Abstract:
The invention concerns a process for producing a diagnostic test element for analyzing a body fluid in which a lancing member that can puncture a body part is provided with a collecting channel for body fluid obtained by the puncture, wherein the collecting channel exhibits capillary action, and wherein a sensor member for an optical or electrochemical measurement is connected to the lancing member. According to the invention, the sensor member and the lancing member can be joined together as interlocking connecting components wherein a measuring element of the sensor member is inserted into the collecting channel through an insertion opening of the lancing member.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application is a continuation of International Application No. PCT/US2007/065918, filed Apr. 4, 2007, which claims the benefit of International Application PCT/EP2006/009945, filed Oct. 15, 2006, which claims the benefit of European Application 05022535.8 filed Oct. 15, 2005, the entire disclosures of which are hereby incorporated by reference. 
     
    
     TECHNICAL FIELD 
       [0002]    The invention generally concerns a process for producing a diagnostic test element suitable for analyzing a body fluid. The diagnostic test element has a lancing member that can puncture a body part to obtain a body fluid sample. The lancing member is provided with a capillary collecting channel for body fluid obtained by the puncture. The test element also has a sensor member for an optical or electrochemical measurement is connected to the lancing member. 
       BACKGROUND 
       [0003]    Blood sugar self-monitoring is usually carried out several times daily as part of an insulin treatment regimen to control diabetes. It is therefore desirable to minimize the number of handling steps the patient is required to carry out and to ensure a relatively painless and highly reliable blood sugar measurement. Disposable measurement articles are used for hygienic reasons. In conventional blood sugar measurements, samples are generated by finger pricking with lancets and the measurement is carried out on separate detection elements. This requires a large number of handling steps by the patient which can result in errors. Further disadvantages are blood volumes that are too large, non-robust sample transfer procedures, and lack of integration that requires the patient to organize and handle separate devices and disposable supplies. 
       SUMMARY 
       [0004]    Taking this as a starting point, the object of the invention is to further improve the test elements and processes for their production known in the prior art, and in particular to enable practicable mass production and use of more highly integrated test elements that are cost-effective and at the same time reliable, while also allowing relatively simple instrument technology. 
         [0005]    The combination of features stated in the independent claims is proposed to achieve this object. Advantageous embodiments and further developments of the invention are derived from the dependent claims. 
         [0006]    The idea behind the invention is to use test elements in which a small volume sample can be collected and reliably analyzed. A production process is proposed for such test elements in which a lancing member that can puncture a body part is provided with a collecting channel, preferably exhibiting capillary action, for the body fluid obtained by the puncture, and a sensor member for an optical or electrochemical measurement is connected to the lancing member. According to the invention the sensor member and the lancing member are joined together as interlocking connecting components, such that a measuring element of the sensor member is inserted into the collecting channel through an insertion opening in the lancing member. This permits the parts to be separately produced in optimized manufacturing steps at low production costs and subsequently integrated into a compact configuration by a simple interlocking connection. In this configuration a small amount of sample in the collecting channel is sufficient to reliably contact and wet the sensor located therein. This also allows precise positioning tolerances in the test element production process, thereby simplifying tolerance management on the instrument side. In particular, it is not necessary to actively transfer the sample to a separate sensor that is not in the direct sample flow, thereby making possible reliable measurements, even with very small samples of 100 nanolitres or less. Reliable measurement is of special importance because automation of handling steps by the system reduces the demand of ability of the patient to monitor and control the process. 
