DE102004055032A1 - Optical device for determining glucose concentration in interstitial fluid, useful particularly where measured values are used to regulate insulin release - Google Patents

Abstract

Device (A) for determining the concentration of glucose (I) dissolved in interstitial fluid comprises an optical body (2), at least partly surrounded by a measuring matrix (6) that is in contact with the interstitial fluid (7); a light source (1), arranged to direct light into (2); and a detector (3) arranged to detect light transmitted from (2) and emitted in a particular direction, where (2) has a refractive index (RI) that, at a (I) concentration in (7) of 20-800 mg/dl, is 0.175 to 0.00005 greater than the RI of (6). An independent claim is also included for determining the concentration of (I) in interstitial fluid using the new device.

Description

The The present invention relates to an apparatus and a method for determining the concentration of interstitial fluid dissolved glucose. The device can be fully or partially implanted and is suitable for long-term use.

A good metabolism of diabetics is difficult to achieve. Especially with an intensive insulin therapy are so far frequent blood sugar regulations needed by the patient himself. Times and altitude the insulin doses must have factors which affect the blood sugar level, be adjusted. A punctual Blood glucose self-testing on conventional Invasive way is not only painful and uncomfortable to them also gives only snapshots of the times of blood collection predominant blood glucose content. Continuous glucose monitoring (CGM) On the other hand, it can detect the real fluctuations of the blood sugar level over longer periods of time and show when strong deviations from the prevalent in the healthy Range of blood glucose levels occur. The development of a suitable for everyday use Glucose sensor, which delivers continuously accurate values, the conclusions on allow the current blood glucose levels, is also the first Step in the development of an artificial pancreas.

clinical Studies have shown that for a continuous glucose monitoring measurements of glucose content in interstitial fluid (ISF) can be used as well as glucose determinations in capillary blood or in venous Blood. To do this minimally invasive glucose sensors either stung through the skin be or interstitial fluid must be through the skin out of the body transported (for example by microdialysis).

in the The prior art discloses biosensors which contain the enzyme glucose oxidase, immobilized on the gate of a field effect transistor and by oxidation of the glucose corresponding to the glucose concentration generate electrical signal, which then with the glucose concentration is correlated. A disadvantage of such biosensor systems However, they only have a limited shelf life and functionality from several hours to several days. The reason is in that on the one hand often the enzymatic structure is modified by immobilization in such a way that the enzyme is no longer identical to the in vivo enzyme, and on the other hand, aging of the immobilized enzyme occurs which, after a short time, leads to the total loss of glucose oxidizing ability to lead.

WHERE 90/01697 has a device for blood glucose monitoring to the object with a waveguide in contact with the blood, the one Kern and a (partially interrupted) cladding, one Light source, which is optically connected to one end of the waveguide is, a light detector that generates a signal depending from the light transmitted through the waveguide, and a An insulin management element that detects one of the patient Light dependent Allocates amount of insulin.

EP 0 398 407 B1 relates to a device for measuring the refractive index of a fluid, which is in particular intended to measure the density of this fluid or the concentration of a substance dissolved in this fluid and which comprises a rod which protrudes into the fluid and has a refractive index which is slightly larger as that of the fluid, wherein the rod at the end not immersed in the fluid is provided with a light source radiating into the rod and a light detector and the part of the rod to be immersed in the fluid is partially surrounded by an enclosure which allows only total reflection of the light, while at the location of the part or parts of the bar which are not surrounded by the enclosure, refracted light may leak into the fluid depending on the refractive index of the fluid. The cladding consists of a layer of a medium which has a lower refractive index than the rod, in particular of gas or vacuum and which is enclosed in a transparent tube. The tube consists in particular of quartz. If the density of the liquid is relatively small, the refractive index of the liquid will also be relatively small, resulting in a small critical angle, so that a relatively large amount of reflected light will occur and only a small refraction. Thus, a not inconsiderable part of the light, which is refracted after reflection at the lower part of the sensor of the prior art, falls on the detector. The magnitude of the electrical signal generated by the detector is a measure of the refractive index and consequently the density of the liquid. However, since this sensor is essentially designed to measure the density or concentration of aggressive liquids, such as sulfuric acid in a battery, as well as its design, this sensor is not suitable for measuring glucose concentration in interstitial fluid.

DE 195 40 456 relates to a method for measuring the glucose concentration in a liquid which contains, in addition to glucose, several other constituents, two measurements being carried out on the liquid to be examined, wherein in each case an optical or an electrical parameter is determined during a measurement, wherein the liquid to be determined is subjected to at least one measurement of a filtration, which separates certain components of the liquid before the measurement of the latter, and wherein the glucose concentration of the liquid from the two measured values is determined. The optical parameter may be the refractive index. The measurement is carried out in particular with glucose-containing blood. A disadvantage is that, for example, membranes are needed, which filter out all components that are larger than a glucose molecule. Such membranes must have a very low separation limit. However, this affects the diffusion rate of the desired permeants. Furthermore, molecules whose molecular weight is only slightly above the cut-off of such a membrane can not be completely excluded for a long time. There will always be a slight transport and this then leads to an undesired drift of the measuring system. Furthermore, the method is expensive, since two exclusion methods and two measurements are necessary to determine the glucose concentration.

task The present invention is therefore, the disadvantages mentioned to avoid the prior art and an apparatus and a method to provide the glucose concentration, the glucose concentration differences can detect very sensitive.

• • einem optischen Körper, der zumindest teilweise mit einer Messmatrix umgeben ist, wobei die Messmatrix mit der interstitiellen Flüssigkeit in Kontakt steht,
• • mindestens einer Lichtquelle, die so angeordnet ist, dass sie Licht in den optischen Körper hineinstrahlt und
• • einem Detektor, der so angeordnet ist, dass er von dem optischen Körper transmittiertes und in einer bestimmten Richtung emittiertes Licht detektiert,

wobei der optische Körper einen Brechungsindex besitzt, der bei einer Glukosekonzentration der interstitiellen Flüssigkeit von 20 bis 800 mg/dL um 0,175 bis 0,00005, bevorzugt 0,1 bis 0,00005, besonders bevorzugt 0,01 bis 0,00005 größer als der Brechungsindex der Messmatrix ist.This object is achieved by a device for determining the concentration of glucose dissolved in interstitial fluid with

• An optical body which is at least partially surrounded by a measuring matrix, the measuring matrix being in contact with the interstitial fluid,
• • at least one light source, which is arranged so that it radiates light into the optical body and
• A detector which is arranged to detect light transmitted from the optical body and emitted in a certain direction,

wherein the optical body has a refractive index at a glucose concentration of the interstitial fluid of 20 to 800 mg / dL by 0.175 to 0.00005, preferably 0.1 to 0.00005, particularly preferably 0.01 to 0.00005 greater than that Refractive index of the measuring matrix is.

there The refractive indices given refer to air from 20 to 40 ° C and 101.3 kPa and to light of at least one wavelength or wavelength range in the UV range of the spectrum to the near infrared (NIR), outside of any absorption bands of the optical body, preferred on the D-line of sodium.

