WO2000022977A1

WO2000022977A1 - Minimally invasive sensor system

Info

Publication number: WO2000022977A1
Application number: PCT/DE1999/003126
Authority: WO
Inventors: Meinhard Knoll
Original assignee: Meinhard Knoll
Priority date: 1998-10-19
Filing date: 1999-09-28
Publication date: 2000-04-27
Also published as: CA2347378A1; JP2002527177A; DE19848112A1; EP1123040A1; DE19848112C2

Abstract

The invention relates to a minimally invasive sensor system for determining the concentration of substances in the human body. Sensor systems of this type are used in medical diagnosis, for example, for determining the concentration of glucose in blood or in the interstitial liquid, during the treatment of diabetics. The inventive minimally invasive sensor system is comprised of a hollow probe (3) which is provided for withdrawing a fluid from tissues and which is arranged on a support (2). A sensor (S) with a sensor element is also arranged on the support. The sensor (S) comprises a flow-through channel which is in spatial contact with the sensor element and which is directly connected to the interior of the hollow probe (3). The connection can also be provided with the aid of a hollow body connection (4). Micro-fluidic elements are used for the hollow probe (3), the hollow body connection (4) and for the sensor (S) so that the sensor (S) can carry out direct and continuous measurements of substance concentrations of liquids which are withdrawn from the tissue via the hollow probe (3).

Description

Minimally invasive sensor system

The invention relates to a minimally invasive sensor system for determining substance concentrations in the human body. Such sensor systems are used in medical diagnostics, for example for determining the concentration of glucose in the blood or in the interstitial fluid in the therapy of diabetics.

According to the prior art, for example in D. Moskone et al. "Ultrafiltrate Sampling Device for Continuous Monitoring", Medical and Biological Engineering and Computing, "1996, Volume 34, pages 290-294, sensor systems for measuring glucose in blood consist of an ultrafiltration probe which is connected to a thin and long tube

Storage of the tissue fluid obtained is connected. The stored in this storage hose is obtained at regular intervals Tissue fluid is transferred to a sensor that determines the glucose concentration in the tissue fluid. The interstitial tissue fluid is obtained from the subcutaneous tissue with the help of negative pressure through an ultrafiltration membrane in an ultrafiltration probe placed as a loop. The sample volumes are in the range of a few 100 nl / min. In order to further increase the volumes that can be fed to the sensor, after collecting and temporarily storing the tissue fluid obtained, it is additionally diluted by means of a dilution buffer. A disadvantage of such ultrafiltration processes is that such systems can only be used for batch-wise sample measurement, because the

The substance concentrations are measured with a time delay due to the temporary storage. A direct monitoring of substance concentration in humans is therefore not possible.

Another disadvantage of using ultrafiltration probes is that they consist of a hollow fiber membrane. These usually have to be supported by more stable materials in their inner lumen. such

Ultrafiltration probes are not only complex to manufacture, they also have a diameter that is significantly greater than the diameter of thin steel cannulas that are used, for example, in the insulin therapy of diabetics. The acceptance for the implantation of such thick ultrafiltration probes is understandably low in diabetics. The object of the present invention is therefore to provide a sensor system which allows the measurement of substance concentration in the blood or in tissue fluids of living beings directly, continuously and minimally invasively and which can be used simply and comfortably. Furthermore, it is an object of the present invention to provide uses of such minimally invasive sensor systems.

This object is achieved by the minimally invasive sensor system according to claim 1 and the use of such a minimally invasive sensor system according to claim 22.

The minimally invasive sensor system according to the invention has a carrier on which a probe for extracting fluid from tissues of living beings and a flow sensor are arranged. The flow sensor has a sensor element and a flow channel which is in spatial contact with the sensor element. The flow channel and the interior of the hollow probe are directly connected to one another. An advantage of the minimally invasive sensor system according to the invention is, in particular, its small design due to the compact arrangement of the probe and sensor element on / on a carrier, and the direct measurement of the small amount of tissue fluids obtained. This eliminates the need to temporarily store or dilute the tissue fluids obtained before measuring the substance concentrations in the sensor. Consequently, a direct, really continuous and minimally invasive determination of substance Concentrations in the blood or in the tissues of a living being, in particular a human possible. Furthermore, due to the small design and small dimensions of both the carrier, the flow sensor and, in particular, the hollow probe, the load on the patient is very low, so that the acceptance of the minimally invasive sensor system according to the invention is considerably higher among the patients than with the measurement methods according to the prior art Technology.

The sensor system according to the invention can be used to determine physical, chemical and / or biochemical properties, in particular substance concentrations in living beings, in particular in their tissues and body fluids, in vivo.

Advantageous developments of the minimally invasive sensor system according to the invention and its uses are given in the respective dependent claims.

