means of the control apparatus mentioned above, the sample liquid is transported to the reagent cavity  19 , where the reagent  21  required for measurement is mixed with the sample liquid  1 . Further pumping the sample liquid  1  will transfer it into the measurement cavity  20  in which the measurement (described below) is carried out. 
         [0090]    In an alternative embodiment the reagent cavity  19  is integral formed with the pump means  18  and/or with the measurement cavity  20  and/or with the ductwork. The transport of the sample liquid  1  can be controlled by said control apparatus. 
         [0091]      FIG. 6  shows another variation of the first embodiment. Two arrangements of  FIG. 4  with only one receiving cavity  16  are arranged in parallel, wherein a first inlet duct  13  communicates with a second inlet duct  13 ′ connected to second pump means  18 ′. A second intermediate duct  14 ′ leads to a second reagent cavity  19 ′ storing a second reagent  21 ′. A second outlet duct  15 ′ connects the second reagent cavity  19 ′ to the second measurement cavity  20 ′.  FIG. 6  shows only one possible variation of a plurality of different arrangements easily imagined. The sample liquid  1  is shared among the arrangements in parallel. Controlled by the external control apparatus the shared portions of the sample liquid  1  are mixed with different reagents  21 ,  21 ′ during transport. It is apparent to a person skilled in the art that in order to achieve a maximum benefit for a user different types of tests can be combined in one cartridge device  50 . 
         [0092]    In a preferred embodiment the cartridge device  50  comprises four arrangements of  FIG. 4 or 5  having 4 measurement cavities  20 ,  20 ′. Thus measurements can be done with different reagents on the same liquid sample or with same reagents as well to check plausibility. 
         [0093]    Regarding e.g. blood coagulation there are different reagents available which activate or suppress different parts of the coagulation cascade. Pentapharm GmbH (Munich, Germany) for example amongst others provide tests for intrinsic and extrinsic activation of a blood sample (INTEM or EXTEM respectively), and also a test for extrinsic activation in which the thrombocyte function is suppressed by administration of cytochalasin D (FIBTEM). It is state of the art that it is possible by wise combination of such tests to be able to determine very precisely at which point within the coagulation cascade a problem occurs. This is of great importance in order to determine a proper medication. By comparison of the results on an EXTEM test of a pathologic sample to those of a FIBTEM test of the same sample it is possible to e.g. precisely determine if a coagulation disorder results from lack of fibrinogen or a malfunction of platelets. Generally, there are different typical medical scenarios in which coagulation disorders are very likely to occur. For example coagulation disorders occurring during liver transplantation are merely caused by lack of certain coagulation factors etc., while coagulation disorders during open heart surgery are most likely due to the influence of heparin. This means basically that different medical settings require different coagulation tests. Referring to  FIG. 6  it is possible and worthwhile to provide different cartridge devices  50  for different typical operations. It is also possible to combine e.g. an INTEM, an EXTEM and a FIBTEM coagulation test with a platelet aggregometry test within one cartridge. Using such a cartridge the preparation of a measurement which provides almost overall information about the coagulation status of a patient merely requires the two steps of attaching the cartridge device  50  to the measuring system  40  with the external control apparatus and injecting the blood sample as one sample liquid  1 . Considering the significance of more complex and time consuming preparation of several thromboelastography or thromboelastometry tests, it is evident that the invention is of great advantage for easier, safer and more accurate POC-tests. 
         [0094]    It is important to note that the cartridge devices  50  of the described embodiments are suitable for different diagnostic tests like thromboelastometry, thromboelastography, platelet aggregometry and others. Depending on which type of test or tests the cartridge device  50  is designed for, there are different additional parts required which interact with the sample during measurement and/or an external control apparatus. Possible adaptations for thromboelastometry and platelet aggregometry are described below. 
