Abstract:
A method for determining the glucose value in blood or in interstitial liquids and to a glucose sensor including a catheter which has one or more openings in the region of the distal end of the catheter; a first optical waveguide which is arranged in the catheter and which includes a coupling surface at the distal end of the optical waveguide; a measuring probe which is arranged in the region of the distal end of the catheter, is coupled to the coupling surface of the first optical waveguide, and has a mirror arranged opposite the coupling surface of the first optical waveguide and a detection chamber between the coupling surface of the first optical waveguide and the mirror; a detection liquid for glucose in the detection chamber; and a membrane which encloses at least the detection chamber filled with the detection liquid and which has a separation capacity of maximally 20 kDA.

Description:
FIELD OF THE INVENTION 
       [0001]    The invention concerns a glucose sensor and a method for determination of the glucose value in blood or in interstitial fluid, especially in vivo determination in humans or animals. 
       BACKGROUND OF THE INVENTION 
       [0002]    In practice, the measurement of the glucose concentration is usually done indirectly through an enzymatic conversion of the glucose with subsequent detection of the hydrogen peroxide released during the conversion reaction, being proportional to the glucose concentration, or the oxygen consumed, for example, by a color change reaction, a fluorescence measurement, or an electrochemical determination. For this, a blood sample is first placed on a test strip, for example. The drawback to this measurement based on enzymatic conversion of glucose is that it can only be performed discontinuously and therefore needs to be repeated often, and the test strip can only be used once. There is also a quasi-continuous measurement by means of an implanted, enzymatically functionalized sensor surface, based on enzymatic conversion of glucose. But the lifetime of such a sensor is limited by the progressive consumption of the enzyme. Furthermore, the consumption of the enzyme requires a readjusting or calibrating of the sensor at regular intervals (several times a day). Finally, the precision of the best sensors of this type in the relevant measurement range is around 50 to 250 mg/dl with a mean absolute error (MARE) of less than 10%. 
         [0003]    DE 10 2009 010 955 A1 specifies a method and a measurement device for the determination of blood sugar values in the form of the glucose or fructose determination in human blood by means of optical spectroscopy. It is proposed to implant an optical, monolithic, miniaturized spectrometer in the human body, having a measurement cell in the form of a measurement fiber, which is introduced by its fiber end directly into the blood stream of a person. The measurement fiber has a recess at its distal end, constantly washed by blood, and a coupling site at its opposite proximal end, which is connected to a light-conducting disk. The light-conducting disk forms a unit with a silicon disk, on which is arranged an evaluating unit. The evaluating unit evaluates the measurement data, stores it or transmits it by telemetry to an insulin pump or a heart rate monitor for display. This arrangement records a remitted absorption spectrum of the scattered light in the blood stream of the person, from which the blood sugar value and/or other blood values are determined. The drawback to this method and measurement device is, in particular, that the recess in the measurement fiber forms a predetermined breaking point and increases the risk of the end of the measurement fiber breaking off during improper handling or careless movement of the patient, getting into the blood stream, and endangering the patient. Another drawback is that the absorption measurement in the blood can be influenced by other effects, such as a buildup of blood cells in the area of the recess, which would impair the glucose detection accuracy. Document US 2009/0088615 A1 teaches the same measurement principle. 
         [0004]    Furthermore, there have been studies with the participation of the inventor on glucose determination by measurement of differential absorbance in the near infrared spectrum, as described for example in the article “A minimally invasive chip based near infrared sensor for continuous glucose monitoring”, L. Ben Mohamadi et al, Proc. of SPIE Vol. 8427 84270K-1. In this method, a perfusion solution is pumped by means of a dialysis pump through a subcutaneously or intravenously applied dialysis needle (catheter), across a semipermeable membrane (typically with a separation capacity of 20 kDa), which is not permeable to blood cells and larger fat or protein molecules, but is so for the perfusate and the glucose, the glucose diffusing from the blood or interstitial fluid into the perfusate. The specimen (analyte) so obtained is transported into a microfluidic chip with infrared light source and a photosensitive detector (GaAs photodiode), where a change in the NIR absorption dependent on the glucose concentration is compared against a reference measurement at a reference cell filled with pure liquid. This so-called absorption difference measurement provides a measurement precision with a mean absolute relative error (MARE) of around 5%. The drawback to this measurement method, among other things, is the large distance between the sampling point of the analyte, i.e., the dialysis needle on the one hand, and the detection cell on the other hand, in conjunction with a low flow rate of the perfusate/analyte, which is required for an adequate buildup of glucose in the perfusate. 