The Operation of this device is based on the refractive index difference between the optical body and at least partially surrounding the measuring matrix. The optical Body serves as a light guide into which the light from the light source is coupled is partially transmitted to the detector due to total reflection becomes. The amount of light that is due to refraction in the measurement matrix can escape and thus is not transmitted to the detector, hangs (there where the optical body and the measuring matrix have an interface) from the relationship the refractive indices of the optical body and the measuring matrix. The refractive index of the measuring matrix is again dependent on their glucose concentration. change As the concentration of glucose in the measurement matrix changes, so does also their refractive index and this change is with the device according to the invention due to a change Transmission detectable by the optical body. The higher the Glucose concentration is, the higher is the refractive index of the matrix and the smaller the difference the refractive indices of the material of the optical body and the measuring matrix. The smaller the difference of the refractive indices of the Optical body material and the measurement matrix is, the larger the critical angle of total reflection and the less light gets through the optical body transmitted and thus detected by the detector. With help a suitable evaluation is the detected light intensity in a the glucose concentration proportional signal transferred.

When Measuring matrix serves e.g. a measuring liquid, which has a for glucose permeable Membrane is in contact with the interstitial fluid. As measuring liquid For example, a glucose-containing saline solution can be used. If a measuring fluid used as a measuring matrix over a membrane with the interstitial liquids is in contact, so there is a diffusive balance between the two liquids one. The glucose concentration in the measuring fluid therefore reflects the Glucose concentration in the interstitial fluid again.

However, a gel which at least partially surrounds the optical body, which is in contact with the interstitial fluid and alters its refractive index as a function of the glucose concentration of the interstitial fluid, can also serve as a measuring matrix. Such gels are known in the art. They change their degree of swelling selectively depending on the glucose concentration and hence their refractive index. For example, a fibrous optical body may be coated with such a gel.

suitable Gels include crosslinked polymeric gels containing groups that react directly or indirectly with glucose. Those directly reacting with glucose Groups are those that bind more strongly with glucose than with other groups bound in the gel through which the gel is crosslinked. By linking these groups to glucose, the crosslinking of the Gels diminished. In other configurations form directly with glucose Reactive groups about Glucose from a network. The crosslinking of a gel is thereby strengthened.

Indirectly Glucose-reactive groups are those in which reaction products a reaction of glucose with another group or species to changes cross-linking and / or swelling.

Examples such gels are listed in US 20020155425 A1. Contains gels that react directly with glucose for example, phenylboronic acid, Lectins such as concavalin A, glucokinase, xylomerase, isolactin I and crosslinked groups or polymers, such as polyols, with these groups Polyglucosides, geminal hydroxy group or the like, wherein a competitive exchange of these groups takes place with glucose.

Indirectly Glucose-reactive gels are, for example, pH-sensitive gels with immobilized GOD and catalase. Glucose is made with the help of GOD to gluconic acid oxidized. gluconic causes protonation of the pH-sensitive groups of the pH-sensitive gel and causes swelling or shrinkage of the gel, depending on the type the sensitive groups.

The Crosslinking of a gel is coupled with its swelling. The swelling in turn has a strong influence on the density and thus on the refractive index of the gel.

Becomes the gel layer thicker than 1 micron executed are the outcoupling effects of light in direct contact of Tissues with the gel layer so low that on the use of a additional membrane can be waived, provided that the below requirements to the Biocompatibility are met.

When But measuring matrix can also at least partially surrounding the optical body porous Layer (e.g., a porous gel) that interfere with the interstitial liquid is in contact and does not react sensitively to glucose. This embodiment the measurement matrix changes their refractive index by the change the concentration of ingredients in a solution that is in the pores. The measurement matrix is in direct contact with the interstitial liquid and the transport of glucose into or out of the measuring matrix is accomplished by Diffusion.

For such a porous one Layer materials come into question in a suitable porous form can be provided and which, optionally with the assistance of additives, give wettable pore surfaces. It can both organic and inorganic materials or combinations thereof be used. According to the invention is the Refractive index of the optical body at a glucose concentration of the interstitial fluid of 20 to 800 mg / dL 0.175 to 0.00005 above the refractive index of with the interstitial fluid in contact porous Layer. The material of the porous Layer itself can have a refractive index, which is only slightly different from the refractive index of the optical body. This plays but with increasing porosity a minor role.

The Production of such, the optical body at least partially surrounding porous measuring matrix can be done in a similar way as the production of a crosslinked gel or a porous one Membrane. Exemplary production methods are phase inversion, Sintering, etching, Plasma polymerization or other methods known in the art. The thickness of the as porous Layer executed Measuring matrix is preferably between 1 and 100 microns, more preferably between 1 and 10 μm. One The advantage of such a measuring matrix is its easy wettability with interstitial fluid, wherein the contact of gas bubbles with the optical body prevented can be. For For purposes of storage the pores of the porous ones Layer with a soluble, biocompatible Substance filled become. Another advantage is that with sufficiently fine-pored execution of porous Layer, no membrane is necessary to make a contact between the optical body and the tissue surrounding it if necessary.

at The present invention reflects the glucose concentration in the measurement matrix the glucose concentration in the interstitial fluid again. The glucose content of the interstitial fluid is again in directly related to the glucose concentration in the blood.

The inventively small difference in refractive index between the optical body and the measuring matrix results in a high measuring sensitivity of the device according to the invention in determining the glucose concentration in interstitial fluid. Already small changes of the glucose content of the measuring matrix result clearly, from Noise to be distinguished, detected by the detector signal changes.

at of the present invention is e.g. the refractive index n 20 / D one optical body, the one directly in equilibrium with the interstitial fluid standing measurement matrix forms an interface, between 1.330 and 1.505, preferably between 1.334 and 1.359, more preferably between 1.334 and 1.343, when the refractive index of the measuring matrix between 1.334 and 1.337

The uses solution according to the invention advantageously a physical principle for quantification of glucose in body fluids and avoids the formation of reaction products. This comes it does not cause local depletion of glucose, nor is it one further component, such as oxygen as a reaction component, necessary. Likewise, the reaction of tissue to reaction products is excluded. The solution according to the invention allows furthermore, a long-term use without unacceptable drift in sensitivity of the measuring system with very high analytical performance. There no Enzymes or other sensitive reagents involved in the detection are sterilization of measuring systems according to the invention only by the components are limited. When using electronic components according to MIL specification is a sterilization in steam at 121 ° C for 15 minutes or in ethylene oxide gas possible without performance degradation. Because no enzymes or other sensitive reagents at the detection is involved as well a storage over long time without loss of power possible. Opposite the stand In technical terms, the solution according to the invention is further distinguished by that no membrane that has to exclude certain components safely, a reliable one Required to obtain measurement signal becomes.

