US20170354360A1 - Medical sensor system for detecting a feature in a body - Google Patents
Medical sensor system for detecting a feature in a body Download PDFInfo
- Publication number
- US20170354360A1 US20170354360A1 US15/631,823 US201715631823A US2017354360A1 US 20170354360 A1 US20170354360 A1 US 20170354360A1 US 201715631823 A US201715631823 A US 201715631823A US 2017354360 A1 US2017354360 A1 US 2017354360A1
- Authority
- US
- United States
- Prior art keywords
- reservoir
- sensor system
- medical
- pores
- sensor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Images
Classifications
-
- 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
- A61B5/1468—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 chemical or electrochemical methods, e.g. by polarographic means
- A61B5/1473—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 chemical or electrochemical methods, e.g. by polarographic means invasive, e.g. introduced into the body by a catheter
- A61B5/14735—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 chemical or electrochemical methods, e.g. by polarographic means invasive, e.g. introduced into the body by a catheter comprising an immobilised reagent
-
- 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
- A61B5/14503—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 invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
-
- 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
- A61B5/14535—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 haematocrit
-
- 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
- A61B5/14539—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 pH
-
- 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
- A61B5/14546—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 analytes not otherwise provided for, e.g. ions, cytochromes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
- B01D69/14—Dynamic membranes
- B01D69/141—Heterogeneous membranes, e.g. containing dispersed material; Mixed matrix membranes
- B01D69/148—Organic/inorganic mixed matrix membranes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
- B01D71/06—Organic material
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F15—FLUID-PRESSURE ACTUATORS; HYDRAULICS OR PNEUMATICS IN GENERAL
- F15C—FLUID-CIRCUIT ELEMENTS PREDOMINANTLY USED FOR COMPUTING OR CONTROL PURPOSES
- F15C1/00—Circuit elements having no moving parts
- F15C1/008—Other applications, e.g. for air conditioning, medical applications, other than in respirators, derricks for underwater separation of materials by coanda effect, weapons
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
- F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
- F16K99/00—Subject matter not provided for in other groups of this subclass
- F16K99/0001—Microvalves
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
- A61B2562/02—Details of sensors specially adapted for in-vivo measurements
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
- A61B2562/02—Details of sensors specially adapted for in-vivo measurements
- A61B2562/028—Microscale sensors, e.g. electromechanical sensors [MEMS]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
- A61B2562/04—Arrangements of multiple sensors of the same type
Definitions
- the invention relates to a medical sensor system for detecting at least one feature in at least one human and/or animal body.
- sensor systems In medicine, sensor systems are used wherein at least parts of the systems are inserted or implanted directly in a body of a patient in order to capture actual physiological conditions as precisely and directly as possible.
- Publication WO 2008/154416 A2 in combination with U.S. Pat. No. 6,527,762 B1, discloses a sensor that can be implanted in the body, wherein a sensor has a reservoir capped by a thin metal film. By use of a thermal process wherein a voltage is applied, the cap is irreversibly removed to expose the interior of the sensor. The sensor's interior is continually subjected to degradation processes, and moreover, pieces of the metal film can enter the body, which can be harmful.
- the invention seeks to provide a medical sensor system for detecting a feature in a body, and which can be flexibly used, and implemented in a robust manner that is resistant to error.
- sensor refers to a component that can detect a physical and/or chemical property of a parameter in the sensor's environment, qualitatively and/or chemical property of a parameter in the sensor's environment, qualitatively and/or quantitatively, preferably as a quantity to be measured.
- a “sensor system” refers to a system having at least one sensor, and which can include further components, such as further sensors, a housing, electronic components, a power supply, a telemetry unit, a control unit, an anchoring device, and/or any other suitable component.
- a “feature” refers to a parameter such as a pH value, a charge (e.g. of an ion or a polyelectrolyte), a temperature, a mass, an aggregation state, water content, hematocrit value, and/or a presence or absence and/or a quantity of an analyte or other substance (such as a fat, a salt, an ion, a polyelectrolyte, a sugar, a nucleotide, DNA, RNA, a peptide, a protein, an antibody, an antigen, a drug, a toxin, a hormone, a neurotransmitter, a metabolite, a metabolic product, and/or any other analyte of interest).
- a pH value e.g. of an ion or a polyelectrolyte
- a temperature e.g. of an ion or a polyelectrolyte
- a mass e
- a “feature” also refers to so-called biomarkers which form a variable component of the human or animal body, such as albumins/globulins, alkaline phosphatase, alpha-1-globulin, alpha-2-globulin, alpha-1-antitrypsin, alpha-1-fetoprotein, alpha-amylases, alpha-hydroxybutyrate-dehydrogenase, is ammonia, antithrombin III, bicarbonate, bilirubin, carbohydrate antigen 19-9, carcinoembryonic antigens, chloride, cholesterol, cholinesterase, cobalamin/vitamin B12, coeruloplasmin, C-reactive proteins, cystatin C, D-dimers, iron, erythropoetin, erythrocytes, ferritin, fetuin-A fibrinogen, folic acid/vitamin B9, free tetrajodthyronine (fT4), free trijodth
- any other feature of interest for detection can be detected by the sensor system.
- the feature preferably relates to a variable component of the animal body and/or human body.
- a preferred version of the sensor system is used to detect a member of the cystatin family of the cysteine protease inhibitors, particularly to detect cystatin C.
- the sensor system includes at least one sensor and at least one cap of a reservoir of the sensor, wherein the cap is designed as a controllable organic membrane.
- “Reservoir of the sensor” or “sensor reservoir” refers to a space, a chamber, and/or a cavity of the sensor in contact with a detection system of the sensor, and/or on and preferably in which the detection system is disposed. Furthermore, the sensor reservoir encloses a volume that contains or has the feature to be detected.
- Cap refers to a device and/or a component of the sensor reservoir that closes the sensor reservoir in at least one operating state of the sensor system, and/or prevents the sample volume from entering into and/or emerging from the sensor reservoir. The cap is therefore a functional component of the sensor.
- Controllable is intended to mean that the membrane can be switched via at least one signal from at least one selected starting state to a selected end state.
- the signal is an influence that can act from outside of the sensor system, such as radiation, infrared, visible light, ultrasound, an electrical field, a magnetic field, a protein, a peptide, a polyelectrolyte, a change in a pH value, a change in ion concentration, a temperature change, and/or any other effect suitable for use as a signal.
- a volume of the membrane can be controlled.
- organic membrane refers to a separating layer and/or a thin film which includes at least one component based on a carbon compound.
- the controllable organic membrane can change its state in response to the triggering signal in a manner such that at least a portion of the membrane is permeable to the analyte, thereby providing the analyte with access to the detection system. Moreover, the controllable organic membrane can be changed, reversibly and steplessly, between an open state and a closed state of the reservoir. “Steplessly” refers to the possibility of adjusting the opening width of the membrane to any width up to a maximum limit. “Reversibly” means in a manner than can be reversed. By making it possible to reverse the change, the detection system disposed in the sensor reservoir can be protected against interfering molecules that could attack, degrade, and/or destroy the sensor. Other interfering factors that can impair the proper functioning of the sensor are also minimized in this manner As a result, a sensor system having a particularly long service life can be provided.
- controllable organic membrane is advantageously closed before an initial use or an initial measurement run of the sensor, thereby effectively protecting the sensor against disturbing influences such as dirt, dust, excessive humidity, dryness, temperature fluctuations, and/or harmful molecules before initial start-up. It is additionally advantageous when the controllable organic membrane can be closed between the individual measurements, thereby ensuring that the components of the sensor system can remain stable.
- the controllable organic membrane includes at least one pore, the diameter of which can be changed in a reversible manner, whereby the state of the membrane (and passage of an analyte into the sample volume) can be structurally adapted to allow passage of different molecules and/or analytes.
- at least one of the opening of the pore and the closing of the pore can be controlled.
- the pore is preferably a nanopore with a maximum diameter of approximately 1 ⁇ m.
- the pores need not have a round shape/contour, and can alternatively or additionally have oval, triangular, square, or other polygonal shapes, star-shapes, or any other desirable shapes.
- the nanopores make it easy to prevent structures such as cells, large molecules, or molecular aggregates having a greater dimension than the diameter of the nanopores from entering the sample volume from the sensor's environment and interfering with the detection system.
- the membrane preferably includes a large number of similar pores that are distributed evenly over a surface of the membrane, though an inhomogeneous pore distribution is also possible.
- the pore diameter is steplessly adjustable, which enables it to be used with a large number of analytes.
- the controllable organic membrane preferably includes at least one material that has a changeable redox (reduction of oxidation) state, enabling the permeability of the membrane to be easily and reliably changed.
- the redox state can be changed chemically, electrically, and/or via other means.
- controllable organic membrane is electrically controllable, in particular, if the pores (e.g., their size and/or shape) are electrically controllable. In preferred versions of the invention, this occurs by applying a voltage of approximately 2 V at most. When the nanopores are fully open, the volume of the material having the changeable redox state is at its minimum. When a voltage is applied, the volume of the material changes, thereby reducing the pore diameter.
- the volume increase may usefully be made dependent on the level of the voltage that is applied for a certain period of time, or on the period of time during which a certain voltage is applied; in either case, the voltage need be applied only for a certain period of time, and need not be constantly maintained to effect a change in pore size.
- the procedure may then be reversed by applying a voltage with reverse polarity, or by use of analogous methods, resulting in a reduction of the volume of the material.