The hollow probe has microscopic and / or macroscopic openings for taking up the tissue or body fluids. The hollow probe can be designed as a terminal hollow probe which is open at the end facing away from the flow sensor and / or perforated or porous on its outer surface. It is thereby achieved that the tissue fluid or body fluid enters the hollow probe through the openings and, for example, with a device for generating a vacuum, in particular a suction pump or a vacuum container, which is located on the side of the probe facing away from the hollow probe Flow channel of the flow sensor is arranged, is transported in the direction of the flow sensor. When using microfluidic elements for the hollow probe, the hollow body connection between the hollow probe and the flow sensor and for the

Flow sensors can measure particularly small amounts of tissue fluid.

To stabilize the hollow probe, this can be a reinforcement, for example a wire

Needle or a fiber bundle, for example a glass fiber bundle or a carbon fiber bundle. If this reinforcement carrier can be removed, it can be removed after placing the hollow probe into the subcutaneous tissue, so that the wearing comfort for the minimally invasive sensor system according to the invention is improved for a patient.

The flow of the interstitial fluid or the tissue fluid in the direction of the hollow probe and thus the amount of collected fluid to be measured can be improved in that at least one electrode which can be switched as a cathode is arranged on the carrier. A large-area anode can be used as the counter electrode. When a voltage is applied to the cathode, for example, the interstitial fluid is drawn in the direction of the cathode, ie in the direction of the carrier, and a flow is thereby generated in the direction of the hollow probe. As a further effect, the skin swells in the area of the cathode, so that a larger volume of interstitial fluid is present in the area of the hollow probe. Ideally, the hollow probe itself or the reinforcement beam, if it remains in the hollow probe, it is designed to be electrically conductive and switchable as a cathode. This results in an alignment of the above-described electrophoretic / electroosmotic flow of the interstitial fluid towards the hollow probe. In this case, the hollow probe can consist of electrically conductive material, for example stainless steel or a noble metal, or it can be electrically conductive, for example with a metal, vapor-deposited. A further amplification and alignment of the electrophoretic / electroosmotic flow of the interstitial fluid is effected if further electrodes which can be switched as cathode are arranged on the carrier.

The hollow probe of the minimally invasive sensor system according to the invention is not necessarily designed as an ultrafiltration probe. In this case it is favorable to arrange a fluid filter between the hollow probe and the flow sensor. Furthermore, it is advantageous to provide a gas bubble trap in this area in order to remove unwanted gas bubbles from the fluid flow within the hollow body connection or the flow sensor in order to avoid malfunctions in the measuring system.

Since the hollow probe collects interstitial fluid or body fluid that contains other constituents in addition to the substance to be measured, there can be a gap between the hollow probe and the flow sensor

Preoxidation reactor to remove these interfering substances. Flow sensors are suitable as flow sensors for the minimally invasive sensor system according to the invention, which comprise a base plate, a plate-shaped channel carrier arranged thereon with a channel-like recess and a plate-shaped sensor carrier in turn arranged thereon with a flat recess for receiving a sensor element or instead of the plate-shaped sensor carrier a flat sensor element . The base plate, the channel carrier and the sensor carrier or the sensor element are stacked to one another in a sealing manner so that the planar recess or the planar sensor element are located above the channel-like recess in the channel carrier. This creates a flow sensor with minimal

Dimensions that are suitable to measure the small amounts of liquid precisely and immediately continuously. The hollow probe itself can be arranged on the carrier so that one end breaks through the base plate and into the channel-like

Recess protrudes into the channel support.

Another advantageous flow sensor, which is suitable for measuring the small amounts of liquid collected, consists of a plate-shaped sensor carrier in which at least one tapering containment containing the sensor element is introduced, which extends between the two surfaces of the sensor carrier and at least one with the second surface of the sensor carrier connected plate contains. In the area of the interface between sensor carrier and plate, for example in the surface of the sensor carrier or in the surface of the plate or also partially in both, a channel-like depression is formed which is in contact with the smaller opening of the containment, which is located at the interface between the sensor carrier and the plate. This provides a flow sensor that enables optimal measurement of the liquids flowing through with minimal dimensions of the flow channel.

The carrier of the minimally invasive sensor system can also be designed as a base plate or as a plate-like channel carrier of the flow sensor with a channel-like recess. In this case, a particularly compact and simple construction of the minimally invasive sensor system according to the invention results.

Here, too, the sensor system can consist of a plate-shaped substrate into which a containment that tapers between the two surfaces is introduced, the containment containing the sensor element and having a smaller, tapered opening on the side facing the carrier or the channel .

In this arrangement too, the hollow probe can be arranged on the carrier in such a way that it breaks through the carrier designed as the base plate of the sensor element and projects into the channel. Carrier, hollow probe and sensor thus form an extremely compact unit with very short paths of the fluid obtained between the extraction point in the tissue and the sensor element. The minimally invasive sensor system according to the invention can be used in particular for determining the substance concentration in tissues or body fluids in vivo, in particular for determining the glucose concentration in the blood and / or the interstitial fluid of the subcutaneous tissue of humans. The area of application therefore relates in particular to medical, in particular human medical diagnostics and therapy, the use in diabetes therapy to control the blood sugar level and to determine the insulin doses to be used in the foreground. Some advantageous exemplary embodiments of the minimally invasive sensor system according to the invention are described below.