The optical body can dip in the device according to the invention only with a part of its surface in the measuring matrix, but it can also be completely surrounded with measuring matrix. The material of the optical body is selected so that its refractive index is in the above-mentioned range and that it has sufficient transparency for the light emitted from the light source. In a preferred embodiment of the present invention, the optical body is made of a polymer, in particular of a fluorine-containing polymer. Advantages of these polymers include their refractive index, which is well suited to the invention, and their biocompatibility. The fluorine-containing polymer is preferably at least one polymer selected from the group
Polyhexafluorpropylentetrafluorethylen (FEP), Polypentadecafluoroctylacrylat, Polyvinylnonadecafluordecanoat, poly (tetrafluoro-3- (heptafluoropropoxy) propyl) acrylate, polytetrafluoroethylene (PTFE), Polyhexafluorpropylentetrafluorethylenvinylfluorid (THV), Polyundecafluorhexylacrylat, perfluoroalkoxy polymers (PFA), polyethylene tetrafluoroethylene (ETFE), Polynonafluorpentylacrylat, poly (tetrafluoro 3- (trifluoromethoxy) propyl) acrylate), polypentafluorovinylpropionate, polyheptafluorobutylacrylate, polytrifluorovinylacetate, polyoctafluoropentylacrylate, polymethyl-3,3,3-trifluoropropylsiloxane, polypentafluoropropyl acrylate, poly (2-heptafluorobutoxy) ethylacrylate, polyfluorotrifluoroethylene (PCTFE), poly-2,2,3 , 4,4-hexafluorobutyl acrylate, polytrifluoroethyl acrylate, poly 2 - (1,1,2,2-tetrafluoroethoxy) ethyl acrylate, polytrifluoroisopropyl methacrylate, poly (2,2,2-trifluoro-1-methylethyl) methacrylate, poly-2-trifluoroethoxyethyl acrylate, polyvinylidene fluoride ( PVDF), polyethylene chlorotrifluoroethylene (ECTFE), polytrifluoroethyl methac rylate, poly-2-fluoroethyl methacrylate and poly-4-fluoro-2-trifluoromethylstyrene.

According to an alternative preferred embodiment of the present invention, the optical body is made of a fluorine-free polymer. An advantage of these materials is their ease of processing. The fluorine-free polymer is preferably at least one polymer selected from the group
Polymethylhydrosiloxane, polydimethylsiloxane, polyhexylmethylsiloxane, polymethyloctylsiloxane, polyisobutylmethacrylate, polyisobutylvinylether, polyhexadecylmethylsiloxane, polyethylvinylether, polymethyltetradecylsiloxane, polyethyleneglycolmonomethylether, poly-n-butylvinylether, poly-3-butoxypropylenglycol, poly-n-pentylvinylether, poly-n-hexylvinylether, polyoctylvinylether, polyvinyl-n- octyl acrylate, poly-2-ethylhexyl vinyl ether, poly-n-decyl vinyl ether, poly-2-methoxyethyl acrylate, polyacryloxypropylmethylsiloxane, poly (4-methyl-1-pentene), poly-3-methoxypropylene glycol, poly-t-butyl methacrylate, poly-n-dodecyl vinyl ether , Poly-3-ethoxypropyl acrylate, polyvinyl propionate, polyvinyl acetate, polymethyl vinyl ether, polyethyl acrylate, polymethyl vinyl ether, poly-3-methoxypropyl acrylate, poly-1-octadecene, poly-2-ethoxyethyl acrylate, polyisopropyl acrylate, poly-1-decene, polylauryl methacrylate, poly-sec-butyl-viyl ether , Poly-n-butyl acrylate, polydodecyl methacrylate, polyethylene succinate, polytetradecyl methacrylate, Cellulose acetate butyrate, cellulose acetate, polyvinylformate, polyethylenevinylacetate, polymethyloctylsilane, ethylcellulose, polymethylacrylate, polydicyanopropylsiloxane, polyoxymethylene, poly-sec-butylmethacrylate, polydimethylsiloxane-alpha-methylstyrene, poly-n-hexylmethacrylate, poly-n-butylmethacrylate, polyethylenedimethacrylate, poly-2-ethoxyethylmethacrylate, Poly-n-propyl methacrylate, polyethylene maleate, polyethyl methacrylate, polyvinyl butyral, poly (3,3,5-trimethylcyclohexyl) methacrylate, poly (2-methyl-2-nitropropyl) methacrylate, polydimethylsiloxane-diphenylsiloxane, poly-1,1-diethylpropyl methacrylate, polytriethylcarbinyl methacrylate, polymethylmethacrylate, Poly (2-decyl-1,4-butadiene), polypropylene, polyvinyl butyral with 11% polyvinyl alcohol, polymercaptopropylmethylsiloxane, polyethylglycolate methacrylate, poly-3-methylcyclohexylmethacrylate, polycyclohexyl-alpha-ethoxyacrylate, methylcellulose, poly-4-methylcyclohexylmethacrylate and polydecamethylene glycol dimethacrylate.

Is a commercially available, suitable for the present invention, tetrafluoroethylene / hexafluoropropylene copolymer (FEP), for example, Dyneon ^® fluorine Thermoplastic FEP 6307 from Dyneon, Burgkirchen. It has a refractive index of n 25 / D = 1.336. Polyvinylnonadecafluorodecanoate is another suitable polymer with a refractive index of n 25 / D = 1.3340, which can also be used as cladding in optical bodies made of a material with a higher refractive index. Advantageous in the use of plastics is the ability to form the optical element inexpensively in the extrusion, injection molding or injection-compression molding and complete with little further effort, if necessary, with membrane, coating (cladding) and electro-optical and electronic elements.

In a preferred embodiment In the present invention, the optical body is a rod or a fiber in the form of a circular cylinder, in particular a straight circular cylinder. This geometric shape of the optical body is due to its simplicity advantageous. It allows one Simplification of production and improvement of reproducibility in the production. The light is irradiated in such a way shaped optical body preferably over an end face of the circular cylinder, the smooth running is. The executed as a circular cylinder optical body is located in the device according to the invention at least with a part of its lateral surface in contact with the measuring matrix.

A optionally provided in the present invention membrane is for Glucose permeable, as well for small and medium sized molecules but preferably not for high molecular components of the interstitial fluid or for cells. High molecular weight molecules are those with a molecular weight> 40,000 g / mol. At a Modification of the surface of the optical body in such a way that an attachment occurs in the area of contact with the measuring matrix of proteins is largely prevented, a membrane can be used Be that only for Cells impermeable is.