         [0095]      FIG. 7 a    is a schematic drawing of a first embodiment of a probe element  22  arranged in the measurement cavity  20  (see also  FIGS. 10 b  and 13 c   ).  FIGS. 7 b  and 7 c    show a second embodiment of the cartridge device  50  in form of a cartridge body  30  which comprises only the measurement cavity  20 . In the shown example this cavity  20  is accessible via a ductwork  15 ,  15 ′ through a cavity wall. Alternatively the cavity  20  can be filled through a cover  31 , e.g. by injection needles or the like. 
         [0096]    The probe element  22  comprises the probe pin  3  (see  FIG. 1 ) which is connected to a flange  24  and a fixing section  25  via an intermediate section  23 . The probe element  22  is formed as a rotational part and further comprises a connector section  26  formed as a bore extending within the probe element  22  along its longitudinal axis, which is the rotational axis  5  as well (see  FIG. 3 ). 
         [0097]    The probe element  22  is arranged in the measurement cavity  20  of the cartridge body  30  of the cartridge device  50  as shown in  FIG. 7   b.  The measurement cavity  20  is covered by the cover  31  (see also  FIGS. 10 b  and 13 c   ). The cover  31  comprises an opening with fixing means  32  above the measurement cavity  20 . The probe element  22  is arranged such that its fixing section  25  corresponding to the fixing means  32  engage with them. In this manner the probe element  22  is detachably fixed to the cover  31 . The fixing means  32  in this example are equipped with a circular nose corresponding to a circular notch of the fixing section  25  of the probe element  22 . Other fixing means e.g. clip means or the like are possible. The flange  24  is in contact to the inner side of the cover  31 . 
         [0098]    During attaching the cartridge device  50  to the measuring system  40  (see also  FIG. 13 c   ) the shaft  6  of the measuring system  40  (see  FIG. 3  and  FIGS. 13   a . . . c ) is inserted with its bottom portion, an insert section  6   a,  into the connector section  26 . By insertion into the connector section  26  of the probe element  22  the probe element  22  will be detached from the cover  31  not before the insert section  6   a  is completely inserted in the connector section  26 . Then the probe element  22  will be put into in a measuring position as shown in  FIG. 7 c    and kept there. The insert section  6   a  of the shaft  6  is engaged with the connector section  26  of the probe element  22  e.g. by friction, clip means, thread or the like. In case of a thread the probe element  22  will be hold by the engagement with or perforation of the cover  31 . The shaft  6  having a corresponding thread on its insert section  6   a  will be inserted into the connector section of the probe element  22  by rotation until the insert section  6   a  will be completely inserted into the connector section  26 . Then the shaft  6  can be pushed down and/or rotated together with the fully engaged probe element  22  until the probe element  22  will be detached from the cover  31 .  FIG. 7 c    shows the sample liquid  1 , which has been pumped into the measurement cavity  20 . The probe pin  3  of the probe element  22  is immersed in the sample liquid  1 . A measurement as described above can be carried out. After the measurement the cartridge device  50  is detached from the measuring system  40 , wherein the shaft  6  is drawn up together with the probe element  22  against the cover  31 . The insert section  6   a  of the shaft  6  will be drawn out of the connector section  25  of the probe element  22  the flange  24  thereof contacting and sealing the opening of the cover  31 . Instead of a flange  24  the upper end of the probe element  22  can have a larger diameter than the opening in the cover  31 . It is preferred that the insert section  6   a  of the shaft  6  and the measurement cavity  20 ,  20 ′ are formed symmetrically. 
         [0099]    It is also possible to insert the insert section  6   a  of the shaft  6  into the connector section  26  of the probe element  22  and push the probe element  22  down until its bottom contacts the bottom of the measurement cavity  20 ,  20 ′ ensuring that the insert section  6   a  is completely inserted into the connector section  26 . Then the shaft  6  will be moved up into the measuring resp. working position of the probe element  22  as shown in  FIG. 7   c.    