         [0007]    The invention is described in more detail in the following with reference to the embodiment examples shown schematically in the drawing. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0008]      FIG. 1  shows a blood sugar measuring instrument with a diagnostic test element used therein as a consumable unit in a diagrammatic representation; 
           [0009]      FIG. 2  shows an embodiment of the test element in a partial perspective representation; 
           [0010]      FIG. 3  shows an exploded diagram of the test element according to  FIG. 2  comprising a lancing member, a sensor based on wire electrodes and a holder; 
           [0011]      FIG. 4  shows an embodiment of an optical test element in a perspective view; 
           [0012]      FIGS. 5 and 6  show various production steps for the test element according to  FIG. 4 ; 
           [0013]      FIGS. 7 and 8  show another embodiment of an electrochemical test element in a representation corresponding to  FIGS. 2 and 3 ; 
           [0014]      FIG. 9  shows the sensor member of the test element according to  FIG. 7  in a partial side-view; 
           [0015]      FIGS. 10 to 12  show another embodiment of an electrochemical test element in a representation corresponding to  FIGS. 7 to 9 ; 
           [0016]      FIG. 13  shows a device for the continuous manufacture of a light guide composite member of the test element; 
           [0017]      FIG. 14  shows an enlarged section of  FIG. 13 ; 
           [0018]      FIG. 15  shows the light guide composite member in a perspective view; 
           [0019]      FIG. 16  shows a device for producing label-like measuring elements for the test element in a side-view; 
           [0020]      FIGS. 17 and 18  show enlarged sections of  FIG. 16 ; 
           [0021]      FIG. 19  shows a device for equipping test elements with lancing members in a diagrammatic representation; 
           [0022]      FIG. 20  shows a sectional top-view of the device according to  FIG. 19 ; and 
           [0023]      FIG. 21  shows a device for hydrophilically coating the lancing members of the test elements. 
       
    
    
     DETAILED DESCRIPTION 
       [0024]    The test elements  10  shown in the drawing can be used as consumables for blood sugar measurement in a hand-held device  12  designed for this purpose wherein glucose can be detected directly in the test element using a minimal amount of sample. For this purpose the test elements  10  comprise a lancing member  14  having a slot-shaped collecting channel  16 , a sensor member  18  for an optical or electrochemical measurement in the collecting channel  16 , and a holder  20  for the lancing member and the sensor member. 
         [0025]    As illustrated in  FIG. 1  a plurality of test elements  10  in, for example, a drum-like magazine  22  can be moved successively into an active working position with respect to a ring-shaped support  24  with a puncture opening for a finger tip  26  of a user. A lancing drive  28  which engages into the magazine  22  enables a reciprocating lancing movement of the test element  10  along a lancing axis  30 . In this connection the tip of the lancing member  14  points in the distal direction towards the body part while a coupling end  32  of the test element is coupled to a suitable gripper member  34  of the lancing drive  28  for mechanical drive and signal coupling. The body fluid (blood or tissue fluid) which is taken up in the collecting channel  16  by the lancing process, can be directly optically or electrochemically analyzed by the sensor member  18 . The signal analysis takes place in an evaluation unit  36  in the instrument. This also enables the result of the measurement to be displayed to the user so that the blood sugar can be checked on the spot without complicated handling steps. 
         [0026]    As shown in  FIGS. 2 and 3  the shaft-like elongate lancing member  14  has a transverse continuous longitudinal slot forming the collecting channel  16 . This enables, optionally by means of capillary action, the transfer of a microscopic amount of liquid into the proximal measuring zone  38 . The elongate slit opening on both sides ensures an effective liquid uptake without the risk of blockage by cell components. In order to collect blood as gently and pain-free as possible, the collecting channel  16  is designed to have a volume of only a few tens of nanolitres. 
         [0027]    According to  FIG. 3  the sensor member  18  has several parallel electrode wires  40  in order to achieve a high degree of measurement reliability through redundant detection of measured values. The electrode wires are either continuously coated with a test reagent, or only coated at the ends in order to enable electrochemical detection of the analyte in the body fluid. For this purpose the coated ends of the wire protrude in a self-supporting manner into the internal cross-section of the collecting channel  16  in the area of the measuring zone  38 . In this manner the wire ends form a measuring element  42  which is electrically insulated inside the channel from the channel wall by a free space, and body fluid can flow against and wet the front of the measuring element. In this arrangement a few nanolitres of blood are sufficient for an integrated detection of measured values in the test element  10 . 
         [0028]    Some specific methods for manufacturing test elements  10  configured in this manner are described in the following. In general the sensor member  18  and the lancing member  14  are joined in an interlocking manner whereby the measuring element  42  is inserted into the collecting channel  16 . 