- the change in volume is dependent on the structural design of the membrane as well as its materials and the stimulus applied to effect the change.
- the material that can change its redox state is preferably an electroactive polymer or other material.
- an electroactive polymer or other material if a mixture of polypyrrole (PPy) and dodecylbenzene sulfonic acid (DBS) is used as the electroactive polymer, sodium ions are inserted into the polymer during a voltage-controlled reduction of the polymer. This insertion of sodium ions induces a strongly lateral change in volume of the electroactive polymer, which therefore closes the pores for the analyte. The reversibility of this procedure allows controlled opening and closing of the pores, and therefore controlled and repeatable sensor measurements. The volume of the polymer can be partially changed via the extent of the reduction of the polymer.
- the redox states of the electroactive polymer are created using different applied voltages, and are retained when the voltage is switched off. As a result, the polymer and pore diameter can be advantageously adjusted for analytes of different sizes.
- the detection system includes a receptor layer that brings about a measurable reaction with the feature to be measured, thereby allowing detection of the feature to be measured.
- the “receptor” can be one or more substances chosen from the classes of peptides, proteins (in particular enzymes), antibodies and their fragments, RNA, DNA, nucleotides, fats, sugars, salts, ions, cyclic macromolecules (such as ionophores, crown ethers, and cryptands), acyclic macromolecules, or other suitable substances.
- the receptor layer is preferably an antibody layer on a seFET (single electron Field Effect Transistor).
- the membrane, or the polymer or other material therein which has a changeable redox state is applied to a nanoporous substance which defines a carrier structure.
- the membrane or the material having the changeable redox state is disposed at least on inner surface of the pores of the nanoporous substance.
- the nanopores of the carrier structure can be used as the basic framework of the pore structure.
- the pore diameter is dependent on the analyte to be detected.
- the pore diameter is selected such that the membrane is permeable to molecules of the analyte, but poses a barrier for larger molecules.
- the pores might have a maximum diameter of 1 um, preferably a maximum of 250 nm, furthermore preferably 100 nm, advantageously a maximum of 50 nm, and particularly preferably a maximum of 10 nm.
- the pores can have a maximum diameter of 500 nm, preferably a maximum of 100 nm, furthermore preferably 50 nm, advantageously a maximum of 10 nm, and particularly preferably a maximum of 1 nm.
- the pores may assume any shape wherein the maximum dimension is sized as described above.
- the nanoporous substance preferably contains a metal oxide such as Al 2 O 3 , In 2 O 3 , MgO, ZnO, CeO 2 Co 3 O 4 , and/or the carrier structure at least contains TiO 2 , though other nanoporous substances could be used.
- TiO 2 allows a particularly lightweight, biocompatible, and bioinert carrier structure.
- the nanopore structure may be composed of nanotubes for easy and reproducible synthesis. These highly regular structures can be created relatively easily using an anodizing process. The pore size and layer thickness of this substrate can be easily adjusted by appropriate selection of manufacturing process parameters.
- the carrier structure thickness of hundreds of micrometers is typically much greater than the diameter of the nanotubes.
- the controllable organic membrane preferably has at least one structure on the top side thereof that prevents the adhesion of cells and molecules, to prevent biofouling.
- TiO 2 nanostructures can themselves prevent cell adhesion.
- the complete sensor system is biologically degradable so that it need not be removed from the patient's body once it loses functionality, thereby avoiding the need for invasive explantation procedures.
- Complete biodegradability also avoids the presence of potentially harmful substances within the patient's body, as may be the case where a non-biocompatible and degradable sensor were used. It is particularly advantageous if the controllable organic membrane is installed on a carrier structure that has high biocompatibility, thereby making it possible to minimize or entirely prevent rejection reactions and inflammatory responses that may affect patient health.
- the sensor is preferably designed to determine the feature in a quantitative manner, whereby it may determine the concentration of an analyte in (for example) bodily fluids such as blood, urine, interstitial fluid or lacrimal fluid.
- bodily fluids such as blood, urine, interstitial fluid or lacrimal fluid.
- a first sensor may be designed as a measurement sensor
- a second sensor may be designed as a reference sensor, wherein the two of them form a single piece.
- single piece means that the measurement sensor and the reference sensor are defined by the same components, and/or that functionality would be lost if the two were separated.
- the sensor reservoir is designed such that it is used in a first mode to perform a reference measurement, and in a second mode which takes place subsequently to the first mode to measure the analyte.
- a pore size is selected that is smaller than a diameter of the analyte, thereby preventing the analyte from entering the sample volume.
- molecules or structures that are smaller than the analyte can enter the sample volume.
- the pore size can then be adapted to the size of the analyte, thereby enabling the analyte to enter the sample volume.
- the measurement signal of the reference measurement can then be subtracted as a background signal (or otherwise removed) from the measurement signal of the analyte measurement to provide a final measured value.
- the background signal caused by interfering matter can be easily determined by use of a simple design.
- the first (measurement) sensor and the second (reference) sensor are preferably disposed in the sensor system such that they are spatially separated. Any type of suitable sensor can be used for the second sensor, though the second sensor preferably includes a reference reservoir which encloses a reference volume, and a (preferably electrically) switchable organic membrane.
- the two sensors preferably differ in terms of the configuration of their switchable membranes and in terms of the pore sizes implemented therein.
- the membrane pore size of the first (measurement) sensor allows the analyte to enter the sample volume.
- a smaller pore size in the second (reference) sensor prevents the analyte from entering the reference volume.
- the final measured value is obtained by correcting the measurement sensor signal using the reference signal.
- the different porosities of the measurement sensor and the reference sensor are selected by using different voltage levels and/or by applying the voltage to the sensors' membranes for different durations.
- This design has the advantage that drift and aging processes occur simultaneously in both sensors, and where the measurement sensor and the reference sensor are configured with at least substantially the same detection system, it is possible to collect information on the drift (e.g. degradation of the detection system, change in temperature, and other effects) of one sensor with respect to the other.
- the measured values can be corrected for drift by using a suitable correction term, or can be compensated for by using a suitable electrical, mechanical, chemical/biochemical, or other method. If the drift is so great that these mechanisms are no longer effective, then sensors installed in parallel with the “aged” sensors, which were previously left dormant, might be activated.
- the invention also involves a medical sensor array having at least two sensor systems. They can be identically-configured sensor systems that are activated in succession to detect, or determine the concentration of, the same analyte. Alternatively or additionally, the sensor systems can be used simultaneously to measure the analyte and also perform a reference measurement. Another alternative or additional arrangement is to have an array of sensor systems that can detect different analytes and/or their concentrations, either simultaneously or in succession. The use of several sensor systems can allow an effective extension of the limited service life of a single sensor system.
- the invention also involves a medical implant which incorporates the medical sensor system, or an array of such systems.
- the sensor system can be used in any suitable implant, such as an implant for recording physiological parameters, a cardiac pacemaker, a defibrillator, a brain pacemaker, a renal pacemaker, a duodenal pacemaker, a cardiac implant, artificial heart valves, a cochlear implant, a retinal implant, a dental implant, an implant for joint replacement, a vascular prosthesis, a drug delivery system, or particularly advantageously, a stent, such as a coronary stent, a renal artery stent, or a ureteral stent.
- the sensor system can assist in the function of such implants.
- At least a part of the surface of the implant can have hydrophobic or hydrophilic properties, and it can have a cationic, anionic, or metallic character, depending on the implant's usage.
- Inorganic or organic molecules can be bonded to the surface via physical adsorption or covalent bonds such as polymers, peptides, proteins, aptamers, molecularly imprinted polymers, RNA, DNA, siRNA, and nanoparticles.
- the surface can have nanostructuring or microstructuring.
- round, spherical, cylindrical, conical, square, rectangular, or elongated structures including grooves, tubes, solid cylinders, hollow cylinders, balls, hemispheres, cuboids, and cubes, can be applied to or removed from the surface.
- a partially bioresorbable or biodegradable surface is also feasible.
- the senor or the implant can include a telemetry device which is used to transmit the measured values to an external device.
- the telemetry device can be designed to be bidirectional, thereby making it possible to control the implanted sensor or implant using an external device.
- the sensor or implant can be a subcomponent of a body-area network, i.e. further sensors, which are likewise interconnected via wireless telemetry and/or which communicate with an external device, can detect physiologically relevant parameters in parallel, such as pressure, pulse, EKG, EEG, biochemical parameters, and/or other desirable parameters.
- the invention is also directed to methods for operating medical sensor systems and/or implants such as those described above.
- FIG. 1 a schematic view of an exemplary sensor system according to the invention, shown from above,
- FIG. 2A a schematic view of a cross section along the line II-II through the sensor system depicted in FIG. 1 , with the pores closed,
- FIG. 2B the sensor system depicted in FIG. 2 a with the pores in an open state, for purposes of making a reference measurement
- FIG. 2C the sensor system depicted in FIG. 2 a with the pores in an open state, for purposes of making an analyte measurement
- FIG. 3A a detailed depiction of a pore shown in FIG. 2 a , in the closed state
- FIG. 3B a detailed depiction of a pore shown in FIG. 2 c , in the open state
- FIG. 4 the sensor system depicted in FIG. 1 , including additional components
- FIG. 5A an implant equipped with a sensor system according to FIG. 1 ,
- FIG. 5B an alternative implant equipped with a sensor array having four sensor systems according to FIG. 1 ,
- FIG. 6 a schematic view of a cross section of an alternative sensor system which includes a measurement sensor and a reference sensor having pores which are open to different extents,
- FIG. 7A another alternative implant equipped with a sensor system according to FIG. 6 .
