CA2347378A1 - Minimally invasive sensor system - Google Patents
Minimally invasive sensor system Download PDFInfo
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- CA2347378A1 CA2347378A1 CA002347378A CA2347378A CA2347378A1 CA 2347378 A1 CA2347378 A1 CA 2347378A1 CA 002347378 A CA002347378 A CA 002347378A CA 2347378 A CA2347378 A CA 2347378A CA 2347378 A1 CA2347378 A1 CA 2347378A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
- A61B10/02—Instruments for taking cell samples or for biopsy
- A61B10/0233—Pointed or sharp biopsy instruments
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14507—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
- A61B5/1451—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid
- A61B5/14514—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid using means for aiding extraction of interstitial fluid, e.g. microneedles or suction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase
- A61B5/14865—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
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- Animal Behavior & Ethology (AREA)
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- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
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- Optics & Photonics (AREA)
- Biophysics (AREA)
- Emergency Medicine (AREA)
- Measurement Of The Respiration, Hearing Ability, Form, And Blood Characteristics Of Living Organisms (AREA)
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 invasion relates to a minimally invasive sensor system for determining substance concentrations in the human body. Sensor systems of this type are used in medical diagnostics, for example to determine the concentration of glucose in the blood or in the in-terstitial fluid in the treatment of diabetics.
According to prior art, which is given for example in D. Moskone et al. "Ultrafiltrate Sampling Device for Continuous Monitoring," Medical and Biological Engi-neering and Computing, 1996, volume 34, pages 290 to 294, sensor systems for measuring glucose in the blood consist of an ultrafiltration probe which is connected to a thin and long hose f:or storing the tissue fluid obtained. At regular time intervals, the tissue fluid obtained and stored in this storage hose is transferred to a sensor which determines the concentration of glucose to be found in the tissue fluid. The interstitial tissue fluid is here ob-tained from the subcutaneous tissue with the aid of negative pressure through an ultrafiltration membrane in an ultrafiltration probe laid subcutaneously as a loop. The sample volumes are in the region of sev-eral 100 nl/min. In order to increase further the volumes which can be supplied to the sensor, after collection and interim storage of the tissue fluid obtained, the latter is in addition diluted by means of a dilution buffer. What is disadvantageous about ultrafiltration methods of this type is that such systems can only be used for sample measurement in batches, since the measurement of the substance con-centrations takes place at a considerable time lag as a result of the .interim storage. Direct monitoring of substance concentration on the human being is thus not possible.
A further disadvantage in the use of ultrafiltration probes consists in the fact that they consist of a hollow-fibre membrane. These probes must generally be supported by more stable materials in their inner lumen. Ultrafiltration probes of this kind are not only expensive to manufacture but they also have a diameter which is significantly greater than the di-ameter of thin steel cannulae which are used for ex-ample in insulin therapy for diabetics. Understanda-bly, therefore, the willingness of a diabetic to ac-cept implantation of thick ultrafiltration probes of this type is low.
The object of the present invention, therefore, is to make available a sensor system which permits the measurement of substance concentration in the blood or in tissue fluids of living creatures directly, continuously and in a minimally invasive manner and can be applied simply and pleasantly. Furthermore it is the object of the present invention to make avail-able uses of such minimally invasive sensor systems.
This object is accomplished by the minimally invasive sensor system according to claim 1 and the use of a minimally invasive sensor system of this type accord-ing to claim 22.
The minimally invasive sensor system according to the invention has a support to which a probe for sampling fluid from the tissues of living creatures and a flow sensor are disposed. The flow sensor has a sensor element and a flow channel which is in spatial con-tact with the sensor element. The flow channel and the cavity of the hollow probe are directly connected to one another. What is advantageous about the mini-mally invasive sensor system according to the inven-tion is in particular its small design as a result of the compact arrangement of probe and sensor element on/at a support and the direct measurement of the small amounts of tissue fluids obtained. In this way interim storage or dilution of the tissue fluids ob-tained, before measuring the substance concentrations in the sensor, become superfluous. Consequently di-rect, really continuous and minima:Lly invasive deter-mination of substance concentrations in the blood or in the tissues o.f a living creature, especially a hu-man being is possible. Furthermore, through the small design and small dimensions both of the sup-port, of the flow sensor and also in particular of the hollow probe, the stress to the patient is only very low, such that acceptance of the minimally inva-sive sensor system according to the invention is con-siderably higher with patients than is the case with measurement methods according to prior art.
The sensor system according to the invention can be used to determine physical, chemical and/or biochemi-cal properties, especially substance concentrations in the living creature, especially in its 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.
To receive the tissue or body fluids, the hollow probe has microscopic and/or macroscopic apertures.
The hollow probe can here be configured as a terminal hollow probe which is open at the end remote from the flow sensor and/or is perforated or porous on its surface area. What is thereby accomplished is that the tissue fluid or the body fluid enters the hollow probe via the apertures and is transported in the di-rection of the flow sensor for example by means of a device for creating a vacuum, especially a suction pump or a vacuum container which is arranged on the side of the flow channel of the flow sensor remote from the hollow probe. When microfluidic elements are used for the hollow probe, for the hollow connec-tor between the hollow probe and the flow sensor and for the flow sensor, particularly small amounts of tissue fluid can be measured.
In order to stabilise the hollow probe, said probe can contain a reinforcement support, for example a wire, a needle or a fibre bundle, for example a glass-fibre bundle or a carbon-fibre bundle. If this reinforcement support is removable, it can be removed after the hollow probe has been placed in the subcu-taneous tissue, such that the minimally invasive sen-sor system according to the invention is more com-fortable for the patient to bear.
The flow of the interstitial fluid or the tissue 5 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 connected as the cathode is disposed on the support.
A large-area anode can be used as the counter-electrode. When voltage is applied to the cathode, for example the interstitial fluid is drawn in the direction of the cathode, i.e. in 'the direction of the support and thus a flow is created towards the hollow probe. As a further effect, the skin in the region of the cathode swells, such that a greater volume of interstitial fluid is present in the region of the hollow probe. Ideally the hollow probe itself or the reinforcement support, insofar as it remains in the hollow probe, is designed to be electrically conductive and able to be connected as the cathode.
This produces an alignment of the above-described electrophoretic/a_lectroosmotic flow of the intersti-tial fluid towards the hollow probe. The hollow pro-be can in this case consist of electrically conducti-ve material, for example stainless steel or a noble metal, or have an electrically conductive coating vapour-deposited onto it, for example a metal.
Further strengthening and alignment of the electro-phoretic/electroosmotic flow of the interstitial fluid is effected if additional electrodes which can be connected as the cathode are disposed on the sup-port.
The hollow probe of the minimally invasive sensor sy-stem according to the invention is not necessarily configured as an ultrafiltration probe. In this case it is advisable to arrange a fluid filter between the hollow probe and the flow sensor. Furthermore it is advantageous to provide a gas-bubb:Le trap in this re-gion in order to remove undesired gas bubbles from the fluid flow inside the hollow connector or the flow sensor, in order to avoid interruptions to the measuring system.
Since the hollow probe collects interstitial fluid or body fluid, which besides the substance to be measu-red contains additional constituents, a pre-oxidisation reactor can be arranged between the hol-low probe and the flow sensor to remove these distur-bing substances.
As flow sensors for the minimally invasive sensor sy-stem according to the invention are suitable flow sensors which comprise a base plate, a plate-like channel support disposed thereon with a channel-like recess and a plate-like sensor support disposed in turn thereupon, with a planar recess for incorpora-ting a sensor element, or which have a planar sensor element instead of the plate-like sensor support.
The base plate, the channel support and the sensor support or the sensor element are ;stacked on top of one another forming a seal with one another, in such a way that the p:Lanar recess or the planar sensor element is located above the channel-like recess in the channel support. This produces a flow sensor with minimal dimensions which is suitable for conti-nuously measuring the small amounts of fluid precise-ly and directly. The hollow probe itself can here be so disposed on the support that its one end breaks through the base plate and protrudes into the chan-nel-like recess in the channel support.
According to prior art, which is given for example in D. Moskone et al. "Ultrafiltrate Sampling Device for Continuous Monitoring," Medical and Biological Engi-neering and Computing, 1996, volume 34, pages 290 to 294, sensor systems for measuring glucose in the blood consist of an ultrafiltration probe which is connected to a thin and long hose f:or storing the tissue fluid obtained. At regular time intervals, the tissue fluid obtained and stored in this storage hose is transferred to a sensor which determines the concentration of glucose to be found in the tissue fluid. The interstitial tissue fluid is here ob-tained from the subcutaneous tissue with the aid of negative pressure through an ultrafiltration membrane in an ultrafiltration probe laid subcutaneously as a loop. The sample volumes are in the region of sev-eral 100 nl/min. In order to increase further the volumes which can be supplied to the sensor, after collection and interim storage of the tissue fluid obtained, the latter is in addition diluted by means of a dilution buffer. What is disadvantageous about ultrafiltration methods of this type is that such systems can only be used for sample measurement in batches, since the measurement of the substance con-centrations takes place at a considerable time lag as a result of the .interim storage. Direct monitoring of substance concentration on the human being is thus not possible.
A further disadvantage in the use of ultrafiltration probes consists in the fact that they consist of a hollow-fibre membrane. These probes must generally be supported by more stable materials in their inner lumen. Ultrafiltration probes of this kind are not only expensive to manufacture but they also have a diameter which is significantly greater than the di-ameter of thin steel cannulae which are used for ex-ample in insulin therapy for diabetics. Understanda-bly, therefore, the willingness of a diabetic to ac-cept implantation of thick ultrafiltration probes of this type is low.