Show it:

FIG. 1 shows a minimally invasive sensor system according to the invention;

FIG. 2 shows another minimally invasive sensor system according to the invention;

3 shows two sensor elements for a minimally invasive sensor system according to the invention;

FIG. 4 shows a further minimally invasive sensor system according to the invention;

FIG. 5 shows a sensor for a minimally invasive sensor system according to the invention; FIG. 6 shows a further flow sensor for a minimally invasive sensor system according to the invention;

FIG. 7 shows a minimally invasive sensor system according to the invention;

FIG. 8 shows a minimally invasive sensor system according to the invention;

FIG. 9 shows a minimally invasive sensor system according to the invention;

FIG. 10 hollow probes for a minimally invasive sensor system according to the invention;

FIG. 11 shows a further minimally invasive sensor system according to the invention;

Figure 1 shows examples of the use of a minimally invasive sensor system according to the invention. In FIG. 1 a, the minimally invasive sensor system consists of a carrier 2 on which a flow sensor 5 with a flow channel 6 is arranged.

Furthermore, an extension of the flow channel 6 extends a hollow body connection to a hollow probe 3. The hollow probe 3 is arranged in the carrier 2 and projects beyond the carrier 2 on the side facing away from the flow sensor 5. Furthermore, the flow channel 6 is connected to a system module 8 on the side facing away from the hollow body connection 4 via a hollow body connection 7. The system Tempmodul 8 is further connected via two electrical leads 9, 10 to the sensor element of the flow sensor 5, via which the detected measurement signal is passed. The system module 8 contains electronics E, a battery B for supplying power to the electronics E, a suction pump P in order to apply a vacuum to the hollow body connection 7, the flow channel 6, the hollow body connection 4 and the hollow probe 3, and a collecting container C for the Hollow body connection 7 liquids entering the system module. The measured values determined with the aid of the sensor system and other system data can be shown on a display D in the system module 8.

As shown in FIG. 1 a, the carrier 2 lies on a skin surface 1 with the side on which the hollow probe 3 protrudes from the carrier 2. This means that the hollow probe penetrates the skin surface 1 and protrudes into the patient's subcutaneous tissue.

With the help of the negative pressure generated by the suction pump P in the hollow probe 3, the hollow body connections 4, 7 and the flow channel 6, interstitial subcutaneous tissue fluid is now sucked in through the hollow probe 3 and via the hollow body connection 4 to the flow channel 6 of the flow sensor 5 and further through the hollow body connection 7 to the pump P and then pumped into the collecting container C.

The volumes of the hollow body connections 4 and 7 and the flow channel 6 are very small. FIG. 1b shows a minimally invasive sensor system similar to that in FIG. The same elements are therefore also designated with the same reference symbols as in FIG. In addition to FIG. 1 a, however, there is an electrode on the hollow probe 3,

Cathode can be arranged. Furthermore, the carrier 2 contains a large-area anode on the side facing the skin surface. Cathode 11 and anode 12 are connected via electrical connections 13, 14 to the system module 8, via which a voltage can be applied to both. These voltages and currents are generated with the aid of the battery B and the electronics E in the system module 8. Due to the applied voltage, an electrophoretic / electroosmotic flow of the interstitial tissue fluid towards the cathode 11 results in the subcutaneous area. This leads to a significantly greater flow of the interstitial tissue fluid to the hollow probe 3 and into the hollow probe 3.

This effect can be further enhanced by, as shown in FIG. 1 c, a further additional cathode being arranged on the carrier 2 on the side facing the skin surface 1, which is also connected by the system module 8 via an electrical connection 16. This cathode 15 causes an additional electrophoretic / electroosmotic flow of the interstitial tissue fluid in the subcutaneous tissue. Since a divergence of the electrophoretic / electroosmotic flow occurs perpendicular to the skin surface 1, which is caused by the less permeable upper skin layers, it occurs under the uppermost skin layer to swell the skin in the immediate vicinity of the hollow probe 3. In this way, a larger volume of the interstitial tissue fluid can be conveyed through the hollow probe 3 to the flow sensor 5 with the aid of the pump P. The other reference numerals designate the same elements as in Figures la and lb.

FIG. 2 shows a further exemplary embodiment of a minimally invasive sensor system according to the invention. It has a carrier 2 and a channel carrier 17 with a channel 18 located therein and a channel cover 19 with an opening 20. The carrier 2, the channel carrier 17 and the channel cover 19 are arranged one above the other in a sealing manner.