- FIG. 7B a fourth exemplary implant equipped with a sensor array having four sensor systems according to FIG. 6 .
- FIG. 1 schematically depicts the top of a medical sensor system 10 for detecting a feature 12 in a human body (the body not being shown here), with FIGS. 2 a -2 c showing cross-sectional views along the line II-II in FIG. 1 at different times.
- Feature 12 ( FIG. 2 a ) is an analyte 50 in the form of a protein to be detected.
- the sensor system 10 includes a sensor 14 which is disposed in a housing 52 .
- the sensor 14 includes a sensor reservoir 18 that encloses a sample volume 54 within four sides 56 (with only two sides 56 being shown) and a base 58 .
- a detection system 60 is disposed in the reservoir 18 , and includes a receptor layer 28 composed of antibodies to the protein to be detected, or is designed as an antibody layer on a seFET.
- the senor 14 includes a reservoir cap 16 atop the reservoir 18 , with the cap 16 being disposed on or defining a sixth side 62 of the reservoir 18 .
- the cap 16 closes the sample volume 54 , at least in the closed state thereof, whereby neither the feature (analyte) 12 nor the receptor 60 can enter into or emerge from the sample volume 54 .
- This is the preferred state of the sensor system 10 before a first measurement is performed, and between subsequent measurements.
- the cap 16 is designed as a controllable organic membrane 20 that can be reversibly changed between an open state and a closed state.
- the controllable organic membrane 20 includes pores 22 which are distributed homogeneously over the surface and have a diameter 24 that is reversibly changeable. For clarity, only a few pores 22 are shown in FIG. 1 . In addition, the pores 22 are not shown with true dimensions/proportions, but rather are shown enlarged to better illustrate the operation of the sensor system 10 .
- the cap 16 includes a carrier structure 30 for the controllable organic membrane 20 , which is formed by a nanoporous substrate of TiO 2 and therefore has high biocompatibility.
- the carrier structure 30 is formed by nanotubes 64 which extend perpendicularly to the base 58 of the reservoir 18 , and parallel to each other.
- Each nanotube 64 has a nanopore 66 which is permeable for the analyte 50 .
- the size of the nanopores 66 is determined by the feature 12 to be detected; for example, to measure cystatin C, a diameter of approximately 10 nm is preferred, and to measure glucose, a diameter of approximately 1 nm is preferred.
- each nanopore 66 is coated, on a side 70 facing the base 58 (see FIG. 2 a ), with a conductive material 72 (e.g., with gold using a sputtering process).
- the controllable organic membrane 20 is disposed on the surface facing the sample volume 54 .
- the controllable organic membrane 20 is electropolymerized from a solution of its components on the gold surface of the nanopores 66 .
- the controllable organic membrane 20 is preferably formed by an electroactive polymer or material 74 that includes polypyrrole (PPy) 76 and dodecylbenzene sulfonic acid (DBS) 78 (see FIG. 3 ).
- printed conductor tracks 80 are installed on the carrier structure 30 at the level of the gold coating, and are connected to a control unit 82 integrated in the sensor 14 , thereby enabling the controllable organic membrane 20 to be electrically controlled.
- the pore diameter can be easily adjusted, thereby making it possible to provide a large number of different carrier structures 30 which form the basic frameworks for the controllable organic membrane 20 , in a manner tailored to analyte 50 to be used.
- a discussion of carrier/nanotube construction can be found, for example, in Albu et al., “Self-organized, free-standing TiO2 nanotube membrane for flow-through photocatalytic applications,” Nano Lett. 2007 May; 7(5):1286-9 (Epub 2007 Apr. 25). Both this reference and Bauer et al., “TiO2 nanotubes: Tailoring the geometry in H3PO4/HF electrolytes,” Electrochem. Commun.
- the layer thickness of the membrane 20 is much greater (e.g. several 100 ⁇ m) than a diameter of nanotubes 64 .
- the controllable organic membrane 20 includes a material 26 that has a changeable redox state.
- the control unit 82 which includes a reference electrode 84
- An increase in volume causes the nanopores 66 of the carrier structure 30 and the pores 22 of the controllable organic membrane 20 to close completely; conversely, a reduction in volume causes the nanopores 66 and the pores 22 for analyte 50 to open.
- the opening of the nanopores 66 and the pores 22 can also be regulated partially and steplessly (continuously), thereby making it possible to target different analytes 50 .
- the sensor 14 , the controllable organic membrane 20 , and the carrier structure 30 are connected to the housing 52 in such a manner that substance can be exchanged only via the pore membrane and not via binding sites of the components.
- FIGS. 3 a and 3 b show a pore 22 in a closed state ( FIG. 3 a ) and in an open state ( FIG. 3 b ).
- the electroactive polymer 74 is composed of a matrix 86 of cross-linked, positively charged fibers of polypyrrole 76 .
- DBS dodecylbenzene sulfonic acid
- the pores 22 are closed in the following manner
- positively charged, hydrated sodium ions 88 are inserted into the matrix 86 a by applying a voltage (e.g., 2 volts). There, they result in a significant (up to 30%) lateral change in volume of the electroactive polymer 74 .
- This change in volume causes the pores 22 to close and prevents structures from entering the sample volume 54 .
- the process is reversed by applying a voltage having the opposite polarity, which then results in a reduction of the volume of the polymer 74 .
- the reversibility of this procedure makes it possible to repeatedly open and close the pores 22 .
- the volume of the controllable organic membrane 20 can be changed only partially via the extent of the reduction in the volume of the polymer 74 .
- the particular redox states of the electroactive polymer 74 are created using different applied voltages, and can be retained by switching off the applied voltage.
- the sensor system 10 can also be used to perform a quantitative determination of a concentration of the feature 12 of the analyte 50 , as shown in FIGS. 2 b and 2 c .
- Region 32 defines both a first and a second sensor 14 .
- a first diameter 42 of the pores 22 of the controllable organic membrane 20 is adjusted in a first step and, in a second step, a second diameter 44 of the pores 22 is adjusted, with the first diameter 42 being smaller than second diameter 44 .
- a reference measurement is taken with the goal of ascertaining as many interfering signals as possible.
- the first diameter 42 is adjusted specifically such that the feature 12 or the analyte 50 cannot enter sample volume 54 , e.g., to approximately 5 nm. However, smaller molecules, which could hamper the determination of the analyte 50 , are unable to enter.
- an analyte measurement is taken.
- second diameter 44 is enlarged only to the extent needed for the analyte 50 to enter the sample volume 54 in order to be measured (e.g., to approximately 10 nm for the measurement of cystatin C, or to 1 nm for the measurement of glucose). This can take place by applying different voltages, e.g., 1 V for a reference measurement and 1.5 V for the analyte measurement.
- the diameter can be changed in dependence on the duration for which the voltage is applied. Typical values are 4 minutes for the reference measurement and 5 minutes for the analyte measurement.
- the result of the analyte measurement can be corrected by the result of the reference measurement.
- FIG. 4 shows a schematic illustration of the sensor system 10 with enhancements.
- the sensor system 10 includes a control unit 82 with printed conductor tracks 80 and further electronic components (not depicted), a program memory 90 , a telemetry device 92 , and a power supply 94 .
- the telemetry device 92 uses the telemetry device 92 to transmit the values detected by the sensor system 10 to an external device (not depicted).
- the telemetry device 92 is preferably designed for bidirectional communication, thereby enabling the sensor system 10 to be controlled by an external device.
- the sensor system 10 can communicate via the telemetry device 92 with further implanted devices, e.g. to control therapy or drug delivery by these further implanted devices, depending on the sensor values that are measured.
- further sensor systems 10 , 10 ′ can be combined in a medical sensor array 38 .
- a second sensor system 10 ′ can be activated after the use of a first sensor system 10 or once the end of the service life of the first sensor system 10 has been reached.
- FIGS. 5 a and 5 b illustrate the sensor system 10 ( FIG. 5 a ) or the sensor array 38 ( FIG. 5 b ) in a form suitable for implantation in a body by fastening it to a medical implant 40 using an anchoring device (not shown in detail).
- the implant 40 can be, for example, a memory-effect structure such as a stent, or a meandering structure for implantation in an artery or vein (not depicted).
- the anchoring device can be permanent or detachable.
- FIGS. 6, 7 a and 7 b show alternative versions of the sensor system 10 , the sensor array 38 , and the implant 40 .
- Components, features, and functions that are essentially the same as those previously discussed are labeled using the same reference numerals. The description that follows is primarily limited to the differences from the version presented in FIGS. 1-5 , and to the reader is directed to the description of the version shown in FIGS. 1-5 in regard to the components, features, and functions that remain the same.
- FIG. 6 shows a cross section of an alternative medical sensor system 10 for detecting a feature 12 in a human or animal body, including a sensor 14 which includes a receptor layer 28 as its detection system 60 .
- the sensor system 10 includes two different regions 32 , 36 which are provided as a first sensor 14 and s second sensor 34 .
- the sensors 14 , 34 are disposed in a housing 52 such that they are spatially separated from each other (see FIG. 7 a ).
- the first sensor 14 is a measurement sensor 96
- the second sensor 34 is a reference sensor 98 .