         [0100]      FIGS. 8   a . . . c  are technical drawings of a preferred embodiment of the probe element  22  of  FIG. 7 a      FIG. 8 a    shows a side view and  FIG. 8 b    shows a top view of the probe element  22  parts of which have been described above regarding  FIG. 7   a.  Finally,  FIG. 8 c    illustrates a sectional view along rotational axis  5 . The connector section  26  extends over more than about 75% of the length of the probe element  22 . 
         [0101]    Now a third embodiment of the cartridge device  50  will be described with reference to  FIGS. 9   a, . . . , d  and  FIGS. 10   a, . . . b.    
         [0102]      FIG. 9 a    is a side view of a second embodiment of a third embodiment of the cartridge device  50  according to the invention.  FIG. 9 b    is a sectional view B-B of the cartridge device  50  of  FIG. 9   a.    FIG. 9 c    is a sectional view C-C of the cartridge device of  FIG. 9   a.    FIG. 9 b    is a sectional view D-D of the cartridge device of  FIG. 9   a.    FIG. 10 a    is a top view of the cartridge device of  FIG. 9   a.    FIG. 10 b    is a sectional view E-E of the cartridge device of  FIG. 10   a.    
         [0103]    The cartridge device  50  of this example is equipped with the ductwork  13  and  15 . The ducts are formed with an diameter of approximately 1 mm in this embodiment. The ductwork requires that the cartridge device  50  comprises two parts: the cartridge body  30  and the cover  31 , which are glued or welded together to obtain a leak-proof device. The cartridge body  30  is relative rigid and the cover  31  is formed as an elastic part. So it is possible to integrate the pump means  18  into the cover  31 . Moreover, the cover  31  covers the receiving cavity  16  with the receiving cavity cover  33   a  and forms a type of liner wall  33  and a separation wall  34  forming an inlet for the inlet duct  13  within the receiving cavity  16 . The receiving cavity cover  33   a  might act as a self seal for injection of a sample liquid  1  by a syringe for example. The cover  31  forms top parts of the ductwork  13  an  15  and a cover of the measurement cavity  20  (see also  FIGS. 7   b . . . c ). In this example the pump means  18  comprises a pump membrane  35  formed by the cover  31 . The pump membrane  35  cooperates with a pump cavity  36  termed with a pump cavity bottom  36   a  in the cartridge body  30  below the pump membrane  35 . 
         [0104]    In this embodiment a reagent cavity  19 ,  19 ′ is formed, e.g. by sections of the ductwork or/and the pump means  18 ,  18 ′ in which the reagents can be stored resp. deposited, especially on the pump cavity bottom  36   a,  for example. 
         [0105]    The pump means  18  will now be described with reference to  FIGS. 11   a . . . b  and  FIG. 12 . 
         [0106]      FIG. 11 a    is a sectional view of the pump means  18 ,  18 ′ of the cartridge device  50 ,  FIG. 11 b    is a sectional view of the pump means  16  of  FIG. 11 a    In operated position, and  FIG. 12  is a schematic top view of the pump means  18  of  FIG. 11   a.    
         [0107]    In this example the pump cavity  36  is connected to the inlet duct  13  via an inlet valve  37  and to the outlet valve via an outlet valve  38 . Actuation of the pump membrane  35  (shown in  FIG. 11 b    in a working cycle) by an appropriate actuating means (not shown) of the control apparatus the pump means  18  will create a directed flow of the sample liquid  1  in a flow direction  39  depicted by the arrows. The pump membrane  35  being an integrated part of the cover  31  can be made of the cover material or a part made of another material integrally manufactured with the cover  31 , e.g. two components manufacturing. The valves  37 ,  36  can be a type of non-return valve.  FIG. 12  shows a top view of the pump means in a schematic way. 