Furthermore, FIG. 2a, which is an exploded view of the sensor system according to the invention from FIG. 2b, shows a sensor 5, the outer dimensions of which correspond to the dimensions of the opening 20 in the channel cover 19. The sensor 5 has 2 sensor contact surfaces 21, 22 for deriving the electrical measurement signals. On the side of the carrier facing away from the channel carrier, a hollow probe 3 is arranged, which extends through the carrier 2 into the channel 18 of the channel carrier 17.

Figure 2b shows this minimally invasive sensor system in the assembled state. The same elements are therefore provided with the same reference numerals. In addition to Figure la are the electrical measurement signal derivatives

9, 10, which are connected to the sensor contact surfaces 21, 22. As can be seen here, the sensor element 5 is arranged so that it is longitudinal of the channel 18 between the hollow probe and an outer channel opening 24. At the outer channel opening 24, a hollow body connection 7, for example a hose, is sealingly arranged by means of a seal 23. The interstitial liquid or blood taken up by the hollow probe 3 is now transported through the hollow probe 3 and the channel 18 past the sensor element 5 to the outer channel opening 24 and further through the hollow body connection 7.

The carrier 2, the channel carrier 17 and the channel cover 19 can be produced from polyester film using film technology. The different layers are connected by hot lamination or by gluing. The sensor element 5 is placed in the opening 20 in such a way that the underside of the sensor element forms a firm connection with the surface of the channel carrier 17 by gluing or pressing. The active sensor surface protrudes into the channel 18 on the underside of the sensor 5, which is not shown here. The seal 23 is made of a conventional sealing material such as e.g. Silicone.

FIG. 3 shows 2 sensor elements, such as can be used as sensor elements 5 in FIG. 2, for example.

The sensor element used in FIG. 3a is described, for example, in German patent application P 41 15 414, the disclosure of which is hereby incorporated into this application. The sensor element consists of a silicon carrier 25, which consists on its surface with a dielectric layer 26 of Si0 ₂ and / or Si ₃ N ₄ . Truncated pyramid-shaped openings are made in the silicon carrier by anisotropic etching. These so-called containments 35 are covered on their inner surface with an electrode layer 27, 27 ', 27'',27''', for example made of platinum or Ag / AgCl. A membrane material 28 made of PVA with the enzyme GOD is filled into the containments for a glucose sensor. The membrane 28, 28 'is exposed on the underside of the sensor element and forms the active membrane surface 29, 29'. This also forms the upper boundary of the channel 18 from FIG. 2. The electrode layers 27, 27 ', 27''and27''' can be tapped electrically by means of sensor contact surfaces, as are shown under reference numerals 21, 22 in FIG.

FIG. 3b shows a sensor element as is known from German Patent P 41 37 261.1-52, the disclosure of which is incorporated into this application here. A double matrix membrane 31 is firmly attached to a sensor element carrier 30 with an opening 36. This consists e.g. from a paper soaked in a gel containing the enzyme GOD (glucose oxidase). Two electrodes 33 and 34 are applied to the membrane material 31 by vapor deposition or screen printing. The electrode 33 is made of platinum and the electrode 34 is an Ag / AgCl

Electrode. An active free membrane surface 32 in the opening 36 here forms the upper end of the channel 18 from FIG. 2. The electrodes 33 and 34 correspond to the sensor contact areas 21, 22 from FIG. 2.

In Figure 4 is a minimally invasive sensor system similar to that shown in Figure 2, so that the same reference numerals again designate the same elements as in Figure 2. In contrast to FIG. 2, a further plate-like filter carrier 37 is now arranged between the carrier 2 and the channel carrier 17, which contains a recess with a filter membrane 38 arranged therein. The recess is arranged in the region of the channel 18 in the channel carrier 17 and itself forms part of the channel. The hollow probe 3 is arranged in such a way that it is connected to the cutout for the filter membrane 38 in the filter carrier 37 on its side assigned to the carrier 2. The carrier 2, the filter carrier 37, the channel carrier 17, the sensor carrier 19 and the sensor element 5 are sealingly connected to one another in the same way as in FIG. 2. In this example, the liquid that is collected by the hollow probe 3 is now passed through the filter membrane 38 is passed and only then enters the channel 18 in the channel carrier 17 and continues to be forwarded to the sensor element 5 to the outer opening 24 of the channel. Such a filter membrane can be used to filter out undesirable substances in the case where no ultrafiltration probe is used as a hollow probe.

Figures 5 and 6 show flow sensors corresponding to those in Figure 3a, but the flow channel is integrated into the sensors. Such sensors are known from German Patent P 44 08 352, the disclosure of which is hereby incorporated into the present application. The sensor consists of a silicon carrier 25 in which containments 35 are located. The containments 35 contain sensor membrane material 28 and electrodes 27, 27 ″ which protrude into the containment. The containments taper from one side of the silicon carrier 25 to the other side of the silicon carrier 25. On the side with the smaller opening of the containments, a channel 39 is introduced into the silicon carrier 25 by anisotropic etching, the smaller openings 29 forming the active membrane surfaces, 29 'of the containments is in spatial contact. This channel is closed with a glass cover 40 which is sealingly connected to the silicon carrier by anodic bonding. A channel 39 is thus formed in the silicon carrier 25, in which the liquid collected by the hollow probe is guided past the active membrane surfaces 29, 29 '.