The object of the present invention, therefore, is to make available a sensor system which permits the measurement of substance concentration in the blood or in tissue fluids of living creatures directly, continuously and in a minimally invasive manner and can be applied simply and pleasantly. Furthermore it is the object of the present invention to make avail-able uses of such minimally invasive sensor systems.
This object is accomplished by the minimally invasive sensor system according to claim 1 and the use of a minimally invasive sensor system of this type accord-ing to claim 22.
The minimally invasive sensor system according to the invention has a support to which a probe for sampling fluid from the tissues of living creatures and a flow sensor are disposed. The flow sensor has a sensor element and a flow channel which is in spatial con-tact with the sensor element. The flow channel and the cavity of the hollow probe are directly connected to one another. What is advantageous about the mini-mally invasive sensor system according to the inven-tion is in particular its small design as a result of the compact arrangement of probe and sensor element on/at a support and the direct measurement of the small amounts of tissue fluids obtained. In this way interim storage or dilution of the tissue fluids ob-tained, before measuring the substance concentrations in the sensor, become superfluous. Consequently di-rect, really continuous and minima:Lly invasive deter-mination of substance concentrations in the blood or in the tissues o.f a living creature, especially a hu-man being is possible. Furthermore, through the small design and small dimensions both of the sup-port, of the flow sensor and also in particular of the hollow probe, the stress to the patient is only very low, such that acceptance of the minimally inva-sive sensor system according to the invention is con-siderably higher with patients than is the case with measurement methods according to prior art.
The sensor system according to the invention can be used to determine physical, chemical and/or biochemi-cal properties, especially substance concentrations in the living creature, especially in its 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.
To receive the tissue or body fluids, the hollow probe has microscopic and/or macroscopic apertures.
The hollow probe can here be configured as a terminal hollow probe which is open at the end remote from the flow sensor and/or is perforated or porous on its surface area. What is thereby accomplished is that the tissue fluid or the body fluid enters the hollow probe via the apertures and is transported in the di-rection of the flow sensor for example by means of a device for creating a vacuum, especially a suction pump or a vacuum container which is arranged on the side of the flow channel of the flow sensor remote from the hollow probe. When microfluidic elements are used for the hollow probe, for the hollow connec-tor between the hollow probe and the flow sensor and for the flow sensor, particularly small amounts of tissue fluid can be measured.
In order to stabilise the hollow probe, said probe can contain a reinforcement support, for example a wire, a needle or a fibre bundle, for example a glass-fibre bundle or a carbon-fibre bundle. If this reinforcement support is removable, it can be removed after the hollow probe has been placed in the subcu-taneous tissue, such that the minimally invasive sen-sor system according to the invention is more com-fortable for the patient to bear.
The flow of the interstitial fluid or the tissue 5 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 connected as the cathode is disposed on the support.
A large-area anode can be used as the counter-electrode. When voltage is applied to the cathode, for example the interstitial fluid is drawn in the direction of the cathode, i.e. in 'the direction of the support and thus a flow is created towards the hollow probe. As a further effect, the skin in the region of the cathode swells, such that a greater volume of interstitial fluid is present in the region of the hollow probe. Ideally the hollow probe itself or the reinforcement support, insofar as it remains in the hollow probe, is designed to be electrically conductive and able to be connected as the cathode.
This produces an alignment of the above-described electrophoretic/a_lectroosmotic flow of the intersti-tial fluid towards the hollow probe. The hollow pro-be can in this case consist of electrically conducti-ve material, for example stainless steel or a noble metal, or have an electrically conductive coating vapour-deposited onto it, for example a metal.
Further strengthening and alignment of the electro-phoretic/electroosmotic flow of the interstitial fluid is effected if additional electrodes which can be connected as the cathode are disposed on the sup-port.
The hollow probe of the minimally invasive sensor sy-stem according to the invention is not necessarily configured as an ultrafiltration probe. In this case it is advisable to arrange a fluid filter between the hollow probe and the flow sensor. Furthermore it is advantageous to provide a gas-bubb:Le trap in this re-gion in order to remove undesired gas bubbles from the fluid flow inside the hollow connector or the flow sensor, in order to avoid interruptions to the measuring system.
Since the hollow probe collects interstitial fluid or body fluid, which besides the substance to be measu-red contains additional constituents, a pre-oxidisation reactor can be arranged between the hol-low probe and the flow sensor to remove these distur-bing substances.
As flow sensors for the minimally invasive sensor sy-stem according to the invention are suitable flow sensors which comprise a base plate, a plate-like channel support disposed thereon with a channel-like recess and a plate-like sensor support disposed in turn thereupon, with a planar recess for incorpora-ting a sensor element, or which have a planar sensor element instead of the plate-like sensor support.
The base plate, the channel support and the sensor support or the sensor element are ;stacked on top of one another forming a seal with one another, in such a way that the p:Lanar recess or the planar sensor element is located above the channel-like recess in the channel support. This produces a flow sensor with minimal dimensions which is suitable for conti-nuously measuring the small amounts of fluid precise-ly and directly. The hollow probe itself can here be so disposed on the support that its one end breaks through the base plate and protrudes into the chan-nel-like recess in the channel support.
A further advantageous flow sensor which is suitable for measuring the small amounts of fluid collected comprises a plate-like sensor support in which at least one tapering containment containing the sensor element is introduced which extends between the two surfaces of the sensor support and contains at least one plate connected to the second surface of the sen-sor support. In the region of the boundary surface between the sensor support and the plate, for example in the surface of the sensor support or in the sur-face of the plate or also respectively partially in both of them, a ~~hannel-like depression is formed which is in contact with the smaller aperture of the containment, which aperture is located on the bounda-ry surface between sensor support and plate. Thus a flow sensor is given which, with minimal dimensions of the flow channel, provides an optimal measurement of the fluids flowing through.
The support for the minimally invasive sensor system can be designed simultaneously as the base plate or as the plate-like channel support of the flow sensor with a channel-like recess. In this case a particu-larly compact and simple design of the minimally in-vasive sensor system according to the invention is produced.
Here, too, the sensor system can comprise a substrate configured plate-like and into which a containment tapering between the two surfaces is introduced, the containment containing the sensor element and having on the side facing the support or the side facing the channel a tapered smaller aperture.
In this arrangement too, the hollow probe can be so disposed on the support that it breaks through the support configured as the base plate of the sensor element and protrudes into the channel. Support, hollow probe and sensor thus form an extremely com-pact unit with very short paths of the obtained fluid S between the removal point in the tissue and the sen-sor element.
The minimally invasive sensor system according to the invention can be used in particular to determine ana-lyte concentrations in tissues or body fluids in vi-vo, in particular to determine the glucose concentra-tion in the blood and/or the interstitial fluid of the subcutaneous tissue of a human being. The field of application therefore relates in particular to me-dical, in particular human medical diagnostics and therapeutics, use in diabetes therapy for controlling the blood sugar level and determining the doses of insulin to be used being to the fore. Some advanta-geous embodiments of the minimally invasive sensor system according to the invention are described be-low.
The figures show:
Fig. 1 a minimally invasive sensor system accor-ding to the invention;
Fig. 2 a further minimally invasive sensor system according to the invention;
Fig. 3 two sensor elements for a minimally invasi-ve sensor system according to the inventi-on;
Fig. 4 a further minimally invasive sensor system according to the invention;
The support for the minimally invasive sensor system can be designed simultaneously as the base plate or as the plate-like channel support of the flow sensor with a channel-like recess. In this case a particu-larly compact and simple design of the minimally in-vasive sensor system according to the invention is produced.
Here, too, the sensor system can comprise a substrate configured plate-like and into which a containment tapering between the two surfaces is introduced, the containment containing the sensor element and having on the side facing the support or the side facing the channel a tapered smaller aperture.
In this arrangement too, the hollow probe can be so disposed on the support that it breaks through the support configured as the base plate of the sensor element and protrudes into the channel. Support, hollow probe and sensor thus form an extremely com-pact unit with very short paths of the obtained fluid S between the removal point in the tissue and the sen-sor element.
The minimally invasive sensor system according to the invention can be used in particular to determine ana-lyte concentrations in tissues or body fluids in vi-vo, in particular to determine the glucose concentra-tion in the blood and/or the interstitial fluid of the subcutaneous tissue of a human being. The field of application therefore relates in particular to me-dical, in particular human medical diagnostics and therapeutics, use in diabetes therapy for controlling the blood sugar level and determining the doses of insulin to be used being to the fore. Some advanta-geous embodiments of the minimally invasive sensor system according to the invention are described be-low.
The figures show:
Fig. 1 a minimally invasive sensor system accor-ding to the invention;
Fig. 2 a further minimally invasive sensor system according to the invention;
Fig. 3 two sensor elements for a minimally invasi-ve sensor system according to the inventi-on;
Fig. 4 a further minimally invasive sensor system according to the invention;
Fig. 5 a sensor for a minimally invasive sensor system according to the invention;
Fig. 6 a further flow sensor for a minimally inva-sive sensor system according to the inven-tion;
Fig. 7 a minimally invasive sensor system accor-ding to the invention;
Fig. 8 a minimally invasive sensor system accor-ding to the invention;
Fig. 9 a minimally invasive sen;>or system accor ding to the invention;
Fig. 10 hollow probes for a minimally invasive sen-sor system according to i=he invention;
Fig. 11 a further minimally invasive sensor system accord_Lng to the invention.