         [0005]    This typically causes a time delay from the sampling to the evaluation of around 10 minutes. Moreover, a considerable expense is necessary in order to operate the measurement cell and the reference cell under the same external, especially thermal, conditions, so that any differences will not negatively affect the measurement result. Document DE 20 2007 019 544 U1 teaches the same measurement principle. 
       SUMMARY OF THE INVENTION 
       [0006]    The problem which the present invention proposes to solve is therefore to provide a glucose sensor and a method for the permanent determination of the blood sugar value, enabling a precise and timely in vivo determination of the blood sugar value which is permanently reliable and largely unfalsified by external influences. 
         [0007]    The problem is solved by a glucose sensor and a method for determining a glucose value in blood or in interstitial fluid, comprising the steps of bringing a measuring probe coupled to a coupling surface of a first optical waveguide, which comprises a mirror arranged opposite the coupling surface of the first optical waveguide and a detection chamber between the coupling surface of the first optical waveguide and the mirror, containing a detection fluid for glucose and enclosed by a membrane having a separation capacity of at most 20 kDa, into contact with the blood or the interstitial fluid, wherein the glucose depending on a concentration gradient diffuses out from the blood or the interstitial fluid into the detection fluid or from the detection fluid into the blood or the interstitial fluid, light is coupled into the first optical waveguide and guided through the latter to the detection chamber, reflected at the mirror and taken back through the first optical waveguide, while light in dependence on the glucose concentration in the detection fluid is absorbed in the detection chamber, and an intensity of the light returning from the detection chamber is measured. 
         [0008]    The glucose sensor according to the invention comprises a catheter, having one or more openings in the region of its distal end, a first optical waveguide arranged in the catheter with a coupling surface at its distal end, a measuring probe arranged in the region of the distal end of the catheter and coupled to the coupling surface of the first optical waveguide, having a mirror disposed opposite the coupling surface of the first optical waveguide and a detection chamber between the coupling surface of the first optical waveguide and the mirror, a detection fluid for glucose in the detection chamber, and a membrane, which encloses at least the detection chamber filled with the detection fluid and which is not permeable to cells or most proteins, yet is permeable to glucose. For this purpose, the membrane has a separation capacity of at most 20 kDa. In this way, it is ensured that the detection chamber is protected against the incursion of blood cells and larger molecules such as fats, proteins, and others, while the detection fluid and glucose can diffuse through the membrane. 
         [0009]    Preferably, the detection fluid used is an electrolyte-containing, isotonic, aqueous solution, in order to limit substantially to glucose the exchange through the membrane for purposes of concentration equalization. In particular, so-called Ringer solution will be considered as the detection fluid. 
         [0010]    If the glucose concentration in the detection fluid is initially zero, for example, or at least less than that in the bodily fluid, the exchange will occur at first from the bodily fluid in the direction of the detection fluid. If the probe remains in the blood stream and the glucose concentration in the blood decreases over the course of time, a diffusion of the glucose through the membrane will occur in the reverse direction. 
         [0011]    The optical waveguide with coupled measuring probe is also called hereinafter the measurement channel. 
         [0012]    Accordingly, the method according to the invention specifies that a measuring probe coupled to the coupling surface of a first optical waveguide, which comprises a mirror arranged opposite the coupling surface of the first optical waveguide and a detection chamber between the coupling surface of the first optical waveguide and the mirror, containing a detection fluid for glucose and enclosed by a membrane which is not permeable to cells and proteins yet is permeable to glucose, is brought into contact with the blood or the interstitial fluid, wherein the glucose depending on the concentration gradient diffuses out from the blood or the interstitial fluid into the detection fluid or from the detection fluid into the blood or the interstitial fluid, light is coupled into the first optical waveguide and conducted through the latter to the detection chamber, reflected at the mirror, and taken back through the first optical waveguide, while light in dependence on the glucose concentration in the detection fluid is absorbed in the detection chamber, and the intensity of the light returning from the detection chamber is measured. 
         [0013]    For this, the device preferably comprises furthermore a measuring and evaluating device, which comprises a detector coupled to the first optical waveguide and designed to measure the intensity of the light returning from the detection chamber through the first optical waveguide. 