The realizable diameter of the channel 39 is in the range of a few 10 to a few 100 μm, so that very small sample volumes can be measured. In the arrangement shown in FIG. 6, in addition to the sensor elements 28, 28 ', feed openings 41, 42 are made in the silicon carrier 25, which extend from one side of the silicon carrier to the other and are connected to the channel 39'. Through this feed / discharge opening 41 or 42, the measuring medium is channel 39 '(opening 41) or discharged from the channel 39 '(opening 42). In this case, therefore, the channel 39 'does not emerge from the end face of the silicon carrier 25', since it is limited in length.

FIG. 7 now shows the use of a sensor element according to FIG. 6 in a sensor system which corresponds to that of FIGS. 2 and 3. The same reference numerals therefore designate the same elements as in these figures. In contrast to FIG. 2, the channel carrier 17 'no longer has a single channel 18. Rather, the channel is divided into two sections 18 'and 18' 'separated by a web. The channel section 18 'extends between the opening of the sensor element

Hollow probe and the opening 20 in the sensor carrier. The second channel section 18 ″ extends laterally to the first channel section 18 ′ below the opening 20 of the sensor carrier 19 and the outer opening 24, the two channel sections 18 ′ and 18 ″ being in contact with one another only via the opening 20 of the sensor carrier 19. The sensor element 5 ″ with the sensor contact surfaces 21 ′ and 22 ″ is now a sensor element according to FIG. 6. The sensor element 5 ″ is arranged in the opening 20 such that the feed opening 41 from FIG. 6 with the channel section 18 ′. and the discharge opening 42 from FIG. 6 is connected to the channel section 18 ″. The liquid to be measured is thus guided past the sensor elements 28, 28 'from the hollow probe via the channel section 18' and the supply opening 41 through the channel 39 'and then via the discharge opening 42 and the channel section 18 '' removed from the sensor system according to the invention. The channel 39 'can be designed as a capillary throttle for controlling the liquid flow via the flow resistance of the channel 39'. This technique is known from German Patent P 44 10 224, the disclosure of which is hereby incorporated into the present application.

In order to transport the liquid to be measured from the hollow probe past the sensor element 5 ″, a negative pressure is generated in the cavities of the sensor system according to the invention that communicate with one another. For this purpose, a very simple container or a vacuum container (Vakutainer) can be attached to the opening 24 of the channel section 18 ″. Because of the high flow resistance of the channel 39 'with a small channel cross section, the liquid which enters the channel 39' via the hollow probe 3 is then conveyed at an almost constant flow rate. The flow resistance can also be increased by extending the channel 39 'on the chip itself.

The sensor system shown in FIG. 7 can be further developed as shown in FIG. In addition to the arrangement as shown in FIG. 7 and therefore also designated by the corresponding reference numerals, there is another channel 43 in the channel cover 19 'as a vacuum channel. This channel 43 runs around the opening 20 and is separated from it by a web. Furthermore, the channel opening 18 'in the channel carrier 17' is slightly extended laterally, so that it also the vacuum channel 43 covered. The vacuum channel 43 consequently connects the channel openings 18 ′ and 18 ″ in addition to the opening 20. A gas-permeable membrane is now located between the channel support 17 'and the channel cover 19' in the area in which the channel opening 18 'and the vacuum channel 43 communicate. This means that the vacuum applied to the opening 24 by the pump P or the Vakutainer is applied to the side of the gas-permeable membrane facing the vacuum channel 43. If gas bubbles are contained in the measuring medium, which passes through the hollow probe 3 into the channel section 18 ', the gas is discharged into the vacuum channel 43 via the gas-permeable membrane 44 by means of the negative pressure applied to the gas-permeable membrane on the vacuum channel side. Therefore, the measuring medium, which cannot flow through the gas-permeable membrane but instead enters the integrated flow channel 39 'from FIG. 6 of the sensor element 5'', is degassed. It is also possible to lay a separate vacuum line, for example a hose, between the vacuum channel 43 and the system module 8 (see FIG. 1).

FIG. 9 shows an exemplary embodiment corresponding to that shown in FIG. 2, but in which electrodes 2 'are integrated in the carrier 2' and are used for the electrophoretic / electroosmotic transport of the measuring medium in the subcutaneous tissue. Corresponding elements are, however, designated by corresponding reference symbols as in FIG. 2.