         [0029]    In the embodiment according to  FIGS. 2 and 3  the electrode wires  40  are clamped between two halves  20 ′,  20 ″ of the longitudinally divided holder  20  whereby grooves that are not shown ensure well-defined positioning of the wires. Then the fork-shaped end of the lancing member  14  which is prefabricated from a metallic wire material by a combination of grinding and laser cutting processes or etching is mounted axially on the receiving grooves  44  of the holder  20 . In this process the measuring element  42  of the sensor member  18  is inserted via the proximal slot opening  46  into the collecting channel  16  and moved into the specified position. 
         [0030]      FIG. 4  shows another variant of a test element  10  which is equipped with optical light guides and a reagent pad  48  as a measuring element  42  for a reflection-photometric measurement. The signal is coupled out by an end-face contact with light guides  50  on the instrument side which have a suitable diameter for a reliable signal transmission. 
         [0031]    As shown in  FIG. 5  a composite element  54  consisting of three parallel light guides  52  and a plastic holder  20  is manufactured by coextrusion and then subsequent division into sections. The distal front end of the composite part  54  prefabricated in this manner is then provided with a reagent pad  48  which is dispensed from a tape  56  like a self-adhesive label and glued onto the free ends of the light guides (arrow  58 ). 
         [0032]    In another manufacturing step illustrated in  FIG. 6  the composite part  54  is subsequently clipped or latched onto the lancing member  14  in the direction of the arrow  60 . In this process the reagent pad  48  is also inserted transversely into the collecting channel  16  via the longitudinal slit opening  62  to obtain the configuration shown in  FIG. 4 . The holder  20  embraces the shaft  64  of the lancing member  14  which is slotted and elongated on the rear side, in a shell-shaped manner. This facilitates low-cost production because holder  20  can be combined with the lancing member  14  by a fast snap-on process. When used for measurement the central fiber of the three fibers comprising light guide  52  enables irradiation of the measuring light which is reflected from the rear side of the reagent pad  48  and is detected via the two outer fibers of light guide  52  for a duplicate photometric measurement. 
         [0033]    It is also conceivable that the light guides or the reagent pad  48  are provided with a fluorescent indicator as described in the patent application WO 03/097859 and to which explicit reference is herewith made. Specifically, a liquid polymerizable composition comprising a detection reagent can be applied. After application of the sample to the front side of such a sensor, exciting light, e.g. UV light, is beamed in through a light guide. The fluorescence, e.g. bluelight, generated through the reaction of the analyte with the detection reagent in the polymer layer is detected via the light guide with a detector. Preferably, the polymer layer has a thickness of about 50 microns or less, which allows for comparably short reaction times for generating the fluorescence light when the analyte is detected. In this way, the reaction or measurement time can be shorter than 2 s, preferably shorter than 1 s, thereby enabling a measurement while the lancing member is still in the skin of the body part. It has been found that leaving the lancing member inserted for such a short time interval is fully acceptable for most users. 
         [0034]    The embodiment shown in  FIGS. 7 to 9  differs from the example of  FIGS. 2 and 3  essentially in that instead of coated electrode wires, a printed circuit board  66  is used as a prefabricated sensor member  18 . The distal end of the printed circuit board  66  is provided with two electrically connected reagent fields  68  which protrude freely into the measuring zone  38  to form a measuring element  42 . Also in this case it is manufactured by first clamping the printed circuit board  66  into the two-part holder  20  and then axially mounting the lancing member  14  so that the fork-shaped ends of the lancing member  14  engage in the grooves  44  and the measuring element  42  is positioned in the channel cross-section. 
         [0035]      FIG. 9  shows the electrical connection of the reagent fields  68  via in this case two conductor paths  70  on the printed circuit board  66 . Each of the conductor paths  70  branch over one conductor bridge  72  into a primary conductor path  70 ′ and a secondary conductor path  70 ″ in order to thus be able to carry out an electrical continuity test at least up to the conductor bridge  72  and to detect any interruptions of the conductor paths. This, in addition to the redundant double measurement, further increases the functional reliability. 
         [0036]    A similar embodiment to  FIGS. 7 to 9  is shown in  FIGS. 10 to 12 . However, instead of the printed circuit board  66 , a test strip  74  which is folded transversely is provided as a sensor element  18 . It is again assembled as described above by clamping the test strip  74  into the holder  20  and axially mounting the lancing member  14 . 