In a preferred embodiment of the device according to the invention is between a membrane and the optical body connected to a pump liquid line for conducting measuring liquid serving as a measuring matrix from the membrane the optical body arranged. The optical body is located outside of the body of a Patients and over the liquid line supplied with the glucose-containing measuring matrix. These are to a microdialysis technology, in which the functioning of Capillaries is imitated. A catheter with a thin dialysis fiber is introduced into the subcutaneous tissue under the skin. The Fiber becomes with isotonic liquid flushed. This rinsing liquid (Perfusion) is above a membrane of microdialysis fiber in constant exchange with the interstitial liquid in the vicinity of the catheter. Due to a concentration gradient glucose migrates from the interstitial fluid into the perfusion fluid (Measuring matrix) or vice versa. The flow rate through the catheter is chosen that at the exit of the catheter over the membrane equilibrium adjusts, i. the glucose concentration in the catheter interior is the same the glucose concentration in the interstitial fluid. The measurement matrix enriched with glucose from the interstitial fluid becomes the optical body comprehensive glucose sensor outside of the body pumped. There, the continuous determination of the glucose concentration.

In a preferred embodiment of the device according to the invention, a membrane encloses the optical body. In this embodiment, full or partial implantation of the optical body surrounding the membrane into tissue containing interstitial fluid is provided. In order to avoid a falsification of the measurement result, however, direct contact of the optical body with the membrane must be avoided. Preferably, therefore, spacers are arranged between the optical body and the membrane. The spacers are preferably a coating of the optical body or wires of metal or plastic or plastic-coated metal wires. A metal wire as a spacer may for example consist of gold, nickel, tantalum, platinum or other chemically sufficiently stable metals or alloys. As plastic wires, for example, wires made of PTFE or Teflon ^® AF can be used. For example, a coating as a spacer may be present as a partial cladding of the optical body, areas without cladding serving as an interface between the optical body and the measuring matrix. The partial cladding can be made, for example, from low-refractive plastics.

For example, in this particular embodiment of the present invention where a membrane at least partially encloses the optical body, the optical body may be incorporated into a housing whose walls are at least partially formed by a membrane. About the optical body and the measuring matrix surrounding membrane is a diffusive Gleichge weight with the interstitial fluid of the tissue. Furthermore, in the present invention, the membrane may additionally at least partially enclose the light source and / or the detector. For example, the light source and / or detector may also be incorporated in the housing containing the optical body. If only the optical body is incorporated in such a housing, the light emitted by the light source can be radiated through a suitable window in the housing and the light detected by the detector leave the housing via another or the same window. In a preferred embodiment of the present invention, the optical body is connected to at least one optical waveguide. Light can be conducted from the light source to the optical body and / or from the optical body to the detector via the optical waveguide.

In a preferred embodiment In the present invention, the membrane is a dialysis membrane. High molecular weight components of the body fluid and cells can Dialysis membrane does not happen. Medium sized molecules can spread over one Period of days in the space enclosed by the dialysis membrane accumulate. To ensure that any changes caused thereby the with the device according to the invention certain glucose concentration can be detected and compensated, one can automatic internal calibration are performed. In a special embodiment the device according to the invention is the optical body surrounded by a dialysis fiber membrane, which enters the tissue of a patient can be used, in particular in subcutaneous tissue, in particular in subcutaneous adipose tissue.

As used in the device according to the invention dialysis membranes are, for example, those which are installed in dialyzers, which are sold under the trade name Polyflux ^® by Gambro Hospal GmbH (Planegg-Martinsried), or membranes with similar properties and adapted dimensions. Also membranes of other manufacturers and of other materials can be used successfully for the inventive purpose. Critical to successful use is the ability of the membrane to permanently exclude tissue contact with the optic body, while ensuring that there is no excessive foreign body reaction of the tissue, during which a capsule can be formed which prevents glucose transport from the tissue Slows tissue through the membrane into the measurement matrix to an intolerable extent. For this, the membrane may be provided with suitable modifications that prevent protein attachment and stimulate the formation of vessels in a developing capsule. The membrane must therefore be biocompatible when implanted in the tissue of a patient. In this sense, biocompatibility means that the membrane will not elicit an inflammatory response, that it will not promote cell adhesion and will not stimulate overgrowth. In a preferred embodiment of the present invention, therefore, the membrane has a coating for reducing the attachment of proteins to the membrane. Coatings which reduce the attachment of proteins are described, for example, by J. Hubbell (US 20030133963 A1, US 20020128234 A1). A suitable angiogenic coating is used, for example, by Dexcom, San Diego, USA in long-term implanted glucose sensors.

In a preferred embodiment The present invention is that of the at least one light source emitted light is monochromatic or polychromatic and lies in a wavelength range from 200 nm to 2500 nm, preferably in a range of 350 nm to 1500 nm. As the light source, for example, a halogen lamp, an LED, a VCSEL or another, possibly tunable Lasers are used. As a detector is used in the device according to the invention for example, a photodetector, preferably a photodiode or a photoresistor. The light source and / or the detector can directly on the optical body be attached or arranged at a defined distance to this be. In a designed as a circular cylinder rod or fibrous. optical body in particular by the execution with flat interfaces the possibility created, the light source and / or the detector directly on the optical body to apply, e.g. stick, or organic or inorganic Photoelements e.g. OLEDs or photocells to coat directly.

The Measurement matrix is preferably isotonic in the present invention, sterile, pyrogen-free and biocompatible, since they are in direct contact with the membrane Contact with the interstitial fluid stands. In a preferred embodiment The present invention is the measurement matrix (already before contact with the interstitial fluid) glukosehaltig. It also turns in this case for a specific Time a diffusive equilibrium, since glucose in both directions can diffuse through the membrane. This time is preferably smaller than 600s, more preferably less than 180s.

In order to detect and optionally compensate for changes occurring due to external influences which influence the determined glucose concentration, an automatic calibration of the method according to the invention is preferably carried out ßen device performed. The automatic calibration is preferably performed at predetermined intervals or under the control of an algorithm that appropriately evaluates the glucose signals.

According to one preferred embodiment of present invention, the device according to the invention has an arrangement of liquid lines and valves which are arranged so that the as a measuring liquid present measuring matrix are exchanged for a calibration liquid can. The calibration fluid with a defined and known glucose content becomes from a reservoir for example by means of a pump or by manual pressure the reservoir via a liquid line in the previously filled with measuring matrix Room of the device according to the invention pressed so that she displaces them. The calibration fluid must either flow past the membrane at such a speed that the diffusion of glucose through the membrane does not cause a noticeable change the glucose concentration of the calibration fluid during the calibration time leads or the device must have an interruption element (for example, a Valve), the temporary the contact between the calibration fluid serving as a new measurement matrix and the interstitial fluid interrupts. That through the detector during the calibration time (for example between 5 and 20 seconds) detected signal is expected with a known glucose concentration Signal compared and the deviation of a calibration factor determined, with the glucose concentrations determined after the calibration the interstitial fluid Getting corrected. Advantageously, to carry out a regular calibration only a very small amount of calibration liquid needed. through this calibration can in an advantageous manner changes in the optical properties of the optical body, in the sensitivity of the detector, in the power of the light source (s), in the quality of the coupling and decoupling of light into the optical body or the attachment of, for example, proteins, e.g. at the optical body or the membrane detected and possibly eliminated or compensated.