Fig. 1 shows examples of the use of a minimally inva-sine sensor system according to thE~ invention. The minimally invasive sensor system in Fig. 1a comprises a support 2, on which a flow sensor 5 with a flow channel 6 is arranged.
Furthermore, in extension of the f:Low channel 6, a hollow connector extends to a hollow probe 3. The hollow probe 3 is disposed in the support 2 and prot-rudes beyond the support 2 on the side remote from the flow sensor 5. Furthermore, the flow channel 6 is connected on t=he side remote from the hollow con-nector 4 via a hollow connector 7 to a system module 8. The system module 8 is furthermore connected via .....~.,~,,~...~..~..~... _ _ _m_,~,"~,.",~.,.~..~,~.,..~.m,.,..... ......~._ ., ...._w_ ~....__ two electrical supply lines 9, 10 to the sensor ele-ment of the flow sensor 5, via which the measurement signal detected is led. The system module 8 contains electronics E, a battery B for supplying power to the 5 electronics E, a suction pump P, in order to apply negative pressure to the hollow connector 7, the flow channel 6, the hollow connector 4 <~nd the hollow pro-be 3, and a collecting vessel C for the fluids ente-ring the system module via the hol:Low connector 7.
Fig. 6 a further flow sensor for a minimally inva-sive sensor system according to the inven-tion;
Fig. 7 a minimally invasive sensor system accor-ding to the invention;
Fig. 8 a minimally invasive sensor system accor-ding to the invention;
Fig. 9 a minimally invasive sen;>or system accor ding to the invention;
Fig. 10 hollow probes for a minimally invasive sen-sor system according to i=he invention;
Fig. 11 a further minimally invasive sensor system accord_Lng to the invention.
Fig. 1 shows examples of the use of a minimally inva-sine sensor system according to thE~ invention. The minimally invasive sensor system in Fig. 1a comprises a support 2, on which a flow sensor 5 with a flow channel 6 is arranged.
Furthermore, in extension of the f:Low channel 6, a hollow connector extends to a hollow probe 3. The hollow probe 3 is disposed in the support 2 and prot-rudes beyond the support 2 on the side remote from the flow sensor 5. Furthermore, the flow channel 6 is connected on t=he side remote from the hollow con-nector 4 via a hollow connector 7 to a system module 8. The system module 8 is furthermore connected via .....~.,~,,~...~..~..~... _ _ _m_,~,"~,.",~.,.~..~,~.,..~.m,.,..... ......~._ ., ...._w_ ~....__ two electrical supply lines 9, 10 to the sensor ele-ment of the flow sensor 5, via which the measurement signal detected is led. The system module 8 contains electronics E, a battery B for supplying power to the 5 electronics E, a suction pump P, in order to apply negative pressure to the hollow connector 7, the flow channel 6, the hollow connector 4 <~nd the hollow pro-be 3, and a collecting vessel C for the fluids ente-ring the system module via the hol:Low connector 7.
10 The measurement values obtained with the aid of the sensor system and other system dat<~ can be displayed in the system module 8 via a display D.
As shown in Fig. la, the support 2 lies on a skin surface 1 with the side on which the hollow probe 3 protrudes from the support 2. This means that the hollow probe penetrates the skin surface 1 and re-aches the subcutaneous tissue of the patient.
With the aid of the vacuum created by the suction pump B in the ho:Llow probe 3, the hollow connectors 4, 7 and the flow channel 6, interstitial subcutane-ous tissue fluid is sucked up through the hollow pro-be 3 and pumped via the hollow connector 4 to the flow channel 6 of the flow sensor .5 and on through the hollow connector 7 to pump P and then into the collecting vesse:L C. The volumes of the hollow con-nectors 4 and 7 and of the flow channel 6 are very small.
Fig. lb shows a minimally invasive sensor system ba-sically similar to that of Fig. 1a. Therefore the same elements are also designated with the same refe-rence numerals as in Fig. la. In ;addition to Fig.
1a, here however an electrode which can be connected as the cathode i5 disposed on the hollow probe 3.
As shown in Fig. la, the support 2 lies on a skin surface 1 with the side on which the hollow probe 3 protrudes from the support 2. This means that the hollow probe penetrates the skin surface 1 and re-aches the subcutaneous tissue of the patient.
With the aid of the vacuum created by the suction pump B in the ho:Llow probe 3, the hollow connectors 4, 7 and the flow channel 6, interstitial subcutane-ous tissue fluid is sucked up through the hollow pro-be 3 and pumped via the hollow connector 4 to the flow channel 6 of the flow sensor .5 and on through the hollow connector 7 to pump P and then into the collecting vesse:L C. The volumes of the hollow con-nectors 4 and 7 and of the flow channel 6 are very small.
Fig. lb shows a minimally invasive sensor system ba-sically similar to that of Fig. 1a. Therefore the same elements are also designated with the same refe-rence numerals as in Fig. la. In ;addition to Fig.
1a, here however an electrode which can be connected as the cathode i5 disposed on the hollow probe 3.
Furthermore on the side facing the skin surface, the support 2 contains a large-area anode. Cathode 11 and anode 12 are connected to the system module 8 via electrical connections 13, 14, via which module vol-tage can be applied to both. These voltages and cur-rents are genera=ed with the aid o:f the battery B and the electronics E in the system module 8. As a re-sult of the voltage applied, in the subcutaneous re-gion an electrophoretic/electroosmotic flow of the interstitial body fluid towards tha_ cathode 11 is produced. This ~~an lead to a considerably greater flow of the interstitial tissue fluid to the hollow probe 3 and into the hollow probe 3.
This effect can be further strengthened by, as shown in Fig. 1c, a further additional cathode being arran-ged on the support 2 on the side facing the skin sur-face 1, which cathode is also wired from the system module 8 via an electrical connection 16. This ca-thode 15 causes in the subcutaneous tissue an addi-tional electrophoretic/electroosmotic flow of the in-terstitial tissue fluid. Since a divergence of the electrophoretic/electroosmotic flow occurs per-pendicular to the skin surface l, which can be caused by the less permeable upper layers of the skin, under the uppermost layer of skin there is swelling of the skin in the immediate vicinity of the hollow probe 3.
Thus in this manner, a greater volume of the inter-stitial tissue fluid can be conveyed through the hol-low probe 3 with the aid of the pump P to the flow sensor 5. The additional reference numerals designa-te the same elements as those in Figs. la and 1b.
Fig. 2 shows a further embodiment of a minimally in-vasive sensor system according to the invention. It has a support 2 and a channel support 17 with a chan-nel 18 located therein and a channel cover 19 with an aperture 20. The support 2, the channel support 17 and the channel cover 19 are disposed the one above the other forming a seal with one another. Further-more in Fig. 2a, which is an exploded view of the sensor system according to the invention from Fig.
2b, is shown a sensor 5, the external dimensions of which correspond to the dimensions of aperture 20 in the channel cover 19. The sensor 5 has two sensor contact surfaces 21, 22 to derive the electrical mea-surement signals. On the side of t:he support remote from the channel support is disposed a hollow probe 3 which extends through support 2 into the channel 18 of the channel support 17.
Fig. 2b shows this minimally invasive sensor system in assembled state. The same elements are therefore provided with the same reference numerals. In addi-tion to Fig. la, the electrical measurement signal leads 9, 10 are drawn in, which are connected to the sensor contact surfaces 21, 22. As can be recognised here, the sensor element 5 is so disposed that it is located along the channel 18 between the hollow probe and an external channel aperture 24. At the external channel aperture 24 is disposed a hollow connector 7, for example a ho~~e, forming a seal by means of a seal 23. The interstitial fluid or blood received by the hollow probe 3 is now transported through the hollow probe 3 and channel 18 past the sensor element 5 to the external channel aperture 24 and on through the hollow connector 7.
The support 2, the channel support 17 and the channel cover 19 can be manufactured from polyester film by means of film technology. The different layers are connected by means of hot laminating or by gluing.
This effect can be further strengthened by, as shown in Fig. 1c, a further additional cathode being arran-ged on the support 2 on the side facing the skin sur-face 1, which cathode is also wired from the system module 8 via an electrical connection 16. This ca-thode 15 causes in the subcutaneous tissue an addi-tional electrophoretic/electroosmotic flow of the in-terstitial tissue fluid. Since a divergence of the electrophoretic/electroosmotic flow occurs per-pendicular to the skin surface l, which can be caused by the less permeable upper layers of the skin, under the uppermost layer of skin there is swelling of the skin in the immediate vicinity of the hollow probe 3.
Thus in this manner, a greater volume of the inter-stitial tissue fluid can be conveyed through the hol-low probe 3 with the aid of the pump P to the flow sensor 5. The additional reference numerals designa-te the same elements as those in Figs. la and 1b.
Fig. 2 shows a further embodiment of a minimally in-vasive sensor system according to the invention. It has a support 2 and a channel support 17 with a chan-nel 18 located therein and a channel cover 19 with an aperture 20. The support 2, the channel support 17 and the channel cover 19 are disposed the one above the other forming a seal with one another. Further-more in Fig. 2a, which is an exploded view of the sensor system according to the invention from Fig.
2b, is shown a sensor 5, the external dimensions of which correspond to the dimensions of aperture 20 in the channel cover 19. The sensor 5 has two sensor contact surfaces 21, 22 to derive the electrical mea-surement signals. On the side of t:he support remote from the channel support is disposed a hollow probe 3 which extends through support 2 into the channel 18 of the channel support 17.