         [0014]    Unlike the method first mentioned in the introduction, the measurement principle of the invention is not based on a chemical reaction, but rather on an absorption of light. The patent application DE 10 2009 010 955 A1 likewise mentioned above, and also the article, thus constitute the category. Yet unlike what is mentioned in the patent application, an absorption measurement does not occur directly in the blood, but instead in a measurement fluid kept separate from the blood, yet interacting with the blood by way of a diffusion through a semi-permeable membrane. The latter is also known in principle from the aforementioned article, however the absorption measurement there does not occur directly in the contact area with the blood or the interstitial fluid, but instead at a distance from this, outside the human body, which leads to the above explained problems. The invention for the first time makes it possible to determine the change in the glucose concentration occurring in the blood or in the interstitial fluid indirectly through a detection fluid, yet directly in the body and thus free from the mentioned negative effects, such as an accumulation of blood cells, varying ambient conditions or a long measurement duration, and thus not least of all very precisely. 
         [0015]    The measuring probe is arranged in the region of the distal end of the catheter, where it comes into contact directly in the tissue or the blood stream of the patient with the interstitial fluid or blood (hereinafter subsumed under the term “bodily fluid”), which penetrates into the one or more openings in the catheter. The opening in the most simple instance can be formed in that the catheter is fashioned as a cannula open at the end face and/or comprises an outer wall with a perforated section, which is configured in the axial direction preferably at the height of the measuring probe, and thus encloses it partly or entirely. The catheter in particular forms the supporting structure for the membrane in the area of the measuring probe. 
         [0016]    A cannula open at the end face or even pointed is more of a disadvantage for long-term residence in the body. Preferably, therefore, the catheter is closed at the end face. It is preferably inserted into the body by means of a pointed sleeve or cannula, after which the sleeve is again removed and the catheter remains in the body. 
         [0017]    If the bodily fluid makes contact with the membrane, depending on the glucose concentration in the bodily fluid a diffusion-controlled exchange of glucose through the membrane will occur, until the glucose concentration in the detection fluid and in the bodily fluid is substantially equal. (A complete equalization will only be reached asymptotically.) The light which is coupled into the first optical waveguide at its proximal end leaves it at its distal end via the coupling surface and enters the detection chamber. Here, it passes twice through the detection fluid on its path to the opposite positioned mirror and from the mirror back to the coupling surface. 
         [0018]    The glucose is detected in the near infrared spectrum indirectly by the shifting of an absorption band of water as a result of an interaction with the glucose. This shift can be registered by absorption measurement at certain characteristic wavelengths. It has proven to be advantageous for this to use light with a wavelength between 800 nm and 3000 nm, especially in the overtone band region of around 1000 nm to 2500 nm. The attenuated light is then taken back through the same first optical waveguide and supplied at its proximal end to the detector of the measuring and evaluating device. Here, an intensity measurement is done in familiar manner, from which the absorption and thus the glucose concentration in the detection fluid or the bodily fluid can be ascertained. 
         [0019]    For this purpose, preferably at the proximal end of the optical waveguide there is provided a beam divider or a semitransparent mirror, which lets through the incoming light to the optical waveguide and deflects the guided light back to the detector. Preferably, a 1×2 coupler is used. 
         [0020]    Preferably, the measuring and evaluating device is coupled to a reference channel and designed to measure an intensity of the light in the reference channel and compare it to the intensity of the light returning from the detection chamber through the first optical waveguide. In terms of method, this modification of the invention specifies that a light beam is at first divided, then a first portion of the light is coupled into the first optical waveguide and a second portion of the light is supplied to a reference channel, in which the intensity of the second portion of the light is measured, and then compared to the measured intensity of the light returning from the detection chamber. 
         [0021]    Thus, in the reference channel a reference measurement of the light emitted by a light source takes place, enabling a direct subtraction of light intensity fluctuations from the measurement signal. This method is called hereafter a difference measurement. The difference measurement is generally discussed, for example, in the document DE 10 2004 055 032 A1. 
         [0022]    Especially preferably, there is provided a reference probe arranged in the catheter in the vicinity of the measuring probe and a second optical waveguide arranged in the catheter with a coupling surface at its distal end, wherein the reference probe and the second optical waveguide form the reference channel and the reference probe is coupled to the coupling surface of the second optical waveguide. The reference probe has a mirror arranged opposite the coupling surface of the second optical waveguide and a reference measuring chamber between the coupling surface of the second optical waveguide and the mirror with a reference medium of constant glucose concentration and the measuring and evaluating device comprises a detector coupled to the second optical waveguide. 