The for calibration from the space surrounding the optical body displaced measurement fluid can over a liquid line in a waste container promoted or to the tissue containing the interstitial fluid be delivered, for example, over an extended, intended for it Part of the membrane. The delivery to the tissue is unproblematic, since no reaction products are formed and the liquid retains its biocompatibility. Reservoir and Waste containers for the Measuring and calibration fluid can from thin, diffusion-tight foil bags are formed.

Of Furthermore, in the device according to the invention an additional optical body provided be that constantly at least partially with a calibration liquid of known refractive index is in contact, not with the interstitial fluid in contact, or with a cladding of known refractive index is surrounded. This additional optical body is part of an additional Measuring branch (comparator branch).

If the additional one optical body with a calibration fluid known concentration in contact, so this calibration liquid has a lower refractive index than the additional optical body. Furthermore, it is completed by the interstitial fluid, so that she does not change her composition. The refractive index of calibration solution can e.g. through a defined glucose concentration or through other ingredients (for example, salts) can be adjusted. A change the refractive index of the calibration fluid may then be e.g. on a temperature change based.

If the additional optical body is surrounded by a cladding of known refractive index, this cladding consists of a solid material which has a smaller refractive index than the additional optical body. The cladding may for example be made of Teflon ^® AF from DuPont Fluoroproducts or Polyvinylnonadecafluordecanoat. It preferably has a thickness> 1 μm.

A comparison measurement is carried out using the additional optical body, which makes it possible to take into account the influence of disturbances, such as temperature change or mechanical influences, in the determination of the glucose concentration with the first optical body. The comparator branch changes its transmission with temperature or with a mechanically induced bending of the optical body. The signal from the comparator branch can serve via a suitable algorithm for correcting the signal from the measuring branch and thus increase the accuracy and reliability of the device according to the invention and of the method according to the invention. As the light source for the comparator branch, the same light source can be used, which also irradiates the first optical body. For this purpose, the emitted light is distributed to both optical bodies by suitable measures, for example by a beam splitter. When the intensity of the light source changes, the signal from the comparator branch also changes. Thus, it is also possible fluctuations in the Compensate for light intensity. However, it can also be provided a further light source for illuminating the additional optical body.

These Simple automatic calibration can be done in the present invention also be carried out in a fully implanted measuring system. control measurements the glucose concentration with blood and with for example one Dry chemistry containing gauges are due to the possibilities for automatic calibration in the device according to the invention only very rarely necessary.

In another particular embodiment of the present invention are used instead of a monochromatic Light source multiple monochromatic light sources or a light source with several defined wavelengths used to the optical body the device according to the invention to irradiate. This makes it possible a better correlation of the glucose concentration in the measurement matrix and the signal. Except Glucose affects other dissolved ones Ingredients of the interstitial fluid the refractive index the measuring matrix. When measuring the transmission of light through the optical body at a single wavelength can not between a refractive index change by glucose or be differentiated by other ingredients. With the wavelength changes the refractive index of the measuring matrix as a function of the dissolved substances. This makes it possible by measuring the transmission at two or more wavelengths the Concentration of a substance, in particular the concentration of glucose, in a multi-component solution like the interstitial fluid to determine.

In a preferred embodiment The present invention comprises the device according to the invention a temperature sensor and / or a conductivity sensor for measuring the Temperature and / or conductivity the measuring matrix. The sensors allow temperature and conductivity changes and their effects on the transmission of light in the optical body electronically compensate with suitable algorithms. By the Measurement e.g. The electrical conductivity of the measuring matrix can be changed the concentration of electrolyte components of the measuring matrix detected and with changes the transmission are charged. This will be a more accurate determination the glucose concentration in the measurement matrix and thus also in the Interstitial fluid possible. Instead of a simple conductivity measurement can also be used impedance spectroscopy. This will be the Accuracy improved further.

In a preferred embodiment The present invention comprises the device according to the invention a hollow, needle-shaped, the membrane-containing probe for insertion into subcutaneous tissue, that the interstitial fluid contains on. The needle-shaped Probe preferably has a diameter of 100 microns to 1000 microns. she will introduced into the subcutaneous tissue of a patient, where the membrane with the interstitial fluid is in contact. In this embodiment the device according to the invention can the light source (s), the optical body and the detector in one outside the Tissue arranged part of the device according to the invention are and the optical body becomes then over fluid lines with measuring fluid (Measuring matrix) supplied from the area of the membrane. The optical body and optionally also the light source and / or the detector can but also be arranged in the region of the probe.

The inventive device preferably comprises a housing with the power supply for the light source, the detector, etc., with control electronics, a signal processing, an RF module and optionally with a reservoir for a calibration solution and with a pump, the housing in a device containing a probe outside the tissue remains: A receiver for the RF signal can serve as a display, data storage and alarm, for example.

In another preferred embodiment of the present invention, the device comprises a fully implantable measuring system containing at least the membrane, the measuring matrix and the optical body. The measuring system may further comprise a housing whose walls are at least partially formed by a membrane. The housing is made of a biocompatible material, in particular metal or plastic. The measuring system also preferably contains the light source (s) and the detector as well as the necessary electrical connections. Furthermore, an externally contactless rechargeable power supply, control electronics, signal processing, an RF module and a reservoir with calibration solution, a pump, liquid lines and a waste container, optionally a valve, a temperature sensor and a conductivity sensor can be arranged in the housing of the measuring system be. The measuring system is implanted in the subcutaneous tissue so that the membrane is in contact with interstitial fluid. Preferred implantation areas include subcutaneous adipose tissue, adipose tissue and the abdominal space. To achieve very long service life, the membrane may be provided with an angiogenic coating. In order to minimize distortions caused by movements of the membrane in connection with movements of the patient, a structure, for example in the form of a distance of 2 to 15 mm from the membrane on the housing of ribs attached, which obstructs the tissue from relative movements to the membrane.

Of Furthermore, an external receiver for the RF signal, for example, a watch or a PDA (Personal Digital Assistant) or a similar one Device provided as a display, data memory and alarm be. Such a receiver can also with mobile call devices, such as a mobile phone or with Localization facilities like GPS or both combined and operational get connected.

In a preferred embodiment The present invention is the device of the invention with a glucose-controlled portable or implantable insulin pump combined. An insulin pump can use insulin continuously or as Infuse bolus.