- each sensor 14 , 34 includes a reservoir 18 which encloses a sample volume 54 or a reference volume 100 . Each reservoir 18 is closed using a cap 16 .
- Each cap 16 is designed as an electrically controllable organic membrane 20 , 46 that contains an electroactive polymer 74 composed of polypyrrole and dodecylbenzene sulfonic acid (not shown in detail), thereby enabling the redox state of the material 28 of the polymers 74 to be changed.
- an electroactive polymer 74 composed of polypyrrole and dodecylbenzene sulfonic acid (not shown in detail), thereby enabling the redox state of the material 28 of the polymers 74 to be changed.
- the controllable organic membranes 20 , 46 are each applied to a biocompatible carrier structure 30 composed of TiO 2 . They also include the pores 22 , 48 , the diameter of which is reversibly changeable, thereby enabling the controllable organic membranes 20 , 46 to be reversibly changed between an open state and a closed state of reservoir 18 .
- the reference sensor 98 is used to perform a reference measurement which can be used to obtain a background signal for correction of an analyte measurement of the sensor 14 .
- a first diameter 42 of the pore 48 of the controllable organic membrane 46 is adjusted on the controllable organic membrane 46 of the second sensor 34 (the reference sensor 98 ), and a second diameter 44 of the pore 22 of the controllable organic membrane 20 is adjusted on the controllable organic membrane 20 of the first sensor 14 (the measurement sensor 96 ), wherein the first diameter 42 is smaller than the second diameter 44 .
- the first diameter 42 is specifically adjusted such that the feature 12 or the analyte 50 cannot enter the reference volume 100 of the sensor 34 , e.g.
- the second diameter 44 of the pores 22 of the controllable organic membrane 20 of the first sensor 14 is enlarged only to the extent that the analyte 50 can enter the sample volume 54 in order to be determined, e.g. to approximately 10 nm for the measurement of cystatin C or to approximately 1 nm for the measurement of glucose.
- the design of the sensors 14 , 34 during measurement therefore differs merely by the implemented diameter 42 , 44 of the pores 22 , 48 of the controllable organic membranes 20 , 46 .
- a constant voltage e.g. 2 V
- the diameters can be changed by the duration for which the voltage is applied, e.g., 4 minutes for the controllable organic membrane 20 of the first sensor 14 (the measurement sensor 96 ), and 5 minutes for the controllable organic membrane 46 of the second sensor 34 (the reference sensor 98 ).
- the sensors 14 , 34 , the controllable organic membranes 20 , 46 , and the carrier structure 30 are connected to the housing 52 in a manner such that substances can be exchanged only via the pore membranes and not via binding sites of the components.
- controllable organic membranes 20 , 46 it would also be possible to design the controllable organic membranes 20 , 46 as a single membrane having two parts that can be controlled independently of each other.
- a second sensor system 10 ′ can be activated after one or more uses of the first sensor system 10 , or once the end of the service life of the first sensor system 10 has been reached.
- the sensor system 10 ( FIG. 7 a ) or the sensor array 38 ( FIG. 7 b ) can be implanted in a body by fastening it to a medical implant 40 using an anchoring device (not shown in detail).
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Physics & Mathematics (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Optics & Photonics (AREA)
- Chemical & Material Sciences (AREA)
- Surgery (AREA)
- Biophysics (AREA)
- Pathology (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Medical Informatics (AREA)
- Molecular Biology (AREA)
- General Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dispersion Chemistry (AREA)
- Mechanical Engineering (AREA)
- Inorganic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Emergency Medicine (AREA)
- Theoretical Computer Science (AREA)
- Fluid Mechanics (AREA)
- Measurement Of The Respiration, Hearing Ability, Form, And Blood Characteristics Of Living Organisms (AREA)
Abstract
Description
- This is a continuation of U.S. Utility patent application Ser. No. 13/2489095 filed Sep. 29, 2011 now U.S. Pat. No. 9,687,182, which in turn claims the benefit of U.S. Provisional Patent Application No. 61/390,621, filed on Oct. 7, 2011. Both of these prior applications are hereby incorporated by reference in their entireties.
- The invention relates to a medical sensor system for detecting at least one feature in at least one human and/or animal body.
- In medicine, sensor systems are used wherein at least parts of the systems are inserted or implanted directly in a body of a patient in order to capture actual physiological conditions as precisely and directly as possible.
- Publication WO 2008/154416 A2, in combination with U.S. Pat. No. 6,527,762 B1, discloses a sensor that can be implanted in the body, wherein a sensor has a reservoir capped by a thin metal film. By use of a thermal process wherein a voltage is applied, the cap is irreversibly removed to expose the interior of the sensor. The sensor's interior is continually subjected to degradation processes, and moreover, pieces of the metal film can enter the body, which can be harmful.
- The invention seeks to provide a medical sensor system for detecting a feature in a body, and which can be flexibly used, and implemented in a robust manner that is resistant to error. In this context, “sensor” refers to a component that can detect a physical and/or chemical property of a parameter in the sensor's environment, qualitatively and/or chemical property of a parameter in the sensor's environment, qualitatively and/or quantitatively, preferably as a quantity to be measured. A “sensor system” refers to a system having at least one sensor, and which can include further components, such as further sensors, a housing, electronic components, a power supply, a telemetry unit, a control unit, an anchoring device, and/or any other suitable component. A “feature” refers to a parameter such as a pH value, a charge (e.g. of an ion or a polyelectrolyte), a temperature, a mass, an aggregation state, water content, hematocrit value, and/or a presence or absence and/or a quantity of an analyte or other substance (such as a fat, a salt, an ion, a polyelectrolyte, a sugar, a nucleotide, DNA, RNA, a peptide, a protein, an antibody, an antigen, a drug, a toxin, a hormone, a neurotransmitter, a metabolite, a metabolic product, and/or any other analyte of interest). A “feature” also refers to so-called biomarkers which form a variable component of the human or animal body, such as albumins/globulins, alkaline phosphatase, alpha-1-globulin, alpha-2-globulin, alpha-1-antitrypsin, alpha-1-fetoprotein, alpha-amylases, alpha-hydroxybutyrate-dehydrogenase, is ammonia, antithrombin III, bicarbonate, bilirubin, carbohydrate antigen 19-9, carcinoembryonic antigens, chloride, cholesterol, cholinesterase, cobalamin/vitamin B12, coeruloplasmin, C-reactive proteins, cystatin C, D-dimers, iron, erythropoetin, erythrocytes, ferritin, fetuin-A fibrinogen, folic acid/vitamin B9, free tetrajodthyronine (fT4), free trijodthyronine (fT3), gamma-glutamyl transferase, glucose, glutamate dehydrogenase, glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, glycohemoglobin, hematocrit, hemoglobin, haptoglobin, uric acid, urea, HDL cholesterol, homocysteine, immunoglobulin A, immunoglobulin E, immunoglobulin G, immunoglobulin M, INR, calium, calcium, creatinine, creatine kinase, copper, lactate, lactate dehydrogenase, LDL cholesterol, leukocytes, lipase, lipoprotein, magnesium, corpuscular hemoglobins, myoglobin, sodium, NT-proBNP/BNP, phosphate, prostate-specific antigens, reticulocytes, thrombocytes, transferrin, triglycerides, troponin T, or drugs such as muscarinic receptor antagonists, neuromuscular blocking substances, cholesterol esterase inhibitors, adrenoceptor agonists, indirectly acting sympathomimetics, methylxanthine, alpha-adrenoreceptor antagonists, ergot alkaloids, beta-adrenoceptor antagonists, inactivation inhibitors, antisympathonics, 5-HT receptor agonists, histamine receptor agonists, histamine receptor antagonists, analgesics, local anesthetics, sedatives, anticonvulsants, convulsants, muscle relaxants, antiparkinsonians, neuroleptics, antidepressants, lithium, tranquillizers, immunsuppressants, antirheumatics, antiarrhythmics, antibiotics, ACE inhibitors, aldosterone receptor antagonists, diuretics, vasodilatators, positive inotropic substances, antithrombotic/thrombolytic substances, laxatives, antidiarrheal agents, pharmaceuticals for adiposity, uricostatics, uricosurics, antilipemics, antidiabetics, antithypoglycemia, hormones, iodized salts, threostatics, iron, vitamins, trace elements, virostatics, antimycotics, antituberculotics, and substances for tumor chemotherapy. However, any other feature of interest for detection can be detected by the sensor system. The feature preferably relates to a variable component of the animal body and/or human body. A preferred version of the sensor system is used to detect a member of the cystatin family of the cysteine protease inhibitors, particularly to detect cystatin C.
- The sensor system includes at least one sensor and at least one cap of a reservoir of the sensor, wherein the cap is designed as a controllable organic membrane. “Reservoir of the sensor” or “sensor reservoir” refers to a space, a chamber, and/or a cavity of the sensor in contact with a detection system of the sensor, and/or on and preferably in which the detection system is disposed. Furthermore, the sensor reservoir encloses a volume that contains or has the feature to be detected. “Cap” refers to a device and/or a component of the sensor reservoir that closes the sensor reservoir in at least one operating state of the sensor system, and/or prevents the sample volume from entering into and/or emerging from the sensor reservoir. The cap is therefore a functional component of the sensor. “Controllable” is intended to mean that the membrane can be switched via at least one signal from at least one selected starting state to a selected end state. The signal is an influence that can act from outside of the sensor system, such as radiation, infrared, visible light, ultrasound, an electrical field, a magnetic field, a protein, a peptide, a polyelectrolyte, a change in a pH value, a change in ion concentration, a temperature change, and/or any other effect suitable for use as a signal. Preferably, a volume of the membrane can be controlled. The term “organic membrane” refers to a separating layer and/or a thin film which includes at least one component based on a carbon compound.