         [0023]    In connection with this design, we shall speak in the following of an “absorption difference measurement”. The layout of the reference measuring chamber and the layout of the detection chamber are very similar, and especially in their geometrical dimensions they are even identical. The same holds for the first and the second optical waveguide. In this way, and moreover also due to the physical proximity of the reference probe and the measuring probe, the beam path in the reference channel and in the measurement channel is for the most part identical. Moreover, the measurement conditions, especially the thermal conditions to which the measuring probe and the reference probe are exposed during the measurement, are practically identical. A comparing of the intensity measurements in the measurement channel and the reference channel therefore enables a subtraction of almost all systematical errors and thus a further distinct enhancement of the precision of the measurement. In this way, it is possible to achieve a measurement precision of not more than 5% mean absolute relative error (MARE). A further improvement can be achieved if, advantageously, the number of wavelengths used is increased, i.e., by using light of several discrete wavelengths instead of light with one wavelength during the measurement. 
         [0024]    The absorption difference measurement can be carried out preferably with two separate detectors for the measurement channel and the reference channel. Although the same detector can also be used for the reference channel that is coupled to the measurement channel, this requires a sequential measurement, which runs counter to certain advantages of the absorption difference measurement and therefore will only be considered in connection with pulsed measurement at short time intervals. 
         [0025]    The reference medium is preferably essentially water or an aqueous solution, because the changes in the water absorption upon dissolution of glucose are especially pronounced. In order for the reference probe to provide the most reliable possible comparison value, especially preferably one will use an aqueous solution of equivalent effect in regard to the measurement method, i.e., the absorption behavior, and again preferably without glucose, fats or proteins. Detection fluid and reference medium accordingly need not be solutions of perfectly identical ingredients, apart from the glucose concentration, but instead it is enough for them to have the same effect in regard to the measurement method/absorption behavior. 
         [0026]    Naturally, these conditions are best fulfilled when the reference medium and the detection medium are identical except for the glucose concentration. Therefore, according to one advantageous embodiment of the invention, the same isotonic solutions are used as reference medium in the beginning in the reference measuring chamber, for example the mentioned Ringer solution. The glucose concentration then changes only in the detection chamber as a consequence of the measurement. 
         [0027]    One advantageous embodiment of the glucose sensor specifies that the membrane encloses the detection chamber filled with the detection fluid between the coupling surface of the first optical waveguide and the mirror. “Encloses” in the sense here means that the detection chamber is defined as a volume bounded all around. The detection fluid is enclosed therein not in the narrower sense, because it stands in an exchange by diffusion through the membrane with the bodily fluid surrounding the catheter. Even so, it is a physically bounded volume with detection fluid, as opposed to the systems according to DE 20 2007 019 544 U1, for example. This embodiment requires no technical expense to move the detection fluid in a circulation or a permanent exchange. 
         [0028]    In this embodiment, the reference probe preferably has a partition, where the partition encloses the reference measurement chamber filled with the reference medium between coupling surface of the second optical waveguide and the mirror and holds back the reference medium therein. 
         [0029]    Once again, a very similar design layout of the measuring probe and the reference probe is emphasized here, while the partition is functionally distinguished from the membrane in that it is not (also) permeable to glucose and especially preferably not to the reference medium, so that the glucose concentration in the reference medium remains constant. The detection chamber and the reference measuring chamber are thus fluidically separated in this embodiment. 
         [0030]    An alternative configuration to two separate detection and reference measurement chambers calls for the glucose sensor to have a flow channel, in which the reference probe and the measuring probe are arranged and which can receive the flow of the detection fluid or the reference medium, while the membrane forms a wall section of the flow channel in the region of the measuring probe and holds the detection fluid back in the flow channel. 
         [0031]    Furthermore, the glucose sensor in this configuration preferably comprises a delivery device, which is connected to the flow channel and designed to generate a flow of the detection fluid or the reference fluid through the flow channel. 
         [0032]    Under these circumstances, the reference probe and the measuring probe are especially preferably arranged in this sequence one behind the other in the flow direction in the flow channel. 