• (a) Kontaktieren einer Messmatrix mit der interstitiellen Flüssigkeit,
• (b) Beleuchten eines optischen Körpers mit Licht durch eine Lichtquelle, wobei der optische Körper zumindest teilweise mit der Messmatrix umgeben ist, und wobei der optische Körper einen Brechungsindex besitzt, der bei einer Glukosekonzentration der interstitiellen Flüssigkeit von 20 bis 800 mg/dL um 0,175 bis 0,00005, bevorzugt 0,1 bis 0,00005, besonders bevorzugt 0,01 bis 0,00005 größer als der Brechungsindex der Messmatrix ist,
• (c) Detektieren des in einer bestimmten Richtung aus dem optischen Körper austretenden Lichts mittels eines Detektors und
• (d) Bestimmen der Konzentration der Glukose auf der Grundlage des in Schritt (c) detektierten Lichts.

The invention further relates to a method for determining the concentration of glucose dissolved in interstitial fluid, comprising the following steps:

• (a) contacting a measurement matrix with the interstitial fluid,
• (b) illuminating an optical body with light through a light source, wherein the optical body is at least partially surrounded by the measurement matrix, and wherein the optical body has a refractive index which is 0.175 at a glucose concentration of the interstitial fluid of 20 to 800 mg / dL is up to 0.00005, preferably 0.1 to 0.00005, particularly preferably 0.01 to 0.00005 greater than the refractive index of the measuring matrix,
• (c) detecting the light emerging from the optical body in a certain direction by means of a detector and
• (d) determining the concentration of glucose based on the light detected in step (c).

there The refractive indices given refer to air from 20 to 40 ° C and 101.3 kPa and to light of at least one wavelength or wavelength range in the UV range of the spectrum to the near infrared (NIR), outside of any absorption bands of the optical body, preferred on the D-line of sodium.

For the inventive method apply (if applicable) all above to the device according to the invention taken statements.

The Illuminating the optical body takes place with monochromatic light or with light of several wavelengths. The Lighting is continuous or in pulses of a duration from 1ps to 1000s. Contacting the measurement matrix with the interstitial liquid can over one for Glucose permeable Membrane done.

Preferably the detection in the method according to the invention in the reflection or in the transmission mode carried out. In transmission mode, the detector measures that through the optical body (from one side to the other) transmitted light. light source and detector are arranged on different sides of the optical body. In reflection mode, the light is transmitted through the optical body a reflective surface guided, reflected, returned and detected near the position of the light source by the detector.

In a particular embodiment the method according to the invention For example, the glucose concentration determined in step (d) is used to control used the insulin delivery of an insulin pump. Further, it is preferable for calibration at least partially surrounding the optical body Measuring matrix in step (a) by a calibration solution with known composition replaced to a calibration of the device perform.

Based the drawing, the invention is explained in more detail below.

It shows:

1 two schematic representations of devices according to the invention, which are operated in the transmission mode,

2 a schematic representation of a device according to the invention, which is operated in the reflection mode,

3 with a device according to the invention at certain glucose concentrations and wavelengths certain transmission curves,

4 a loss curve determined with a device according to the invention at 950 nm and different glucose concentrations,

5 a schematic representation of a device according to the invention, which is inserted into the subcutaneous tissue and

6 a schematic representation of an implanted device according to the invention.

1 shows two schematic representations of devices according to the invention, which are operated in the transmission mode and based on which in the following the operation of the inventions To the device is explained.

The device according to the invention in each case contains a light source 1 , an optical body 2 and a detector 3 , In the upper structure in 1 These three components are separated and spaced from each other. In the lower structure are both the light source 1 as well as the detector 3 on the optical body 2 directly attached, for example glued on. The optical body 2 is in both cases shown a rod in the form of a right circular cylinder. In the upper structure encloses a membrane 4 the optical body 2 , In the lower structure encloses the membrane 4 the light source 1 , the optical body 2 and the detector 3 , The light source 1 emits light that enters the optical body 2 is coupled. The coupled light 5 is indicated as a single beam. The optical body 2 has a refractive index n ₁ . This refractive index n ₁ is greater than the refractive index n _{2 of} the measuring matrix 6 separating the space between the membrane 4 and the optical body 2 crowded. The refractive index n ₁ is at a glucose concentration of the interstitial fluid between 20 to 800 mg / dL, for example, by 0.01 to 0.00005 greater than the refractive index n _{2 of} the measuring matrix 6 , The refractive index n _{2 of} the measuring matrix 6 depends on the glucose concentration in the measurement matrix 6 from. This glucose concentration will in turn be due to the glucose concentration in the membrane 4 surrounding interstitial fluid 7 determined, because over the membrane 4 sets a diffusive equilibrium. From the coupled light 5 becomes a part 8th due to total reflection to the detector 3 transmitted. Another part 9 will be at the interface 10 between the optical body 2 and the measurement matrix 6 into the measurement matrix 6 broken in and is thus through the detector 3 not detectable. The amount 9 to light, due to refraction in the measurement matrix 6 can escape and therefore not to the detector 3 is transmitted depends on the ratio of refractive indices n _{1 of} the optical body 2 and n _{2 of} the measurement matrix 6 from. The smaller the difference between n ₁ and n ₂ , the less light 8th is through the detector 3 detected (the transmission is low). The refractive index n ₂ increases with the glucose concentration of the measuring matrix 6 and thus the transmission decreases. By means of an evaluation electronics (not shown), the detected signal is converted into a value proportional to the glucose concentration.

2 shows a schematic representation of a device according to the invention, which is operated in the reflection mode.

In this construction, the light source 1 and the detector 3 on the same side of the optical body 2 arranged. From the light source 1 emitted light 11 gets into the optical body 2 coupled. The coupled light 5 is at the interface as described above 10 between the optical body 2 and measuring matrix 6 totally reflected 8 or broken 9 , The totally reflected share 8th will be at the end of the optical body 2 at one as a mirror 12 acting layer reflects and the reflected light 13 will turn at the interface 10 totally reflected 8th' or broken 9 ' so that only the totally reflected light 8th' from the detector 3 can be detected. The height of the detected signal depends, as with respect 1 described by the glucose concentration in the measurement matrix 6 from.

3 shows transmission curves, which were determined with a device according to the invention at different glucose concentrations and wavelengths.

On the y-axis is the transmission T in% and on the x-axis the Wavelength λ in nm plotted. The measuring matrix was water with 0.9% NaCl and 0 to 1000 mg / dL glucose used.

The curves a to h were recorded at different glucose concentrations, with the glucose concentration rising from a to h. (a: 0 mg / dL glucose, h: 1000 mg / dL glucose). As an optical body 2 a fiber of FEP with a refractive index of n = 1.344 was used. The transmission curves clearly show that the transmission through the optical body 2 decreases with increasing glucose concentration. Furthermore, the determined transmission values are wavelength-dependent. This wavelength dependency is taken into account in the present invention through the use of at least one monochromatic or polychromatic light source. The choice of a suitable wavelength results in a signal sensitive to changes in glucose concentration which distinguishes the present invention.

4 shows a transmission curve, which was determined with a device according to the invention at a certain wavelength and different glucose concentrations.