Fig. 2b shows this minimally invasive sensor system in assembled state. The same elements are therefore provided with the same reference numerals. In addi-tion to Fig. la, the electrical measurement signal leads 9, 10 are drawn in, which are connected to the sensor contact surfaces 21, 22. As can be recognised here, the sensor element 5 is so disposed that it is located along the channel 18 between the hollow probe and an external channel aperture 24. At the external channel aperture 24 is disposed a hollow connector 7, for example a ho~~e, forming a seal by means of a seal 23. The interstitial fluid or blood received by the hollow probe 3 is now transported through the hollow probe 3 and channel 18 past the sensor element 5 to the external channel aperture 24 and on through the hollow connector 7.
The support 2, the channel support 17 and the channel cover 19 can be manufactured from polyester film by means of film technology. The different layers are connected by means of hot laminating or by gluing.
Placing the sensor element 5 in aperture 20 is effec-ted in such a way that the lower side of the sensor element is securely connected to the surface of the channel support 1.7 by gluing or contact pressure.
Here the active =sensor surface protrudes on the un-derside, not shown, of the sensor 5 into the channel 18. The seal 23 consists of a conventional sealing material such as e.g. silicone.
Fig. 3 shows two sensor elements such as can be used for example as sensor elements 5 iTl Fig. 2.
The sensor element used in Fig. 3a is described for example in the German patent application P 41 15 414, the disclosure ow which is hereby :incorporated in this application. The sensor elemc=_nt comprises a si-licon substrate 25 which consists at its surface of a dielectric layer 26 formed from SiO~ and/or Si3N4.
Apertures in the shape of a truncated pyramid are in-troduced into the silicon substrate by anisotropic etching. These so-called containments 35 are covered at their inner surface with an electrode layer 27, 27', 27" , 27" ', formed for example from platinum or Ag/AgCl. The containments are filled with a membrane material 28 formed from PVA with the enzyme GOD for a glucose sensor. On the underside of the sensor ele-ment the membrane 28, 28' is exposed and forms the active membrane 29, 29'. This forms simultaneously the upper limitation of the channel 18 of Fig. 2.
The electrode layers 27, 27', 27" and 27" ' can be electrically tapped by means of sensor contact surfa-ces, as are represented by reference numerals 21, 22 in Fig. 2.
Fig. 3b shows a sensor element such as is known from German patent P 41 37 261.1-52, the disclosure of which is hereby incorporated in this application. A
. double matrix membrane 31 is securely attached to a sensor element support 30 with an opening 36. This membrane consists for example of a paper which is sa-y turated with a gel which contains the enzyme GOD
(glucose oxidasej. To the membrane material 31 are attached two electrodes 33 and 34 by vapour depositi-on or screen printing. Electrode 33 consists of pla-tinum and electrode 34 is an Ag/AgCl electrode. An active free membrane surface 32 in opening 36 here forms the upper germination of channel 18 of Fig. 2.
Electrodes 33 and 34 correspond to the sensor contact surfaces 21, 22 of Fig. 2.
In Fig. 4 is a minimally invasive sensor system simi-lar to the one shown in Fig. 2, such that the same reference numerals again designate the same elements as in Fig. 2. Unlike Fig. 2, a further plate-like filter support 3'7 is now disposed between the support 2 and the channel support 17, the filter carrier con-taming a recess with a filter membrane 38 disposed therein. The recess is here disposed in the region of channel 18 in channel support 17 and itself forms a part of the channel. The hollow probe 3 is so ar-ranged that it is connected to the recess for the filter membrane 38 in the filter support 37 on the side of the recess associated with support 2. Sup-port 2, filter support 37, channel support 17, sensor support 19 and sensor element 5 are connected to one another to form a seal in the same manner as in Fig.
2. In this example, the fluid which is collected by the hollow probe 3 is now led through the filter mem-brane 38 and only then enters channel 18 in channel support 17 and is conveyed further on sensor element 5 to the external aperture 24 of the channel. Unde-sired substances can be filtered out by a filter mem-brane of this sort in the case where no ultrafiltra-tion probe is used as the hollow probe.
Figs. 5 and 6 show flow sensors corresponding to tho-se in Fig. 3a, the flow channel being however inte-5 grated into the sensors.
Sensors of this type are known from the German patent P 44 08 352, the disclosure of which is hereby incor-porated in the present application. The sensor con-sists of a silicon substrate 25 in which containments 10 35 are located. The containments 35 contain sensor membrane materia:L 28 and electrodes 27, 27" , which protrude into the containment. The containments ta-per from one side of the silicon substrate 25 to the other side of the silicon substrate 25. On the side 15 of the containments with the smaller aperture, a channel 39 is introduced into the silicon substrate by anisotropic etching, which substrate is in spa-tial contact witx~ the active smaller apertures 29, 29', forming membrane surfaces, of the containments.
20 This channel is closed with a glass cover 90, which is connected in a sealed manner to the silicon sub-strate by anodic bonding. Thus there is formed in the silicon substrate 25 a channel 39 in which the fluid collected by the hollow probe is led past the 25 active membrane surfaces 29, 29'.
The achievable diameters of the channel 39 lie in the region between several 10 to several 100 Vim, such that very small sample volumes can be measured. In the arrangement shown in Fig. b, in addition to the sensor elements 28, 28', feed apertures 41, 42 are introduced into the silicon substrate 25, and extend from one side of the silicon substrate to the other and are connected to the channel 39'. Through this feed/drainage aperture 41 or 92, the measurement me-dium is led towards channel 39 (aperture 41) or away from channel 39 (aperture 42). In this case therefo-re the channel 39' does not emerge on the end face of the silicon substrate 25' since it is limited in length.
Fig. 7 shows now the use of a sensor element accor-ding to Fig. 6 in a sensor system which corresponds to that of Figs. 2 and 3. The same reference nume-rats therefore designate the same elements as in the-se figures. In contrast to Fig. 2, the channel sup-port 17' no longer has a single channel 18. Rather the channel is divided into two portions 18' and 18"
separated from one another by a web. Channel portion 18' extends between the hollow probe aperture on the sensor element side and aperture 20 in the sensor support. The second channel portion 18" extends si-deways to the first channel portion 18' below apertu-re 20 of the sensor support 19 and the external aper-ture 24, the two channel portions 18 and 18" merely being in contact with one another 'via aperture 20 of the sensor support 19. Sensor element 5" with the sensor contact surfaces 21' and 22" is now a sensor element as per Fig. 6. Here the sensor element 5"
is so disposed in aperture 20 that the feed aperture 41 from Fig. 6 is in communication with channel por-tion 18' and the discharge aperture 42 of Fig. 6 with channel portion 18" . Thus the fluid to be measured is led from the Follow probe via channel portion 18' and feed aperture 41 through channel 39' past sensor elements 28, 28' and then via the discharge aperture 42 and channel portion 18" out of the sensor system according to the invention. Channel 39' can be con-figured as a capillary throttle to control the fluid flow via the flow resistance of 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 convey the fluid to be measured from the hollow probe past. the sensor element 5" , in the in-ter communicating cavities of the sensor system ac-cording to the invention a vacuum is produced. For this purpose a very simple container or a vacuum con-tainer (vacutainer) can be attached to aperture 24 of channel portion 18" . As a result of the high flow resistance of channel 39' with a law channel cross-section, the fluid which enters channel 39' via the hollow probe 3 is then conveyed at practically a con-stant flow rate. The flow resistance can also be in-creased by channel 39' being itself lengthened on the chip.
The sensor system shown in Fig. 7 c:an be further de-veloped as shown in Fig. 8. In addition to the ar-rangement, as Shawn in Fig. 7 and therefore also de-signated with the respective corresponding reference numerals, a further channel 43 is located in the channel cover 19' as the vacuum channel. This chan-nel 43 runs around aperture 20 and is separated from the latter by a web. Furthermore c:hannel aperture 18' in channel support 17' is slightly extended at the side so that it also covers the vacuum channel 43. The vacuum channel 43 consequently connects, in addition to aperture 20, channel apertures 18' and 18" . Between channel support 17' and channel cover 19' there is now situated a gas-permeable membrane in the region in which channel aperture 18' and vacuum channel 43 communicate. This means that at the sides of the gas-permeable membrane facing the vacuum chan-nel 43, the vacuum applied by the pump P or the vacutainer to aperture 24 is present. If gas bubbles are contained in the measurement medium which reaches the channel portion 18' through the hollow probe 3, the gas is led away with the aid of the vacuum pre-y sent on the vacuum channel side of the gas-permeable membrane, via the gas-permeable membrane 44 into the vacuum channel 43. Therefore the measurement medium, which cannot flow through the gas-:permeable membrane but enters the integrated flow channel 39' of Fig. 6 of the sensor element 5" , is degasified. It is also possible to lay a separate vacuum line, e.g. a hose between vacuum channel 43 and system module 8 (see Fig. 1) .
Fig. 9 shows an embodiment according to that shown in Fig. 2, in which however there are integrated in the support 2' electrodes which serve the electrophore-tic/electroosmotic transport of the measurement medi-um in the subcutaneous tissue. Corresponding ele-ments are however designated with corresponding refe-rence numerals to those in Fig. 2.
On a support 2' is disposed at an angle an electri-cally conductive hollow probe 3' formed from stain-less steel, which extends from the underside of sup-port 2' into the channel 18 in the channel support 17 and the cavity of which communicates with channel 18.
In support 2' are disposed furthermore electrical track conductors 48, 49 and 50, electrically insula-ted from one another and which are provided with con-nection contacts 51, 52 or 53 for .applying voltages.
Track conductor 49 is here electrically connected to the hollow probe. Furthermore on the surface of sup-port 2' facing the skin surface a:re located two electrodes 12' and 15' which are connected in an electrically conductive manner to 'the track conduc-tors 50 or 48 via feedthroughs of support 2'. Elec-trode 12' is here a large-area anode which is dispo-sed roughly centrally on the underside of support 2'.
Electrode 15' is disposed to the side of the point at which the hollow probe 3' breaks through support 2' above the free end of the obliquely disposed hollow probe 3' on the underside of support 2' and serves as the cathode. This cathode 15' is a platinum cathode or an Ag/AgCl cathode. The outer end of the hollow probe 3' has a pointed tip and is open at the front as is usual for cannulae in medical technology. Not represented, however, is an embodiment in which the hollow probe is perforated on its outer peripheral surface so that in this case an even greater sample volume can be removed from the subcutaneous tissue.
If now via conta~~ts 51 and 52 a negative voltage is applied to the cathode 15' or the :hollow probe 3' and a positive voltage is applied to t:he anode 12' via the connection c~~ntact 53, an electrophore-tic/electroosmotic transport of the interstitial fluid is produced in the direction of the hollow pro-be 3'. Furthermore the tissue below the cathode 15' swells, such that an increased volume of interstitial fluid is available to be taken as a sample. Since the cathode 15' is disposed directly above the free end of the hollow probe 3', the flow of the intersti-tial fluid is directed towards the open end of the hollow probe 3', and this results in further improved sampling.
If the hollow probe 3' is itself not electrically conductive, the electrical contact to the column of fluid in the hol:Low probe 3' is provided via contact 11' (Fig. 9a).
Fig. 9b shows the sensor system described in Fig. 9a in assembled state.
Fig. 10 shows various embodiments of a hollow probe 3' for a minima lly invasive sensor system according to the invention. The hollow probe 3' comprises a 5 cylindrical body formed from stainless steel. It is electrically conductive and can simultaneously act as the hollow probe and as the cathode, for example in the embodiment o:f a sensor system according to Fig.
9. The outer end of these hollow probes can have a 10 pointed tip and be open at the front as is usual for cannulae in medical technology. It can also be per-forated on its peripheral surface or be provided with pores.
Fig. lOb shows a hollow probe 3" which is produced 15 from Teflon, polyamide or some othc=_r plastics materi-al and thus has hose-like properties. The Teflon membrane can here be perforated on its surface area and thus be permeable for the interstitial fluid.
Perforation of this type in Teflon or other membrane 20 materials can be produced by means of lasers. With corresponding perforation, the hollow probe 3" can also be used as an ultrafiltration hollow fibre.
The hose-like consistency of the hollow probe 3" re-presented in Fig. lOb means that the vacuum in the hollow probe lumen possibly produces a collapse of the hollow probe during measurement.. Therefore the hollow probe is provided with a reinforcement support 54, for example a wire which can simultaneously serve as the hollow probe cathode. Two or more wires can also be twisted to form a reinforcement support.
In Fig. lOc is shown a further reinforced hollow pro-be 3" ', the reinforcement support 55 comprising a fibre bundle. Carbon-fibre bundles or glass-fibre bundles are particularly suitable for this purpose.
If carbon-fibre bundles are used as reinforcement supports, they can simultaneously nerve as cathodes as a result of their electrical conductivity.
The hollow probes described here typically have out-side diameters of between 0.1 and 2 mm, preferably however, between 0.4 and 0.5 mm.
The hollow probes according to Fig. 10 can also be produced from such otherwise ~>nown materials as are used for dialysi~~ and ultrafiltrati.on hollow fibres.
It is also possible to configure the reinforcement support 54 as a gas-bubble trap. To this end, the reinforcement support consists e.g. of a Teflon hose, the wall of whicr: is gas-permeable. The inner lumen of the Teflon hose is connected to vacuum. This hap-pens in a similar manner to that in the embodiment according to Fig. 8 via a channel 43.
A further embodiment of a sensor system according to the invention is represented in Fig. 11 in conjunc-tion with Fig. 2. Corresponding elements are desi-gnated by corresponding reference numerals to those in Fig. 2. In contrast to Fig. 2, however, hollow probe 3 is here replaced by a flexible hollow probe 3I" formed from a perforated Teflon catheter. This flexible hollow probe cannot, however, be easily inserted into the subcutaneous tissue. In hollow probe 3I~ there is therefore a stabilisation needle 57 as a reinforcement support. This needle is intro-duced through a silicone septum 56 on the channel co-ver 19 through channel 18 in the channel support 17 into the hollow probe 3I~. The septum 56 must here be sufficiently impermeable to maintain the vacuum created in channel 18. What is advantageous about this embodiment is that the stabilisation needle 57 can be removed by pulling it out of the hollow probe 3I" as soon as the hollow probe 3I" is inserted into the subcutaneous tissue. By this :means the stress on the support for the minimally invasive sensor system during the bearing time is greatly reduced and pati-ents' acceptance of a sensor system of this type is increased.
Fig. llb shows this sensor system in assembled state.
Advantageously, the sensor systems according to the invention can be equipped with flow controls in order to indicate an interruption of the flow. A particu-larly simple embodiment of these flow controls arises from two glucose sensors being disposed the one be-hind the other in a flow channel 6 of the sensor 5 (see Fig. 1). Since the conventional glucose sen-sors, generally known in prior art, convert the ana-lyte by means of enzymes, a smaller glucose concen-tration is produced at the second sensor in compari-son with the first sensor. If the signal of the se-cond sensor now follows the signal of the first sen-sor in time with a smaller absolute signal, it can be assumed that the flow of the interstitial tissue fluid is not interrupted.
_.~..~..w......,~"~,.~,....~.~,_~..~.....,..,.~....~"..~,.,~."...~...~..M
._... .
Here the active =sensor surface protrudes on the un-derside, not shown, of the sensor 5 into the channel 18. The seal 23 consists of a conventional sealing material such as e.g. silicone.
Fig. 3 shows two sensor elements such as can be used for example as sensor elements 5 iTl Fig. 2.
The sensor element used in Fig. 3a is described for example in the German patent application P 41 15 414, the disclosure ow which is hereby :incorporated in this application. The sensor elemc=_nt comprises a si-licon substrate 25 which consists at its surface of a dielectric layer 26 formed from SiO~ and/or Si3N4.
Apertures in the shape of a truncated pyramid are in-troduced into the silicon substrate by anisotropic etching. These so-called containments 35 are covered at their inner surface with an electrode layer 27, 27', 27" , 27" ', formed for example from platinum or Ag/AgCl. The containments are filled with a membrane material 28 formed from PVA with the enzyme GOD for a glucose sensor. On the underside of the sensor ele-ment the membrane 28, 28' is exposed and forms the active membrane 29, 29'. This forms simultaneously the upper limitation of the channel 18 of Fig. 2.
The electrode layers 27, 27', 27" and 27" ' can be electrically tapped by means of sensor contact surfa-ces, as are represented by reference numerals 21, 22 in Fig. 2.
Fig. 3b shows a sensor element such as is known from German patent P 41 37 261.1-52, the disclosure of which is hereby incorporated in this application. A
. double matrix membrane 31 is securely attached to a sensor element support 30 with an opening 36. This membrane consists for example of a paper which is sa-y turated with a gel which contains the enzyme GOD
(glucose oxidasej. To the membrane material 31 are attached two electrodes 33 and 34 by vapour depositi-on or screen printing. Electrode 33 consists of pla-tinum and electrode 34 is an Ag/AgCl electrode. An active free membrane surface 32 in opening 36 here forms the upper germination of channel 18 of Fig. 2.
Electrodes 33 and 34 correspond to the sensor contact surfaces 21, 22 of Fig. 2.
In Fig. 4 is a minimally invasive sensor system simi-lar to the one shown in Fig. 2, such that the same reference numerals again designate the same elements as in Fig. 2. Unlike Fig. 2, a further plate-like filter support 3'7 is now disposed between the support 2 and the channel support 17, the filter carrier con-taming a recess with a filter membrane 38 disposed therein. The recess is here disposed in the region of channel 18 in channel support 17 and itself forms a part of the channel. The hollow probe 3 is so ar-ranged that it is connected to the recess for the filter membrane 38 in the filter support 37 on the side of the recess associated with support 2. Sup-port 2, filter support 37, channel support 17, sensor support 19 and sensor element 5 are connected to one another to form a seal in the same manner as in Fig.
2. In this example, the fluid which is collected by the hollow probe 3 is now led through the filter mem-brane 38 and only then enters channel 18 in channel support 17 and is conveyed further on sensor element 5 to the external aperture 24 of the channel. Unde-sired substances can be filtered out by a filter mem-brane of this sort in the case where no ultrafiltra-tion probe is used as the hollow probe.
Figs. 5 and 6 show flow sensors corresponding to tho-se in Fig. 3a, the flow channel being however inte-5 grated into the sensors.
Sensors of this type are known from the German patent P 44 08 352, the disclosure of which is hereby incor-porated in the present application. The sensor con-sists of a silicon substrate 25 in which containments 10 35 are located. The containments 35 contain sensor membrane materia:L 28 and electrodes 27, 27" , which protrude into the containment. The containments ta-per from one side of the silicon substrate 25 to the other side of the silicon substrate 25. On the side 15 of the containments with the smaller aperture, a channel 39 is introduced into the silicon substrate by anisotropic etching, which substrate is in spa-tial contact witx~ the active smaller apertures 29, 29', forming membrane surfaces, of the containments.
20 This channel is closed with a glass cover 90, which is connected in a sealed manner to the silicon sub-strate by anodic bonding. Thus there is formed in the silicon substrate 25 a channel 39 in which the fluid collected by the hollow probe is led past the 25 active membrane surfaces 29, 29'.
The achievable diameters of the channel 39 lie in the region between several 10 to several 100 Vim, such that very small sample volumes can be measured. In the arrangement shown in Fig. b, in addition to the sensor elements 28, 28', feed apertures 41, 42 are introduced into the silicon substrate 25, and extend from one side of the silicon substrate to the other and are connected to the channel 39'. Through this feed/drainage aperture 41 or 92, the measurement me-dium is led towards channel 39 (aperture 41) or away from channel 39 (aperture 42). In this case therefo-re the channel 39' does not emerge on the end face of the silicon substrate 25' since it is limited in length.
Fig. 7 shows now the use of a sensor element accor-ding to Fig. 6 in a sensor system which corresponds to that of Figs. 2 and 3. The same reference nume-rats therefore designate the same elements as in the-se figures. In contrast to Fig. 2, the channel sup-port 17' no longer has a single channel 18. Rather the channel is divided into two portions 18' and 18"
separated from one another by a web. Channel portion 18' extends between the hollow probe aperture on the sensor element side and aperture 20 in the sensor support. The second channel portion 18" extends si-deways to the first channel portion 18' below apertu-re 20 of the sensor support 19 and the external aper-ture 24, the two channel portions 18 and 18" merely being in contact with one another 'via aperture 20 of the sensor support 19. Sensor element 5" with the sensor contact surfaces 21' and 22" is now a sensor element as per Fig. 6. Here the sensor element 5"
is so disposed in aperture 20 that the feed aperture 41 from Fig. 6 is in communication with channel por-tion 18' and the discharge aperture 42 of Fig. 6 with channel portion 18" . Thus the fluid to be measured is led from the Follow probe via channel portion 18' and feed aperture 41 through channel 39' past sensor elements 28, 28' and then via the discharge aperture 42 and channel portion 18" out of the sensor system according to the invention. Channel 39' can be con-figured as a capillary throttle to control the fluid flow via the flow resistance of 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 convey the fluid to be measured from the hollow probe past. the sensor element 5" , in the in-ter communicating cavities of the sensor system ac-cording to the invention a vacuum is produced. For this purpose a very simple container or a vacuum con-tainer (vacutainer) can be attached to aperture 24 of channel portion 18" . As a result of the high flow resistance of channel 39' with a law channel cross-section, the fluid which enters channel 39' via the hollow probe 3 is then conveyed at practically a con-stant flow rate. The flow resistance can also be in-creased by channel 39' being itself lengthened on the chip.
The sensor system shown in Fig. 7 c:an be further de-veloped as shown in Fig. 8. In addition to the ar-rangement, as Shawn in Fig. 7 and therefore also de-signated with the respective corresponding reference numerals, a further channel 43 is located in the channel cover 19' as the vacuum channel. This chan-nel 43 runs around aperture 20 and is separated from the latter by a web. Furthermore c:hannel aperture 18' in channel support 17' is slightly extended at the side so that it also covers the vacuum channel 43. The vacuum channel 43 consequently connects, in addition to aperture 20, channel apertures 18' and 18" . Between channel support 17' and channel cover 19' there is now situated a gas-permeable membrane in the region in which channel aperture 18' and vacuum channel 43 communicate. This means that at the sides of the gas-permeable membrane facing the vacuum chan-nel 43, the vacuum applied by the pump P or the vacutainer to aperture 24 is present. If gas bubbles are contained in the measurement medium which reaches the channel portion 18' through the hollow probe 3, the gas is led away with the aid of the vacuum pre-y sent on the vacuum channel side of the gas-permeable membrane, via the gas-permeable membrane 44 into the vacuum channel 43. Therefore the measurement medium, which cannot flow through the gas-:permeable membrane but enters the integrated flow channel 39' of Fig. 6 of the sensor element 5" , is degasified. It is also possible to lay a separate vacuum line, e.g. a hose between vacuum channel 43 and system module 8 (see Fig. 1) .
Fig. 9 shows an embodiment according to that shown in Fig. 2, in which however there are integrated in the support 2' electrodes which serve the electrophore-tic/electroosmotic transport of the measurement medi-um in the subcutaneous tissue. Corresponding ele-ments are however designated with corresponding refe-rence numerals to those in Fig. 2.
On a support 2' is disposed at an angle an electri-cally conductive hollow probe 3' formed from stain-less steel, which extends from the underside of sup-port 2' into the channel 18 in the channel support 17 and the cavity of which communicates with channel 18.
In support 2' are disposed furthermore electrical track conductors 48, 49 and 50, electrically insula-ted from one another and which are provided with con-nection contacts 51, 52 or 53 for .applying voltages.
Track conductor 49 is here electrically connected to the hollow probe. Furthermore on the surface of sup-port 2' facing the skin surface a:re located two electrodes 12' and 15' which are connected in an electrically conductive manner to 'the track conduc-tors 50 or 48 via feedthroughs of support 2'. Elec-trode 12' is here a large-area anode which is dispo-sed roughly centrally on the underside of support 2'.
Electrode 15' is disposed to the side of the point at which the hollow probe 3' breaks through support 2' above the free end of the obliquely disposed hollow probe 3' on the underside of support 2' and serves as the cathode. This cathode 15' is a platinum cathode or an Ag/AgCl cathode. The outer end of the hollow probe 3' has a pointed tip and is open at the front as is usual for cannulae in medical technology. Not represented, however, is an embodiment in which the hollow probe is perforated on its outer peripheral surface so that in this case an even greater sample volume can be removed from the subcutaneous tissue.
If now via conta~~ts 51 and 52 a negative voltage is applied to the cathode 15' or the :hollow probe 3' and a positive voltage is applied to t:he anode 12' via the connection c~~ntact 53, an electrophore-tic/electroosmotic transport of the interstitial fluid is produced in the direction of the hollow pro-be 3'. Furthermore the tissue below the cathode 15' swells, such that an increased volume of interstitial fluid is available to be taken as a sample. Since the cathode 15' is disposed directly above the free end of the hollow probe 3', the flow of the intersti-tial fluid is directed towards the open end of the hollow probe 3', and this results in further improved sampling.
If the hollow probe 3' is itself not electrically conductive, the electrical contact to the column of fluid in the hol:Low probe 3' is provided via contact 11' (Fig. 9a).
Fig. 9b shows the sensor system described in Fig. 9a in assembled state.
Fig. 10 shows various embodiments of a hollow probe 3' for a minima lly invasive sensor system according to the invention. The hollow probe 3' comprises a 5 cylindrical body formed from stainless steel. It is electrically conductive and can simultaneously act as the hollow probe and as the cathode, for example in the embodiment o:f a sensor system according to Fig.
9. The outer end of these hollow probes can have a 10 pointed tip and be open at the front as is usual for cannulae in medical technology. It can also be per-forated on its peripheral surface or be provided with pores.
Fig. lOb shows a hollow probe 3" which is produced 15 from Teflon, polyamide or some othc=_r plastics materi-al and thus has hose-like properties. The Teflon membrane can here be perforated on its surface area and thus be permeable for the interstitial fluid.
Perforation of this type in Teflon or other membrane 20 materials can be produced by means of lasers. With corresponding perforation, the hollow probe 3" can also be used as an ultrafiltration hollow fibre.
The hose-like consistency of the hollow probe 3" re-presented in Fig. lOb means that the vacuum in the hollow probe lumen possibly produces a collapse of the hollow probe during measurement.. Therefore the hollow probe is provided with a reinforcement support 54, for example a wire which can simultaneously serve as the hollow probe cathode. Two or more wires can also be twisted to form a reinforcement support.
In Fig. lOc is shown a further reinforced hollow pro-be 3" ', the reinforcement support 55 comprising a fibre bundle. Carbon-fibre bundles or glass-fibre bundles are particularly suitable for this purpose.
If carbon-fibre bundles are used as reinforcement supports, they can simultaneously nerve as cathodes as a result of their electrical conductivity.
The hollow probes described here typically have out-side diameters of between 0.1 and 2 mm, preferably however, between 0.4 and 0.5 mm.
The hollow probes according to Fig. 10 can also be produced from such otherwise ~>nown materials as are used for dialysi~~ and ultrafiltrati.on hollow fibres.
It is also possible to configure the reinforcement support 54 as a gas-bubble trap. To this end, the reinforcement support consists e.g. of a Teflon hose, the wall of whicr: is gas-permeable. The inner lumen of the Teflon hose is connected to vacuum. This hap-pens in a similar manner to that in the embodiment according to Fig. 8 via a channel 43.
A further embodiment of a sensor system according to the invention is represented in Fig. 11 in conjunc-tion with Fig. 2. Corresponding elements are desi-gnated by corresponding reference numerals to those in Fig. 2. In contrast to Fig. 2, however, hollow probe 3 is here replaced by a flexible hollow probe 3I" formed from a perforated Teflon catheter. This flexible hollow probe cannot, however, be easily inserted into the subcutaneous tissue. In hollow probe 3I~ there is therefore a stabilisation needle 57 as a reinforcement support. This needle is intro-duced through a silicone septum 56 on the channel co-ver 19 through channel 18 in the channel support 17 into the hollow probe 3I~. The septum 56 must here be sufficiently impermeable to maintain the vacuum created in channel 18. What is advantageous about this embodiment is that the stabilisation needle 57 can be removed by pulling it out of the hollow probe 3I" as soon as the hollow probe 3I" is inserted into the subcutaneous tissue. By this :means the stress on the support for the minimally invasive sensor system during the bearing time is greatly reduced and pati-ents' acceptance of a sensor system of this type is increased.
Fig. llb shows this sensor system in assembled state.
Advantageously, the sensor systems according to the invention can be equipped with flow controls in order to indicate an interruption of the flow. A particu-larly simple embodiment of these flow controls arises from two glucose sensors being disposed the one be-hind the other in a flow channel 6 of the sensor 5 (see Fig. 1). Since the conventional glucose sen-sors, generally known in prior art, convert the ana-lyte by means of enzymes, a smaller glucose concen-tration is produced at the second sensor in compari-son with the first sensor. If the signal of the se-cond sensor now follows the signal of the first sen-sor in time with a smaller absolute signal, it can be assumed that the flow of the interstitial tissue fluid is not interrupted.
_.~..~..w......,~"~,.~,....~.~,_~..~.....,..,.~....~"..~,.,~."...~...~..M
._... .
Furthermore it is advantageous to arrange a pre-oxidation reactor before the glucose sensor between the hollow probe and the sensor element. With the aid of this reactor, disturbing substances can be kept away from the sensor by pre-oxidation. Since in this process there is also a flow over the pre-oxidation reactor, the ratio of the flows between pre-oxidation reactor and the downstream glucose sen-sor can serve as control parameters for the flow of the interstitial tissue fluid in channel 6 of the sensor 5 (Fig. 1). A pre-oxidation reactor of this type, connected upstream, can be produced by means of the same technology as the sensors described here, for example as p~=r Fig. 5 and Fig. 6.
In the minimally invasive sensor systems presented in Figs. 2, 4, 7 to 9, the supports 2, channel support 17, channel cover 19 and the filter support 37 or the corresponding elements consist of plastics materials such as polyvinyl chloride (PVC), polyethylene (PE), polyoxymethylene (POM), polycarbonate (PC), ethylene propylene copolymer (EPDM), polyvinylidene chloride (PVDC), polychlorotrifluoroethylene (PCTFE), po-lyvinyl butyral (PVB), cellulose acetate (CA), poly-propylene (PP), polymethyl methacrylate (PMMA), po-lyamide (PA), tetrafluoroethylene hexafluoropropylene copolymer (FEP), polytetrafluoroethylene (PTFE), phe-nol-formaldehyde (PF), epoxide (EP), polyurethane (PUR), polyester (UP), silicone, melamine-formaldehyde (MF), urea-formaldehyde (UF), aniline-formaldehyde, capton or the li~:e.
In the minimally invasive sensor systems presented in Figs. 2, 4, 7 to 9, the supports 2, channel support 17, channel cover 19 and the filter support 37 or the corresponding elements consist of plastics materials such as polyvinyl chloride (PVC), polyethylene (PE), polyoxymethylene (POM), polycarbonate (PC), ethylene propylene copolymer (EPDM), polyvinylidene chloride (PVDC), polychlorotrifluoroethylene (PCTFE), po-lyvinyl butyral (PVB), cellulose acetate (CA), poly-propylene (PP), polymethyl methacrylate (PMMA), po-lyamide (PA), tetrafluoroethylene hexafluoropropylene copolymer (FEP), polytetrafluoroethylene (PTFE), phe-nol-formaldehyde (PF), epoxide (EP), polyurethane (PUR), polyester (UP), silicone, melamine-formaldehyde (MF), urea-formaldehyde (UF), aniline-formaldehyde, capton or the li~:e.
The supports 2, channel support 17, channel cover 19 and filter support 37 can be connected by gluing, welding or laminating. Particularly for laminating, special laminating films are available which can be hot-laminated (e. g. CODOR film formed from polyethy lene and polyester of the company TEAM CODOR, Marl, Germany. The thickness of the individual films for the supports 2, channel support 17, channel cover 19 or filter support 37 can be between 10 and several 1000 ~,m, preferably about several 100 Vim. The flat surface dimensions of the support 2 and of the other supports and covers are in the region of a few cm, for example 2 x 3 cm for support 2 from Fig. 2. The underside of the support 2 is again advantageously provided completely or partially with an adhesive layer formed from adhesive materials which are compa-tible with the skin and which provides secure adhesi-on on the surface of the skin.
The anode 12, cathodes 11 and 15' and the track con-ductors 48, 49, SO in the corresponding drawings and likewise the connection contacts 51, 52 and 53 can be produced by screen printing or a thin-film method.
The materials used for this can be screen printing pastes based on noble metals and other metals. The layers produced by means of the than-film method can comprise noble metals such as platinum, gold, silver or chloridised silver layers (Ag/AgCl). The thick-ness of these layers for the anodes, cathodes and track conductors and connection contacts can be bet-ween several 100 nm and several ~tm.
The anode 12, cathodes 11 and 15' and the track con-ductors 48, 49, SO in the corresponding drawings and likewise the connection contacts 51, 52 and 53 can be produced by screen printing or a thin-film method.
The materials used for this can be screen printing pastes based on noble metals and other metals. The layers produced by means of the than-film method can comprise noble metals such as platinum, gold, silver or chloridised silver layers (Ag/AgCl). The thick-ness of these layers for the anodes, cathodes and track conductors and connection contacts can be bet-ween several 100 nm and several ~tm.
Claims (37)
1. Minimally invasive sensor system having at least one hollow probe (3), at least one sensor (S) with a sensor element and a flow channel (6) in spatial contact with said sensor element, wherein the sensor system has a support (2) on which the at least one hollow probe (3), the at least one sensor (S) and the flow channel (6) are disposed and wherein the at least one hollow probe (3) is configured as a probe for sampling a fluid from tissues and the cavity of the hollow probe (3) is connected directly or via a hollow connector (4) to the flow channel (6).
2. Sensor system according to claim 1, character-ised in that the hollow probe (3) has micro-scopic and/or macroscopic apertures.
3. Sensor system according to one of the preceding claims, characterised in that the hollow probe (3) is a terminal hollow probe.
4. Sensor system according to one of the preceding claims, characterised in that the hollow probe (3) is open at its end remote from the sensor and/or is perforated or porous on its surface area.
5. Sensor system according to one of the preceding claims, characterised in that the flow channel (6) of the sensor (S) is connected on the side remote from the probe (3) to a device for creat-ing a vacuum, especially a suction pump (P) or a vacuum container.
6. Sensor system according to one of the preceding claims, characterised in that the hollow probe (3), the hollow connector (4), the flow channel (6) and/or the sensor (S) are microfluidic ele-ments.
7. Sensor system according to one of the preceding claims, characterised in that there is disposed in the hollow probe (3) a reinforcement support (54).
8. Sensor system according to claim 7, character-ised in that the reinforcement support (54) is a wire, a needle, a fibre bundle, a glass-fibre bundle and/or a carbon-fibre bundle.
9. Sensor system according to claim 7, character-ised in that the reinforcement support is con-figured as a gas-bubble trap.
10. Sensor system according to claim 9, character-ised in that the reinforcement support has at least partially a hose with a gas-permeable wall.
11. Sensor system according to one of claims 8 to 10, characterised in that the reinforcement sup-port (54) is removable.
12. Sensor system according to one of the preceding claims, characterised in that at least one elec-trode which can be connected as the cathode (15') is disposed on the support.
13. Sensor system according to one of claims 7 to 12, characterised in that the reinforcement sup-port (54) is electrically conductive and can be connected as the cathode.
14. Sensor system according to the preceding claim, characterised in that the reinforcement support (54) consists of an electrically conductive ma-terial or has an electrically conductive coat-ing.
15. Sensor system according to the preceding claim, characterised in that the reinforcement support (54) consists of stainless steel or a noble metal or has metal vapor-deposited onto it.
16. Sensor system according to one of the preceding claims, characterised in that the hollow probe (3) consists of plastics material.
17. Sensor system according to at least one of the preceding claims, characterised in that the hol-low probe (3) is electrically conductive and can be connected as the cathode.
18. Sensor system according to the preceding claim, characterised in that the hollow probe (3) con-sists of an electrically conductive material or has an electrically conductive coating.
19. Sensor system according to the preceding claim, characterised in that the hollow probe (3) con-sists of stainless steel or a noble metal or has metal vapour-deposited onto it.
20. Sensor system according to one of the preceding claims, characterised in that an additional electrode which can be connected as the cathode is disposed on the support (2).
21. Sensor system according to one of the preceding claims, characterised in that a large-area elec-trode which can be connected as an anode is dis-posed on the support (2).
22. Sensor system according to one of the preceding claims, characterised in that a fluid filter (38) is disposed between the hollow probe (3) and the sensor (S).
23. Sensor system according to one of the preceding claims, characterised in that a gas-bubble trap (44) is disposed between the hollow probe (3) and the sensor (S).
24. Sensor system according to one of the preceding claims, characterised in that a pre-oxidation reactor is disposed between the hollow probe (3) and the sensor (S).
25. Sensor system according to one of the preceding claims, characterised in that the sensor (S) has a base plate (2), a plate-like channel support (17) with a channel-like recess (18) and a plate-like sensor support (19) with a planar re-cess to incorporate the sensor element (21, 22) and/or a planar sensor element, the base plate (2), the channel support (17) and the sensor support and/or the sensor element being stacked on top of one another forming a seal with one another, in such a way that the planar recess and/or the planar sensor element are located above the channel-like recess (18).
26. Sensor system according to the preceding claim, characterised in that the hollow probe (3) is disposed breaking through the base plate (2) in such a way that one of its ends protrudes into the channel-like recess (18).
27. Sensor system according to of claims 1 to 24, characterised in that the sensor (S) comprises a substrate (25) configured plate-like in which at least one containment (35) tapering from the front surface of the substrate (25) to the sec-ond surface is introduced, the containment (35) containing the sensor element having a larger aperture on the front surface and a smaller ap-erture on the second surface and with at least one plate (40) connected to the second surface and at least one channel-like cavity (39) in contact with the smaller aperture of the con-tainment (35) and serving as the measuring cham-ber and which is formed in the substrate (25) or in the plate (40) or in both.
28. Sensor system according to one of claims 25 to 27, characterised in that t:he support of the sensor system is configured as a plate-like sub-strate or as a plate-like channel support.
29. Sensor system according to one of the preceding claims, characterised in that the flow channel (39) is in spatial contact with at least two sensor elements disposed the one behind the other in the flow direction of the flow channel (39).
30. Sensor system according to at least one of the preceding claims, characterised in that the sup-port and possibly the base plate, the channel support, the sensor support, the filter support, the plate-like substrate and/or the plate con-nected to the second surface of the substrate consists of plastics materials such as polyvinyl chloride (PVC), polyethylene (PE), polyoxymeth-ylene (POM), polycarbonate (PC), ethylene pro-pylene copolymer (EPDM), polyvinylidene chloride (PVDC), polychloro-trifluoroethylene (PCTFE), polyvinyl butyral (PVB), cellulose acetate (CA), polypropylene (PP), polymethyl methacrylate (PMMA), polyamide (PA), tetrafluoroethylene hexafluoropropylene copolymer (FEP), polytetra-fluoroethylene (PTFE), phenol-formaldehyde (PF), epoxide (EP), polyurethane (PUR), polyester (UP), silicone, melamine-formaldehyde (MF), urea-formaldehyde (UF), aniline-formaldehyde, capton.
31. Sensor system according to claim 30, character-ised in that the support and possibly the base plate, the channel support, the sensor support, the filter support, the plate-like substrate and/or the plate connected to the second surface of the substrate which are formed from plastics materials have a thickness of between 10 µm and several 1000 µm, advantageously about 100 µm.
32. Sensor system according to claim 30, character-ised in that the support and the sensor, possi-bly the base plate, the channel support, the sensor support, the filter support, the plate-like substrate and/or the plate connected to the second surface of the substrate are/is connected by gluing, welding and/or laminating.
33. Use of a minimally invasive sensor system ac-cording to at least one of the preceding claims to determine physical, chemical and/or biochemi-cal properties in living creatures.
34. Use according to the preceding claim to deter-mine analyte concentrations in tissues and body fluids in vivo.
35. Use according to one of the two preceding claims to determine the glucose concentration in blood and/or interstitial fluid of a human being.
36. Use according to one of claims 33 to 35 in medi-cal, particularly human medical diagnostics and therapeutics.
37. Use according to the previous claim in the treatment of diabetes.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1998148112 DE19848112C2 (en) | 1998-10-19 | 1998-10-19 | Minimally invasive sensor system |
| DE19848112.8 | 1998-10-19 | ||
| PCT/DE1999/003126 WO2000022977A1 (en) | 1998-10-19 | 1999-09-28 | Minimally invasive sensor system |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2347378A1 true CA2347378A1 (en) | 2000-04-27 |
Family
ID=7884918
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002347378A Abandoned CA2347378A1 (en) | 1998-10-19 | 1999-09-28 | Minimally invasive sensor system |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1123040A1 (en) |
| JP (1) | JP2002527177A (en) |
| CA (1) | CA2347378A1 (en) |
| DE (1) | DE19848112C2 (en) |
| WO (1) | WO2000022977A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10780222B2 (en) | 2015-06-03 | 2020-09-22 | Pacific Diabetes Technologies Inc | Measurement of glucose in an insulin delivery catheter by minimizing the adverse effects of insulin preservatives |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10003507B4 (en) | 2000-01-27 | 2004-06-03 | Knoll, Meinhard, Prof. Dr. | Device and method for the removal of liquids from the body's own tissue and determination of substance concentrations in this liquid |
| US6603987B2 (en) * | 2000-07-11 | 2003-08-05 | Bayer Corporation | Hollow microneedle patch |
| GB0030929D0 (en) | 2000-12-19 | 2001-01-31 | Inverness Medical Ltd | Analyte measurement |
| DE10105549A1 (en) * | 2001-02-06 | 2002-08-29 | Roche Diagnostics Gmbh | System for monitoring the concentration of analytes in body fluids |
| DE10141732A1 (en) * | 2001-08-25 | 2003-03-06 | Horst Frankenberger | Method and device for long-term determination of the concentration of at least one substance in a body fluid |
| EP1479344A1 (en) | 2003-05-22 | 2004-11-24 | Roche Diagnostics GmbH | Direct monitoring of interstitial fluid composition |
| US20040193202A1 (en) | 2003-03-28 | 2004-09-30 | Allen John J. | Integrated lance and strip for analyte measurement |
| US7473264B2 (en) | 2003-03-28 | 2009-01-06 | Lifescan, Inc. | Integrated lance and strip for analyte measurement |
| BRPI0414067A (en) | 2003-09-03 | 2006-10-24 | Life Patch International Inc | personal diagnostic device and method of using the same |
| ATE426358T1 (en) * | 2006-07-22 | 2009-04-15 | Hoffmann La Roche | PORTABLE MEASURING DEVICE FOR DETERMINING A MEDICALLY SIGNIFICANT ANALYTE CONCENTRATION |
| US20100209300A1 (en) * | 2007-01-26 | 2010-08-19 | Diramo A/S | Analysis system with a remote analysing unit |
| KR101288400B1 (en) * | 2012-07-10 | 2013-08-02 | 주식회사 유엑스엔 | Measuring method of blood sugar level, apparatus and system thereof |
| KR101636781B1 (en) * | 2015-02-09 | 2016-07-07 | 주식회사 에이엠피올 | Intercellular fluid extraction structure for detecting glucose |
| KR101879940B1 (en) * | 2016-08-30 | 2018-07-18 | 최규동 | Pilot Bio-Signal Monitoring System using Wearable Continuous Body Fluid checking apparatus |
| CN108149334B (en) * | 2016-12-05 | 2021-03-09 | 中国科学院大连化学物理研究所 | Method for preparing microfiber with complex shape based on microfluidic chip and special chip |
| KR102051811B1 (en) * | 2017-07-27 | 2019-12-04 | 고려대학교산학협력단 | Biosensor for measuring glucose comprising cytoplasmic filter |
| CN108031236A (en) * | 2017-12-15 | 2018-05-15 | 山东佳星环保科技有限公司 | A kind of indoor air-purification device |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8725936D0 (en) * | 1987-11-05 | 1987-12-09 | Genetics Int Inc | Sensing system |
| AT393213B (en) * | 1989-02-08 | 1991-09-10 | Avl Verbrennungskraft Messtech | DEVICE FOR DETERMINING AT LEAST ONE MEDICAL MEASURING SIZE |
| DE4115414C2 (en) * | 1991-05-10 | 1995-07-06 | Meinhard Prof Dr Knoll | Process for the production of miniaturized chemo- and biosensor elements with an ion-selective membrane as well as carriers for these elements |
| DE4137261C2 (en) * | 1991-11-13 | 1995-06-29 | Meinhard Prof Dr Knoll | Miniaturized sensor element for determining substance concentrations in liquids and process for its production |
| DE4401400A1 (en) * | 1994-01-19 | 1995-07-20 | Ernst Prof Dr Pfeiffer | Method and arrangement for continuously monitoring the concentration of a metabolite |
| DE4408352C2 (en) * | 1994-03-12 | 1996-02-08 | Meinhard Prof Dr Knoll | Miniaturized substance-recognizing flow sensor and method for its production |
| DE4410224C2 (en) * | 1994-03-24 | 1996-02-29 | Meinhard Prof Dr Knoll | Miniaturized flow analysis system |
| DE4426694C2 (en) * | 1994-07-28 | 1998-07-23 | Boehringer Mannheim Gmbh | Device for long-term determination of the content of at least one substance in body fluids |
| US5568806A (en) * | 1995-02-16 | 1996-10-29 | Minimed Inc. | Transcutaneous sensor insertion set |
| DE19612105C2 (en) * | 1996-03-27 | 1998-11-05 | Inst Diabetestechnologie Gemei | Method and arrangement for determining the concentration of a metabolite in biological tissue |
-
1998
- 1998-10-19 DE DE1998148112 patent/DE19848112C2/en not_active Expired - Fee Related
-
1999
- 1999-09-28 WO PCT/DE1999/003126 patent/WO2000022977A1/en not_active Application Discontinuation
- 1999-09-28 JP JP2000576758A patent/JP2002527177A/en active Pending
- 1999-09-28 CA CA002347378A patent/CA2347378A1/en not_active Abandoned
- 1999-09-28 EP EP99970579A patent/EP1123040A1/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10780222B2 (en) | 2015-06-03 | 2020-09-22 | Pacific Diabetes Technologies Inc | Measurement of glucose in an insulin delivery catheter by minimizing the adverse effects of insulin preservatives |
| US11135369B2 (en) | 2015-06-03 | 2021-10-05 | Pacific Diabetes Technologies Inc | Measurement of glucose in an insulin delivery catheter by minimizing the adverse effects of insulin preservatives |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1123040A1 (en) | 2001-08-16 |
| DE19848112A1 (en) | 2000-06-08 |
| JP2002527177A (en) | 2002-08-27 |
| WO2000022977A1 (en) | 2000-04-27 |
| DE19848112C2 (en) | 2001-12-13 |
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