An electrically conductive hollow probe 3 'made of stainless steel is arranged obliquely on a carrier 2' extends from the underside of the carrier 2 ′ into the channel 18 in the channel carrier 17 and the interior thereof communicates with the channel 18. Electrical conductors 48, 49 and 50 which are electrically insulated from one another and which are provided with connecting contacts 51, 52 and 53 for applying voltages are also arranged in the carrier 2 '. The conductor track 49 is electrically connected to the hollow probe. Furthermore, there are two electrodes 12 'and 15' on the surface of the carrier 2 'facing the skin surface, which electrodes are electrically conductively connected to the conductor tracks 50 and 48 via plated-through holes of the carrier 2'. The electrode 12 'is a large-area anode, which is arranged approximately centrally on the underside of the carrier 2'. The electrode 15 'is arranged on the side of the point of penetration of the hollow probe 3' through the carrier 2 'above the free end of the obliquely arranged hollow probe 3' on the underside of the carrier 2 'and serves as a cathode. This cathode 15 'is a platinum cathode or an Ag / AgCl cathode. The outer end of the hollow probe 3 'is pointed, as is customary in the case of cannulas in medical technology, and is open at the front. However, an embodiment is not shown in which the hollow probe is perforated on its outer peripheral surface, so that in this case an even larger sample volume can be removed from the subcutaneous tissue. Are now via the contacts 51 and 52 to the cathode 15 'or the hollow probe 3' a negative voltage and to the anode 12 'via the

Terminal contact 53 applies a positive voltage, so there is an electrophoretic / electroosmotic transport of the interstitial fluid in Direction of the hollow probe 3 '. Furthermore, the tissue swells beneath the cathode 15 ', so that an increased volume of interstitial fluid is available for taking the sample. Because the cathode 15 'is arranged directly above the free end of the hollow probe 3', the flow of the interstitial fluid is directed towards the open end of the hollow probe 3 'and this results in an even further improved sampling.

If the hollow probe 3 'itself is not electrically conductive, the electrical contact to the liquid column in the hollow probe 3' is made via the contact 11 '(FIG. 9a).

FIG. 9b shows the sensor system described in FIG. 9a in the assembled state.

FIG. 10 shows various embodiments of a hollow probe 3 'for a minimally invasive sensor system according to the invention. The hollow probe 3 'consists of a cylindrical body made of stainless steel. It is electrically conductive and can serve simultaneously as a hollow probe and as a cathode, for example in the embodiment of a sensor system according to FIG. 9. The outer end of these hollow probes can, as is the case with cannulas in medical technology, be pointed and open at the front. It can also be perforated on its circumferential surface or provided with pores.

FIG. 10b shows a hollow probe 3 ″, which is made of Teflon, polyimide or another plastic is and thus has hose-like properties. The Teflon membrane can be perforated on its outer surface and thus be permeable to the interstitial fluid. Such perforation in Teflon or other membrane materials can be produced with lasers. With appropriate perforation, the hollow probe 3 ″ can also be used as an ultrafiltration hollow fiber.

The tube-like consistency of the hollow probe 3 ″ shown in FIG. 10b means that the negative pressure in the hollow probe lumen may produce a hollow probe collapse during the measurement. The hollow probe is therefore provided with a reinforcement carrier 54, for example a wire, which at the same time acts as

Hollow probe cathode can be used. Two or more wires can also be twisted to form a reinforcing bar.

A further reinforced hollow probe 3 '' 'is shown in FIG. 10c, wherein the reinforcement carrier 55 consists of a fiber bundle. Carbon fiber or glass fiber bundles are particularly suitable for this. If carbon fiber bundles are used as reinforcement beams, they can also serve as cathodes due to their electrical conductivity.

The hollow probes described here typically have outer diameters between 0.1 and 2 mm, but preferably 0.4 to 0.5 mm.

10 can also be produced from such otherwise known materials, used for hollow dialysis and ultrafiltration fibers.

It is also possible to design the armoring carrier 54 shown in FIG. 10b as a gas bubble trap.

For this, the reinforcement beam is e.g. from a Teflon tube, the wall of which is gas permeable. The inner lumen of the Teflon tube is connected to a vacuum. This takes place in a manner similar to that in the exemplary embodiment according to FIG. 8 via a channel 43.

A further exemplary embodiment for a sensor system according to the invention is shown in FIG. 11 based on FIG. 2. Corresponding elements are designated with corresponding reference symbols as in FIG. 2. In contrast to FIG. 2, however, the hollow probe 3 is replaced by a flexible hollow probe 3 ^IV made of a perforated Teflon catheter. However, this flexible hollow probe cannot be easily inserted into the subcutaneous tissue. A stabilizing needle 57 is therefore located in the hollow probe 3 ^IV as a reinforcement carrier. This needle is through a silicone septum 56 on the channel cover 19 through the channel 18 in the

Channel carrier 17 inserted into the hollow probe 3 ^IV . The septum 56 must be sufficiently dense to maintain the negative pressure generated in the channel 18. It is advantageous in this embodiment that the stabilizing needle 57 is pulled out of the

Hollow probe 3 ^IV can be removed as soon as the hollow probe 3 ^IV is inserted into the subcutaneous tissue. This creates a burden on the wearer of this minimally invasive sensor system according to the invention is greatly reduced during wearing time and the acceptance of such a sensor system is increased for the patients.