On the Y-axis the losses V are plotted in% (100% - transmission T in%) and on the X-axis the glucose concentration C in mg / dL. The curve was using one as an optical body 2 Goodfellow commercial fiber from FEP, based in Bad Nauheim, Germany, with a diameter of 0.28 mm and a refractive index of 1.344. The fiber was cut to a length of 40 mm perpendicular to its longitudinal axis.

It shows a significant signal change in dependence from the glucose concentration of the measurement matrix.

5 shows a schematic representation of a device according to the invention, which is inserted into the subcutaneous tissue.

The device is operated in transmission mode. The optical body 2 is between the light source 1 (LED) and the detector 3 arranged and connected directly to these. The optical body 2 and the detector 3 are from a membrane 4 surround. On the inside of the membrane 4 is the measuring matrix 6 , on the outside interstitial fluid 7 , Between the liquids 6 . 7 finds a diffusive glucose exchange 14 over the membrane 4 instead of. The light emitted from the light source becomes, as explained above, depending on the refractive index difference between the optical body 2 and measuring matrix 6 partially in the optical body 2 directed to the detector and partly at the interface 10 , Broken. Separate from the ensemble of light source 1 , Membrane 4 , optical body 2 and detector 3 is schematically a housing 15 represented, for example, the power supply, the control electronics and signal processing. The in the case 15 containing components are via wires 16 with the light source 1 and the detector 3 connected. The wires 16 also serve as spacers 17 between the optical body 2 and membrane 4 , The device in 5 is inserted into the subcutaneous tissue, leaving the membrane with interstitial fluid 7 is in contact. For this purpose penetrates a needle-shaped probe, including the membrane 4 , the optical body 2 and the detector 3 contains the skin 18 , The device according to the invention can remain in this position for several days and continuously the glucose concentration in the interstitial fluid 7 determine.

6 shows a schematic representation of an implanted device according to the invention.

The implanted device contains an inductively externally rechargeable power supply unit 19 , at least one light source 1 , a measuring branch 20 and a comparator branch 21 , a detector 3 and a signal transmission unit 22 , The measuring branch 20 includes an optical body 2 that by measurement matrix 6 and a membrane 4 is surrounded. That from the optical body 2 into the measurement matrix 6 broken light 9 and the glucose exchange 14 over the membrane 4 are indicated by arrows. The implantable device includes one outside the skin 18 arranged external unit 23 , which includes, for example, an electronic control system, a power supply, a receiver and a signal processing and which cooperates with the implanted under the skin components of the device according to the invention. The comparator branch 21 includes a second optical body 24 who was having a cladding 25 through which substantially no light from the second optical body is provided 24 is broken, since the known refractive index of the cladding 25 smaller than the refractive index of the optical body 24 is. With the help of the comparator branch 21 can eg changes the intensity of the light source 1 , Temperature changes and mechanical loads (eg bending of the optical body 2 . 24 ) and taken into account in determining the glucose concentration.

A calibration of the device according to the invention can be achieved by a short-term replacement of the measuring matrix 6 against a calibration fluid 26 take place with known glucose concentration. The calibration fluid 26 displaces it from the membrane 4 surrounded measuring matrix, which has a derivative 27 into a waste container (not shown) or tissue surrounding the implanted device. Out of the with the calibration liquid 26 measured transmission, a calibration factor can be calculated to take into account subsequently determined glucose concentrations.

1

light source

2

optical body

3

detector

4

membrane

5

be coupled light

6

measurement matrix

7

interstitial liquid

8th, 8th'

total reflected light

9 9 '

broken light

10

interface

11

emitted light

12

mirror

13

reflected light

14

glucose exchange

15

casing

16

wires

17

spacer

18

skin

19

Power supply unit

20

measuring branch

21

Komparatorzweig

22

Signal transmission unit

23

external unit

24

second optical body

25

cladding

26

calibration liquid

27

derivation

Claims (32)