- The controllable organic membrane can change its state in response to the triggering signal in a manner such that at least a portion of the membrane is permeable to the analyte, thereby providing the analyte with access to the detection system. Moreover, the controllable organic membrane can be changed, reversibly and steplessly, between an open state and a closed state of the reservoir. “Steplessly” refers to the possibility of adjusting the opening width of the membrane to any width up to a maximum limit. “Reversibly” means in a manner than can be reversed. By making it possible to reverse the change, the detection system disposed in the sensor reservoir can be protected against interfering molecules that could attack, degrade, and/or destroy the sensor. Other interfering factors that can impair the proper functioning of the sensor are also minimized in this manner As a result, a sensor system having a particularly long service life can be provided.
- The controllable organic membrane is advantageously closed before an initial use or an initial measurement run of the sensor, thereby effectively protecting the sensor against disturbing influences such as dirt, dust, excessive humidity, dryness, temperature fluctuations, and/or harmful molecules before initial start-up. It is additionally advantageous when the controllable organic membrane can be closed between the individual measurements, thereby ensuring that the components of the sensor system can remain stable.
- The controllable organic membrane includes at least one pore, the diameter of which can be changed in a reversible manner, whereby the state of the membrane (and passage of an analyte into the sample volume) can be structurally adapted to allow passage of different molecules and/or analytes. Preferably, at least one of the opening of the pore and the closing of the pore can be controlled. The pore is preferably a nanopore with a maximum diameter of approximately 1 μm. The pores need not have a round shape/contour, and can alternatively or additionally have oval, triangular, square, or other polygonal shapes, star-shapes, or any other desirable shapes. The nanopores make it easy to prevent structures such as cells, large molecules, or molecular aggregates having a greater dimension than the diameter of the nanopores from entering the sample volume from the sensor's environment and interfering with the detection system. The membrane preferably includes a large number of similar pores that are distributed evenly over a surface of the membrane, though an inhomogeneous pore distribution is also possible. Preferably the pore diameter is steplessly adjustable, which enables it to be used with a large number of analytes.
- The controllable organic membrane preferably includes at least one material that has a changeable redox (reduction of oxidation) state, enabling the permeability of the membrane to be easily and reliably changed. The redox state can be changed chemically, electrically, and/or via other means.
- For simplicity and convenience, it is useful if the controllable organic membrane is electrically controllable, in particular, if the pores (e.g., their size and/or shape) are electrically controllable. In preferred versions of the invention, this occurs by applying a voltage of approximately 2 V at most. When the nanopores are fully open, the volume of the material having the changeable redox state is at its minimum. When a voltage is applied, the volume of the material changes, thereby reducing the pore diameter. The volume increase may usefully be made dependent on the level of the voltage that is applied for a certain period of time, or on the period of time during which a certain voltage is applied; in either case, the voltage need be applied only for a certain period of time, and need not be constantly maintained to effect a change in pore size. The procedure may then be reversed by applying a voltage with reverse polarity, or by use of analogous methods, resulting in a reduction of the volume of the material. The change in volume is dependent on the structural design of the membrane as well as its materials and the stimulus applied to effect the change.
- The material that can change its redox state is preferably an electroactive polymer or other material. As an example, if a mixture of polypyrrole (PPy) and dodecylbenzene sulfonic acid (DBS) is used as the electroactive polymer, sodium ions are inserted into the polymer during a voltage-controlled reduction of the polymer. This insertion of sodium ions induces a strongly lateral change in volume of the electroactive polymer, which therefore closes the pores for the analyte. The reversibility of this procedure allows controlled opening and closing of the pores, and therefore controlled and repeatable sensor measurements. The volume of the polymer can be partially changed via the extent of the reduction of the polymer. The redox states of the electroactive polymer are created using different applied voltages, and are retained when the voltage is switched off. As a result, the polymer and pore diameter can be advantageously adjusted for analytes of different sizes.
- The detection system includes a receptor layer that brings about a measurable reaction with the feature to be measured, thereby allowing detection of the feature to be measured. The “receptor” can be one or more substances chosen from the classes of peptides, proteins (in particular enzymes), antibodies and their fragments, RNA, DNA, nucleotides, fats, sugars, salts, ions, cyclic macromolecules (such as ionophores, crown ethers, and cryptands), acyclic macromolecules, or other suitable substances. The receptor layer is preferably an antibody layer on a seFET (single electron Field Effect Transistor).
- In a preferred version of the invention, the membrane, or the polymer or other material therein which has a changeable redox state, is applied to a nanoporous substance which defines a carrier structure. Preferably, the membrane or the material having the changeable redox state is disposed at least on inner surface of the pores of the nanoporous substance. As a result, the nanopores of the carrier structure can be used as the basic framework of the pore structure. The pore diameter is dependent on the analyte to be detected. Preferably, the pore diameter is selected such that the membrane is permeable to molecules of the analyte, but poses a barrier for larger molecules. If the analyte to be detected is a protein (or an analyte of similar size), the pores might have a maximum diameter of 1 um, preferably a maximum of 250 nm, furthermore preferably 100 nm, advantageously a maximum of 50 nm, and particularly preferably a maximum of 10 nm. For smaller analytes, the pores can have a maximum diameter of 500 nm, preferably a maximum of 100 nm, furthermore preferably 50 nm, advantageously a maximum of 10 nm, and particularly preferably a maximum of 1 nm. The pores may assume any shape wherein the maximum dimension is sized as described above.
- The nanoporous substance preferably contains a metal oxide such as Al2O3, In2O3, MgO, ZnO, CeO2 Co3O4, and/or the carrier structure at least contains TiO2, though other nanoporous substances could be used. TiO2 allows a particularly lightweight, biocompatible, and bioinert carrier structure. In addition, the nanopore structure may be composed of nanotubes for easy and reproducible synthesis. These highly regular structures can be created relatively easily using an anodizing process. The pore size and layer thickness of this substrate can be easily adjusted by appropriate selection of manufacturing process parameters. The carrier structure thickness of hundreds of micrometers is typically much greater than the diameter of the nanotubes.
- The controllable organic membrane preferably has at least one structure on the top side thereof that prevents the adhesion of cells and molecules, to prevent biofouling. As an example, TiO2 nanostructures (as discussed above) can themselves prevent cell adhesion.
- Preferably, the complete sensor system is biologically degradable so that it need not be removed from the patient's body once it loses functionality, thereby avoiding the need for invasive explantation procedures. Complete biodegradability also avoids the presence of potentially harmful substances within the patient's body, as may be the case where a non-biocompatible and degradable sensor were used. It is particularly advantageous if the controllable organic membrane is installed on a carrier structure that has high biocompatibility, thereby making it possible to minimize or entirely prevent rejection reactions and inflammatory responses that may affect patient health.
- The sensor is preferably designed to determine the feature in a quantitative manner, whereby it may determine the concentration of an analyte in (for example) bodily fluids such as blood, urine, interstitial fluid or lacrimal fluid.
- Where the sensor system incorporates two or more sensors for two or more different analytes or other features, space and components savings can be achieved where the sensors are provided at the same region. To illustrate, a first sensor may be designed as a measurement sensor, and a second sensor may be designed as a reference sensor, wherein the two of them form a single piece. (In this context, “single piece” means that the measurement sensor and the reference sensor are defined by the same components, and/or that functionality would be lost if the two were separated.) The sensor reservoir is designed such that it is used in a first mode to perform a reference measurement, and in a second mode which takes place subsequently to the first mode to measure the analyte. To perform the reference measurement, a pore size is selected that is smaller than a diameter of the analyte, thereby preventing the analyte from entering the sample volume. However, molecules or structures that are smaller than the analyte can enter the sample volume. To perform the analyte measurement, the pore size can then be adapted to the size of the analyte, thereby enabling the analyte to enter the sample volume. The measurement signal of the reference measurement can then be subtracted as a background signal (or otherwise removed) from the measurement signal of the analyte measurement to provide a final measured value. Thus, the background signal caused by interfering matter can be easily determined by use of a simple design.
- Another version of the sensor system uses first and second sensors at two different regions, thereby making it possible to measure the analyte and perform the reference measurement simultaneously for time savings. The first (measurement) sensor and the second (reference) sensor are preferably disposed in the sensor system such that they are spatially separated. Any type of suitable sensor can be used for the second sensor, though the second sensor preferably includes a reference reservoir which encloses a reference volume, and a (preferably electrically) switchable organic membrane. The two sensors preferably differ in terms of the configuration of their switchable membranes and in terms of the pore sizes implemented therein. The membrane pore size of the first (measurement) sensor allows the analyte to enter the sample volume. A smaller pore size in the second (reference) sensor prevents the analyte from entering the reference volume. The final measured value is obtained by correcting the measurement sensor signal using the reference signal. The different porosities of the measurement sensor and the reference sensor are selected by using different voltage levels and/or by applying the voltage to the sensors' membranes for different durations.