         [0033]    In the above described alternative configuration, the detection fluid as well as the reference medium are no longer enclosed in the detection chamber of the measuring probe or the reference measuring chamber of the reference probe. Instead, the detection chamber and the reference measuring chamber form open measuring chambers, receiving the continuous flow of the detection or reference fluid delivered through the flow channel. The flow channel is formed in the area of the reference probe preferably by an inner tube arranged in the catheter and in the area of the measuring probe by the membrane arranged in the catheter. When the flowing detection fluid first passes through the reference probe it has not yet flowed past the membrane and therefore has not yet made contact with the glucose from the bodily fluid. Therefore, the detection fluid at first has the functional purpose of the reference medium with (up to that point) constant glucose concentration. After it has passed through the reference probe and reached the section of the membrane, a diffusion-controlled glucose exchange takes place, so that the measuring probe arranged in the area of the membrane makes contact with altered glucose concentration in the detection fluid. Two design configurations of the flow channel shall be explained below with the help of the sample embodiments. 
         [0034]    Especially preferably, the first and/or the second optical waveguide comprises a multimode or a monomode fiber. The multimode fiber is preferable, because it does not limit the optical power as much as the monomode fiber and thus the measurement sensitivity is on the whole better. Basically, the first and/or the second optical waveguide can be formed from a single fiber or from fiber bundles. 
         [0035]    By a glucose sensor in the sense of this document is meant both a unit with or without its own light source and likewise with or without its own measuring and evaluating device, i.e., in particular, also the bare catheter with waveguide and measuring probe. However, preferably it comprises its own light source coupled to the first optical waveguide and, if present, to the reference channel. 
         [0036]    The reference channel is preferably powered by the same light source which also powers the measurement channel, because then it is possible to eliminate for the most part fluctuations in light intensity at the source side. 
         [0037]    In this case, the glucose sensor comprises a beam divider hooked up between the light source and the first optical waveguide, which is designed to couple a first portion of the light into the first optical waveguide and supply a second portion of the light to a reference channel. 
         [0038]    Accordingly, the method according to the invention specifies that the light beam coming from the light source is at first divided, then a first portion of the light is coupled into the first optical waveguide and the second portion of the light is coupled into the second optical waveguide and guided through this to the reference measurement chamber, reflected on the mirror, and returned through the second optical waveguide, while light is absorbed in the reference measuring chamber depending on the glucose content in the reference medium, and the intensity of the light returned from the reference measuring chamber is measured and compared with the measured intensity of the light returned from the detection chamber. 
         [0039]    The light source, especially the infrared light source, preferably comprises an LED or several LEDs. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0040]    Further details and benefits of the invention will be further explained in the following with the aid of sample embodiments, making reference to the figures. There are shown: 
           [0041]      FIG. 1 , a first sample embodiment of the glucose sensor with an optical waveguide in a catheter and separate reference channel outside of the catheter; 
           [0042]      FIG. 2 , a second sample embodiment of the glucose sensor with a first optical waveguide and measuring probe and a second optical waveguide and reference probe in a catheter; 
           [0043]      FIG. 3 , a cutout view of the distal end of the catheter with a first embodiment of the measuring probe and the reference probe; 
           [0044]      FIG. 4 , the distal end of the catheter with a second embodiment of the measuring probe and the reference probe and 
           [0045]      FIG. 5 , the distal end of the catheter with a different arrangement of the measuring probe and the reference probe. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0046]    The sample embodiment of the glucose sensor of the invention per  FIG. 1  comprises a catheter  10  with a distal end  12 , which is shaped as a needle tip or cannula and has an opening  14  at its front end. In the catheter  10  is arranged an optical waveguide  16 , having a coupling surface  20  at its distal end  18 . Moreover, in the region of the distal end  12  of the catheter  10  there is arranged a measuring probe  22  which is optically coupled to the coupling surface  20  of the optical waveguide  16 . The measuring probe  22  comprises a detection chamber  24  filled with a detection fluid for glucose and a mirror  26  arranged facing the coupling surface  20 . Details shall be explained below with the aid of  FIGS. 3 to 5 . 
         [0047]    The glucose sensor in this form can be injected subcutaneously or into a person&#39;s blood stream, whereupon blood or interstitial fluid penetrates by virtue of capillary forces through the end opening  14  into the cavity of the catheter  10  and comes into contact there with the measuring probe  22 . 
         [0048]    Furthermore,  FIG. 1  shows, schematically simplified, a housing  28 , in which both a light source  30  and a measuring and evaluating device are assembled. The measuring and evaluating device for its part comprises a detector  32  coupled to the optical waveguide  10  and furthermore an electronic reading unit, not shown. This is designed to measure the intensity of the light returning from the detection chamber  24  through the optical waveguide  10  and optionally to display it or put it out as a control signal, for example for a connected insulin pump. 