Device for determining the concentration of interstitial fluid ( 7 ) dissolved glucose, characterized by An optical body ( 2 ), which at least partially with a measuring matrix ( 6 ), the measurement matrix ( 6 ) with the interstitial fluid ( 7 ), • a light source ( 1 ), which is arranged to transmit light into the optical body ( 2 ) and • a detector ( 3 ) arranged so as to be separated from the optical body ( 2 ) transmitted light and emitted in a certain direction, wherein the optical body ( 2 ) has a refractive index which is at a glucose concentration of the interstitial fluid ( 7 ) from 20 to 800 mg / dL is 0.175 to 0.00005 greater than the refractive index of the measuring matrix. Device according to claim 1, characterized by a glucose-permeable membrane ( 4 ) through which the measurement matrix ( 6 ) with the interstitial fluid ( 7 ) is in contact. Device according to a the claims 1 or 2, characterized in that the measuring matrix comprises a measuring liquid, a gel with glucose concentration dependent refractive index or a porous one Layer is. Device according to one of claims 1 to 3, characterized in that the optical body ( 2 ) contains at least one fluorine-containing or one fluorine-free polymer. Device according to claim 4, characterized in that the fluorine-containing polymer at least a polymer selected from the group polyhexafluoropropylene tetrafluoroethylene (FEP), polypentadecafluorooctyl acrylate, Polyvinyl nonadecafluorodecanoate, poly (tetrafluoro-3- (heptafluoropropoxy) propyl) acrylate, Polytetrafluoroethylene (PTFE), polyhexafluoropropylene tetrafluoroethylene vinyl fluoride (THV), Polyundecafluorohexyl acrylate, perfluoroalkoxy polymers (PFA), polyethylene tetrafluoroethylene (ETFE), polynonafluoropentyl acrylate, poly (tetrafluoro-3- (trifluoromethoxy) propyl) acrylate), Polypentafluorovinylpropionate, polyheptafluorobutylacrylate, polytrifluorovinylacetate, Polyoctafluoropentyl acrylate, polymethyl-3,3,3-trifluoropropylsiloxane, polypentafluoropropyl acrylate, Poly (2-heptafluorobutoxy) ethyl acrylate, polyfluorotrifluoroethylene (PCTFE), Poly-2,2,3,4,4-hexafluorobutyl acrylate, polytrifluoroethyl acrylate, poly2- (1,1,2,2-tetrafluoroethoxy) ethyl acrylate, Polytrifluoroisopropyl methacrylate, poly (2,2,2-trifluoro-1-methylethyl) methacrylate, Poly-2-trifluorethoxyethylacrylat, Polyvinylidene fluoride (PVDF), polyethylene chlorotrifluoroethylene (ECTFE), Polytrifluoroethyl methacrylate, poly-2-fluoroethyl methacrylate and poly-4-fluoro-2-trifluoromethylstyrene. Device according to claim 4, characterized in that the fluorine-free polymer at least a polymer selected from the group polymethylhydrosiloxane, polydimethylsiloxane, polyhexylmethylsiloxane, Polymethyloctylsiloxane, polyisobutylmethacrylate, polyisobutylvinylether, Polyhexadecylmethylsiloxane, polyethylvinylether, polymethyltetradecylsiloxane, Polyethylene glycol monomethyl ether, poly-n-butyl vinyl ether, poly-3-butoxypropylene glycol, Poly-n-pentyl vinyl ether, poly-n-hexyl vinyl ether, polyoctyl vinyl ether, Polyvinyl-n-octyl acrylate, poly-2-ethylhexyl vinyl ether, poly-n-decyl vinyl ether, Poly-2-methoxyethyl, Polyacryloxypropylmethylsiloxane, poly (4-methyl-1-pentene), poly-3-methoxypropylene glycol, Poly-t-butylmethacrylate, poly-n-dodecylvinylether, poly-3-ethoxypropylacrylate, Polyvinyl propionate, polyvinyl acetate, polymethyl vinyl ether, polyethyl acrylate, Polymethyl vinyl ether, poly-3-methoxypropyl acrylate, poly-1-octadecene, Poly-2-ethoxyethyl acrylate, polyisopropyl acrylate, poly-1-decene, polylauryl methacrylate, Poly-sec-butyl-viyl ether, poly-n-butyl-acrylate, polydodecyl-methacrylate, Polyethylene succinate, polytetradecyl methacrylate, cellulose acetate butyrate, Cellulose acetate, polyvinyl formate, polyethylene vinyl acetate, polyethyl octyl silane, Ethylcellulose, polymethylacrylate, polydicyanopropylsiloxane, polyoxymethylene, Poly-sec-butyl methacrylate, polydimethylsiloxane-alpha-methylstyrene, Poly-n-hexyl methacrylate, Poly-n-butylmethacrylate, polyethylenedimethacrylate, poly-2-ethoxyethylmethacrylate, Poly-n-propyl methacrylate, polyethylene maleate, polyethyl methacrylate, Polyvinyl butyral, poly (3,3,5-trimethylcyclohexyl) methacrylate, poly (2-methyl-2-nitropropyl) methacrylate, Polydimethylsiloxanediphenylsiloxane, poly-1,1-diethylpropylmethacrylate, Polytriethylcarbinylmethacrylate, polymethylmethacrylate, poly (2-decyl-1,4-butadiene), Polypropylene, polyvinyl butyral with 11% polyvinyl alcohol, polymercaptopropylmethylsiloxane, Polyethyl glycolate methacrylate, poly-3-methylcyclohexyl methacrylate, Polycyclohexyl-alpha-ethoxyacrylate, methylcellulose, poly-4-methylcyclohexylmethacrylate and polydecamethylene glycol dimethacrylate. Device according to one of claims 1 to 6, characterized in that the optical body ( 2 ) is a rod or a fiber in the form of a circular cylinder. Device according to one of claims 2 to 7, characterized in that between the membrane ( 4 ) and the optical body ( 2 ) a fluid line connected to a pump for conducting measurement matrix ( 6 ) from the membrane ( 4 ) to the optical body ( 2 ) is arranged. Device according to one of claims 2 to 7, characterized in that the membrane ( 4 ) the optical body ( 2 ) at least partially encloses. Device according to claim 9, characterized in that the membrane ( 4 ) the light source ( 1 ) at least partially encloses. Device according to one of claims 9 or 10, characterized in that the membrane ( 4 ) the detector ( 3 ) at least partially encloses. Device according to one of claims 9 to 11, characterized in that between the optical body ( 2 ) and the membrane ( 4 ) Spacers ( 17 ) are arranged. Device according to claim 12, characterized in that the spacers ( 17 ) a coating of the optical body ( 2 ) or wires of metal or plastic or plastic coated wires. Device according to one of claims 2 to 13, characterized in that the membrane ( 4 ) a coating for reducing the attachment of proteins to the membrane ( 4 ) having. Device according to one of claims 2 to 14, characterized in that the membrane ( 4 ) is a dialysis membrane. Device according to one of claims 1 to 15, characterized in that the from the at least one light source ( 1 ) emitted light is monochromatic or polychromatic and is in a wavelength range of 200 nm to 2500 nm. Device according to one of claims 1 to 16, characterized in that the at least one light source ( 1 ) and / or the detector ( 3 ) directly on the optical body ( 2 ) is attached. Device according to one of claims 1 to 17, characterized in that the optical body ( 2 ) is connected to at least one optical waveguide. Device according to one of claims 1 to 18, characterized in that the detector ( 3 ) is a photodiode or a photoresistor. Device according to one of claims 1 to 19, characterized in that the measuring matrix ( 6 ) is glucose-containing. Device according to one of claims 1 to 20, characterized by an arrangement of liquid lines and valves which are arranged so that the measuring matrix ( 6 ) against a calibration fluid ( 26 ) can be exchanged. Device according to one of claims 1 to 21, characterized by an interruption element for the temporary interruption of the contact between measuring matrix ( 6 ) and interstitial fluid ( 7 ). Device according to one of claims 1 to 22, characterized by an additional optical body ( 24 ), which at least partially with a calibration liquid ( 26 ) or by a cladding ( 25 ) is surrounded with a known refractive index. Device according to claim 23, characterized by a front of the light source ( 1 ) arranged beam splitter or at least one further light source for illuminating the additional optical body ( 24 ). Device according to one of claims 1 to 24, characterized by a hollow, needle-shaped, the membrane ( 4 for insertion into subcutaneous tissue containing the interstitial fluid ( 7 ) contains. Device according to one of claims 1 to 25, characterized in that the device comprises a fully implantable measuring system, the at least the measuring matrix ( 6 ) and the optical body ( 2 ) contains. Method for determining the concentration of glucose dissolved in interstitial fluid, comprising the following steps: (a) contacting a measuring matrix ( 6 ) with the interstitial fluid, (b) illuminating an optical body ( 2 ) with light through a light source ( 1 ), wherein the optical body ( 2 ) at least partially with the measuring matrix ( 6 ), and wherein the optical body ( 2 ) has a refractive index which is at a glucose concentration of the interstitial fluid ( 7 ) from 20 to 800 mg / dL is greater than the refractive index of the measuring matrix by 0.175 to 0.00005, (c) detecting in a certain direction the optical body ( 2 ) emitted light by means of a detector ( 3 and (d) determining the concentration of glucose based on the light detected in step (c). Method according to claim 27, characterized in that the detection in the reflection or Transmission mode performed becomes. Method according to one the claims 27 or 28, characterized in that the lighting is continuous or in pulses lasting from 1ps to 100s. Method according to one the claims 27 to 29, characterized in that in step (d) certain Glucose concentration to control the insulin delivery of an insulin pump is used. Method according to one of claims 27 to 30, characterized in that for calibration, the optical body ( 2 ) at least partially surrounding measuring matrix ( 6 ) in step (a) is replaced by a calibration solution of known composition. Method according to one the claims 27 to 31, characterized in that the steps (a) to (d) be performed with light of at least two different wavelengths.