- This design has the advantage that drift and aging processes occur simultaneously in both sensors, and where the measurement sensor and the reference sensor are configured with at least substantially the same detection system, it is possible to collect information on the drift (e.g. degradation of the detection system, change in temperature, and other effects) of one sensor with respect to the other. The measured values can be corrected for drift by using a suitable correction term, or can be compensated for by using a suitable electrical, mechanical, chemical/biochemical, or other method. If the drift is so great that these mechanisms are no longer effective, then sensors installed in parallel with the “aged” sensors, which were previously left dormant, might be activated.
- The invention also involves a medical sensor array having at least two sensor systems. They can be identically-configured sensor systems that are activated in succession to detect, or determine the concentration of, the same analyte. Alternatively or additionally, the sensor systems can be used simultaneously to measure the analyte and also perform a reference measurement. Another alternative or additional arrangement is to have an array of sensor systems that can detect different analytes and/or their concentrations, either simultaneously or in succession. The use of several sensor systems can allow an effective extension of the limited service life of a single sensor system.
- The invention also involves a medical implant which incorporates the medical sensor system, or an array of such systems. The sensor system can be used in any suitable implant, such as an implant for recording physiological parameters, a cardiac pacemaker, a defibrillator, a brain pacemaker, a renal pacemaker, a duodenal pacemaker, a cardiac implant, artificial heart valves, a cochlear implant, a retinal implant, a dental implant, an implant for joint replacement, a vascular prosthesis, a drug delivery system, or particularly advantageously, a stent, such as a coronary stent, a renal artery stent, or a ureteral stent. The sensor system can assist in the function of such implants.
- At least a part of the surface of the implant can have hydrophobic or hydrophilic properties, and it can have a cationic, anionic, or metallic character, depending on the implant's usage. Inorganic or organic molecules can be bonded to the surface via physical adsorption or covalent bonds such as polymers, peptides, proteins, aptamers, molecularly imprinted polymers, RNA, DNA, siRNA, and nanoparticles. The surface can have nanostructuring or microstructuring. To provide the surface structure, round, spherical, cylindrical, conical, square, rectangular, or elongated structures, including grooves, tubes, solid cylinders, hollow cylinders, balls, hemispheres, cuboids, and cubes, can be applied to or removed from the surface. A partially bioresorbable or biodegradable surface is also feasible.
- It is also possible to attract and immobilize specific structures, e.g. from a bodily fluid, such as certain proteins or cells, on the surface and incite the cells to proliferate. For this purpose, antigens, peptides, proteins, antibodies, aptamers, molecularly imprinted polymers and oligonucleotides (DNA, RNA, PNA, LNA) can be adhered or covalently bound to the surface.
- Furthermore, the sensor or the implant can include a telemetry device which is used to transmit the measured values to an external device. The telemetry device can be designed to be bidirectional, thereby making it possible to control the implanted sensor or implant using an external device. The sensor or implant can be a subcomponent of a body-area network, i.e. further sensors, which are likewise interconnected via wireless telemetry and/or which communicate with an external device, can detect physiologically relevant parameters in parallel, such as pressure, pulse, EKG, EEG, biochemical parameters, and/or other desirable parameters.
- The invention is also directed to methods for operating medical sensor systems and/or implants such as those described above.
- Exemplary versions of the invention will now be discussed with reference to the figures, which illustrate:
-
FIG. 1 a schematic view of an exemplary sensor system according to the invention, shown from above, -
FIG. 2A a schematic view of a cross section along the line II-II through the sensor system depicted inFIG. 1 , with the pores closed, -
FIG. 2B the sensor system depicted inFIG. 2a with the pores in an open state, for purposes of making a reference measurement, -
FIG. 2C the sensor system depicted inFIG. 2a with the pores in an open state, for purposes of making an analyte measurement, -
FIG. 3A a detailed depiction of a pore shown inFIG. 2a , in the closed state, -
FIG. 3B a detailed depiction of a pore shown inFIG. 2c , in the open state, -
FIG. 4 the sensor system depicted inFIG. 1 , including additional components, -
FIG. 5A an implant equipped with a sensor system according toFIG. 1 , -
FIG. 5B an alternative implant equipped with a sensor array having four sensor systems according toFIG. 1 , -
FIG. 6 a schematic view of a cross section of an alternative sensor system which includes a measurement sensor and a reference sensor having pores which are open to different extents, -
FIG. 7A another alternative implant equipped with a sensor system according toFIG. 6 , and -
FIG. 7B a fourth exemplary implant equipped with a sensor array having four sensor systems according toFIG. 6 . - In the figures, functionally equivalent or equivalently acting elements are denoted with the same reference numerals. The figures are schematic illustrations of the invention, and do not depict specific parameters. In addition, the figures only reflect exemplary versions of the invention and are not intended to limit the invention to the versions that are illustrated. So as to avoid unnecessary repetitions, elements in a particular figure that are not described in detail below are provided with a reference to the respective description of the elements in the preceding figures.
-
FIG. 1 schematically depicts the top of amedical sensor system 10 for detecting a feature 12 in a human body (the body not being shown here), withFIGS. 2a-2c showing cross-sectional views along the line II-II inFIG. 1 at different times. Feature 12 (FIG. 2a ) is an analyte 50 in the form of a protein to be detected. Thesensor system 10 includes asensor 14 which is disposed in ahousing 52. As shown inFIG. 2a , thesensor 14 includes a sensor reservoir 18 that encloses asample volume 54 within four sides 56 (with only twosides 56 being shown) and abase 58. A detection system 60 is disposed in the reservoir 18, and includes a receptor layer 28 composed of antibodies to the protein to be detected, or is designed as an antibody layer on a seFET. - In addition, the
sensor 14 includes areservoir cap 16 atop the reservoir 18, with thecap 16 being disposed on or defining asixth side 62 of the reservoir 18. Thecap 16 closes thesample volume 54, at least in the closed state thereof, whereby neither the feature (analyte) 12 nor the receptor 60 can enter into or emerge from thesample volume 54. This is the preferred state of thesensor system 10 before a first measurement is performed, and between subsequent measurements. Thecap 16 is designed as a controllableorganic membrane 20 that can be reversibly changed between an open state and a closed state. For this purpose, the controllableorganic membrane 20 includespores 22 which are distributed homogeneously over the surface and have adiameter 24 that is reversibly changeable. For clarity, only afew pores 22 are shown inFIG. 1 . In addition, thepores 22 are not shown with true dimensions/proportions, but rather are shown enlarged to better illustrate the operation of thesensor system 10. - Moreover, the
cap 16 includes acarrier structure 30 for the controllableorganic membrane 20, which is formed by a nanoporous substrate of TiO2 and therefore has high biocompatibility. Thecarrier structure 30 is formed bynanotubes 64 which extend perpendicularly to thebase 58 of the reservoir 18, and parallel to each other. Eachnanotube 64 has ananopore 66 which is permeable for the analyte 50. The size of thenanopores 66 is determined by the feature 12 to be detected; for example, to measure cystatin C, a diameter of approximately 10 nm is preferred, and to measure glucose, a diameter of approximately 1 nm is preferred. Theinner surface 68 of eachnanopore 66 is coated, on aside 70 facing the base 58 (seeFIG. 2a ), with a conductive material 72 (e.g., with gold using a sputtering process). The controllableorganic membrane 20 is disposed on the surface facing thesample volume 54. The controllableorganic membrane 20 is electropolymerized from a solution of its components on the gold surface of thenanopores 66. The controllableorganic membrane 20 is preferably formed by an electroactive polymer or material 74 that includes polypyrrole (PPy) 76 and dodecylbenzene sulfonic acid (DBS) 78 (seeFIG. 3 ). To control the controllableorganic membrane 20, printed conductor tracks 80 are installed on thecarrier structure 30 at the level of the gold coating, and are connected to acontrol unit 82 integrated in thesensor 14, thereby enabling the controllableorganic membrane 20 to be electrically controlled. - When manufacturing the
carrier structure 30 or thenanotubes 64, the pore diameter can be easily adjusted, thereby making it possible to provide a large number ofdifferent carrier structures 30 which form the basic frameworks for the controllableorganic membrane 20, in a manner tailored to analyte 50 to be used. A discussion of carrier/nanotube construction can be found, for example, in Albu et al., “Self-organized, free-standing TiO2 nanotube membrane for flow-through photocatalytic applications,” Nano Lett. 2007 May; 7(5):1286-9 (Epub 2007 Apr. 25). Both this reference and Bauer et al., “TiO2 nanotubes: Tailoring the geometry in H3PO4/HF electrolytes,” Electrochem. Commun. 2006, 8, 1321-1325 (which is cited in Albu et al) discuss how the geometry of the nanotubes can be tailored during the formation process. The layer thickness of themembrane 20 is much greater (e.g. several 100 μm) than a diameter ofnanotubes 64. - Due to the electroactive polymer 74, the controllable