         [0108]    An external force exerted on the pump membrane  35  increase the pressure within the pump cavity  36  and opens outlet valve  38  and doses inlet valve  37 . Releasing the external force the elastic pump membrane  35  returns into the position shown in  FIG. 11 a    whereby outlet valve  38  will be closed and inlet valve  37  opened to let sample liquid  1  into the pump cavity  36 . This mechanism is state of the art according to DE10135569. In context with the present invention the actuation means of the control apparatus activating the pump membrane  35  from outside has the advantage of strict separation between those parts coming into contact with the sample liquid  1  and the control apparatus. At the same time the total number of parts required for the cartridge device  50  being a disposable part as well is kept on a minimum. 
         [0109]    Now the measuring system  40  according to the invention is described in an embodiment with reference to  FIGS. 13   a . . . c.    
         [0110]      FIG. 13 e   , is a side view of an embodiment of the measuring system  40 ,  FIG. 13 b    is a top view of the measuring system  40  of  FIG. 13   a,  and  FIG. 13 c    is a sectional view H-H of the measuring system  40  of  FIG. 13   b.    
         [0111]    The measuring system  40  comprises an interface element  41  to which the cartridge device  50  is attached and fixed. The interface element  41  is shown in  FIGS. 13 a  to 13 c    in way of example as a base plate. The function of the interface element  41  is to support the shaft  6  and to maintain its position and thus the position of the probe element  22  fixed to the insert section  6   a  in a measurement position. The interface element  41  can be connected to the whole cover  31  as shown in  FIGS. 13 a  to 13 c    or only to parts of the cover  31 , e.g. surrounding the rotation axis  5 . The shaft  6  is rotatable supported in a bearing  7  within a shaft passage  44  ( FIG. 13 c   ) and can be rotated around the rotation axis  5  (see also  FIG. 3 ) by driving the spring  9  via driving means (not shown). The detecting means  10  cooperate with the mirror  8  fixed on the shaft  3 , also shown in  FIG. 3 . The control apparatus mentioned above is not shown as well, but easy to imagine. Its actuation and/or operating means can access the pump means  18  through an opening pump access  42  in the interface element  41 . The receiving cavity  16  is accessible through another inlet opening  43 . These and other different passages or passage ways of the interface element  41  to have access to the cartridge device  50  and/or its cover  31  are illustrated by  FIG. 13 b    as a top view of the measuring system  40  of  FIG. 13 a   . Passage holes  44   a  are arranged next to the rotational axis  5  to form an access to the cover  31  above the measurement cavity  20 ,  20 ′, e.g. for injection of liquid sample or reagents. Additional access passage holes can be arranged in the interface element  41 , e.g. above the ductwork to access said ductwork. 
         [0112]      FIG. 13 c    illustrates a sectional view H-H of  FIG. 13 b    showing the mounted cartridge device  50  and the measuring system  40 . The shaft  6  with its insert section  6   a  is inserted into the probe element  22  and keeps it in a measurement position as mentioned above. This embodiment comprises only one measurement cavity  20 , but it is apparent to a person skilled in the art that modifications and combinations of the invention can be carried out in different ways. 
         [0113]    Thus it is possible to e.g. arrange a reagent receptacle  19   b  in a blister receptacle e.g. as shown in  FIG. 14  which is a sectional view of the reagent receptacle  19   b  of a third embodiment of the cartridge device  50  according to the invention. The receptacle  19   b  contains reagent  21  hold within a chamber defined by a buster cover  49 , a bottom part  48  and a frame  47  hold in a retaining ring  46  within an reagent cover opening  45  in the cover  31  above the reagent cavity  19 ,  19 ′ with a reagent cavity bottom  19   a,    19   a ′. Upon exertion of a force by the control apparatus onto the blister cover  49  the bottom part  48  will open and discharge the reagent  21  into the reagent cavity  19 ,  19 ′. The receptacle  19   b  can be fixed to the cover by e.g. clip means as depicted. The frame  47  can be a reinforced ring. The blister cover  49  is reinforced so that it will not break when a force is exerted on it. Thus the leak-tightness of the cartridge device  50  will be ensured. In this way a unitized construction system can be made, wherein the respective reagents can be easily integrated into the cartridge device  50 . It is also advantageous that the reagents can be designed as a small component being cooled reap, transported and supplied easily. 