Figure 11b shows this sensor system in the assembled state.

The sensor systems according to the invention can advantageously be equipped with flow controls in order to indicate an interruption of the flow. A particularly simple embodiment of this flow control arises from the fact that two glucose sensors are arranged one behind the other in a flow channel 6 of the sensor 5 (see FIG. 1). Since the conventional glucose sensors which are generally known in the prior art convert the analyte enzymatically, the second sensor has a lower glucose concentration than the first sensor. If the signal of the second sensor now follows the signal of the first sensor with a lower absolute signal, it can be assumed that the flow of the interstitial tissue fluid is not interrupted.

Furthermore, it is advantageous to arrange a pre-oxidation reactor in front of the glucose sensor between the hollow probe and the sensor element. With its help, interfering substances can be kept away from the sensor by pre-oxidation. Since a current also flows through the preoxidation reactor, the ratio of the currents between the preoxidation reactor and the downstream glucose sensor can be as Control parameters for the flow of the interstitial tissue fluid in the channel 6 of the sensor 5 (FIG. 1) are used. Such an upstream pre-oxidation reactor can be produced using the same technology as the sensors described here, for example according to FIGS. 5 and 6.

In the case of the minimally invasive sensor systems presented in FIGS. 2, 4, 7 to 9, there are the supports 2, channel supports 17, the channel cover 19 and the

Filter carrier 37 or the corresponding elements made of plastics such as polyvinyl chloride (PVC), polyethylene (PE), polyoxymethylene (POM), polycarbonate (PC), ethylene / propylene-COP. (EPDM), polyvinylidene chloride (PVDC), polychlorotrifluoroethylene (PCTFE), polyvinyl butyral (PVB), cellulose acetate (CA), polypropylene (PP), polymethyl methacrylate (PMMA), polyamide (PA), tetrafluoroethylene / hexafluoropropylene-COP. (FEP), polytetrafluoroethylene (PTFE), phenol formaldehyde (PF), epoxy (EP), polyurethane (PUR), polyester (UP), silicone, melamine formaldehyde (MF), urea formaldehyde (UF), aniline formaldehyde , Capton or the like.

The connection between the carriers 2, channel carrier 17, channel cover 19 and filter carrier 37 can be made by gluing, welding or laminating. Special laminating foils are available especially for lamination, which can be hot laminated (e.g. CODOR foil made of polyethylene and

Polyester from TEAM CODOR, Mari, Germany). The thickness of the individual foils for the carrier 2, channel carrier 17, channel cover 19 or filter carrier 37 can be between 10 and a few 1000 μm, preferably a few 100 μm. The areal expansions of the carrier 2 and the other carriers and covers are in the range of a few cm, for example for the carrier 2 from FIG. 2 at 2 × 3 cm. The underside of the carrier 2 is in turn advantageously provided in whole or in part with an adhesive layer made of skin-compatible adhesive materials, which ensures reliable adhesion to the skin surface.

The anode 12, cathodes 11 and 15 'as well as the conductor track 48, 49, 50 in the corresponding drawings and also the connection contacts 51, 52 and 53 can be produced by screen printing or thin-film processes. The materials used for this can be screen printing pastes based on precious metals and metals. The layers produced using the thin-film process can consist of precious metals such as platinum, gold, silver or chloride-coated silver layers (Ag / AgCl). The thickness of these layers for the anodes, cathodes and conductor tracks and connection contacts can be between a few 100 nm to a few μm.

Claims

claims

1. Minimally invasive sensor system with at least one probe for removing a fluid

Tissues and at least one sensor element, characterized in that a hollow probe, a sensor with a sensor element and a flow channel in spatial contact are arranged on a support and the interior of the hollow probe is connected directly to the flow channel of the sensor, possibly via a hollow body connection is.

2. Sensor system according to claim 1, characterized in that the hollow probe has microscopic and / or macroscopic openings.

3. Sensor system according to at least one of the preceding claims, characterized in that the hollow probe is a terminal hollow probe.

4. Sensor system according to at least one of the preceding claims, characterized in that the hollow probe is open at its end facing away from the sensor and / or is perforated or porous on its outer surface.

5. Sensor system according to at least one of the preceding claims, characterized in that the flow channel of the sensor on the side facing away from the probe with a device for detecting Generation of a vacuum, in particular a suction pump or a vacuum container, is connected.

6. Sensor system according to at least one of the preceding claims, characterized in that the hollow probe, the hollow body connection, the flow channel and / or the sensor are microfluidic elements.