         [0049]    The light, indicated by the beam  34 , is returned within the optical waveguide  16  on the same path by which it arrives at the measuring probe  22 . Therefore, the returning beam must be deflected at a beam divider  36  or a one-sided or partly transparent mirror and routed to the detector  32 . 
         [0050]    Moreover, an entirely separate reference channel  38  is shown in the housing  28 , comprising its own light source  40  and its own detector  42 . The reference channel in this simple embodiment serves merely to detect any fluctuations in the power supply voltage or in the ambient conditions, especially the temperature of the electronics, and to eliminate their effects on the measurement signal by comparing the reference signal to the measurement signal and preferably subtracting it. Of course, this only represents one of various options for the monitoring of systematic errors. A more precise monitoring of systematic errors occurs, for example, when the reference channel  38  and the measurement channel use a common light source, whose beam is divided before entering the optical waveguide and coordinated with a detector of the reference channel. A further improved reference measurement is shown by the sample embodiment of  FIG. 2 . 
         [0051]    The glucose sensor of  FIG. 2  comprises a catheter  50  with a distal end  52  shaped as a needle tip or cannula, at the end of which once again there is an opening  54 . In the catheter  50  there is arranged a first optical waveguide  56 , at whose distal end  58  is provided a coupling surface  60  for the coupling of light into a measuring probe  62 . The measuring probe  62  as in the previous example comprises a detection chamber  64  between the coupling surface  60  and a mirror  66  arranged opposite the coupling surface and it contains (at least during the measurement) a detection fluid for glucose in the bodily fluid. 
         [0052]    The glucose sensor, in contrast to the example in  FIG. 1 , moreover comprises a second optical waveguide  70  in the catheter  50 , having at its distal end  72  a coupling surface  74 , to which a reference probe  76  is optically coupled. The reference probe  76  comprises a mirror  78  disposed opposite the coupling surface  74  of the second optical waveguide  70  and a reference measuring chamber  80  between the coupling surface  74  and the mirror  78 , which is filled with a reference medium with constant glucose concentration. The second optical waveguide  70  and the reference probe  76  form here the reference channel. 
         [0053]    The glucose sensor in this sample embodiment moreover comprises in a schematically depicted housing  82  a light source  84 , which supplies light to both the measuring probe  62  and the reference probe  76 . For this purpose, the light emitted by the light source  84  is divided by means of a beam divider  86  into two beams, one of which is coupled into the first optical waveguide  56  and one into the second optical waveguide  70 . The light returning from the measuring probe  62  through the first optical waveguide  50  arrives by way of another beam portion  88  or a one-sided or partly transparent mirror at a first detector  90  of a measuring and evaluating device likewise present in the housing  82 . Similarly, the light returning from the reference probe  76  via the second optical waveguide  70  is deflected by a third beam divider  92  and routed to a second detector  94  of the measuring and evaluating device. 
         [0054]    In contrast with the sample embodiment of  FIG. 1 , the measurement conditions of the reference channel are made even more similar to the measurement conditions of the measurement channel. This is due primarily to the physical proximity between the measuring probe  62  and the reference probe  76 , which are both located in the region of the distal end  52  of the catheter  50 , and the largely identical guidance of the light to and from the measuring and evaluating device. Moreover, the identical conditions are also created in that both channels use the same light source  84 . As a result, fluctuations in the light intensity caused at the source can be eliminated and differences in the physical conditions during the measurement (temperature differences) avoided, by comparing the measurement signal with the reference signal and subtracting the latter from the former. 
         [0055]      FIG. 3  is a more detailed representation of the catheter  100  in the region of its distal end  102 . As an example, this embodiment comprises a rounded catheter tip  103 . The catheter has several openings  104  in the form of a peripheral perforation of the catheter wall, through which the bodily fluid can get into a cavity  132  of the catheter. The catheter is inserted in the body at the desired position, preferably with the aid of a hollow needle, and then the hollow needle is drawn out. 
         [0056]    As explained in connection with the sample embodiment of  FIG. 2 , there are arranged in the catheter a first optical waveguide  108  with a measuring probe  110  optically coupled to its end-side coupling surface  109  and a second optical waveguide  112  with a reference probe  114  optically coupled to its end-side coupling surface  113 . The measuring probe  110  comprises, in turn, a detection chamber  115  filled with a detection fluid for glucose and a mirror  116  disposed opposite the coupling surface  109 . The mirror  116  here is formed, for example, as a mirrored surface of a piece of fiber  118 . 