         [0114]    It is also possible to insert reagent receptacles into provided cavities being connected to the ductwork. The reagents can be designed as globules with an appropriate diameter so that they cannot flow through openings into the ductwork before being dissolved by the sample liquid. 
         [0115]      FIG. 15  is a schematic drawing of a second embodiment of a probe element  22 ′. The probe element  22 ′ is arranged in the measurement cavity  20 . The probe pin  3  is provided with a dimple  29  at its bottom side. The dimple  29  forms with a nose  29   a  a toe bearing to support the probe element  22 ′. The probe element  22 ′ is similar to the probe element  22  of  FIG. 7   a,  but has no fixing section  25 , only the flange  24 . The connector section  26  comprises a top end formed with an insertion guide  27  for the insertion section  6   a  of the shaft. The probe element  22 ′ is hold in the measurement cavity  20  in a specific manner so that the insertion section  6   a  of the shaft  6  can be inserted easily through an opening  32   a  of the cover  31  which has no fixing means. The insertion section  6   a  can engage with a groove  28  inside the connector section  26  of the probe element  22 ′. After that engagement which is supported by the toe bearing the shaft  6  will be drawn up together with the probe element  22 ′ in the measuring position. It is a matter of fact that other engagement means can be used. 
       LIST OF REFERENCE NUMERALS 
       [0116]      1  Sample liquid 
         [0117]      2  Cup 
         [0118]      3  Probe pin 
         [0119]      4  Torsion wire 
         [0120]      5  Rotation axis 
         [0121]      6  Shaft 
         [0122]      6   a  Insert section 
         [0123]      7  Bearing 
         [0124]      8  Mirror 
         [0125]      9  Spring 
         [0126]      10  Detecting means 
         [0127]      11  Base plate 
         [0128]      12  Cup holder 
         [0129]      13 ,  13 ′ Inlet duct 
         [0130]      14 ,  14  Intermediate duct 
         [0131]      15 ,  15 ′ Outlet duct 
         [0132]      16 ,  16 ′ Receiving cavity 
         [0133]      17  Branch duct 
         [0134]      18 ,  18 ′ Pump means 
         [0135]      19 , 19 ′ Reagent cavity 
         [0136]      19   a,    19 ′ a  Regents cavity bottom 
         [0137]      19   b  Reagent receptacle 
         [0138]      20 ,  20 ′ Measurement cavity 
         [0139]      21 ,  21 ′ Reagent 
         [0140]      22 ,  22 ′ Probe element 
         [0141]      23  Intermediate section 
         [0142]      24  Flange 
         [0143]      25  Fixing section 
         [0144]      26  Connector section 
         [0145]      27  Insertion guide 
         [0146]      28  Groove 
         [0147]      29  Dimple 
         [0148]      29   a  Nose 
         [0149]      30  Cartridge body 
         [0150]      31  Cover 
         [0151]      32  Fixing means 
         [0152]      32   a  Opening 
         [0153]      33  Wall 
         [0154]      33   a  Receiving cavity cover 
         [0155]      34  Separation wall 
         [0156]      35  Pump membrane 
         [0157]      36  Pump cavity 
         [0158]      36   a  Pump cavity bottom 
         [0159]      37  Inlet valve 
         [0160]      38  Outlet valve 
         [0161]      39  Flow direction 
         [0162]      40  Measuring system 
         [0163]      41  Interface element 
         [0164]      42  Pump access 
         [0165]      43  inlet opening 
         [0166]      44  Shaft passage 
         [0167]      44   a  Passage hole 
         [0168]      45  Reagent cover opening 
         [0169]      46  Retaining ring 
         [0170]      47  Frame 
         [0171]      48  Bottom foil 
         [0172]      49  Blister cover 
         [0173]      50  Cartridge device

Technology Classification (CPC): 1