7. Sensor system according to at least one of the preceding claims, characterized in that a reinforcing support, for example a wire, a needle or a fiber bundle, for example a glass fiber bundle or carbon fiber bundle, is arranged in the hollow probe.

8. Sensor system according to the preceding claim, characterized in that the reinforcement carrier is removable.

Sensor system according to at least one of the preceding claims, characterized in that at least one electrode which can be switched as a cathode is arranged on the carrier.

10. Sensor system according to at least one of the preceding claims, characterized in that the hollow probe and / or the reinforcement carrier are electrically conductive and switchable as a cathode.

11. Sensor system according to the preceding claim, characterized in that the hollow probe and / or the reinforcement carrier consists of an electrically conductive material or is coated in an electrically conductive manner.

12. Sensor system according to at least one of claims 7 to 11, characterized in that the hollow probe and / or the reinforcement carrier consists of plastic, stainless steel or a noble metal and / or is vapor-coated with a metal.

13. Sensor system according to at least one of the preceding claims, characterized in that a further electrode which can be switched as a cathode is arranged on the carrier.

14. Sensor system according to at least one of the preceding claims, characterized in that a large-area, switchable as anode electrode is arranged on the carrier.

15. Sensor system according to at least one of the preceding claims, characterized in that a fluid filter is arranged between the hollow probe and the sensor.

16. Sensor system according to at least one of the preceding claims, characterized in that a gas bubble trap is arranged between the hollow probe and the sensor.

17. Sensor system according to at least one of the preceding claims, characterized in that a pre-oxidation reactor is arranged between the hollow probe and the sensor.

18. Sensor system according to at least one of the preceding claims, characterized in that the sensor has a base plate, a plate-shaped channel carrier with a channel-like recess and a plate-shaped sensor carrier with a flat recess for receiving the sensor element and / or a flat sensor element, the Base plate, the channel carrier and the sensor carrier and / or the sensor element are stacked on top of one another in such a way that the flat recess and / or the flat sensor element is located above the channel-like recess.

19. Sensor system according to the preceding claim, characterized in that the hollow probe

Base plate is arranged so that one end protrudes into the channel-like recess.

20. Sensor system according to at least one of claims 1 to 17, characterized in that the sensor consists of a plate-shaped substrate in which at least one from the front surface of the substrate to the second surface tapered containment is introduced, the containment containing the sensor element a larger opening on the front surface and on the second surface has a smaller opening and with at least one plate connected to the second surface and at least one channel-shaped contact with the smaller opening of the containment than

Measuring chamber serving cavity, which is formed in the substrate or in the plate or in both.

21. Sensor system according to at least one of claims 18 to 20, characterized in that the carrier of the sensor system is designed as a plate-shaped substrate or as a plate-shaped channel carrier.

22. Sensor system according to at least one of the preceding claims, characterized in that the flow channel is in spatial contact with at least two sensor elements arranged one behind the other in the flow direction of the flow channel.

23. Sensor system according to at least one of the preceding claims, characterized in that the carrier and optionally the base plate, the channel carrier, the sensor carrier, the filter carrier, the plate-shaped substrate and / or the plate connected to the second surface of the substrate made of plastics such as polyvinyl chloride ( PVC), polyethylene (PE),

Polyoxymethylene (POM), polycarbonate (PC), ethylene / propylene COP. (EPDM), polyvinylidene chloride (PVDC), polychlorotrifluoroethylene (PCTFE), polyvinyl butyral (PVB), cellulose acetate (CA), polypropylene (PP), polymethyl methacrylate (PMMA), polyamide (PA), tetrafluoroethylene / hexafluoropropylene-COP. (FEP), polytetrafluoroethylene (PTFE), phenol-formaldehyde (PF), epoxy (EP), polyurethane (PUR), polyester (UP), silicone, melamine-formaldehyde (MF), urea-formaldehyde (UF), aniline-formaldehyde , Capton or the like.

24. Sensor system according to claim 23, characterized in that the carrier and optionally the base plate, the channel carrier, the sensor carrier, the filter carrier, the plate-shaped substrate and / or with the second surface of the

Substrate-connected plate made of plastics have a thickness of 10 microns to a few 1000 microns, advantageously around 100 microns.

25. Sensor system according to claim 23, characterized in that the carrier and the sensor, optionally the base plate, the channel carrier, the sensor carrier, the filter carrier, the plate-shaped substrate and / or the plate connected to the second surface of the substrate by gluing, Welding and / or laminating are connected.

26. Use of a minimally invasive sensor system according to at least one of the preceding

Claims for the determination of physical, chemical and / or biochemical properties in living beings.

27. Use according to the preceding claim for determining substance concentrations in tissues and body fluids in vivo.

28. Use according to one of the two preceding claims for determining the glucose concentration in blood and / or interstitial fluid in humans.

29. Use according to at least one of claims 26 to 28 in medical, in particular human medical diagnostics and therapeutics.

30. Use according to the preceding claim in diabetes therapy.