         [0037]    As also illustrated in  FIG. 12 , the concept of the folded test strip  74  has various advantages. The manufacture can start with a planar structure in the form of a thin flexible foil strip. This is provided with conductor paths  70  and with reagent fields  68  at their contact ends while still in an unfolded form. Subsequently the equipped foil strips are folded up in the middle so that the strip halves  76 ′,  76 ″ can be glued together. The reagent fields  68  then protrude freely from the front face in the area of the rounded bending site so that liquid can flow against and wet the reagent fields in the channel  16 . 
         [0038]    Special process steps are illustrated in  FIGS. 13 to 21  which allow an advantageous continuous mass production through different stations. 
         [0039]    Firstly according to  FIG. 13  three parallel light guides  52  in the form of polymer fibers are fed from reels and laminated between the foil strips  78  to form a composite strand  80 . In a subsequent embossing station the outer contour of the composite strand  80  is shaped by embossing rollers  82 . As shown in  FIG. 14  this enables both the receiving grooves  44  and a coupling structure  84  for a positive locking gripper coupling to be created. The reshaped composite strand  80  is subsequently severed at the cutting lines  86  to thus obtain the composite parts  54  shown in  FIG. 15 . 
         [0040]    The distal front end  86  of the composite part  54  is equipped with measuring elements in the rotary station  88  shown in  FIG. 16 . The reagent pads  84  provided for this should have an adequate homogeneity in the required small dimensions—for example 200×400 μm. For this purpose a test chemistry is firstly knife-coated over a large area of a wide test tape  90 . Then the test tape  90  is reduced to a narrow central strip by parallel cutting rollers  92 . As shown in  FIG. 17 , the desired reagent pads  48  can be cut out of the central strip by a punching device  94 . The reagent pads  48  are finally applied to the composite parts  54  at another rotary position of the rotary station  88 . For this purpose a transfer device  96  is provided in which a plurality of composite parts  54  are stacked. The transfer takes place by means of a pneumatic unit  98  which successively brings the composite parts  54  into an end face contact with the self-adhesive reagent pads  48  by means of a blast of air. 
         [0041]    The composite parts  54  prepared in this manner are provided with lancing members  14  in the assembly station shown in  FIGS. 19 and 20 . The prefabricated lancing members  14  can in this process be conveyed to the transfer device  96  in depressions  100  of a blister tape  102 . The test element storage in the depressions  100  in a blister tape  102  sealed by cover foils  104  also enables a separate sterilization of the lancing members  14 , for example by irradiation, without damaging the test chemistry. The axial sliding assembly motion of the lancing members  14  onto the composite parts  54  is in turn effected by means of a blast of air by a pneumatic unit  106 . 
         [0042]    The metallic lancing members  14  can be provided with a hydrophilic layer in order to support the uptake of body fluid in the collecting channel  16 . For this purpose the lancing members  14 , either before or after they are mounted on the finally packaged test elements  10 , can be brought into contact with an absorbent application ring  110  at the application station  108  shown in  FIG. 21 , the ring being impregnated with a suitable hydrophilic coating substance. The amount of substance applied to the lancing member  14  can then be accurately controlled by means of the contact time. 
         [0043]    A further possibility to produce the light fiber structure is to generate the fibers in situ on or within an embossed part of a tape or foil-like carrier. In this process a thin layer of low refractive index transparent polymer, for example epoxy, is deposited onto a structural substrate to form a base layer. This is then over-coated by a thin layer of photosensitive high refractive index transparent polymer. This layer is processed by UV photolithography to selectively remove material, leaving the light guides as generally parallel strips of high refractive index polymer bonded to the low refractive index base layer. Finally, a layer of low refractive index polymer is flow-coated over the light guides and polymerized to form a solid layer. The result is that high refractive index light guides are surrounded on all sides by lower refractive index transparent polymer, forming functional independent light guides. Suitable materials are available commercially, for example, under the tradenames EpoCore and EpoClad epoxy polymer resins supplied by the German company Micro Resist Technology. Particular advantages of such photolithographic processes for manufacturing the parallel light guides include low cost volume production and the ability to vary the geometry of the light guides along their length. For example, the light guides may be tapered to transition from a small reagent pad to a larger optical interface with the measuring instrument.