         [0057]    The detection chamber  115  in this embodiment is bounded around its periphery by a membrane  120  which is permeable to glucose, but not to cells and most proteins. The membrane for its part is enclosed around its periphery by a supporting element  121 , which confers the necessary mechanical stability on the membrane and holds the mirror  116  and the coupling surface  109  at a defined distance. The supporting element  121  can be formed from a rigid metal or plastic tube, which is perforated on at least one section for purposes of the glucose exchange. The supporting element  121  is connected together with the membrane  120  at one axial end to the optical waveguide  108  and at the other axial end to the fiber piece  118 , while the joints  122  at both ends also form a seal for the detection chamber  115 . The supporting element  121  and the membrane  120  can be glued fluid-tight for this purpose to the optical waveguide  108  and the fiber piece  118 , for example by means of silicone adhesive. 
         [0058]    The structural design of the reference probe  114  is identical. This as well comprises a cavity, the reference measuring chamber  124 , as well as a mirror  126  arranged opposite the coupling surface  113  of the second optical waveguide  112 , which is likewise formed by a one-sided mirrored piece of glass fiber  128 . The reference measuring chamber  124  formed between the coupling surface  113  and the mirror  126  is enclosed by a partition  130 , which encapsulates the reference medium situated therein and separates it entirely from the surrounding bodily fluid in the cavity  132  in the catheter tip  102 , so that no exchange of glucose, detection fluid or other substances can occur between the reference measuring chamber  124  and the cavity  132 . The partition here is likewise designed with a membrane located on the inside and a stiffening supporting element surrounding the membrane at its periphery. But the supporting element here is fashioned as a circumferentially enclosed tube for purposes of sealing. Basically, no membrane is needed for the reference probe, since no permeability is required. But in order to create identical conditions in the reference probe  114  and the measuring probe  110 , especially the same thermal conditions, a largely identical design is preferable. In this case as well, the optical waveguide  112  as well as the piece of fiber  128  forming the mirror  126  is glued fluid-tight into the tubular or hoselike partition section  130  in the area of the joints  122 . 
         [0059]    If the needle-shaped distal end  102  of the catheter  100  is injected, bodily fluid gets in through the openings  104  and  106  to the cavity  132  of the catheter and makes contact with the membrane  120  of the measuring probe  110  as well as the partition  130  of the reference probe  114 . In this way, the measuring probe and the reference probe find themselves at the same thermal level. However, the glucose can only get into the detection chamber  115  through the membrane  120 , where a loss of intensity occurs by virtue of an absorption of the light coupled in, which can be detected with the previously represented measuring and evaluating device of  FIG. 2  and compared to the measurement result of the reference channel. 
         [0060]      FIG. 4  shows a second configuration of the catheter  150  in the region of its distal end  152 , whose needle-shaped tip has the same shape as the previously described sample embodiment, along with openings. The glucose sensor also comprises a first optical waveguide  158  with a coupling surface  159  at its distal end, to which the measuring probe  160  is coupled in the above described manner. Once again, the second optical waveguide  162  has a coupling surface  163  with reference probe  164  coupled to it. 
         [0061]    In contrast with the previously described sample embodiment, however, the detection chamber  165  and the reference measuring chamber  174  are not individually sealed off, but instead fashioned with an open wall, so that an exchange of the reference medium or the detection fluid, hereinafter subsumed under the term perfusate, can occur. This takes placed in controlled manner, in that an inner tube  180  is provided, surrounding the second optical waveguide  162  and the reference probe  164 , and being open at its distal end  182 . Furthermore, the inner tube  180  together with the first optical waveguide  158  and the measuring probe  160  is surrounded by a semipermeable membrane  184 , which divides the interior of the catheter  150  in an internal chamber  186 , which is tight to the perfusate but open to the glucose, and an external chamber  188 . The inner tube  180  is attached, at the pressure side, at its proximal end (not shown) to a delivery device (not shown). The internal chamber  186  inside the membrane  184  is connected to the suction side of the delivery device. The delivery device is designed to delivery the perfusate and generates a flow of the perfusate through the inner tube  180  into the internal chamber  186 , as indicated by the flow arrows  190 . Thus, the inner tube  180  forms, together with the membrane  184 , a flow channel in which the reference probe  164  and, downstream, the measuring probe  160  are arranged. This ensures that the reference probe  168  is bathed in a reference medium with constant glucose concentration, and the medium then gets into the internal chamber  186 , where it takes up or surrenders glucose through the membrane  184  by virtue of diffusion. It then makes contact with the measuring probe  160 , where a different absorption of the light can be detected as a function of the glucose. 