organic membrane 20 includes a material 26 that has a changeable redox state. As a result, it is possible to change or control the redox states via contacts between theconductive material 72 and the control unit 82 (which includes a reference electrode 84), and therefore change or control the volume of the electroactive polymer 74 or the controllableorganic membrane 20. An increase in volume causes thenanopores 66 of thecarrier structure 30 and thepores 22 of the controllableorganic membrane 20 to close completely; conversely, a reduction in volume causes thenanopores 66 and thepores 22 for analyte 50 to open. Since the reduction of oxidation of the electroactive polymer 74 can take place to a partial extent, the opening of thenanopores 66 and thepores 22 can also be regulated partially and steplessly (continuously), thereby making it possible to target different analytes 50. - The
sensor 14, the controllableorganic membrane 20, and thecarrier structure 30 are connected to thehousing 52 in such a manner that substance can be exchanged only via the pore membrane and not via binding sites of the components. -
FIGS. 3a and 3b show apore 22 in a closed state (FIG. 3a ) and in an open state (FIG. 3b ). The electroactive polymer 74 is composed of amatrix 86 of cross-linked, positively charged fibers ofpolypyrrole 76. During polymerization, when the gold layer is being applied, negatively charged dodecylbenzene sulfonic acid (DBS)molecules 78 are inserted into thematrix 86 and, due to their size, are unable to diffuse out of thematrix 86, and represent the negatively charged counterions to the positively chargedmatrix 86 of thepolypyrrole 76. When thepolypyrrole 76 is fully reduced, it becomes electrically neutral. - The
pores 22 are closed in the following manner To compensate for the negative charge of theDBS molecules 78, positively charged, hydratedsodium ions 88 are inserted into thematrix 86 a by applying a voltage (e.g., 2 volts). There, they result in a significant (up to 30%) lateral change in volume of the electroactive polymer 74. This change in volume causes thepores 22 to close and prevents structures from entering thesample volume 54. The process is reversed by applying a voltage having the opposite polarity, which then results in a reduction of the volume of the polymer 74. The reversibility of this procedure makes it possible to repeatedly open and close thepores 22. Furthermore, the volume of the controllableorganic membrane 20 can be changed only partially via the extent of the reduction in the volume of the polymer 74. The particular redox states of the electroactive polymer 74 are created using different applied voltages, and can be retained by switching off the applied voltage. - The
sensor system 10 can also be used to perform a quantitative determination of a concentration of the feature 12 of the analyte 50, as shown inFIGS. 2b and 2c .Region 32 defines both a first and asecond sensor 14. To detect the feature 12, afirst diameter 42 of thepores 22 of the controllableorganic membrane 20 is adjusted in a first step and, in a second step, asecond diameter 44 of thepores 22 is adjusted, with thefirst diameter 42 being smaller thansecond diameter 44. In the first step, a reference measurement is taken with the goal of ascertaining as many interfering signals as possible. Thefirst diameter 42 is adjusted specifically such that the feature 12 or the analyte 50 cannot entersample volume 54, e.g., to approximately 5 nm. However, smaller molecules, which could hamper the determination of the analyte 50, are unable to enter. In the second step, an analyte measurement is taken. In this case,second diameter 44 is enlarged only to the extent needed for the analyte 50 to enter thesample volume 54 in order to be measured (e.g., to approximately 10 nm for the measurement of cystatin C, or to 1 nm for the measurement of glucose). This can take place by applying different voltages, e.g., 1 V for a reference measurement and 1.5 V for the analyte measurement. As an alternative, if a constant voltage is applied (e.g. 2 V), the diameter can be changed in dependence on the duration for which the voltage is applied. Typical values are 4 minutes for the reference measurement and 5 minutes for the analyte measurement. To obtain a final measured result of the concentration of the analyte 50, the result of the analyte measurement can be corrected by the result of the reference measurement. -
FIG. 4 shows a schematic illustration of thesensor system 10 with enhancements. In addition to the first (measurement) and second (reference)sensors sensor system 10 includes acontrol unit 82 with printed conductor tracks 80 and further electronic components (not depicted), aprogram memory 90, atelemetry device 92, and apower supply 94. Using thetelemetry device 92, the values detected by thesensor system 10 can be transmitted to an external device (not depicted). Thetelemetry device 92 is preferably designed for bidirectional communication, thereby enabling thesensor system 10 to be controlled by an external device. Furthermore, thesensor system 10 can communicate via thetelemetry device 92 with further implanted devices, e.g. to control therapy or drug delivery by these further implanted devices, depending on the sensor values that are measured. - As shown in
FIG. 5b ,further sensor systems medical sensor array 38. In that case, asecond sensor system 10′ can be activated after the use of afirst sensor system 10 or once the end of the service life of thefirst sensor system 10 has been reached. -
FIGS. 5a and 5b illustrate the sensor system 10 (FIG. 5a ) or the sensor array 38 (FIG. 5b ) in a form suitable for implantation in a body by fastening it to amedical implant 40 using an anchoring device (not shown in detail). Theimplant 40 can be, for example, a memory-effect structure such as a stent, or a meandering structure for implantation in an artery or vein (not depicted). The anchoring device can be permanent or detachable. -
FIGS. 6, 7 a and 7 b show alternative versions of thesensor system 10, thesensor array 38, and theimplant 40. Components, features, and functions that are essentially the same as those previously discussed are labeled using the same reference numerals. The description that follows is primarily limited to the differences from the version presented inFIGS. 1-5 , and to the reader is directed to the description of the version shown inFIGS. 1-5 in regard to the components, features, and functions that remain the same. -
FIG. 6 shows a cross section of an alternativemedical sensor system 10 for detecting a feature 12 in a human or animal body, including asensor 14 which includes a receptor layer 28 as its detection system 60. Thesensor system 10 includes twodifferent regions first sensor 14 and ssecond sensor 34. Thesensors housing 52 such that they are spatially separated from each other (seeFIG. 7a ). Thefirst sensor 14 is a measurement sensor 96, and thesecond sensor 34 is a reference sensor 98. Furthermore, eachsensor sample volume 54 or areference volume 100. Each reservoir 18 is closed using acap 16. Eachcap 16 is designed as an electrically controllableorganic membrane - The controllable
organic membranes biocompatible carrier structure 30 composed of TiO2. They also include thepores organic membranes - The reference sensor 98 is used to perform a reference measurement which can be used to obtain a background signal for correction of an analyte measurement of the
sensor 14. For this purpose, in order to detect the feature 12, afirst diameter 42 of thepore 48 of the controllableorganic membrane 46 is adjusted on the controllableorganic membrane 46 of the second sensor 34 (the reference sensor 98), and asecond diameter 44 of thepore 22 of the controllableorganic membrane 20 is adjusted on the controllableorganic membrane 20 of the first sensor 14 (the measurement sensor 96), wherein thefirst diameter 42 is smaller than thesecond diameter 44. Thefirst diameter 42 is specifically adjusted such that the feature 12 or the analyte 50 cannot enter thereference volume 100 of thesensor 34, e.g. approximately 5 nm when cystatin C is measured, and is less than 1 nm when glucose is measured. Smaller molecules, which could hamper the determination of the analyte 50, are unable to enter, however. Thesecond diameter 44 of thepores 22 of the controllableorganic membrane 20 of the first sensor 14 (the measurement sensor 96) is enlarged only to the extent that the analyte 50 can enter thesample volume 54 in order to be determined, e.g. to approximately 10 nm for the measurement of cystatin C or to approximately 1 nm for the measurement of glucose. The design of thesensors diameter pores organic membranes organic membrane 20 of the first sensor 14 (the measurement sensor 96), and 1.5 V to the controllableorganic membrane 46 of the second sensor 34 (the reference sensor 98). As an alternative, if a constant voltage is applied (e.g. 2 V), the diameters can be changed by the duration for which the voltage is applied, e.g., 4 minutes for the controllableorganic membrane 20 of the first sensor 14 (the measurement sensor 96), and 5 minutes for the controllableorganic membrane 46 of the second sensor 34 (the reference sensor 98). - The
sensors organic membranes carrier structure 30 are connected to thehousing 52 in a manner such that substances can be exchanged only via the pore membranes and not via binding sites of the components. - It would also be possible to design the controllable
organic membranes -
Several sensor systems medical sensor array 38, as shown inFIG. 7b . In this case, asecond sensor system 10′ can be activated after one or more uses of thefirst sensor system 10, or once the end of the service life of thefirst sensor system 10 has been reached. - As implied by
FIGS. 7a and 7b , the sensor system 10 (FIG. 7a ) or the sensor array 38 (FIG. 7b ) can be implanted in a body by fastening it to amedical implant 40 using an anchoring device (not shown in detail). - It will be apparent to those skilled in the art that numerous modifications and variations of the described examples and versions of the invention are possible in light of the foregoing discussion. The described examples and versions are presented for purposes of illustration only, and it is the intent to cover all such modifications and alternate versions that come within the scope of the claims below, or which are legally equivalent thereto.