         [0062]    The configuration of  FIG. 5  resembles that of  FIG. 4  in functional respect, since a flow channel is also configured here. However, the design measures are different. First of all, there are also provided here in a catheter  200  in the region of its distal end  202  a first optical waveguide  208  with a measuring probe  210  coupled to it and a second optical waveguide  212  with a reference probe  214  coupled to it. Likewise in this sample embodiment the measuring probe  210  and the reference probe  214  are fashioned with an open wall. Once more, the second optical waveguide  214  and the reference probe  214  are surrounded by an inner tube  230 . The major design difference consists in that the semipermeable membrane  234  is glued, fluid-tight, to the inner tube  230 , as indicated by the joints  235 , and continues the flow channel of the inner tube  230  with substantially the same cross section. The semipermeable membrane  234  is fashioned as a tube or hose. This time, it only surrounds the measurement cell  210  and not also the inner tube. 
         [0063]    Like before, the inner tube  230  can be connected at the pressure side and the membrane  234  at the suction side to a delivery device. Thus, the perfusate can be delivered with a flow  240  from the reference probe  214  to the measuring probe  210 . Thus, here as well it is assured that first the reference probe  214  makes contact with a reference medium with constant glucose concentration and only after taking up glucose is contact made with the measuring probe  210 . 
         [0064]    Downstream from the measuring probe  210 , the membrane  234  can pass, in a manner not shown, into a second inner tube, which is completely fluid-tight, because no longer is any permeability to glucose required there. The first and, if present, the second inner tube in all embodiments, as well as the catheters, are preferably made of refined steel, transitional metal such as titanium, precious metals or plastics. 
       LIST OF REFERENCE SYMBOLS 
       [0000]    
       
           10  Catheter 
           12  Distal end of catheter 
           14  Opening of catheter 
           16  First optical waveguide 
           18  Distal end of first optical waveguide 
           20  Coupling surface of first optical waveguide 
           22  Measuring probe 
           24  Detection chamber 
           26  Mirror 
           28  Housing 
           30  Light source 
           32  Detector 
           34  Light beam 
           36  Beam divider 
           38  Reference channel 
           40  Light source 
           42  Reference detector 
           50  Catheter 
           52  Distal end of catheter 
           54  Opening of catheter 
           56  First optical waveguide 
           58  Distal end of first optical waveguide 
           60  Coupling surface of first optical waveguide 
           62  Measuring probe 
           64  Detection chamber 
           66  Mirror 
           70  Second optical waveguide 
           72  Distal end of second optical waveguide 
           74  Coupling surface of second optical waveguide 
           76  Reference probe 
           78  Mirror 
           80  Reference measuring chamber 
           82  Housing 
           84  Light source 
           86  Beam divider 
           88  Beam divider 
           90  Detector 
           92  Beam divider 
           94  Detector 
           100  Catheter 
           102  Distal end 
           103  Rounded catheter tip 
           104  Opening 
           108  First optical waveguide 
           109  Coupling surface of first optical waveguide 
           110  Measuring probe 
           112  Second optical waveguide 
           113  Coupling surface of second optical waveguide 
           114  Reference probe 
           115  Detection chamber 
           116  Mirror 
           118  Fiber piece 
           120  Membrane 
           121  Supporting element 
           122  Joint 
           124  Reference measuring chamber 
           126  Mirror 
           128  Fiber piece 
           130  Partition 
           132  Internal chamber of catheter 
           150  Catheter 
           152  Distal end of catheter 
           158  First optical waveguide 
           159  Coupling surface of first optical waveguide 
           160  Measuring probe 
           165  Detection chamber 
           162  Second optical waveguide 
           163  Coupling surface of second optical waveguide 
           164  Reference probe 
           174  Reference measuring chamber 
           180  Inner tube 
           182  Distal end of inner tube 
           184  Membrane 
           186  Internal chamber 
           188  External chamber 
           190  Flow direction 
           200  Catheter 
           202  Distal end of catheter 
           208  First optical waveguide 
           210  Measuring probe 
           212  Second optical waveguide 
           214  Reference probe 
           230  Inner tube 
           234  Membrane 
           235  Joint 
           240  Flow direction