Claims (20)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15/631,823 US20170354360A1 (en) | 2010-10-07 | 2017-06-23 | Medical sensor system for detecting a feature in a body |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US39062110P | 2010-10-07 | 2010-10-07 | |
US13/248,095 US9687182B2 (en) | 2010-10-07 | 2011-09-29 | Medical sensor system for detecting a feature in a body |
US15/631,823 US20170354360A1 (en) | 2010-10-07 | 2017-06-23 | Medical sensor system for detecting a feature in a body |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/248,095 Continuation US9687182B2 (en) | 2010-10-07 | 2011-09-29 | Medical sensor system for detecting a feature in a body |
Publications (1)
Publication Number | Publication Date |
---|---|
US20170354360A1 true US20170354360A1 (en) | 2017-12-14 |
Family
ID=44719673
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/248,095 Active 2036-04-27 US9687182B2 (en) | 2010-10-07 | 2011-09-29 | Medical sensor system for detecting a feature in a body |
US15/631,823 Abandoned US20170354360A1 (en) | 2010-10-07 | 2017-06-23 | Medical sensor system for detecting a feature in a body |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/248,095 Active 2036-04-27 US9687182B2 (en) | 2010-10-07 | 2011-09-29 | Medical sensor system for detecting a feature in a body |
Country Status (2)
Country | Link |
---|---|
US (2) | US9687182B2 (en) |
EP (1) | EP2438861B1 (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9444030B2 (en) * | 2013-05-10 | 2016-09-13 | Wisconsin Alumni Research Foundation | Nanoporous piezoelectric polymer films for mechanical energy harvesting |
GB2520921A (en) * | 2013-10-14 | 2015-06-10 | Phillipa Kay Scott | Protein monitor and correcting device |
US10629800B2 (en) | 2016-08-05 | 2020-04-21 | Wisconsin Alumni Research Foundation | Flexible compact nanogenerators based on mechanoradical-forming porous polymer films |
US11077475B2 (en) | 2017-05-23 | 2021-08-03 | International Business Machines Corporation | Neuro-chemical sensor with inhibition of fouling on nano-electrode |
US10583282B2 (en) | 2017-11-13 | 2020-03-10 | International Business Machines Corporation | Neuro-stem cell stimulation and growth enhancement with implantable nanodevice |
US11627915B2 (en) | 2018-12-12 | 2023-04-18 | Lucas J. Myslinski | Device, method and system for implementing a physical area network for detecting head injuries |
US11395930B2 (en) | 2018-12-12 | 2022-07-26 | Lucas J. Myslinski | Device, method and system for implementing a physical area network for detecting effects of the sun |
US10265017B1 (en) | 2018-12-12 | 2019-04-23 | Lucas J. Myslinski | Device, method and system for implementing a physical area network for cancer immunotherapy |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20010029348A1 (en) * | 1999-02-18 | 2001-10-11 | Bio Valve Technologies, Inc., Delaware Corporation | Electroactive pore |
US20060057737A1 (en) * | 2004-09-01 | 2006-03-16 | Santini John T Jr | Multi-cap reservoir devices for controlled release or exposure of reservoir contents |
US20090326279A1 (en) * | 2005-05-25 | 2009-12-31 | Anna Lee Tonkovich | Support for use in microchannel processing |
US20100241086A1 (en) * | 2006-09-29 | 2010-09-23 | Ofer Yodfat | Flluid deliver system with electrochemical sensing of analyte concentration levels |
US9492109B2 (en) * | 2010-10-07 | 2016-11-15 | Biotronik Se & Co. Kg | Medical sensor system |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5290240A (en) | 1993-02-03 | 1994-03-01 | Pharmetrix Corporation | Electrochemical controlled dispensing assembly and method for selective and controlled delivery of a dispensing fluid |
DE19853286B4 (en) * | 1998-11-19 | 2005-03-03 | Gesellschaft für Schwerionenforschung mbH | Method for controlling a chemical valve |
DE60018582T2 (en) | 1999-08-18 | 2006-01-19 | Microchips, Inc., Bedford | THERMALLY ACTIVATABLE MICROCHIP AS CHARGING DEVICE FOR CHEMICALS |
CA2386151A1 (en) | 1999-10-12 | 2001-04-19 | Marc Madou | Reactive polymeric valve, dispensing devices and methods using same |
WO2001064344A2 (en) * | 2000-03-02 | 2001-09-07 | Microchips, Inc. | Microfabricated devices for the storage and selective exposure of chemicals and devices |
DE10044565B4 (en) | 2000-09-08 | 2005-06-30 | Gesellschaft für Schwerionenforschung mbH | An electrolytic cell, its use and method of etching a membrane clamped in the cell, and methods of switching an etched cell clamped membrane from pass-to-pass and vice versa |
CA2545715C (en) * | 2003-11-13 | 2012-10-16 | Medtronic Minimed, Inc. | Long term analyte sensor array |
US8273075B2 (en) | 2005-12-13 | 2012-09-25 | The Invention Science Fund I, Llc | Osmotic pump with remotely controlled osmotic flow rate |
DE102006025344A1 (en) * | 2006-05-31 | 2007-12-06 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Arrangement of a biologically functional membrane, sensor arrangement, filter arrangement and their uses |
JP2009544393A (en) | 2006-07-27 | 2009-12-17 | コーニンクレッカ フィリップス エレクトロニクス エヌ ヴィ | Drug delivery system with heat-switchable membrane |
WO2008095940A1 (en) | 2007-02-05 | 2008-08-14 | Dublin City University | Flow analysis apparatus and method |
US8649840B2 (en) | 2007-06-07 | 2014-02-11 | Microchips, Inc. | Electrochemical biosensors and arrays |
US8999378B2 (en) * | 2008-09-24 | 2015-04-07 | President And Fellows Of Harvard College | Porous electroactive hydrogels and uses thereof |
-
2011
- 2011-09-29 US US13/248,095 patent/US9687182B2/en active Active
- 2011-10-04 EP EP11183754.8A patent/EP2438861B1/en not_active Not-in-force
-
2017
- 2017-06-23 US US15/631,823 patent/US20170354360A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20010029348A1 (en) * | 1999-02-18 | 2001-10-11 | Bio Valve Technologies, Inc., Delaware Corporation | Electroactive pore |
US20060057737A1 (en) * | 2004-09-01 | 2006-03-16 | Santini John T Jr | Multi-cap reservoir devices for controlled release or exposure of reservoir contents |
US20090326279A1 (en) * | 2005-05-25 | 2009-12-31 | Anna Lee Tonkovich | Support for use in microchannel processing |
US20100241086A1 (en) * | 2006-09-29 | 2010-09-23 | Ofer Yodfat | Flluid deliver system with electrochemical sensing of analyte concentration levels |
US9492109B2 (en) * | 2010-10-07 | 2016-11-15 | Biotronik Se & Co. Kg | Medical sensor system |
Also Published As
Publication number | Publication date |
---|---|
US9687182B2 (en) | 2017-06-27 |
EP2438861A1 (en) | 2012-04-11 |
US20120088994A1 (en) | 2012-04-12 |
EP2438861B1 (en) | 2018-06-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20170354360A1 (en) | Medical sensor system for detecting a feature in a body | |
US9492109B2 (en) | Medical sensor system | |
Boehler et al. | Tutorial: guidelines for standardized performance tests for electrodes intended for neural interfaces and bioelectronics | |
Sakakida et al. | Ferrocene-mediated needle-type glucose sensor covered with newly designed biocompatible membrane | |
Cogan et al. | Sputtered iridium oxide films for neural stimulation electrodes | |
US8936794B2 (en) | Conducting polymer nanotube actuators for precisely controlled release of medicine and bioactive molecules | |
US6773429B2 (en) | Microchip reservoir devices and facilitated corrosion of electrodes | |
JP2006525853A (en) | Biointerface membrane incorporating bioactive agent | |
CA2386151A1 (en) | Reactive polymeric valve, dispensing devices and methods using same | |
US20200093964A1 (en) | Medical implant with porous plasma polymer coating | |
ES2720780T3 (en) | Method to detect an interfering contribution in a biosensor | |
Asplund et al. | Anti-inflammatory polymer electrodes for glial scar treatment: bringing the conceptual idea to future results | |
US20230329592A1 (en) | Abrasion protected microneedle and indwelling eab sensors | |
US20120123235A1 (en) | Implantable theranostic article | |
DE102011081472A1 (en) | Medical sensor system useful in medical implant for detecting at least one feature of animal and/or human body, comprises at least one sensor, first feature carrier, second feature carrier and feature carrier receptor | |
Voskerician et al. | Sensor biocompatibility and biofouling in real‐time monitoring | |
Ausri et al. | Recent advances and challenges: Translational research of minimally invasive wearable biochemical sensors | |
Saylor et al. | Separation-based methods combined with microdialysis sampling for monitoring neurotransmitters and drug delivery to the brain | |
KR102427230B1 (en) | Blood glucose sensor using self-charging capacitor | |
US20210212605A1 (en) | Biocompatible sleeve for glucose sensors | |
Kulinsky et al. | System-based approach for an advanced drug delivery platform | |
Simon et al. | Precise neurotransmitter-mediated communication with neurons in vitro and in vivo using organic electronics | |
Schreiner et al. | New concept of biosensor for analysis of neuromotor dysfunctions | |
Gupta | Development of a Wearable Noninvasive Biomarker Sensing Platform | |
Arnold | In Vivo Chemical Sensing—Opportunities and Challenges |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: FRAUNHOFER GESELLSCHAFT, GERMANY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BODE, SVEN, DR.;BUNGE, ANDREAS, DR.;BIELA, SARAH, DR.;AND OTHERS;SIGNING DATES FROM 20110830 TO 20110913;REEL/FRAME:043634/0464 Owner name: BIOTRONIK SE & CO. KG, GERMANY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:FRAUNHOFER GESELLSCHAFT ZUR FOERDERUNG DER ANGEWANDTEN FORSCHUNG E.V.;REEL/FRAME:043634/0489 Effective date: 20130822 Owner name: BIOTRONIK SE & CO. KG, GERMANY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BODE, SVEN, DR.;BUNGE, ANDREAS, DR.;BIELA, SARAH, DR.;AND OTHERS;SIGNING DATES FROM 20110830 TO 20110913;REEL/FRAME:043634/0464 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: FINAL REJECTION MAILED |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |