New! View global litigation for patent families

CN1905835B - 分析物监测和药物递送的医疗装置 - Google Patents

分析物监测和药物递送的医疗装置 Download PDF

Info

Publication number
CN1905835B
CN1905835B CN 200480030548 CN200480030548A CN1905835B CN 1905835 B CN1905835 B CN 1905835B CN 200480030548 CN200480030548 CN 200480030548 CN 200480030548 A CN200480030548 A CN 200480030548A CN 1905835 B CN1905835 B CN 1905835B
Authority
CN
Grant status
Grant
Patent type
Application number
CN 200480030548
Other languages
English (en)
Other versions
CN1905835A (zh )
Inventor
C·王
E·A·霍姆斯
J·海华德
S·罗伊
Original Assignee
赛拉诺斯股份有限公司
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Grant date
Family has litigation

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/07Endoradiosondes
    • A61B5/073Intestinal transmitters
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/0002Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network
    • A61B5/0015Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network characterised by features of the telemetry system
    • A61B5/0024Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network characterised by features of the telemetry system for multiple sensor units attached to the patient, e.g. using a body or personal area network
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/0002Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network
    • A61B5/0031Implanted circuitry
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/14Devices for taking samples of blood ; Measuring characteristics of blood in vivo, e.g. gas concentration within the blood, pH-value of blood
    • A61B5/1405Devices for taking blood samples
    • A61B5/1411Devices for taking blood samples by percutaneous method, e.g. by lancet
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14507Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
    • A61B5/1451Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid
    • A61B5/14514Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid using means for aiding extraction of interstitial fluid, e.g. microneedles or suction
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14542Measuring 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 blood gases
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14546Measuring 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1455Measuring 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 optical sensors, e.g. spectral photometrical oximeters
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1455Measuring 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 optical sensors, e.g. spectral photometrical oximeters
    • A61B5/14551Measuring 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 optical sensors, e.g. spectral photometrical oximeters for measuring blood gases
    • A61B5/14556Measuring 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 optical sensors, e.g. spectral photometrical oximeters for measuring blood gases by fluorescence
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1468Measuring 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
    • A61B5/1473Measuring 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1468Measuring 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
    • A61B5/1477Measuring 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 non-invasive
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/150007Details
    • A61B5/150015Source of blood
    • A61B5/150022Source of blood for capillary blood or interstitial fluid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/150007Details
    • A61B5/150206Construction or design features not otherwise provided for; manufacturing or production; packages; sterilisation of piercing element, piercing device or sampling device
    • A61B5/150221Valves
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/150007Details
    • A61B5/150206Construction or design features not otherwise provided for; manufacturing or production; packages; sterilisation of piercing element, piercing device or sampling device
    • A61B5/150229Pumps for assisting the blood sampling
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/150007Details
    • A61B5/150206Construction or design features not otherwise provided for; manufacturing or production; packages; sterilisation of piercing element, piercing device or sampling device
    • A61B5/150251Collection chamber divided into at least two compartments, e.g. for division of samples
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/150007Details
    • A61B5/150206Construction or design features not otherwise provided for; manufacturing or production; packages; sterilisation of piercing element, piercing device or sampling device
    • A61B5/150274Manufacture or production processes or steps for blood sampling devices
    • A61B5/150282Manufacture or production processes or steps for blood sampling devices for piercing elements, e.g. blade, lancet, canula, needle
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/150007Details
    • A61B5/150343Collection vessels for collecting blood samples from the skin surface, e.g. test tubes, cuvettes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/150007Details
    • A61B5/150847Communication to or from blood sampling device
    • A61B5/150854Communication to or from blood sampling device long distance, e.g. between patient's home and doctor's office
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/150007Details
    • A61B5/150847Communication to or from blood sampling device
    • A61B5/150862Communication to or from blood sampling device intermediate range, e.g. within room or building
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/150007Details
    • A61B5/150847Communication to or from blood sampling device
    • A61B5/15087Communication to or from blood sampling device short range, e.g. between console and disposable
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/150969Low-profile devices which resemble patches or plasters, e.g. also allowing collection of blood samples for testing
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/150977Arrays of piercing elements for simultaneous piercing
    • A61B5/150984Microneedles or microblades
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/151Devices specially adapted for taking samples of capillary blood, e.g. by lancets, needles or blades
    • A61B5/15101Details
    • A61B5/15103Piercing procedure
    • A61B5/15107Piercing being assisted by a triggering mechanism
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/151Devices specially adapted for taking samples of capillary blood, e.g. by lancets, needles or blades
    • A61B5/15101Details
    • A61B5/15115Driving means for propelling the piercing element to pierce the skin, e.g. comprising mechanisms based on shape memory alloys, magnetism, solenoids, piezoelectric effect, biased elements, resilient elements, vacuum or compressed fluids
    • A61B5/15117Driving means for propelling the piercing element to pierce the skin, e.g. comprising mechanisms based on shape memory alloys, magnetism, solenoids, piezoelectric effect, biased elements, resilient elements, vacuum or compressed fluids comprising biased elements, resilient elements or a spring, e.g. a helical spring, leaf spring, or elastic strap
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/151Devices specially adapted for taking samples of capillary blood, e.g. by lancets, needles or blades
    • A61B5/15101Details
    • A61B5/15115Driving means for propelling the piercing element to pierce the skin, e.g. comprising mechanisms based on shape memory alloys, magnetism, solenoids, piezoelectric effect, biased elements, resilient elements, vacuum or compressed fluids
    • A61B5/15119Driving means for propelling the piercing element to pierce the skin, e.g. comprising mechanisms based on shape memory alloys, magnetism, solenoids, piezoelectric effect, biased elements, resilient elements, vacuum or compressed fluids comprising shape memory alloys
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/151Devices specially adapted for taking samples of capillary blood, e.g. by lancets, needles or blades
    • A61B5/15101Details
    • A61B5/15115Driving means for propelling the piercing element to pierce the skin, e.g. comprising mechanisms based on shape memory alloys, magnetism, solenoids, piezoelectric effect, biased elements, resilient elements, vacuum or compressed fluids
    • A61B5/15121Driving means for propelling the piercing element to pierce the skin, e.g. comprising mechanisms based on shape memory alloys, magnetism, solenoids, piezoelectric effect, biased elements, resilient elements, vacuum or compressed fluids comprising piezos
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/151Devices specially adapted for taking samples of capillary blood, e.g. by lancets, needles or blades
    • A61B5/15101Details
    • A61B5/15115Driving means for propelling the piercing element to pierce the skin, e.g. comprising mechanisms based on shape memory alloys, magnetism, solenoids, piezoelectric effect, biased elements, resilient elements, vacuum or compressed fluids
    • A61B5/15123Driving means for propelling the piercing element to pierce the skin, e.g. comprising mechanisms based on shape memory alloys, magnetism, solenoids, piezoelectric effect, biased elements, resilient elements, vacuum or compressed fluids comprising magnets or solenoids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/151Devices specially adapted for taking samples of capillary blood, e.g. by lancets, needles or blades
    • A61B5/15101Details
    • A61B5/15115Driving means for propelling the piercing element to pierce the skin, e.g. comprising mechanisms based on shape memory alloys, magnetism, solenoids, piezoelectric effect, biased elements, resilient elements, vacuum or compressed fluids
    • A61B5/15125Driving means for propelling the piercing element to pierce the skin, e.g. comprising mechanisms based on shape memory alloys, magnetism, solenoids, piezoelectric effect, biased elements, resilient elements, vacuum or compressed fluids comprising a vacuum or compressed fluids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/151Devices specially adapted for taking samples of capillary blood, e.g. by lancets, needles or blades
    • A61B5/15186Devices loaded with a single lancet, i.e. a single lancet with or without a casing is loaded into a reusable drive device and then discarded after use; drive devices reloadable for multiple use
    • A61B5/15188Constructional features of reusable driving devices
    • A61B5/1519Constructional features of reusable driving devices comprising driving means, e.g. a spring, for propelling the piercing unit
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/157Devices characterised by integrated means for measuring characteristics of blood
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/41Detecting, measuring or recording for evaluating the immune or lymphatic systems
    • A61B5/414Evaluating particular organs or parts of the immune or lymphatic systems
    • A61B5/417Evaluating particular organs or parts of the immune or lymphatic systems the bone marrow
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/42Detecting, measuring or recording for evaluating the gastrointestinal, the endocrine or the exocrine systems
    • A61B5/4222Evaluating particular parts, e.g. particular organs
    • A61B5/4238Evaluating particular parts, e.g. particular organs stomach
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/48Other medical applications
    • A61B5/4836Diagnosis combined with treatment in closed-loop systems or methods
    • A61B5/4839Diagnosis combined with treatment in closed-loop systems or methods combined with drug delivery
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/48Other medical applications
    • A61B5/4848Monitoring or testing the effects of treatment, e.g. of medication
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/68Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6801Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
    • A61B5/683Means for maintaining contact with the body
    • A61B5/6832Means for maintaining contact with the body using adhesives
    • A61B5/6833Adhesive patches
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/68Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6847Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
    • A61B5/685Microneedles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/68Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6847Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
    • A61B5/6865Access ports
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/72Signal processing specially adapted for physiological signals or for diagnostic purposes
    • A61B5/7271Specific aspects of physiological measurement analysis
    • A61B5/7282Event detection, e.g. detecting unique waveforms indicative of a medical condition
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2560/00Constructional details of operational features of apparatus; Accessories for medical measuring apparatus
    • A61B2560/04Constructional details of apparatus
    • A61B2560/0406Constructional details of apparatus specially shaped apparatus housings
    • A61B2560/0412Low-profile patch shaped housings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532Measuring 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1486Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142Pressure infusion, e.g. using pumps
    • A61M5/145Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons
    • A61M2005/14513Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons with secondary fluid driving or regulating the infusion
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/168Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body
    • A61M5/172Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic
    • A61M5/1723Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic using feedback of body parameters, e.g. blood-sugar, pressure
    • A61M2005/1726Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic using feedback of body parameters, e.g. blood-sugar, pressure the body parameters being measured at, or proximate to, the infusion site
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0023Drug applicators using microneedles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00General characteristics of the apparatus
    • A61M2205/02General characteristics of the apparatus characterised by a particular materials
    • A61M2205/0244Micromachined materials, e.g. made from silicon wafers, microelectromechanical systems [MEMS] or comprising nanotechnology
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00General characteristics of the apparatus
    • A61M2205/35Communication
    • A61M2205/3546Range
    • A61M2205/3569Range sublocal, e.g. between console and disposable
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00General characteristics of the apparatus
    • A61M2205/35Communication
    • A61M2205/3576Communication with non implanted data transmission devices, e.g. using external transmitter or receiver
    • A61M2205/3592Communication with non implanted data transmission devices, e.g. using external transmitter or receiver using telemetric means, e.g. radio or optical transmission
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00General characteristics of the apparatus
    • A61M2205/50General characteristics of the apparatus with microprocessors or computers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142Pressure infusion, e.g. using pumps
    • A61M5/14244Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body
    • A61M5/14276Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body specially adapted for implantation
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/10Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/02Identification, exchange or storage of information
    • B01L2300/023Sending and receiving of information, e.g. using bluetooth
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/02Identification, exchange or storage of information
    • B01L2300/024Storing results with means integrated into the container
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/06Auxiliary integrated devices, integrated components
    • B01L2300/0627Sensor or part of a sensor is integrated
    • B01L2300/0636Integrated biosensor, microarrays
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/06Auxiliary integrated devices, integrated components
    • B01L2300/0627Sensor or part of a sensor is integrated
    • B01L2300/0654Lenses; Optical fibres
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/08Geometry, shape and general structure
    • B01L2300/0809Geometry, shape and general structure rectangular shaped
    • B01L2300/0816Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00Moving or stopping fluids
    • B01L2400/04Moving fluids with specific forces or mechanical means
    • B01L2400/0403Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0406Moving fluids with specific forces or mechanical means specific forces capillary forces
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00Moving or stopping fluids
    • B01L2400/04Moving fluids with specific forces or mechanical means
    • B01L2400/0403Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0415Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00Moving or stopping fluids
    • B01L2400/04Moving fluids with specific forces or mechanical means
    • B01L2400/0403Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0472Diffusion
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00Moving or stopping fluids
    • B01L2400/04Moving fluids with specific forces or mechanical means
    • B01L2400/0475Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0487Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502707Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the manufacture of the container or its components
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502761Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502769Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements
    • B01L3/502776Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements specially adapted for focusing or laminating flows
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/00029Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor provided with flat sample substrates, e.g. slides
    • G01N2035/00099Characterised by type of test elements
    • G01N2035/00158Elements containing microarrays, i.e. "biochip"

Abstract

本发明涉及可摄取、可植入或可配戴的医疗装置,该装置包括:包含能够与疾病标记生物分析物相互作用的生物活性剂的微阵列;包含至少一种治疗剂并能够从医疗装置释放该治疗剂的储库;多个微芯片,微芯片包括:能够获得疾病标记生物分析物与生物活性剂之间相互作用的物理参数数据的微阵列扫描装置,能够将物理参数数据与分析物相互作用分布图进行比较的生物统计识别装置,任选地能够控制治疗剂从储库释放的治疗剂释放装置,能够促进微阵列扫描装置、生物统计识别装置和治疗剂释放装置之间通讯的接口装置;以及驱动医疗装置的能源。具体地说,本发明涉及能够检测体液中分析物的医疗装置,该装置包括:至少一个能够获得体液样品的微针;第一微通道,样品通过其流动并与至少一个微针流体连通;与第一微通道流体连通的第二微通道,缓冲液通过其流动,第二通道包括含生物活性剂的微阵列;检测生物活性剂和体液中分析物之间相互作用的微阵列扫描装置;以及接口装置。

Description

分析物监测和药物递送的医疗装置

[0001] 发明背景

[0002] 1.发明领域

[0003] 本发明涉及诊断和药物递送领域。更具体地涉及能够监测体液分析物水平和任选地释放合适治疗剂的医疗装置和方法。

[0004] 2.背景

[0005] 非常需要能够检测生物大分子活性或药物浓度水平的“点护理”(“pointof care")装置,因为这样的话,不需要对患者进行实验室随访,从而节约时间和费用。现代微阵列技术的最有价值方面之一是能够检测生物大分子功能障碍、导致疾病的畸形和变异。 然而,这种能力未被完全利用,因为这些阵列未被掺入可摄取、可植入或可配戴的点护理装置。通过分析稳定在载玻片上的固定化分析物,将其插入机器或活生物体外部手动分析,现代微阵列技术限于生物大分子及其代谢物的表征。

[0006] 因为全血含有细胞、血小板、无数的蛋白质和其它大分子,涉及血液的分析通常需要预处理样品以除去这些组分。将预处理步骤整合入点护理装置中增加了装置本身的成本,因而使用该装置在财政上不可行。例如,目前市场上的一些装置使用全血进行分析;其中有用于测定血载分析物(最显著的是胆固醇)的Boehringer Mannheim,s Reflotron™ 系统,和iStatTM(iMat Inc.),进行许多关键的护理分析,包括电解质、一般化学物质、血气和血液学。Reflotron™依赖干燥化学技术,将酶和其它反应元素固定在试验条带的表面。 分析是量热活性分析,其中反应产生颜色变化,从而表明存在的分析物的量。Ktat™依赖电化学检测以产生信号。无论哪一种情况,分别取血样(一半通过轻刺手指)然后置于芯片(或iStat的卡盒)上,反应发生并由外部检测单元分析。这些现有监测系统通常要求使用者轻刺自己并需要多个步骤以得到结果,因而不适当且不方便。这样,需要可重复、自动和精确监测体液如血液的可配戴的装置。

[0007] 在某些全身性生物样品如血液、尿液或粪便不能提供关于疾病状态下细微分子变化的足够信息的情况下,点护理装置也是有用的。在这种情况下,即使临床医师可正确定出疾病的确切部位,只有在对患者的风险大、疼痛大和费用大的情况下才能得到用于分析的生物学样品。此外,当例如通过经皮或静脉内方式全身给予药物大体上治疗患体,即使可定位待治疗的疾病,也需要点护理装置。这里,不需要全身性给药,因为药物常常对不需要治疗的身体部分有不良作用,或因为身体疾病部位的治疗需要全身性给药不能达到的高浓度药物。例如,当全身给予患者时,一些药物(例如,化学治疗药物如那些用于治疗癌症和其它增殖性疾病的药物)可导致不良副作用。因此,常常需要检测疾病并在体内的局部部位给予药物。

[0008] 因此,需要能够检测生物大分子活性或药物浓度水平的点护理装置,也可根据生物大分子活性或药物浓度水平的变化在体内的局部部位给予特定治疗剂。所有文章、出版物和专利全部被纳入本文作为参考。此外,2003年9月11日提交的临时专利申请序列号 60/501,847也被纳入本文作为参考。

[0009] 发明概述[0010] 本发明的一方面涉及医疗装置,该医疗装置包括:包含能够与疾病标记生物分析物相互作用的生物活性剂的微阵列;包含至少一种治疗剂并能够从医疗装置释放该治疗剂的储库;多个微芯片,该微芯片包括能够获得疾病标记生物分析物与生物活性剂之间相互作用的物理参数数据的微阵列扫描装置,能够将物理参数数据与分析物相互作用分布图进行比较的生物统计识别装置,能够控制治疗剂从储库释放的治疗剂释放装置,能够促进微阵列扫描装置、生物统计识别装置和治疗剂释放装置之间通讯的接口装置;以及驱动医疗装置的能源。

[0011] 在本发明这方面的一个实施方式中,所述装置可被涂覆,涂层为具有通道的生物稳定聚合物。在本发明这方面的另一个实施方式中,聚合物是多孔的。

[0012] 在另一个实施方式中,体液转运通过微流体通道,通过微阵列上的压力差使分子移动。在一个实施方式中,使用渗透泵以驱使流体通过装置顶部。在另一个实施方式中,由通过个人局域网(Personal Area Network)技术传导体内的固有电流驱动流体转运。

[0013] 在本发明这方面的又一个实施方式中,微阵列包含微珠。在另一个实施方式中,生物活性剂是核酸。在又一个实施方式中,生物活性剂是多肽。在又一个实施方式中,生物活性剂是免疫球蛋白。

[0014] 在本发明医疗装置的另一个实施方式中,生物活性剂是荧光标记的。在另一个实施方式中,生物活性剂是用纳米晶体(nanocrystal)荧光标记的。

[0015] 在又一个实施方式中,疾病标记生物分析物是核酸。在再一个实施方式中,疾病标记生物分析物是多肽。在另一个实施方式中,疾病标记生物分析物是免疫球蛋白。

[0016] 在再一个实施方式中,多个微芯片含有硅锗。

[0017] 在另一个实施方式中,微阵列扫描装置包含光导纤维元件。

[0018] 在另一个实施方式中,分析物相互作用分布图存储在生物统计识别装置中。在一个可选实施方式中,分析物相互作用分布图存储在医疗装置的外部。

[0019] 在另一个实施方式中,医疗装置具有多个储库。

[0020] 在另一个实施方式中,接口装置包括个人局域网。

[0021] 在另一个实施方式中,能源是电池。在一个可选实施方式中,能源由个人局域网提{共。

[0022] 本发明的另一方面涉及检测和治疗患者疾病的方法,该方法包括:给予患者涂覆的医疗装置,该医疗装置包括:包含能够与疾病标记生物分析物相互作用的生物活性剂的微阵列;包含至少一种治疗剂并能够从医疗装置释放该至少一种治疗剂的至少一个储库; 多个微芯片,该微芯片包括:能够获得疾病标记生物分析物与生物活性剂之间相互作用的物理参数数据的微阵列扫描装置、能够将物理参数数据与分析物相互作用分布图进行比较的生物统计识别装置、能够控制治疗剂从储库释放的治疗剂释放装置、能够促进微阵列扫描装置、生物统计识别装置和治疗剂释放装置之间通讯的接口装置;以及驱动医疗装置的能源;能使医疗装置吞咽的生物相容涂层,通过患者肠道并自然地排泄,。

[0023] 在方法的一个实施方式中,涂层是具有通道的生物稳定聚合物。在另一个实施方式中,聚合物是多孔的。

[0024] 在方法的再一个实施方式中,微阵列包含微珠。在另一个实施方式中,生物活性剂是核酸。在再一个实施方式中,生物活性剂是多肽。在又一个实施方式中,生物活性剂是免疫球蛋白。

[0025] 在本发明方法的另一个实施方式中,生物活性剂是荧光标记的。在另一个实施方式中,生物活性剂是用纳米晶体荧光标记的。

[0026] 在方法的又一个实施方式中,疾病标记生物分析物是核酸。在再一个实施方式中, 疾病标记生物分析物是多肽。在另一个实施方式中,疾病标记生物分析物是免疫球蛋白。

[0027] 在方法的再一个实施方式中,多个微芯片含有硅锗。

[0028] 在方法的另一个实施方式中,微阵列扫描装置包含光导纤维元件。

[0029] 在方法的另一个实施方式中,分析物相互作用分布图存储在生物统计识别装置中。在一个可选的实施方式中,分析物相互作用分布图存储在医疗装置的外部。

[0030] 在方法的另一个实施方式中,采用多个储库。

[0031 ] 在方法的另一个实施方式中,接口装置包括个人局域网。

[0032] 在方法的另一个实施方式中,能源是电池。在一个可选的实施方式中,能源由个人局域网提供。

[0033] 在方法的另一个实施方式中,通讯由外部计算机监测。在另一个实施方式中,外部计算机指导治疗剂的释放。

[0034] 本发明的另一方面涉及能够检测体液中分析物的医疗装置,包括:至少一个能够获得体液样本的微针;第一微通道,样品通过其流动并与至少一个微针流体连通;与第一微通道流体连通的第二微通道,缓冲液通过其流动,第二通道包括具有生物活性剂的微阵列;检测生物活性剂和体液中分析物之间相互作用的微阵列扫描装置;和能够促进所述微阵列扫描装置和生物统计识别装置之间通讯的接口装置。

[0035] 在一个实施方式中,体液是血液。在另一个实施方式中,至少一个微针是多个微针。在又一个实施方式中,微针的直径约为10-200微米。在再一个实施方式中,微针能够吸取约100微升的血液。在另一个实施方式中,第一微通道的直径约为100微米。在另一个实施方式中,第二微通道的直径约为100微米。

[0036] 在再一个实施方式中,流过第一微通道的体液中的分析物扩散进入第二微通道并与生物活性剂相互作用。在另一个实施方式中,流过第一微通道的体液中的分析物扩散进入第二微通道并通过结合生物活性剂竞争地置换标记的分析物。在再一个实施方式中,标记的分析物以预定量提供。在另一个实施方式中,标记的分析物用荧光团部分标记。在又一个实施方式中,微阵列是具有特异性结合体液中分析物的抗体涂层的第二微通道的一部分。在再一个实施方式中,微阵列扫描装置包括全内部反射荧光(TIRF)光谱仪。

[0037] 在本发明这方面的另一个实施方式中,生物统计识别装置位于装置的外部并通过无线传输通讯。在另一个实施方式中,分析物是胰岛素,生物活性剂是是对胰岛素特异的抗体。在再一个实施方式中,分析物是葡萄糖,生物活性剂是对葡萄糖特异的抗体。在又一个实施方式中,装置以贴片形式配戴在皮肤上。

[0038] 在本发明这方面的再一个实施方式中,分析物是疾病标记。

[0039] 在本发明这方面的另一个实施方式中,医疗装置还包括其中具有治疗剂的储库和治疗剂释放装置,治疗剂释放装置能够响应来自生物统计识别装置的指令而控制治疗剂从储库的释放。在另一个实施方式中,分析物是葡萄糖,治疗剂是胰岛素。在再一个实施方式中,分析物和治疗剂是相同的。[0040] 在本发明这方面的另一个实施方式中,医疗装置具有至少一个一次性分析装置和非一次性分析读数装置,一次性分析装置包括至少一个微针、第一微通道和第二通道,非一次性分析读数装置包括微阵列扫描装置和接口装置。在再一个实施方式中,分析装置和分析读数装置相互光连通。在再一个实施方式中,有多种匹配单一分析读数装置的一次性分析装置。

[0041] 在另一个实施方式中,微阵列包括用生物活性剂官能化的单根玻璃光导纤维的未包覆部分,其中单根玻璃光导纤维的未包覆部分与第二微通道流体接触。或者,微阵列可包括许多用生物活性剂官能化的单根玻璃光导纤维的未包覆部分,其中单根玻璃光导纤维的未包覆部分与第二微通道流体接触。

[0042] 从下面的具体描述,本发明的其它优点对本领域技术人员将显而易见,其中,只显示和描述了本发明的优选实施方式,仅仅以实现本发明所考虑的最佳模式的示例性方式。 如将要理解的,不背离本发明,本发明包括其它和不同的实施方式,以及能在各个明显的方面改进的一些细节。没有一些或所有这些具体的细节,可实施本发明。在其它例子中,为避免不必要地模糊本发明,因而没有具体详细描述熟知的操作过程。因此,附图和说明被认为是示例性的,而不是限制性的。

[0043] 附图简要说明

[0044] 图1是本发明示例性医疗装置的示意图。该装置具有生物稳定聚合物涂层1以及在该优选实施方式中的渗透泵2,以促进流体移动通过装置的多孔涂层3。装置包括:包含能够与疾病标记生物分析物相互作用的生物活性剂的微阵列4 ;包含治疗剂并能够从医疗装置释放该治疗剂的储库10 ;多个微芯片5,7,8,9,6,10,12,13和14,该微芯片包括:能够获得疾病标记生物分析物与生物活性剂之间相互作用的物理参数数据的微阵列扫描装置 7、能够将物理参数数据与分析物相互作用分布图进行比较的生物统计识别装置9、能够控制治疗剂从诸储库和检查点13和14释放治疗剂的治疗剂释放装置10、能够促进微阵列扫描装置7、生物统计识别装置9和治疗剂释放装置10之间通讯的接口装置8 ;以及驱动医疗装置的能源15。此外,示例性装置还包括用于个人局域网5和6的发射器,用于PAN和手持式计算机监测器15或外部计算机网络16之间的通讯传输通道。此外,示例性装置包括用于在释放前混合治疗剂的隔室11。

[0045] 图2显示了外用贴片实施方式中的本发明装置。它被配戴在皮肤上,能够释放治疗剂。此外,它能够与外部网络对接。

[0046] 图3显示了与外部服务器无线通讯的多个医疗装置,这里是以贴片的形式。外部服务器可包括生物统计识别装置及生物活性剂与分析物之间相互作用的物理参数数据的药物动力学数据库。

[0047] 图4(a) 100微米直径的微针大概是人头发的直径。(b)硅微针的阵列。

[0048] 图5(a)显示了其贴片实施方式的本发明装置100的多种视图。示例性贴片长2cm, 宽0.5。其厚度约为1.5mm。贴片包含多个微针12。(b)显示了贴片装置的内部特征。装置具有储库13,血流从微针12泵入储库13 ;包含缓冲剂的第二储库14 ;汇合缓冲剂1¾和血液进口 1¾的层流的共同微通道15 ;以及废弃物接受器16。此外,图中显示装置可分成两部分:具有微针、微通道和微阵列IOOa的一次性层以及具有微阵列扫描装置和其它电子设备的与一次性部分光连通的非一次性部分100b。[0049] 图6(a)显示了在应用于患者之前如何包装贴片100。贴片可覆盖有保护层17和具有贴片基底18,应用时微针将穿透基底18。基底18提供维持微针在应用前无菌的附加益处。粘合剂19用于将贴片固定于受试者的皮肤。此外,可除去保护层20以暴露粘合层 19。

[0050] 图7显示了如何将多个贴片100同时应用于患者。然后,可相继激活多个贴片以长时间检测分析物。

[0051] 图8(a)是示例性层流微通道15的侧视图,血液从两个进口微通道中的一个进口 1¾进入。血液含有细胞21、各种蛋白质25以及待测分析物22。流体以平行流方式流动, 分子仅通过扩散横穿界面。如(b)所示,只有小分子分析物22到达对壁,与表面上预先结合于生物活性剂23的荧光标记分析物分子M发生平衡交换。在该实施例中,涂覆有生物活性剂23的通道壁构成微阵列。

[0052] 图9显示了全内部反射期间产生的瞬逝场概念。瞬逝场延伸超过介质的不多于一个波长,光束在介质中移动。

[0053] 图10显示了光导纤维沈如何利用全内部反射荧光来检测生物活性剂与微阵列上出现的分析物之间相互作用的荧光指示的变化。光导纤维可具有多种构型。例如,它可沿层流通道15的长度平行运行。或者,多个光纤可终止于通道内且本身涂覆有生物活性剂。 第一 1¾和第二 1¾微通道相互流体连通。只有小分子将扩散穿过微阵列的扩散界面,即官能化传感器表面。TIRF光谱仪的荧光检测不延伸超过该表面的一个波长。

[0054] 图11显示了微阵列一部分的光导纤维26。光导纤维具有包覆部分31和未包覆部分27。远端未包覆部分27是用与待分析体液中的靶分析物相互作用的生物活性剂官能化。光纤沈的近端与微阵列扫描装置的一部分光连通。连接器观有助于这种连通。在连接器上方输入将光导向光纤分离器31,光纤分离器31再引导光通过光纤输入检测器如光二极管检测器30。如本文所述,光纤的官能化未包覆部分27构成层流微通道15的壁的一部分,或多个光纤可伸入通道15。

[0055] 图12显示了采用TIRF传感器的微阵列和微阵列扫描装置的示例性部分。来自激光器33的输入激光引导通过多模光纤沈,50:50光纤分离器31的输出支路到达官能化未包覆光纤27上。一种分析的情况下,由于体液中存在的分析物的竞争性结合过程,从生物活性剂置换荧光团标记的分析物,结果瞬逝波处耦合入光纤的光子能量降低。这种光密度的降低可由光二极管及相关放大器检测。分析物22和生物活性剂23间相互作用的发射荧光特征返回耦合入光纤内并向检测器30传播,几乎没有激光干扰。耦合于光纤的激光提供 660mm处的光。在一个实施例中,系统以200 μ m芯官能化光纤和分离器或62. 5 μ m芯官能化光纤和分离器运行。整个系统的光纤芯直径相同。无论是62. 5或200 μ m芯系统,激发较高级的光纤模(芯的边缘)既能使瞬逝波能量最大又能使1X2耦合器运行更加一致。根据光纤芯直径这是不同的。

[0056] 图13显示了 Atto 655荧光团的荧光和吸光度。

[0057] 图14是配戴在人手臂上的模型分析读数装置的图像。

[0058] 图15是0. 1 μ 1/秒的PBS流和0. 02 μ 1/分钟血流在微通道中的两处融合的图像。 用肉眼看,扩散界面处两种流间几乎没有混合。然而,具有较高扩散系数的分子将通过扩散界面。[0059] 图16是细胞、牛血清白蛋白和万古霉素的扩散系数的图像。

[0060] 图17显示了本发明示例性装置。A)图显示装置可分成两部分:具有微针、微通道和微阵列IOOa的一次性层和具有微阵列扫描装置和其它电子设备的与一次性部分光连通的非一次性部分100b。B)贴片的一次性部分IOOa包含储库13,血液从微针泵入储库;包含缓冲剂的第二储库14 ;汇合缓冲剂1¾和血液进口 1¾的层流的共同微通道15 ;以及废弃物接受器16。此外,显示了包括微阵列的光导纤维的未包覆部分沈。C) 一起显示了几个一次性和非一次性部分。

[0061] 发明详述

[0062] 以其最基本的形式,本发明涉及一种用作传感器的医疗装置,定性和/或定量地检测体液中的分析物。这种分析物可潜在地指示疾病或药物或药物代谢物。此外,这种装置还能够响应传感器输入而释放治疗剂。这样,又提供了连续的诊断和药物治疗。本发明装置是可植入的、可摄取的或可作为贴片配戴在皮肤上。

[0063] 装置能够在生物流体中取样分析物。生物流体包括但不限于血液、血清、尿液、胃液和消化液、眼泪、唾液、粪便、精液以及来源于肿瘤组织的间隙液。

[0064] 使吸入医疗装置的体液与从体液中取样生物分析物的微阵列接触。可以医疗装置中释放流体,且可含有治疗剂,响应特定分析物的存在或不存在而释放。最优选地,由泵如微流体泵或渗透泵促进体液流入或从医疗装置流出。在另一个实施方式中,通过加压的微流体通道使流体在微阵列上流动,进行分子转运。在另一个实施方式中,通过个人局域网 (PAN)发射机或压电或磁传感器传导固有电流,进行分子转运。

[0065] 对于可植入的实施方式,将装置密封在内窥镜导管的尖端,用于实时分析和体内药物浓度的模型的建立。例如,装置可与血管、胃或胆的支架相连。在另一个实施方式中, 将装置密封在支架内。在另一个实施方式中,将装置包装在聚合物系统中以植入体内,透镜可放置在眼、气体和空气污染的外部传感器的背面,以及实时监测中所需的其它物件。

[0066] 在一个实施方式中,装置是贴片的形式,如图2所示。优选地,装置是粘合贴片,外用于皮肤以用作全血分析物的监测器。更优选地,血分析物是药物,由贴片监测其水平。这种药物治疗范围窄,血中以微摩尔浓度存在。最优选地,在贴片上直接测定血中靶分析物分子的浓度和/或同一性,然后将这些信息传送到内部或外部数据存储系统。

[0067] 设想使用至少一个,如果不是多个微针贴片通过皮肤取血,如图4所示。优选地, 微针约是人头发的尺寸,并具有集成微储库或吸收池。微针无痛地穿过皮肤并取微量血样。更优选地,微针收集约0. 01-1微升,优选约0. 05-0. 5微升,最优选约0. 1-0. 3微升的毛细血管血,并将它们递送至贴片储库中。优选地,微针由硅构成,直径约为10-200,优选约50-150,最优选100微米,使其可基本无痛地应用于皮肤。由于贴片大概置于不如指尖很好刺到的身体区域上,例如毛细血管密度可能较低。为确保针实际上由针取毛细血管血,可进行多次采血,如图4所示。优选地,这种微针是Pelikan (Palo Alto, CA)和/或 Kumetrix(Union City, CA)销售的类型,也可见美国专利6,503,231。

[0068] 在另一个实施方式中,设想使用聚合物针,其中一些被能够基于大小或特异性分离靶分子的多孔凝胶和聚合物涂覆。凝胶包括但不限于多氯化合物(polychlorimeride) 和多孔聚碳酸酯弹性体。

[0069] 一般来说,可用于制备本文所述微针的显微制造过程包括:光刻术;刻蚀技术,例如湿法化学、干燥和光敏抗蚀剂除去;硅的热氧化;电镀和无电镀;扩散过程,例如硼、 磷、砷和锑的扩散;离子注入;薄膜沉积,例如蒸发(细丝、电子束、闪蒸、遮蔽和分步覆盖)、溅射、化学气相淀积(CVD)、外延(气相、液相和分子束)、电镀、丝网印刷和成层。一般参见 Jaeger,〈〈微电子制造导论〉〉(Introduction to Microelectronic Fabrication) (Addison-ffesleyPublishing Co. ,Reading Mass. 1988) ;Runyan等,《半导体集成电路处理技术》(Semiconductor Integrated Circuit Processing Technology) (Addison-ffesley Publishing Co. , Reading Mass. 1990) ;IEEE 微电子机械系统会议记录(Proceedings of the IEEE Micro Electro Mechanical SystemsConference) 1987-1998 ;Rai-Choudhury 编,《显微光刻术手册》(Handbook ofMicrolithography) 0《显微机械加工与显微制造》( Micromachining&Microfabrication)(SPIE Optical Engineering Press, Bellingham, Wash. 1997)。或者,可在硅晶片中铸造针,然后用常规金属丝切割技术镀镍、金、钛或各种其它生物相容金属。另一个实施方式中,针可由生物聚合物制成。微针的制造和用于所述装置是根据 Mukerjee 等,传感器和致动器(Sensors andActuators) A :Physical,第 114 卷, 第2-3期,2004年9月1日,第沈7-275页所述方法,全部被纳入本文作为参考。

[0070] 虽然优选装置能够多次测定,但微针只能用一次。优选地,通过机械致动器插针和取针并丢弃用过的针和重新装上新针,进行多次取血。开发机械技术且可在非常小而容量很高的磁盘驱动器(例如,IBM微驱器)中制造,具有类似运行且成本要求低。优选地,微致动器是用半导体样分批过程制造的MEMS (微机械加工的电机系统)装置。这种致动器包括镍钛合金、气动或压电装置。最小针的厚度约为1-10,优选约2-6,最优选约4微米,高度超过约10-100,优选约30-60,最优选约40微米。

[0071] 或者,针由弹簧-螺线管系统驱动,其中销钉触发紧密卷曲的小型弹簧的释放以产生驱动所需的足够的力和运动范围。

[0072] 在一个实施方式中,本发明贴片装置具有两个可分离组件:具有多个微针、微通道和微阵列(分析装置)的一次性部分;以及具有微阵列扫描装置的非一次性部分,它能够传送分析物与生物识别装置微阵列上的生物活性剂相互作用的结果,优选地通过无线传输,

例如蓝牙® (分析读数装置)(见图5)。在该实施方式中,从非一次性部分除去用过的一次

性部分,而非一次性部分保留在受试者的身体上。然后,将具有新针的新的一次性部分应用于已在患者身体上的非一次性部分。新的一次性部分能够定量或定性地检测与上述用过的一次性部分相同或不同的分析物,如图7所示。在该实施方式中,一旦用过的一次性部分的微针被血块阻塞,优选使用新的一次性部分。非一次性部分也可包含一个或多个一次性部分。在该装置中,每个一次性部分能够同时检测不同的分析物。或者,每个一次性部分可检测相同的分析物,但是以在离散的时间段取体液(如血液)的方式相继驱动。在该装置中, 通过在一段时间后配置一次性部分,装置可在延长的时间内检测分析物。优选地,装置具有 12个一次性部分,通过每2小时配置新的一次性部分,可在M小时内检测分析物。

[0073] 在可吞咽或可植入的实施方式中,优选用“生物稳定聚合物”涂覆装置,生物稳定聚合物是指长时间暴露(例如一周、六个月、一年或更长)于体液、组织等时不发生明显降解的材料,因而使装置能够通过整个胃肠道。优选吸入体液并通过聚合物中的孔或通道从医疗装置中释放,如图1所示。

[0074] 本发明这方面某些实施方式的生物稳定涂覆材料是多孔聚合物材料,其特征为相互连接的孔的尺寸足够使含治疗剂的体液流入医疗装置和从医疗装置中释放。多孔聚合物材料优选特征在于,平均直径至少约为5微米,更优选至少约为8微米,最优选至少约为10 微米。本实施方式中使用的由冻干获得多孔结构的合适的聚合物包括任何合适的生物稳定聚合物,例如聚氨酯(包括聚氨酯分散体)、乙烯醋酸乙烯聚合物、水凝胶如交联明胶、葡聚糖、聚羧酸、纤维素聚合物、明胶、聚乙烯吡咯烷酮、马来酸酐聚合物、丙烯酸胶乳分散体、聚酰胺、聚乙烯醇、聚氧化乙烯、糖胺聚糖、多糖、聚酯、聚丙烯酰胺、聚醚以及它们的混合物和共聚物。

[0075] 这里所用的术语“分析物”指体组织和体液中发现的抗体、血清蛋白、胆固醇、多糖、核酸、药物和药物代谢物等。在另一个实施方式中,分析物是任何生物分析物、标记物、 基因、蛋白质、代谢物、激素或其组合,可显示用于分析以确定身体状态或病症所需的生物学状态。本发明装置的目的是定性和/或定量地“检测”体液中的分析物。优选地,周期性进行这种检测。最优选地,实时进行检测。在一个实施方式中,以微摩尔-纳摩尔浓度存在的分析物是非常有效的化学治疗剂,例如氨基糖苷类或抗生素如万古霉素,由于分析物具有窄的治疗范围,因此非常需要每分钟进行监测。

[0076] 通过连续监测体内分析物水平,本发明装置可使研究者优化治疗和剂量方案并迅速地开发实验性药物的药物动力学模型。现在可以快得多和更精确的方式进行靶标确认、 先导物优化和化合物优化(治疗范围和毒性研究),因为除开发靶标先导物外,监测谷浓度也能够快速消除或确认给药方案的靶标。因此,本发明装置可用于降低是否进入II和III 期临床试验的不确定性,从而减少注册时间和药物开发的总成本。而且,本发明装置提供了基于荧光分析(仍是良好的灵敏度标准)检测新型化合物的药物浓度的方法,首次提供了基于靶荧光的溶液以监测新型化合物。

[0077] 在这里术语“疾病标记”指可检测的分析物,例如体液和组织中发现的抗体、血清蛋白、胆固醇、多糖、核酸、药物和药物代谢物等,体内存在或不存在且已知与疾病相关。分析物使得能够检测某些生理状态,也可表明正常健康的生理学。在这里称为“正常”或“健康”生物分析物。优选地,本发明生物识别装置检测疾病标记,基于识别1)疾病标记生物分析物和微阵列上生物活性剂和2)正常生物分析物与微阵列上的生物活性剂间相互作用的物理特征间的物理参数数据。疾病标记生物分析物可检测某些生理状态,例如感染、炎症、 自身免疫疾病、癌症等。本发明包括目前本领域技术人员已知的疾病标记和未来将要知道的疾病标记。疾病标记的存在表明疾病的存在并确保释放治疗剂。

[0078] 疾病标记生物分析物可以是在经历无用增殖的细胞中过度表达或过度活化的基因或其产物。例如,可将本发明装置植入肿瘤或疑似含肿瘤的组织如活组织检查步骤后留下的空洞或间隙。如果本发明检测到生物分析物或这种生物分析物突变的过度活化形式如疾病标记的浓度增加,则释放治疗剂如细胞毒性剂。这些疾病标记生物分析物表明异常的细胞增殖如癌症、新内膜增殖导致动脉狭窄、银屑病等。可通过分析组织中的基因表达并将其与已知肿瘤基因表达模式匹配或将其与已知正常表达模式比较,来检测疾病标记生物分析物。在优选的实施方式中,微阵列用于检测由特定核苷酸序列的存在、不存在或过度表达限定的疾病标记生物分析物的存在,包括单核苷酸多态性(SNP)、mRNA或特异性蛋白质如酶、抗体或抗原。

[0079] 在一个实施方式中,疾病标记生物分析物是肿瘤特异性抗原。例如,这种抗原在癌细胞的表面表达或从癌细胞释放,例如肿瘤特异性抗原MUC-1。通过检测核酸或蛋白质活性来检测MUC-I的表达,可触发细胞毒性剂如治疗剂的释放。

[0080] 另一个例子涉及受体酪氨酸激酶(RTKs),它是促有丝分裂转导的关键酶。RTKs是大分子跨膜蛋白,具有细胞外表皮生长因子(EGF)的配体结合域,如表皮生长因子(EGF)是一种细胞内部分,起磷酸化胞质溶胶蛋白上的酪氨酸氨基酸残基的激酶作用从而介导细胞增殖。基于与不同受体酪氨酸激酶结合的生长因子家族,已知多种类型的受体酪氨酸激酶。 I类激酶如受体酪氨酸激酶的EGF-R家族包括EGF、HER2_neu、erbB、Xmrk, DER和let23受体。这些受体常常存在于普通人体癌如乳腺癌、肺的鳞状上皮细胞癌、膀胱癌、食管癌、胃肠癌如结肠癌、直肠癌或胃癌、白血病和卵巢癌、支气管癌或胰腺癌。测试其它人体肿瘤组织的受体酪氨酸激酶的EGF家族,期望在其它癌症如甲状腺癌和子宫癌中确立其广泛分布。 具体地说,在正常细胞中很少检测到EGFR酪氨酸激酶活性,而在恶性细胞中常常可检测到。近年来,显示EGFR在许多人体癌症如脑癌、肺鳞状上皮细胞癌、膀胱癌、胃癌、乳腺癌、 颈癌、食管癌、妇科肿瘤和甲状腺肿瘤中过度表达。受体酪氨酸激酶在其它细胞增殖疾病如银屑病中也是重要的。EGFR紊乱的特征为正常不表达EGFR的细胞表达EGFR,或EGFR活性增加导致异常的细胞增殖,和/或不适当的EGFR水平的存在。已知EGFR是由其配基EGF以及转化生长因子α (TGF-α)激活的。Herf-neu蛋白也属于I类受体酪氨酸激酶(RTK)家族的成员。Her2-neU蛋白在结构上与EGFR相关。这些受体具有相同的分子结构,在胞质功能域内含有两个富含半胱氨酸区域和胞质功能域内结构相关的酶区域。因此,通过检测核酸或蛋白质活性来检测RTK表达的异常高水平或信号活性可构成疾病标记,并确保RTK抑制剂或细胞毒性剂如治疗剂的释放。

[0081] 直接或间接地抑制化学治疗剂的基因的相对高表达构成本发明目的的疾病标记。 例如,DNA修复基因ERCCl的高肿瘤表达确保遗传毒性化学治疗剂释放至高局部浓度而低的全身性浓度。从而达到没有维持全身安全的浓度。另外,已知基因DPD的高肿瘤水平可抑制基于5-FU的化学治疗方案。类似地,DPD的高肿瘤表达确保5-FU化学治疗剂释放至高局部浓度而低的全身性浓度。或者,技术人员也将明白,ERCCl或DPD的高水平预示化学治疗耐药性,分别使用遗传毒性剂或5-FU都是不恰当的。在这种情况下,应从装置分别释放除遗传毒性剂或5-FU外的细胞毒性治疗剂。

[0082] 或者,装置可用于检测一组表明疾病如癌症的疾病标记,并释放高局部浓度的细胞毒性剂如治疗剂。

[0083] 在再一个实施方式中,疾病标记生物分析物可表明炎症,在炎性肠病、多发性硬化、童年期突发糖尿病、银屑病、类风湿性关节炎等的病因学中起关键作用。过去这些疾病通常需要大的全身剂量的潜在有害甾体,以解决局部炎症。生物分析物如TNF-a、IL-U IL-8、IL-2、IL-3、MIF(IL-4)、GM-CSF、INF-Y和TNF-β的高局部浓度是炎症的征兆。检测这种生物分析物的异常高浓度构成疾病标记,并确保抗炎药或抗体如治疗剂的局部释放。

[0084] 在另一个实施方式中,疾病标记生物分析物可预示微生物感染。这样,疾病标记包括病毒和细菌蛋白质或核酸或其片段。例如,检测生物分析物如细菌毒素,包括外毒素和肠毒素以及TSST-1,或其它细菌超抗原、或肉毒杆菌毒素、白喉毒素、炭疽保护抗原、炭疽水肿因子和炭疽致死因子等,以及病毒蛋白如流感血凝素或神经氨酸酶,构成预示感染的疾病标记并确保抗微生物药物或毒素特异性抗体如治疗剂的释放。[0085] 本发明的另一方面涉及微阵列。微阵列是有助于分析物和生物活性剂之间相互作用的本发明装置的部分。在最基本的实施方式中,本文所述“微阵列”可构成任何表面,例如微流体通道,被生物活性剂覆盖或官能化,使得微阵列扫描装置可检测生物活性剂和分析物之间的相互作用。如图8,10,11所示。在另一个实施方式中,微阵列是排列在表面上允许平行进行许多试验或分析的小型试验位点的集合。在本文中,微阵列直接暴露于体液和/或组织,能同时进行多种不同的分析并提供一种或多种生物活性剂与一种或多种生物分析物的相互作用。

[0086] 例如,使用四种不同的免疫测定形式:直接、竞争、置换和夹心,已证明基于荧光的阵列生物传感器测定和定量抗原与固定化抗体结合的能力。Sapsford等,Anal Chem. 2002Mar 1 ;74 (5) : 1061-8 (纳入本文作为参考),使用对固定化在平面波导表面上的 2,4,6_三硝基甲苯(TNT)特异的抗体的模式阵列,同时测定来自不同抗原浓度的信号。对于直接、竞争和置换分析(一步法分析),可实时测定。计算所有四种测定模式的剂量反应曲线,证明阵列生物传感器定量溶液中存在抗原量的能力。

[0087] 在本发明这方面的一个实施方式中,微阵列是玻璃光导纤维上用生物活性剂官能化的区域,如图11所示。在另一个实施方式中,微阵列可具有许多光导纤维,各用相同或不同的生物活性剂官能化。在一个具体的实施方式中,微阵列的生物活性剂是蛋白质如对分析物特异的抗体。可采用两种示例性方法,使蛋白质生物活性剂与玻璃光导纤维结合。第一种根据 Bhatia 等,1998,Analytical Biochemistry, 178408-13 所述。该方法涉及用 3-巯基丙基三甲氧基硅烷官能化表面。然后,用交联剂N-Y-马来酰亚胺丁酰氧基琥珀酰亚胺酯使蛋白活性剂与官能化表面连接。第二种方法涉及使用基于葡聚糖的方法,如Tedeschi 等,2003,Biosensors and Bioelectronics,1985-93 所述。该方法使用缩水甘油基 3-(三甲氧基甲硅烷基)丙基醚,使干净玻璃上的游离羟基与葡聚糖聚合物连接。其中羧酸基团酸化后蛋白生物活性剂与葡聚糖基质结合。任选地,可用分离靶分析物的立体膜涂覆纤维。

[0088] 优选地,纤维直接插入微针中,并用聚合物凝胶涂覆微针的壁用于基于选择性和特异性结合分析。

[0089] 在采用玻璃光导纤维的实施方式中,用光源激发荧光标记的生物活性剂和/或分析物,使得可检测与体液中靶分析物相互作用时的荧光变化。如图11所示。激发的光源可以是激光模块。光可发射入含官能化区域即剥离光纤包覆的区域且用化学方法制备生物活性剂涂覆的光导纤维中。如图9,11所示。由于缺乏包覆,瞬逝波从纤维端点发射,并从荧光标记的生物活性剂或结合于竞争性置换体液样品中分析物的生物活性剂的荧光标记的分析物激发荧光。如图8,11所示。发射光再进入通过相同光纤。回到光纤的光由微阵列扫描装置检测,微阵列扫描装置可包括光导纤维分离器、能除去周围背景光的带通过滤器和光二极管检测器。上述配置的示意图可参见图11。

[0090] 优选地,生物活性剂是能够特异性结合分析物药物的抗体。或者,生物活性剂是能够特异性结合血清抗体的抗原。在后一种实施方式中,本发明装置可检测响应某些免疫刺激如HIV或结核病感染产生的特异性抗体的形成。

[0091] 在另一个实施方式中,微阵列有助于1)疾病标记生物分析物与微阵列上的生物活性剂及幻正常生物分析物与微阵列上的生物活性剂之间的相互作用。在本文中,生物活性剂差异地与正常生物分析物和疾病标记生物分析物相互作用。[0092] 在微阵列的另一个实施方式中,使用微珠阵列。“微球,,或“珠,,或“粒,,或适当的等价物是指小的离散颗粒。珠的组成不同,取决于生物活性剂类型和合成方法。合适的珠组成包括肽、核酸和有机部分合成中使用的组成,包括但不限于,塑料、陶瓷、玻璃、聚苯乙烯、甲基苯乙烯、丙烯酸聚合物、顺磁性材料、氧化钍溶液、石墨碳、二氧化钛、胶乳或交联葡聚糖、如琼脂糖、纤维素、尼龙,也可使用交联胶束和特弗隆。Bangs Laboratories,Fishers Ind.的“微球检测指南”是有用的指导,全部被纳入本文作为参考。珠不需要是球形;可使用不规则粒子。此外,珠可以是多孔的,从而增加用于连接生物活性剂或靶标的珠表面积。 珠的大小为纳米如IOOnm到毫米如1mm,优选的珠约0. 2-200微米,更优选约0. 5-5微米,虽然在一些实施方式中可使用更小或更大的珠。优选地,微球各自包含生物活性剂。

[0093] 本发明的另一方面涉及“生物活性剂”。如本文所用,描述了用于微阵列且可与分析物或差异地与体液或组织中存在的正常和疾病标记生物分析物相互作用的任何分子,例如蛋白质、寡肽、小有机分子、多糖、多核苷酸等。可标记生物活性剂,以使微阵列扫描装置确定与生物分析物相互作用时对生物活性剂特异的某些物理参数的变化。

[0094] 在一个实施方式中,生物活性剂为荧光标记的,可检测其荧光在与体液中的靶分析物相互作用时的变化。或者,生物活性剂与标记的分析物预先结合,使得标记的分析物被体液中的分析物竞争性置换。无论哪种情况,微阵列与体液中的分析物相互作用时微阵列的荧光特征变化,可通过微阵列扫描装置检测。

[0095] 最优选地,用荧光纳米晶体标记分析物或生物活性剂。与有机染料如罗丹明相比, 纳米晶体的亮度至少约为20倍,抗光漂白的稳定性至少约为100倍,发射波谱线宽约为三分之一。例如参见,Bruchez 等,Science, 281 :2013-2016(1998) ;Chan 禾P Nie,Science, 281 :2016-2018(1998) ;Bawendi 等,Annu. Rev. Phys. Chem. 41 :477-496 (1990),所引用的文献被纳入本文作为参考。亮度、稳定性和发射带宽的狭窄都有助于利用相对大量的下述不同颜色(即不同大小的纳米晶体),同时保留其相互分辨和分辨不同量的各纳米晶体的能力。此外,带激发光谱使得可用普通光源激发许多不同的纳米晶体。

[0096] 生物活性剂可包含与蛋白质结构上相互作用所必需的官能团,尤其是氢键,通常包括至少一个胺、羰基、羟基或羧基,优选至少两个官能化学基团。生物活性剂常常包含被一种或多种上述官能团取代的环状碳或杂环结构和/或芳香或聚芳香结构。在生物分子中也发现生物活性剂包括肽、核酸、多糖、脂肪酸、留体、嘌呤、嘧啶、衍生物、结构类似物或其组合。尤其优选核酸和蛋白质。

[0097] 本文所用“与……相互作用”指分析物与微阵列上的生物活性剂之间离子、共价或氢键、蛋白结合、核酸杂交、磁性或疏水吸引或其它可检测的和/或可定量的结合。“差异地与……相互作用”指疾病标记生物分析物与生物活性剂的相互作用不同于生物分析物的正常生理指标。

[0098] 例如,可通过比较生物活性剂与生物分析物相互作用之前、期间或之后的物理特征,检测1)疾病标记生物分析物与生物活性剂以及幻正常生物分析物与生物活性剂间相互作用的物理差异。生物活性剂与生物分析物相互作用时可检测和/或可定量的变化可通过一系列基于所采用的生物活性剂的性质的物理参数来测定。例如,由于生物活性剂与生物分析物的结合或杂交,可检测的和/或可定量的结合由荧光强度或波长的位移证实。

[0099] 在另一个实施方式中,微阵列上(生物活性剂)对特定肿瘤特异性蛋白(疾病标记生物分析物)特异的荧光相关抗体的结合(相互作用),导致生物活性剂的荧光强度可检测的位移。这种刻板的位移表明特定疾病标记的存在以前已凭经验确定,尽管选择合适的生物活性剂和靶疾病标记。虽然非特异性结合可改变生物活性剂的荧光,但它不能以与凭经验确定的结果一致的可预测和刻板的方式进行,因而不能表明疾病标记生物分析物的存在。

[0100] 本发明的一个特征涉及“微阵列扫描装置”。优选由微阵列扫描装置“读取”分析物和微阵列生物活性剂之间相互作用的物理参数数据,传送至生物识别装置以确定体液中分析物的存在、不存在或量。优选地在分析物与生物活性剂之间相互作用时检测微阵列的物理特征。或者,扫描装置能够辨别1)疾病标记生物分析物与微阵列上的生物活性剂及2) 正常生物分析物与微阵列上的生物活性剂之间相互作用的物理特征。

[0101] 本文所用“物理参数数据”包括微阵列扫描装置收集的关于分析物与微阵列上的生物活性剂之间相互作用的信息。将物理参数数据输送至生物统计识别装置用于分析。扫描装置通过收集一种或多种与相互作用有关的物理参数数据,测定生物分析物与微阵列的生物活性剂之间相互作用的物理特征,例如生物电、生物磁或生物化学特征。这些参数包括但不限于:荧光、结合强度、结合特异性、电荷等。

[0102] 优选地,将物理参数数据存储在生物信息学系统中或与生物信息系统中的物理参数数据的存储文件进行比较,生物信息学系统的模型中包括药物基因组学和药物动力学数据用于确定毒性或剂量给药。这不仅能够在现有方法之前几年产生临床试验的数据,而且能够通过实时连续监测消除药物的表观效力与实际毒性之间的现有差异。为决策/非决策过程期间用于临床试验,可通过存储在服务器上的信息,用存储在数据库中的数据进行大规模比较群体研究。这使得更多患者以安全方式较早地进入临床试阶段。在另一个实施方式中,可通过在癌症研究中确定药物途径和效力方面精确度改进的装置,靶向人体组织研究中发现的生物标记。

[0103] 在该特征的一个实施方式中,设计微阵列,使得光导纤维元件能够发射和接收特定波长的光,获得关于生物活性剂与分析物之间相互作用的物理参数数据。在一个实施例中,用预定量的荧光标记分析物基本上饱和微阵列中的生物活性剂,当它们与来自体液的未标记靶分析物相互作用时,未标记的分析物竞争性置换微阵列上标记的分析物,直到与体液内的浓度相当的程度。这样,微阵列扫描装置将检测和输送微阵列上相应降低的荧光。

[0104] 在另一个实施方式中,一旦生物活性剂上的染料吸收光,一些不同波长和强度的光折返,通过相同光纤或光纤束传递至微阵列扫描装置用于定量。光导纤维传递的光之间的相互作用和光吸收染料的性质提供光学基础,用于定性和定量测定分析物和生物活性剂间相互作用显示的物理特征的变化。参见美国专利6,482,593和6,544, 732,全部被纳入本文作为参考。生物统计识别装置接收光和荧光接收信号数据,即物理参数数据,指导治疗剂释放装置释放特定治疗剂。合适的微阵列扫描装置的例子从几种来源,如由Illuminadnc. SanDiego, CA.市售获得。

[0105] 一种检测分析物与生物活性剂间相互作用的荧光差异的方法是通过用检测器检测发射分子附近的发射。另一种可能性是将发射耦合入光纤,由监测器在远端检测。检测荧光的光纤可以是传递输入光的相同光纤或是专门地用于荧光检测的独立光纤。在后一种情况下,必须剥去和处理微阵列检测光纤的包覆,用于最佳耦合。使用邻近光纤的透镜能更有效地返回耦合入光纤,以更精确地聚焦发射光。前述检测器包括(XD、PMT,最优选光二极管检测器。通过使用带通过滤器,检测器很可能对发射的波长有选择性。此检测器可位于传递光纤的远端。

[0106] 连接于微阵列扫描装置的一部分的示例性微阵列光学玻璃纤维如图11所示。图描述了延伸入装置的微通道并构成微阵列的一部分的官能化未包覆光纤。本发明装置的微阵列可包括在分叉光导纤维系统中的至少一根或多根光导纤维。

[0107] 在图中,用抗体生物活性剂官能化光导纤维,并以类似于荧光极化免疫分析的置换分析起作用而建立。由于光纤使用全内部反射(TIR)原理传播光,在裸露区域(即官能化区域)垂直于光纤发射瞬逝波。瞬逝波将被光纤表面上的任何分子吸收,由荧光团(如果存在)发射^okes位移光谱。光纤与光纤分离器光连通,允许光进入官能化未包覆光纤, 并使光从官能化未包覆光纤绕行返回至光二极管检测器。

[0108] 在具有一次性和非一次性部件的本发明装置的贴片实施方式中,一次性部件具有微针、微通道和微阵列。一旦插入,一次性部件的微阵列的光导纤维与相应的光纤分离器和光二极管检测器光连通构成贴片的非一次性部分的微阵列扫描装置的一部分。

[0109] 在微阵列扫描装置的另一个实施方式中,用全内部反射荧光(TIRF)光谱仪,在其与分析物相互作用时检测微阵列的荧光变化。TIRF的原理在图9,10中示意地描述。全内部反射是当光在稠密介质(例如玻璃)中传播时遇到较不稠密介质(例如图9中所示的缓冲剂)的干扰发生的光学现象。如果光以小角度遇到界面,一些光穿过界面(是折射)而一些光反射回到稠密介质中。在某一角度,所有的光都反射。该角度,称为临界角,其值取决于介质的折射率。然而,一些光束的能量传播短距离(优选几百纳米)进入缓冲剂较,产生瞬逝波。如果该能量不被吸收,其返回进入玻璃而可检测到。然而,如果与生物活性剂结合的荧光团分子或标记的分析物是在瞬逝波内,其可吸收光子并激发。这样,可得到激发光背景非常低的荧光。

[0110] 来自单一荧光团的荧光水平极低(每秒几百到几千个光子)。然而,优选以两种方式检测。第一种是使用可产生图像的强化CCD相机,其中结合的荧光团表现为亮点。或者, 可通过针孔使荧光团在光电倍增管(PMT)上成像,可计算检测到光子的数目。优选地,这种微阵列扫描装置采用集成光学系统如Texaslnstruments Spreeta™传感器。更优选地,微阵列扫描装置利用表面胞质团共振,类似的基于瞬逝波的TIRF技术。在这种传感器中,使用极化LED光源与光电检测器阵列同时测定反射光的位置。

[0111] 本发明这方面的另一特征涉及生物统计识别装置,通过分析由微阵列扫描装置收集的物理参数数据如荧光团图像或光子计数,确定分析物的不存在、存在或量。当分析物与微阵列上的生物活性剂相互作用时,微阵列扫描装置将关于相互作用的物理参数数据传递至生物识别装置,生物识别装置再将数据与已知分析物相互作用分布图匹配,以确定分析物的存在、不存在和/或含量。

[0112] 在一个实施方式中,疾病标记生物分析物以刻板和可预测的方式与微阵列上的生物活性剂相互作用,并通过可重复的和可预测的物理参数数据证实这种相互作用。在这里已知数据称为“分析物相互作用分布图”。体外凭经验建立了这种分布图,生物统计识别装置可选取疾病标记和正常分析物的分析物相互作用分布图。生物统计识别装置从微阵列扫描装置接收原始物理参数数据并将该信息与存储的分析物相互作用分布图相比较。生物统计识别装置可选取疾病标记和正常分析物的分析物相互作用分布图。

[0113] 生物统计识别装置在本发明医疗装置中或在外部定位。微阵列扫描装置与生物统计识别装置之间的通讯可通过局域网(LAN)或无线局域网(WLAN)如蓝牙®技术变得更为方便。此外,生物统计识别装置也可存储分析物相互作用分布图并建立分析物相互作用分布图形式的可获得信息的药物动力学数据库。

[0114] 在用于检测和定量分析物存在的尤其优选的配置中,装置是具有微流体通道的贴片,如图5所示。装置具有至少两个注入主通道的进口。血样(含有分析物)注入一个进口, 另一进口注入缓冲液。在小范围,液体在不存在惯性和湍流混合下流动;因此,血液和缓冲液以平行流流动。微通道的直径优选约50-200 μ m,更优选约75-150 μ m,最优选约100 μ m。

[0115] 优选地,通过芯吸或真空将流体以控制的方式泵入通道,激活微针破膜以产生加压牵引力而使流体通过。可通过精确注入塑型或激光蚀刻产生通道。

[0116] 可调节通道大小和微阵列表面化学以计算分析物测量的尺寸。附加气动泵系统和流体阀,或再包括微型-PCR系统和新型化学物质以提高灵敏度。

[0117] 微通道系统使能在官能化通道的表面或通道中央官能化螺纹光纤表面上发生扩散控制的结合事件,以优化光表面积。这使得基于瞬逝波传感器可检测来自流体如全血的分析物,仅仅约1000埃穿透入表面。或者,对于包埋在流体中央的光纤,扩散和分离使得系统更加简单,可在光纤的任一侧取读数。

[0118] 可使用Micronics,Inc of Redmond, WA的技术进行本发明装置中微流体的制造。 具体地说,薄膜塑料层合技术使得可通过激光切割产生三维微流体装置。部件被插入塑料薄膜,然后以适当取向相继层放在一起以形成微流体网络。或者,通道可由聚二甲基硅氧烷 (PDMS)制成,例如,使用温和光刻技术(Duffy等,Anal Chem. , 1998) 0此外,在硅中直接蚀刻通道。一旦构成通道,可通过将生物活性剂固定到玻璃表面而将其引入装置。玻璃表面域可与通道结合形成“帽”或通道的顶表面,使得缓冲流与装载抗体的表面接触。或者,玻璃表面是玻璃光导纤维。光导纤维可以是单一模式或优选地为多模式光纤。可将一根或多根光纤旋入通道中央。在这种情况下,通道可分成围绕中央缓冲流的两股血流,从两个方向都会发生扩散。

[0119] 与细胞物质和大分子不同,例如靶分析物的分子可通过扩散横穿血流/缓冲流/ 流体界面。因为扩散速率与分子大小呈反比,小分子药物比血源性蛋白质或细胞的迁移远得多。这有效地形成基于大小的分离。

[0120] 在一个实施方式中,设计通道以使只有药物分子扩散远至微通道的相对的壁(邻近缓冲流)。该壁构成所述微阵列,因其可用与荧光标记药物分子预结合的预定量的抗药物抗体涂覆。产生平衡交换,一些标记的药物分子被扩散至壁的非标记药物竞争地置换(图 8,19)。交换速率是浓度依赖的,因而可测定血中药物的浓度。重要的是认识到,对于免疫分析,可适应上述过程以实际检测可产生抗体的任何分析物。

[0121] 在前述实施方式中,检测的生物活性剂和分析物间相互作用在通道的缓冲剂侧发生,使用全血样通过TIRF光谱仪进行荧光测量。这样,荧光检测发生在通道的缓冲侧,不会被全血样中的荧光部分模糊。此外,由于测量是在微通道中进行,因而只需要非常少量的样

P

ΡΠ O

[0122] 在具有抗葡萄糖抗体的微阵列的优选贴片实施方式中,可以约0. 01-0. 4μ 1,优选约0. 05-0. 3 μ 1,最优选0. 1-0. 2 μ 1的血样测定葡萄糖浓度。在具有抗万古霉素抗体的微阵列的另一个优选的贴片实施方式中,可以约0.01-0. 4μ 1,优选约0. 05-0. 3μ 1,最优选 0. 1-0. 2μ 1的血样测定万古霉素浓度。此外,在这些实施方式中,可进行小于约1分钟的非常快速测定。

[0123] 在又一个实施方式中,这种装置监测分析物浓度并响应分析物浓度释放治疗剂。 优选地,分析物是特定药物或该药物的代谢物,治疗剂是相同的药物。当药物的治疗窗窄, 并且在血流中或在体内特定部位维持分析物/药物的某一浓度时,尤其优选该配置。因此, 当装置检测血流中或在体内特定部位的药物或其代谢物之一的浓度时,装置可释放一定量的相同药物以将全身或局部药物浓度调节至所需水平。例如,胰岛素或抗生素如万古霉素, 既是靶分析物又是治疗剂。

[0124] 本发明还考虑能够在检测疾病分析物指标即疾病标记分析物时局部递送一种或多种治疗剂的医疗装置。在本发明这方面的实施方式中,装置响应几种疾病标记的检测而释放单一治疗剂。或者,装置可根据不同疾病标记的检测而释放不同的治疗剂。在另一个实施方式中,药物通过微针释放。在另一个实施方式中,治疗剂可释放入装置内的盐水溶液区室用作载流体。在本发明这方面的又一个实施方式中,脂质体包封有治疗剂,并且脂质体上连接有可特异性结合特定细胞型的抗体。该方法根据疾病标记的检测而将大量药物递送至适当的细胞型。

[0125] 装置可包含一个或多个含有治疗剂的储库。储库容纳治疗剂,直到生物识别装置根据疾病标记的检测指令储库以控制的方式释放治疗剂,例如收到关于释放速率和试剂释放量的指令。或者,可将单一释放速率或剂量程序编入装置。储库可含有一种或多种治疗剂的混合物。或者,装置可包含一种或多种治疗剂的几个储库。优选有多个储库。

[0126] “治疗剂”在这里指可用于或适用于治疗与特定生物异常疾病标记如疾病标记分析物相关的疾病。本发明治疗剂是治疗疾病的任何治疗物质,例如包括:优选局部递送的药物化合物如化学治疗剂,留体,治疗性核酸包括DNA、RNA、双链RNA(通过RNA界面)和反义 RNA,或蛋白质如免疫球蛋白、生长因子、抗炎剂或酶抑制剂等。

[0127] 通过从装置释放治疗剂,可优选建立药物的局部有效浓度。例如,在装置的可研究和可植入的实施方式中,对于同一种药物,局部浓度基本上超过全身安全浓度,因此患者基本上没有不适而效力最大。这里包括了适合治疗局部炎症的皮质类固醇的局部释放。此外, 本文还包括了用于治疗感染的病原体特异性抗体。各个临床医生根据患者情况选择确切的制剂和剂量。(例如,参见Fingl等,刊载于《治疗学的药理基础》(The Pharmacological Basis ofTherapeutics),1975, 一章,第一页)。

[0128] 在另一个实施方式中,检测无用细胞增殖的生物分析物指标,并优选局部释放具有抗增殖性效应的治疗剂。例如,西罗莫司(雷怕霉素)或紫杉醇在新内膜增生期间抑制平滑肌细胞增殖非常有效。

[0129] 在响应无用增殖的生物分析物指标存在的另一个实施方式中,从装置释放基于 5-FU的化学治疗剂,包括单独给予5-FU、其衍生物,或与其它化学治疗剂联用如亚叶酸, 或与DPD抑制剂如尿嘧啶、5-乙炔基尿嘧啶、溴乙烯尿嘧啶、胸腺嘧啶、苄氧基苄基尿嘧啶 (BBU)或5-氯-2,4- 二羟基吡啶联用。而且,发现与5-FU或其衍生物和DPD抑制剂5-乙炔基尿嘧啶的组合相比,共同给予通式(I)的5’-脱氧-胞苷衍生物和5-FU或其衍生物可显著改善一种化学治疗剂选择性递送至肿瘤组织。

[0130] 可选地,遗传毒性试剂是形成持久基因组损伤的试剂,在无用细胞增殖的临床控制中优选用作化学治疗剂。遗传毒素诱导的DNA损伤的细胞修复速率,以及通过细胞分裂周期的细胞生长速率,影响遗传毒素疗法的结果。用于治疗多种癌症的遗传毒性化合物的一般种类是DNA烷化剂和DNA插入剂。

[0131] 补骨脂素是已知在皮肤疾病如银屑病、白癜风、真菌感染和皮肤T细胞淋巴瘤的光化学治疗中有用的遗传毒性化合物。《哈里森内科学原理》(Harrison’ s Principles of Internal Medicine),第2部分“疾病的重要表现形式”,第60章(第12版.1991)。另一类可烷化或插入DNA的遗传毒性化合物包括合成或天然来源的抗生素。尤其感兴趣的是抗瘤抗生素,包括但不限于以下化合物:安吖啶;放线菌素A,C,D (也称为更生霉素)或F(也称为KS4);偶氮丝氨酸;博来霉素;洋红霉素(卡柔比星),道诺霉素(柔红霉素)或14-羟基道诺霉素(阿霉素或多柔比星);丝裂霉素A,B或C ;米托蒽醌;普卡霉素(光神霉素) 等。再一类常用的烷化DNA的遗传毒性试剂包括卤乙基亚硝基脲,尤其是氯乙基亚硝基脲。 该类试剂的代表性例子包括卡莫司汀、氯脲菌素、福莫司汀、洛莫司汀、尼莫司汀、雷莫司汀和链脲菌素。商乙基亚硝基脲第一试剂可以是任何上述代表性化合物的类似物或衍生物。

[0132] 目前可通过钼配位化合物如顺钼或奥沙利钼控制的肿瘤包括睾丸癌、子宫内膜癌、子宫颈癌、胃癌、鳞状上皮细胞癌、肾上腺皮质癌、肺小细胞癌以及髓母细胞瘤和成神经细胞瘤。其它细胞毒抗癌治疗剂包括:例如治疗睾丸癌的BEP (博来霉素、依托泊苷、顺钼), 治疗膀胱癌的MVAC (甲氨蝶呤、长春碱、阿霉素、顺钼),治疗肺非小细胞癌的MVP (丝裂霉素 C、长春碱、顺钼)。

[0133] 再一类烷化DNA的遗传毒性试剂包括硫芥和氮芥。该类化合物通过在鸟嘌呤的N7 原子形成共价加合物而首先破坏DNA。该类化合物的代表性例子包括苯丁酸氮芥、环磷酰胺、异环磷酰胺、美法兰、氮芥、新氮芥、曲磷胺等。当需要选择一种或多种预定的基因靶点作为基因座损失的位点时,也可使用与选定细胞的基因组中特定序列共价或非共价相互作用的寡核苷酸或其类似物作为遗传毒性试剂。

[0134] 另一类烷化DNA的试剂包括乙撑亚胺和甲基三聚氰胺。该类化合物包括六甲蜜胺 (六甲三聚氰胺)、三亚乙基磷酰胺(TEPA)、三亚乙基硫代磷酰胺(硫代TEPA)和三亚乙基蜜胺。

[0135] 另一类DNA烷化剂包括烷基磺酸酯如白消安;azinidine类如苯佐替派;其它如米托胍腙、米托蒽醌和丙卡巴胼。该类化合物各自包括代表性化合物的类似物和衍生物。

[0136] 细胞毒治疗剂的其它例子是与细胞特异性抗体复合的抗体,激活血清补体和/或介导抗体依赖细胞毒性。结合细胞的抗体也可连接有毒素(免疫毒素)。免疫毒素的细胞毒部分可以是细胞毒药物或细菌或植物来源的酶活性毒素,或这种毒素的酶活性片段。使用的酶活性毒素及其片段是白喉、白喉毒素的非结合活性片段(来自绿脓假单胞菌)、蓖麻毒蛋白、相思豆毒蛋白、蒴莲根毒素、α-帚曲菌素、油桐蛋白、石竹素蛋白、美洲商陆蛋白(ΡΑΡΙ、ΡΑΡΙΙ和PAP-幻、苦瓜抑制剂、麻疯树毒蛋白、巴豆毒蛋白、石碱草抑制剂、白树毒素、米托洁林、局限曲菌素、酚霉素和依诺霉素。在另一个实施方式中,抗体连接有小分子抗癌药。使用多种双功能蛋白偶联剂制备单克隆抗体和这种细胞毒部分的偶合物。这种试剂的例子有SPDP、IT、亚氨酸酯的双功能衍生物如HCl 二甲基己二酰亚胺酸盐,活性酯如二琥珀酰亚胺基辛二酸酯,醛如戊二醛,双叠氮化合物如双(对叠氮基苯甲酰基)己二胺、 双-重氮衍生物如双(对重氮基苯甲酰基)_乙二胺,二异氰酸酯如甲苯2,6- 二异氰酸酯以及双活性氟化合物如1,5_ 二氟-2,4-二硝基苯。毒素的溶解部分可与抗体的Fab片段连接。通过放射性同位素与抗体结合,可制备治疗癌症的细胞毒放射性药物。本文所用术语“细胞毒部分”包括这种同位素。

[0137] 在一个实施方式中,治疗剂是受体酪氨酸激酶的抑制剂如EGFR和HER2-neu,用作增殖细胞如哺乳动物癌细胞生长的选择性抑制剂。例如,厄尔他丁(erbstatin,EGF受体酪氨酸激酶抑制剂),可降低表达人癌细胞的EGFR生长。苯乙烯的多种衍生物也具有酪氨酸激酶抑制活性,可用作抗肿瘤药物。两种苯乙烯衍生物为I类RTK抑制剂,其有效性已通过减少注入裸小鼠的人鳞状细胞癌的生长来证实。某些4-苯胺基喹唑啉衍生物可用作受体酪氨酸激酶的抑制剂。这些化合物显示的很紧密结构-活性关系提示清楚限定的结合模式,喹唑啉环在腺嘌呤袋中结合,苯胺基环在相邻、独特的亲脂袋中结合。临床上评价了三种4-苯胺基喹唑啉类似物(两种可逆和一种不可逆抑制剂)作为抗癌药。此外,用于治疗HER2-neU过度表达的转移性乳腺癌的单克隆抗体曲妥单抗(赫赛汀™)。kheurle等, Anticancer Res 20 :2091_2096,2000。

[0138] 在另一个实施方式中,当检测微生物病原体的生物分析物指标时,优选局部释放具有抗微生物作用的治疗剂。例如,优选释放抗生素如内酰胺类抗生素、氨基糖苷类、 大环内酯类、林可霉素和克林霉素、四环素类、喹诺酮类、磺胺类、甲氧苄啶-磺胺甲噁唑, 尤其是:阿莫西林(Amoxicillan、Amoxicillan、Amoxicillin)、氨苄西林、力百汀、复方新诺明、克拉霉素制剂、希克罗、西福辛、盐酸环丙沙星制剂、克林霉素、地塞米松制剂、氟康唑制齐U、多西环素、红霉素(erythromyacin、erythtomycin、Erythromycin)、灭滴灵制齐[J、氧氟沙星制剂、头孢力新制剂、左甲状腺素钠制剂、呋喃妥因制剂、甲硝唑(弗来吉尔)、盐酸米诺环素、二甲胺四环素/米诺环素、nizarol、诺氟沙星、制霉菌素、青霉素、Polarol、罗氏芬、磺胺、复方新诺明、链霉素、加替沙星、四环素、替硝唑、盐酸伐昔洛韦制剂、多西环素制剂、希舒美或阿奇霉素。

[0139] 在检测病毒感染的生物分析物指标时,优选释放抗病毒化合物,包括蛋白酶抑制剂如因维拉斯(Invirase)、诺韦、奈非那韦、佳息患或Frotovase、沙奎那韦或其它抗病毒剂如金刚烷胺、金刚乙胺、扎那米韦、奥塞米韦、利巴韦林、AZT、去羟肌苷、扎西他滨、司他夫定、拉米夫定、奈韦拉平、地拉韦唆、碘苷、阿糖腺苷、曲氟尿苷、阿昔洛韦、泛昔洛韦、喷昔洛韦、伐昔洛韦、更昔洛韦、膦甲酸、利巴韦林、金刚烷胺和金刚乙胺、西多福韦、干扰素。

[0140] 在另一个实施方式中,当检测炎症的生物分析物指标时,优选局部释放具有抗炎作用的治疗剂。优选的治疗剂为留体如泼尼松/泼尼松龙,或非留体抗炎药(NSAID)如阿司匹林、布洛芬、萘普生、萘丁美酮、塞来考昔、罗非考昔或伐地考昔。这些治疗剂尤其适用于治疗炎症相关疾病如炎性肠病、类风湿性关节炎等。

[0141] 在另一个实施方式中,当检测高血糖的生物分析物指标时,优选装置释放降低血清葡萄糖水平的治疗剂。例如,当装置检测到葡萄糖水平过高时,装置将释放足够量的胰岛素以使血液中过高的葡萄糖水平回到正常水平。

[0142] 本发明设想具有多个微芯片的医疗装置。优选地,微芯片具有目前可获得的最大处理能力。优选地,多个微芯片相互连通。最优选地,微芯片由硅锗构成。甚至更优选地,微芯片是国际商业机器公司IBM)的CMOS 9S低-k介电绝缘高效芯片,以在操作医疗装置时提供可获得的最高效率、速度和功率。技术人员容易明白,因为下述装置能够包埋在各种数量的微芯片上,装置可具有各种数量的微芯片。

[0143] 而且,通过该系统中独特集成方法可优化装置的每个技术组件。近来,低_k介电绝缘和硅锗技术最大程度地增加了微芯片处理容量和效率。这些芯片适合于光通讯网络, 并且通过将它们与用光信号处理数据的微阵列珠技术结合,优化系统的功率。

[0144] 本发明的另一特征涉及能够从储库控制释放治疗剂的治疗剂释放装置。例如,当生物统计识别装置测定疾病标记的存在时,治疗剂释放装置发生信号以控制的方式从储库释放治疗剂,即它接收关于释放速率和/或待释放药物量的指令。在一个实施方式中,治疗剂释放装置是位于上述含微芯片的装置下方的微芯片,包括控制治疗剂释放的储库。微芯片的基片包含蚀刻、铸模或加工的储库,用作微芯片的支持物。基片可使用任何可用作支持物的材料,适于蚀刻、铸模或加工且可渗透入待传递的分子并到达周围流体如水、有机溶剂、血液、电解质或其它溶液。基片材料的例子包括陶瓷、半导体、可降解和不可降解聚合物。优选基片本身是无毒、无菌和生物相容的。然而,在使用前,可将毒性或非生物相容材料包封在生物相容材料如聚(乙烯醇)或四氟乙烯样材料中。参见美国专利6,491,666,全部被纳入本文作为参考。合适的治疗剂释放装置得自Microchips (Cambridge,MA)。优选地,治疗剂释放装置具有多个储库。在本发明这方面的另一个实施方式中,治疗剂释放装置给予其它装置或外部数据库关于合适的治疗剂释放状态的信号。在又一个实施方式中,以小剂量释放治疗剂作为初步治疗,而治疗剂通过具有独立的无线信号系统的其它微芯片, 独立的无线信号系统作为检查点以确保传递前的正确剂量。

[0145] 本发明另一特征涉及能便于微阵列扫描装置、生物识别装置和任选地,治疗剂释放装置之间通讯的接口装置。优选地,接口装置从生物识别装置接收关于分析物存在、不存在或量的信息,给予治疗剂释放装置信号以从一个或多个储库释放治疗剂或治疗剂的混合物。在一个实施方式中,接口装置具有无线局域网(WLAN)发射机和接受器。具体可见美国专利5,832,296或6,542, 717,全部被纳入本文作为参考。在另一个实施方式中,本发明考虑使用个人局域网(PAN)静电通讯在微芯片间传送信号,利用与治疗剂释放储库结合的治疗剂释放装置,以便从生物识别装置的分析接收各个信号而将药物递送入体内。优选地,在可植入和可摄取的实施方式中,两交界PAN发射机位于微阵列下方:一个交界微阵列扫描装置,另一个交界控制下方储库的治疗剂释放装置。PAN发射机发送释放治疗剂的信号,如阵列结果所示。合适的硬件得自IntervalResearch Corp.,Palo Alto, CA, PAN发射机得自 IBM,Armonk, NY。

[0146] 在本发明这方面的另一个实施方式中,多个微芯片将信息发送至外部源如手持监测装置或无线数据通讯系统操纵的网络总部计算机。在再一个实施方式中,装置是用于治疗糖尿病的贴片,贴片测定胰岛素水平并与测定碳水化合物水平的第二装置或测定汗腺或运算(arithmic)水平的第三装置连通。通过将分析物和不同装置间的相互作用与物理参数数据库进行比较,确定是否释放一定量葡萄糖或胰岛素的处理控制决定是合适的,形成确定葡萄糖/胰岛素释放中必需的其它因素的闭环系统。

[0147] 在另一个实施方式中,本发明具有能源以驱动医疗装置。例如,装置由电池驱动。 在另一个实施方式中,能源由个人局域网提供。[0148] 本发明的用途从军事到商业。例如,感染病毒如SARS、需要实时诊断的国家公民可使用该装置。随着生物恐怖主义的出现,检测病原体方法对全世界国防部的价值日益增加。类似地,本发明可用于检测细菌感染或其它肠相关疾病,通过感染性疾病生长的最大中心之一的肠系统进行立即的实时诊断蛋白质活性。类似地,通过使用选择性体内蛋白阵列和施予对应于靶蛋白类型的抗体或药物,可最大程度地解决例如在乙醛载玻片上对高亲和性和特异性蛋白质配基或模糊感兴趣的肽的BSA进行分离的问题,这些问题目前限制蛋白微阵列技术的应用。此外,本发明装置尤其适用于临床研究,有效监测试验药物的水平和效果以建立药物动力学模型。

[0149] 事实上,本发明装置可用于商业、医疗、研究/教育、军事以及社区服务/慈善应用。

[0150] 实施例

[0151] 实施例1 :光导纤维全内部反射荧光生物传感器说明

[0152] 构建光导纤维全内部反射荧光(TIRF)生物传感器,并构建本文所述微阵列和微阵列扫描装置。参见 Preininger 等(Analytica Chimica Acta,2000,403,67-76)。激光通过一系列光导纤维从激光光源导向细胞流到检测器。该基于光导纤维单元的示意图如图12 所示。在传感器中,输入激光导向通过50:50光导纤维分离器的输出引线到达官能化光纤上。发射的荧光偶联回入光纤并传向检测器,几乎没有激光干扰。这种设计具有以下优点: 开始到结束使用光纤消除了由于自由空间耦合导致的损失;光纤是坚固的光转运体而对振动不敏感,且多根光纤可容易地通过市售光纤连接器连接到一起。因此,微阵列可以是一根光纤的官能化表面或是多根光纤的官能化表面。

[0153]使用 Celebre 等(Measurement Science and Technology,1992,3,1166-1173)所述方法,将传递至光二极管的预期的输出荧光强度作为输入激光功率和Atto 655荧光团的光纤特征的函数(见图13),结果如表1所示,系统参数如下:

[0154] 表面浓度约 200ng/cm2 [Tedeschi 等,Biosensors and Bioelectronics, 2003, 19(2) ,85-93]

[0155]荧光团 Atto 655 (Sigma Aldrich),光谱特征 QY = 0. 3 ε =110,000

[0156] 表1 :作为激光功率和光纤特征的函数的荧光输出[0157]

Figure CN1905835BD00251

[0158] 典型的光二极管(例如I^acific Sensor partl-6_T052Sl)以皮瓦特范围精确测量信号。显然,即使保守估计系统中50%损失,可调节生物传感器的参数,使得输出功率比检测器的最低灵敏度大两个数量级。

[0159] 实施例2 :集成贴片系统

[0160] 示例性贴片装置是自动吸取和采集0. Iml血测定万古霉素的无痛方法。每个贴片有两部分组成:包含一次使用微针和微通道的一次性部分(分析装置),以及包含其余光学、电子和机械构造的可再次使用的部分(分析读数装置)。如图5,7所示。

[0161] 微针自动地无痛吸取少量血液。机械致动器插入针并从撤出。本发明装置在应用贴片后进行几次测定。然而,每个微针只用一次以避免堵塞。多次取血需要机械致动器不仅能够插入针和撤出,而且能够处理用过的针并重新装新针。微针足够尖锐、牢固和微细以完全无痛方式穿过皮肤外层。该设计有助于装置的低成本、一次性、自利用和生物相容性质。

[0162] 在SNF的模具中用光刻技术生产针。贴片装置的“顶部”分析装置部分上的微通道包含层流和储库元件,以及俘获光纤传感器必需的结构。两种独立流体流动元件操作贴片-血液流过针进入储库,血液/缓冲流流过通道。如图5所示。下表显示通道的设计说明。

[0163]表 2

[0164]

Figure CN1905835BD00252
Figure CN1905835BD00261

[0166] 贴片的非一次性部分(分析读数装置)包含12个将要安装到非一次性装置上的单次使用的一次性部分(分析装置)。如图7所示。从Micronics得到常规微流体制造。 说明如下:

[0167] 规格

[0168]

Figure CN1905835BD00262

[0169]

Figure CN1905835BD00271

[0170] 光学传感器微阵列扫描装置基于由激光产生的渐消波激发的生物活性剂和分析物之间相互作用的荧光提供给生物识别装置电信号。根据激光、PIN 二极管和荧光分子损失间的损失折衷确定光学传感器频率。

[0171] 非一次性瞬逝传感光纤(分析读数装置内的微阵列扫描装置)与一次性取血流体子系统(包含分析装置中的微阵列)连接,产生完全一次使用的分析装置。以每分析读数装置6-12组包装分析装置。

[0172] 集成系统最大尺寸的测试类似于图14所示的主体介质装置。

[0173] 血流过微针进入血液储库。缓冲流和血流形成通过通道的层流(图5 ;以黑色显示)。660nm激光激发荧光团,结合于光纤表面(灰色)。血中药物将标记药物置于光纤上, 荧光强度降低。读数装置中光纤末端上的传感器检测信号水平的降低。将该降低记录到生物统计识别装置的相关数据库。

[0174] 装置形成梳状结构;12单元分析模型显示在图7中。图中,控制电路安装在装置的顶部(分析读数装置)。启动机制位于装置底部(分析装置)。

[0175] 读数装置的端视图显示在读数装置底部用于分析装置的空腔。两组件间存在光和机械接口。沿空腔的顶部是12个弹簧,用于迫使微针进入皮肤。还具有释放弹簧的螺线管。 每个弹簧在12个一次性部分之一的顶部上加压。

[0176] 每个分析装置指的一端在分析装置内形成铰链。使得弹簧迫使分析装置向下通过一层覆盖分析装置底部的薄膜。

[0177] 光导纤维通过铰链上方,终止于光学分离器,光学分离器安装于电子印刷电路板的底部。分析装置和分析读数装置间的接口为小的气隙。

[0178] 12个分析装置指之一的端视图显示了包装。分析装置在无菌贴片包装内。

[0179] 微针下方为贴片的一部分,以使针穿透进入皮肤。用粘合剂将贴片保持在适当位置,如图6所示。

[0180] 最后还有保护层。贴片的顶部允许插入读数装置。光信号通过光纤末端和分离器之间密封的一部分。

[0181] 本文中,仅描述了本发明优选实施方式和通用性的几个变化例子。应理解的是,可使用本发明的多种其它组合和环境,而且变化或改进包括在本发明范围内。因此,例如,本领域技术人员将明白或能确定,使用常规实验技术,本文描述了具体物质和方法的多种等价形式。这些等价形式被认为包括在本发明范围内,并被所附权利要求书限定。

Claims (52)

1. 一种医疗装置,所述医疗装置包括:a)多个小型试验位点的一个微阵列,与患者的体液构成流体连通,其中所述的微阵列包含能够与疾病标记生物分析物相互作用的生物活性剂;b)包含至少一种治疗剂并设置成从所述医疗装置释放所述至少一种治疗剂的至少一个储库;c)多个微芯片,所述微芯片包括:i)设置成获得疾病标记生物分析物与生物活性剂之间相互作用的物理参数数据的微阵列扫描装置;ϋ)设置成将所述物理参数数据与分析物相互作用分布图进行比较的生物统计识别装置;iii)设置成控制所述治疗剂从所述储库释放的治疗剂释放装置;iv)设置成促进所述微阵列扫描装置、所述生物统计识别装置和所述治疗剂释放装置之间通讯的接口装置;d)驱动医疗装置的能源。
2.如权利要求1所述的医疗装置,其特征在于,所述装置涂覆有生物相容聚合物。
3.如权利要求2所述的医疗装置,其特征在于,所述聚合物具有通道。
4.如权利要求2所述的医疗装置,其特征在于,所述聚合物是多孔的。
5.如权利要求1所述的医疗装置,其特征在于,所述微阵列包含微珠。
6.如权利要求1所述的医疗装置,其特征在于,所述生物活性剂是核酸。
7.如权利要求1所述的医疗装置,其特征在于,所述生物活性剂是多肽。
8.如权利要求7所述的医疗装置,其特征在于,所述生物活性剂是免疫球蛋白。
9.如权利要求1所述的医疗装置,其特征在于,所述生物活性剂是荧光标记的。
10.如权利要求1所述的医疗装置,其特征在于,所述生物活性剂是用纳米晶体荧光标记的。
11.如权利要求1所述的医疗装置,其特征在于,所述疾病标记生物分析物是核酸。
12.如权利要求1所述的医疗装置,其特征在于,所述疾病标记生物分析物是多肽。
13.如权利要求12所述的医疗装置,其特征在于,所述疾病标记生物分析物是免疫球蛋白。
14.如权利要求1所述的医疗装置,其特征在于,所述多个微芯片含有硅锗。
15.如权利要求1所述的医疗装置,其特征在于,所述微阵列扫描装置包含光导纤维元件。
16.如权利要求1所述的医疗装置,其特征在于,所述分析物相互作用分布图存储在生物统计识别装置中。
17.如权利要求1所述的医疗装置,其特征在于,所述分析物相互作用分布图存储在医疗装置的外部。
18.如权利要求1所述的医疗装置,所述的医疗装置具有多个储库。
19.如权利要求1所述的医疗装置,其特征在于,所述接口装置包括个人局域网。
20.如权利要求1所述的医疗装置,其特征在于,所述能源是电池。
21.如权利要求1所述的医疗装置,其特征在于,所述能源由个人局域网提供。
22.如权利要求1所述的医疗装置,还包括渗透泵。
23.如权利要求1所述的医疗装置,还包括加压微流体通道。
24.如权利要求1所述的医疗装置,还包括指导体液流动的个人局域网发射机。
25.如权利要求1所述的医疗装置,其特征在于,所述的微阵列被连接到微通道上。
26.如权利要求25所述的医疗装置,其特征在于,所述的微通道具有第一入口和第二入口,其中第一入口将体液引入微通道,第二入口将缓冲液从缓冲剂的储物库引入微通道。
27.如权利要求1所述的医疗装置,其特征在于,所述的医疗装置是可摄取的。
28. 一种能够检测体液中分析物的医疗装置,所述装置包括贴片,所述的贴片包括:A)至少一个能够获得体液样品的微针;B)缓冲剂储库;C)具有至少第一入口、第二入口和连接到微通道上的微阵列的微通道,所述的微阵列包含至少一种生物活性剂,其中第一入口与至少一个微针进行流体连通,并将体液引入微通道,其中第二入口将缓冲液从所述的缓冲剂储库引入微通道,结果体液中的分析物扩散进入缓冲液流,使生物活性剂与其中的分析物之间发生相互作用;D)检测生物活性剂和体液中的分析物之间相互作用的微阵列扫描装置;E)将所述相互作用的物理参数数据与分析物相互作用分布图进行比较的生物统计识别装置;和F)能够促进所述微阵列扫描装置和所述生物统计识别装置之间通讯的接口装置。
29.如权利要求观所述的医疗装置,其特征在于,所述体液是血液。
30.如权利要求观所述的医疗装置,其特征在于,所述至少一个微针是多个微针。
31.如权利要求观所述的医疗装置,其特征在于,所述微针直径为10-200微米。
32.如权利要求观所述的医疗装置,其特征在于,所述微针能够取100微升的血。
33.如权利要求观所述的医疗装置,其特征在于,所述微阵列扫描装置检测瞬逝波。
34.如权利要求观所述的医疗装置,其特征在于,体液中的分析物从结合生物活性剂竞争地置换标记的分析物。
35.如权利要求34所述的医疗装置,其特征在于,提供预定量的所述标记的分析物。
36.如权利要求34所述的医疗装置,其特征在于,所述标记的分析物标记有荧光团部分。
37.如权利要求观所述的医疗装置,其特征在于,所述微阵列包括特异性结合体液中分析物的抗体。
38.如权利要求观所述的医疗装置,其特征在于,所述微阵列扫描装置包括全内部反射荧光光谱仪。
39.如权利要求观所述的医疗装置,其特征在于,所述生物统计识别装置位于装置的外部并通过无线传输通讯。
40.如权利要求观所述的医疗装置,其特征在于,所述分析物是胰岛素,所述生物活性剂是对胰岛素特异的抗体。
41.如权利要求观所述的医疗装置,其特征在于,所述分析物是葡萄糖,所述生物活性剂是对葡萄糖特异的抗体。
42.如权利要求观所述的医疗装置,其特征在于,所述的医疗装置以贴片形式配戴在皮肤上。
43.如权利要求观述的医疗装置,其特征在于,所述分析物是疾病标记生物分析物。
44.如权利要求观所述的医疗装置,还包括:G)其中含有治疗剂的储库;和H)治疗剂释放装置,所述治疗剂释放装置能够响应来自生物统计识别装置的指令而控制治疗剂从储库的释放。
45.如权利要求44所述的医疗装置,其特征在于,所述分析物是葡萄糖,所述治疗剂是胰岛素。
46.如权利要求44所述的医疗装置,其特征在于,所述分析物与所述治疗剂相同。
47.如权利要求44所述的医疗装置,其特征在于,所述分析物是治疗剂的代谢物。
48.如权利要求观所述的医疗装置,其特征在于,所述的医疗装置包括至少一个一次性分析装置和非一次性分析读数装置,所述至少一个一次性分析装置包括所述的至少一个微针和所述的微通道,非一次性分析读数装置包括所述的微阵列扫描装置和所述的接口装置。
49.如权利要求48所述的医疗装置,其特征在于,所述分析装置和分析读数装置相互光连通。
50.如权利要求48所述的医疗装置,其特征在于,多种所述的至少一个一次性分析装置与单一分析读数装置匹配。
51.如权利要求观所述的医疗装置,其特征在于,所述微阵列包括一用生物活性剂官能化的单根玻璃光导纤维的未包覆部分,其中单根玻璃光导纤维的未包覆部分构成微通道的壁的一部分。
52.如权利要求观所述的医疗装置,其特征在于,所述微阵列包含许多用生物活性剂官能化的单根玻璃光导纤维的未包覆部分,其中单根玻璃光导纤维的未包覆部分构成微通道的壁的一部分。
CN 200480030548 2003-09-11 2004-09-10 分析物监测和药物递送的医疗装置 CN1905835B (zh)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US50184703 true 2003-09-11 2003-09-11
US60/501,847 2003-09-11
PCT/US2004/029462 WO2005025413A3 (en) 2003-09-11 2004-09-10 Medical device for analyte monitoring and drug delivery

Publications (2)

Publication Number Publication Date
CN1905835A true CN1905835A (zh) 2007-01-31
CN1905835B true CN1905835B (zh) 2011-11-30

Family

ID=34312312

Family Applications (1)

Application Number Title Priority Date Filing Date
CN 200480030548 CN1905835B (zh) 2003-09-11 2004-09-10 分析物监测和药物递送的医疗装置

Country Status (9)

Country Link
US (5) US7291497B2 (zh)
EP (2) EP1662987B1 (zh)
JP (5) JP4603547B2 (zh)
KR (8) KR101556457B1 (zh)
CN (1) CN1905835B (zh)
CA (3) CA2852974C (zh)
DK (1) DK1662987T3 (zh)
ES (1) ES2374563T3 (zh)
WO (1) WO2005025413A3 (zh)

Families Citing this family (366)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6036924A (en) 1997-12-04 2000-03-14 Hewlett-Packard Company Cassette of lancet cartridges for sampling blood
US6391005B1 (en) 1998-03-30 2002-05-21 Agilent Technologies, Inc. Apparatus and method for penetration with shaft having a sensor for sensing penetration depth
CA2399842C (en) 2000-03-02 2006-11-14 Microchips, Inc. Microfabricated devices for the storage and selective exposure of chemicals and devices
US8641644B2 (en) 2000-11-21 2014-02-04 Sanofi-Aventis Deutschland Gmbh Blood testing apparatus having a rotatable cartridge with multiple lancing elements and testing means
DE60219607T2 (de) 2001-01-09 2007-12-27 Microchips, Inc., Bedford Flexible mikrochip-vorrichtungen zur ophthalmologischen und anderen applikation
US8372016B2 (en) 2002-04-19 2013-02-12 Sanofi-Aventis Deutschland Gmbh Method and apparatus for body fluid sampling and analyte sensing
US7892183B2 (en) 2002-04-19 2011-02-22 Pelikan Technologies, Inc. Method and apparatus for body fluid sampling and analyte sensing
WO2002099457A3 (en) * 2001-05-31 2003-03-27 Massachusetts Inst Technology Microchip devices with improved reservoir opening
US7717863B2 (en) 2002-04-19 2010-05-18 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
WO2002100460A3 (en) 2001-06-12 2003-05-08 Don Alden Electric lancet actuator
US8360992B2 (en) 2002-04-19 2013-01-29 Sanofi-Aventis Deutschland Gmbh Method and apparatus for penetrating tissue
US7491178B2 (en) 2002-04-19 2009-02-17 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US9427532B2 (en) 2001-06-12 2016-08-30 Sanofi-Aventis Deutschland Gmbh Tissue penetration device
US7041068B2 (en) 2001-06-12 2006-05-09 Pelikan Technologies, Inc. Sampling module device and method
US7331931B2 (en) 2002-04-19 2008-02-19 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US7909778B2 (en) 2002-04-19 2011-03-22 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US7297122B2 (en) 2002-04-19 2007-11-20 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US7981056B2 (en) 2002-04-19 2011-07-19 Pelikan Technologies, Inc. Methods and apparatus for lancet actuation
US9226699B2 (en) 2002-04-19 2016-01-05 Sanofi-Aventis Deutschland Gmbh Body fluid sampling module with a continuous compression tissue interface surface
US7648468B2 (en) 2002-04-19 2010-01-19 Pelikon Technologies, Inc. Method and apparatus for penetrating tissue
US7976476B2 (en) 2002-04-19 2011-07-12 Pelikan Technologies, Inc. Device and method for variable speed lancet
US7674232B2 (en) 2002-04-19 2010-03-09 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US7229458B2 (en) 2002-04-19 2007-06-12 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US8784335B2 (en) 2002-04-19 2014-07-22 Sanofi-Aventis Deutschland Gmbh Body fluid sampling device with a capacitive sensor
US9248267B2 (en) 2002-04-19 2016-02-02 Sanofi-Aventis Deustchland Gmbh Tissue penetration device
US9795334B2 (en) 2002-04-19 2017-10-24 Sanofi-Aventis Deutschland Gmbh Method and apparatus for penetrating tissue
US8267870B2 (en) 2002-04-19 2012-09-18 Sanofi-Aventis Deutschland Gmbh Method and apparatus for body fluid sampling with hybrid actuation
US7316700B2 (en) 2001-06-12 2008-01-08 Pelikan Technologies, Inc. Self optimizing lancing device with adaptation means to temporal variations in cutaneous properties
US8221334B2 (en) 2002-04-19 2012-07-17 Sanofi-Aventis Deutschland Gmbh Method and apparatus for penetrating tissue
US7232451B2 (en) 2002-04-19 2007-06-19 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US7291117B2 (en) 2002-04-19 2007-11-06 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US8337419B2 (en) 2002-04-19 2012-12-25 Sanofi-Aventis Deutschland Gmbh Tissue penetration device
US7699791B2 (en) 2001-06-12 2010-04-20 Pelikan Technologies, Inc. Method and apparatus for improving success rate of blood yield from a fingerstick
EP1404235A4 (en) 2001-06-12 2008-08-20 Pelikan Technologies Inc Method and apparatus for lancet launching device integrated onto a blood-sampling cartridge
US8579831B2 (en) 2002-04-19 2013-11-12 Sanofi-Aventis Deutschland Gmbh Method and apparatus for penetrating tissue
US7371247B2 (en) 2002-04-19 2008-05-13 Pelikan Technologies, Inc Method and apparatus for penetrating tissue
US9314194B2 (en) 2002-04-19 2016-04-19 Sanofi-Aventis Deutschland Gmbh Tissue penetration device
US7226461B2 (en) 2002-04-19 2007-06-05 Pelikan Technologies, Inc. Method and apparatus for a multi-use body fluid sampling device with sterility barrier release
US7344507B2 (en) 2002-04-19 2008-03-18 Pelikan Technologies, Inc. Method and apparatus for lancet actuation
US7901362B2 (en) 2002-04-19 2011-03-08 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US7547287B2 (en) 2002-04-19 2009-06-16 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US7682318B2 (en) 2001-06-12 2010-03-23 Pelikan Technologies, Inc. Blood sampling apparatus and method
US8702624B2 (en) 2006-09-29 2014-04-22 Sanofi-Aventis Deutschland Gmbh Analyte measurement device with a single shot actuator
US7008403B1 (en) * 2002-07-19 2006-03-07 Cognitive Ventures Corporation Infusion pump and method for use
JP4436258B2 (ja) 2002-08-16 2010-03-24 マイクロチップス・インコーポレーテッド 制御された放出デバイスおよび方法
EP1551499A1 (en) 2002-10-04 2005-07-13 Microchips, Inc. Medical device for neural stimulation and controlled drug delivery
DE60331455D1 (de) * 2002-10-04 2010-04-08 Microchips Inc Medizinische vorrichtung zur gesteuerten arzneimittelverabreichung sowie herzüberwachung und/oder herzstimulation
US7727181B2 (en) 2002-10-09 2010-06-01 Abbott Diabetes Care Inc. Fluid delivery device with autocalibration
US8574895B2 (en) 2002-12-30 2013-11-05 Sanofi-Aventis Deutschland Gmbh Method and apparatus using optical techniques to measure analyte levels
US7488757B2 (en) * 2003-03-24 2009-02-10 Becton, Dickinson And Company Invisible antimicrobial glove and hand antiseptic
US7679407B2 (en) 2003-04-28 2010-03-16 Abbott Diabetes Care Inc. Method and apparatus for providing peak detection circuitry for data communication systems
EP1628567B1 (en) 2003-05-30 2010-08-04 Pelikan Technologies Inc. Method and apparatus for fluid injection
US7850621B2 (en) 2003-06-06 2010-12-14 Pelikan Technologies, Inc. Method and apparatus for body fluid sampling and analyte sensing
CA2852974C (en) * 2003-09-11 2017-06-27 Theranos, Inc. Medical device for analyte monitoring and drug delivery
WO2005033659A3 (en) 2003-09-29 2007-01-18 Pelikan Technologies Inc Method and apparatus for an improved sample capture device
WO2005037095A1 (en) 2003-10-14 2005-04-28 Pelikan Technologies, Inc. Method and apparatus for a variable user interface
US8095197B2 (en) 2003-11-03 2012-01-10 Microchips, Inc. Medical device for sensing glucose
WO2005065414A3 (en) 2003-12-31 2005-12-29 Pelikan Technologies Inc Method and apparatus for improving fluidic flow and sample capture
US20070135697A1 (en) * 2004-04-19 2007-06-14 Therasense, Inc. Method and apparatus for providing sensor guard for data monitoring and detection systems
EP1751546A2 (en) 2004-05-20 2007-02-14 Albatros Technologies GmbH & Co. KG Printable hydrogel for biosensors
US9775553B2 (en) 2004-06-03 2017-10-03 Sanofi-Aventis Deutschland Gmbh Method and apparatus for a fluid sampling device
EP1765194A4 (en) 2004-06-03 2010-09-29 Pelikan Technologies Inc Method and apparatus for a fluid sampling device
WO2006001797A1 (en) 2004-06-14 2006-01-05 Pelikan Technologies, Inc. Low pain penetrating
US7537590B2 (en) * 2004-07-30 2009-05-26 Microchips, Inc. Multi-reservoir device for transdermal drug delivery and sensing
JP5107041B2 (ja) 2004-09-01 2012-12-26 マイクロチップス・インコーポレーテッド レザバ内容物の制御された放出または曝露のための、マルチキャップレザバデバイス
CN101010140A (zh) * 2004-09-03 2007-08-01 皇家飞利浦电子股份有限公司 微流体系统
CA2520670A1 (en) * 2004-09-23 2006-03-23 National Research Council Of Canada Nanocrystal coated surfaces
US20060073208A1 (en) * 2004-10-01 2006-04-06 Allergan, Inc. Cosmetic neurotoxin compositions and methods
US8652831B2 (en) 2004-12-30 2014-02-18 Sanofi-Aventis Deutschland Gmbh Method and apparatus for analyte measurement test time
US7822454B1 (en) 2005-01-03 2010-10-26 Pelikan Technologies, Inc. Fluid sampling device with improved analyte detecting member configuration
US8251907B2 (en) 2005-02-14 2012-08-28 Optiscan Biomedical Corporation System and method for determining a treatment dose for a patient
EP1863559A4 (en) 2005-03-21 2008-07-30 Abbott Diabetes Care Inc Method and system for providing integrated medication infusion and analyte monitoring system
CN101287411B (zh) 2005-04-28 2013-03-06 普罗秋斯生物医学公司 药物信息系统及其用途
US9756874B2 (en) 2011-07-11 2017-09-12 Proteus Digital Health, Inc. Masticable ingestible product and communication system therefor
US8836513B2 (en) 2006-04-28 2014-09-16 Proteus Digital Health, Inc. Communication system incorporated in an ingestible product
US8730031B2 (en) 2005-04-28 2014-05-20 Proteus Digital Health, Inc. Communication system using an implantable device
US8802183B2 (en) 2005-04-28 2014-08-12 Proteus Digital Health, Inc. Communication system with enhanced partial power source and method of manufacturing same
US9198608B2 (en) 2005-04-28 2015-12-01 Proteus Digital Health, Inc. Communication system incorporated in a container
US8912908B2 (en) 2005-04-28 2014-12-16 Proteus Digital Health, Inc. Communication system with remote activation
US7635594B2 (en) * 2005-05-09 2009-12-22 Theranos, Inc. Point-of-care fluidic systems and uses thereof
US8741230B2 (en) 2006-03-24 2014-06-03 Theranos, Inc. Systems and methods of sample processing and fluid control in a fluidic system
JP2006341089A (ja) * 2005-05-13 2006-12-21 Fujikura Ltd 医薬物運搬用器具およびその製造方法
US7768408B2 (en) 2005-05-17 2010-08-03 Abbott Diabetes Care Inc. Method and system for providing data management in data monitoring system
US7791728B2 (en) * 2005-08-11 2010-09-07 Hewlett-Packard Development Company, L.P. System for optically analyzing a substance with a selected single-wavelength
EP1920418A4 (en) 2005-09-01 2010-12-29 Proteus Biomedical Inc Implantable zero-wire communications system
US20070185432A1 (en) * 2005-09-19 2007-08-09 Transport Pharmaceuticals, Inc. Electrokinetic system and method for delivering methotrexate
US20070066934A1 (en) * 2005-09-19 2007-03-22 Transport Pharmaceuticals, Inc. Electrokinetic delivery system and methods therefor
US8880138B2 (en) 2005-09-30 2014-11-04 Abbott Diabetes Care Inc. Device for channeling fluid and methods of use
US7785258B2 (en) 2005-10-06 2010-08-31 Optiscan Biomedical Corporation System and method for determining a treatment dose for a patient
US7583190B2 (en) 2005-10-31 2009-09-01 Abbott Diabetes Care Inc. Method and apparatus for providing data communication in data monitoring and management systems
CN101340935B (zh) * 2005-11-14 2013-05-08 拜奥美特3i有限责任公司 于植入物表面上淀积纳米粒子
EP1957145A4 (en) * 2005-11-30 2011-03-23 3M Innovative Properties Co Microneedle arrays and methods of use thereof
US7826879B2 (en) 2006-02-28 2010-11-02 Abbott Diabetes Care Inc. Analyte sensors and methods of use
EP1996255B1 (en) * 2006-03-02 2013-04-24 Catharos Medical Systems, Inc. Methods and devices for retrieval of a medical agent from a physiological efferent fluid collection site
JP5371741B2 (ja) * 2006-04-24 2013-12-18 フィッツ、リチャード 体液分析装置、当該装置を含むシステム
US8956287B2 (en) 2006-05-02 2015-02-17 Proteus Digital Health, Inc. Patient customized therapeutic regimens
US8163237B2 (en) * 2006-05-08 2012-04-24 Becton, Dickinson And Company Vascular access device pathogenic status indication
US8007999B2 (en) * 2006-05-10 2011-08-30 Theranos, Inc. Real-time detection of influenza virus
US20070276211A1 (en) * 2006-05-26 2007-11-29 Jose Mir Compact minimally invasive biomedical monitor
US20080097352A1 (en) * 2006-09-12 2008-04-24 Beck Patricia A Methods of fabricating microneedles with bio-sensory functionality
EP2087589B1 (en) 2006-10-17 2011-11-23 Proteus Biomedical, Inc. Low voltage oscillator for medical devices
US7972648B2 (en) 2006-10-24 2011-07-05 Biomet 3I, Llc Deposition of discrete nanoparticles on a nanostructured surface of an implant
JP5916277B2 (ja) 2006-10-25 2016-05-11 プロテウス デジタル ヘルス, インコーポレイテッド 摂取可能な制御活性化識別子
US8579853B2 (en) 2006-10-31 2013-11-12 Abbott Diabetes Care Inc. Infusion devices and methods
US20080113391A1 (en) 2006-11-14 2008-05-15 Ian Gibbons Detection and quantification of analytes in bodily fluids
WO2008063626A3 (en) 2006-11-20 2008-07-03 Proteus Biomedical Inc Active signal processing personal health signal receivers
EP2121107B1 (en) * 2006-12-18 2012-10-31 Eatlittle Inc. Device for delivery of a substance
US8858432B2 (en) 2007-02-01 2014-10-14 Proteus Digital Health, Inc. Ingestible event marker systems
CN103066226B (zh) 2007-02-14 2016-09-14 普罗透斯数字保健公司 具有高表面积电极的体内电源
US9636450B2 (en) * 2007-02-19 2017-05-02 Udo Hoss Pump system modular components for delivering medication and analyte sensing at seperate insertion sites
US8932221B2 (en) 2007-03-09 2015-01-13 Proteus Digital Health, Inc. In-body device having a multi-directional transmitter
US9270025B2 (en) 2007-03-09 2016-02-23 Proteus Digital Health, Inc. In-body device having deployable antenna
US7604629B2 (en) * 2007-04-19 2009-10-20 Medtronic Inc. Multi-parameter infection monitoring
US7766862B2 (en) * 2007-04-19 2010-08-03 Medtronic, Inc. Baseline acquisition for infection monitoring
US7682355B2 (en) * 2007-04-19 2010-03-23 Medtronic, Inc. Refined infection monitoring
US20080262332A1 (en) * 2007-04-19 2008-10-23 Medtronic, Inc. Infection monitoring
US20080262374A1 (en) * 2007-04-19 2008-10-23 Medtronic, Inc. Event triggered infection monitoring
US7734353B2 (en) 2007-04-19 2010-06-08 Medtronic Inc. Controlling temperature during recharge for treatment of infection or other conditions
US20080262331A1 (en) * 2007-04-19 2008-10-23 Medtronic, Inc. Infection monitoring
US7998110B2 (en) * 2007-04-25 2011-08-16 Hong Kong Polytechnic University Medical device for delivering drug and/or performing physical therapy
US8540632B2 (en) 2007-05-24 2013-09-24 Proteus Digital Health, Inc. Low profile antenna for in body device
EP2471457A1 (en) 2007-06-07 2012-07-04 Microchips, Inc. Electrochemical biosensors and arrays
WO2008157256A1 (en) * 2007-06-13 2008-12-24 Catharos Medical Systems, Inc. Methods and devices for removal of a medical agent from a physiological efferent fluid collection site
US8597188B2 (en) 2007-06-21 2013-12-03 Abbott Diabetes Care Inc. Health management devices and methods
CA2690870C (en) 2007-06-21 2017-07-11 Abbott Diabetes Care Inc. Health monitor
US8158430B1 (en) 2007-08-06 2012-04-17 Theranos, Inc. Systems and methods of fluidic sample processing
US20090048648A1 (en) * 2007-08-17 2009-02-19 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Self-sterilizing device
US20110160644A1 (en) * 2007-08-17 2011-06-30 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Systems, devices, and methods including catheters configured to release ultraviolet energy absorbing agents
US8753304B2 (en) * 2007-08-17 2014-06-17 The Invention Science Fund I, Llc Systems, devices, and methods including catheters having acoustically actuatable waveguide components for delivering a sterilizing stimulus to a region proximate a surface of the catheter
US20110208023A1 (en) * 2008-12-04 2011-08-25 Goodall Eleanor V Systems, devices, and methods including implantable devices with anti-microbial properties
US8366652B2 (en) * 2007-08-17 2013-02-05 The Invention Science Fund I, Llc Systems, devices, and methods including infection-fighting and monitoring shunts
US8706211B2 (en) 2007-08-17 2014-04-22 The Invention Science Fund I, Llc Systems, devices, and methods including catheters having self-cleaning surfaces
US20110208026A1 (en) * 2008-12-04 2011-08-25 Goodall Eleanor V Systems, devices, and methods including implantable devices with anti-microbial properties
EP2384168B1 (en) * 2008-12-04 2014-10-08 Searete LLC Actively-controllable sterilizing excitation delivery implants
US8702640B2 (en) * 2007-08-17 2014-04-22 The Invention Science Fund I, Llc System, devices, and methods including catheters configured to monitor and inhibit biofilm formation
US20120041285A1 (en) 2008-12-04 2012-02-16 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Systems, devices, and methods including implantable devices with anti-microbial properties
US20110208021A1 (en) * 2008-12-04 2011-08-25 Goodall Eleanor V Systems, devices, and methods including implantable devices with anti-microbial properties
US20090163977A1 (en) * 2007-08-17 2009-06-25 Searete Llc, A Limited Liability Corporation Of The State Of Delaware System, devices, and methods including sterilizing excitation delivery implants with cryptographic logic components
US8734718B2 (en) * 2007-08-17 2014-05-27 The Invention Science Fund I, Llc Systems, devices, and methods including catheters having an actively controllable therapeutic agent delivery component
KR100875713B1 (ko) 2007-08-21 2008-12-26 고려대학교 산학협력단 삼투압펌프를 이용한 그레디언트 발생장치
DE102007039899B3 (de) * 2007-08-23 2009-04-09 Siemens Ag Sensor zum Ermöglichen des Nachweises einer Substanz im Körper eines Lebewesens
WO2009029572A1 (en) * 2007-08-24 2009-03-05 Deka Products Limited Partnership Microneedle systems and apparatus
WO2009042812A1 (en) 2007-09-25 2009-04-02 Proteus Biomedical, Inc. In-body device with virtual dipole signal amplification
US8192360B2 (en) * 2007-09-25 2012-06-05 Pacesetter, Inc. Implantable body fluid analyzer
DK2205968T3 (en) 2007-10-02 2014-02-17 Theranos Inc Modular POC (point of care) Devices and uses thereof
US7972296B2 (en) 2007-10-10 2011-07-05 Optiscan Biomedical Corporation Fluid component analysis system and method for glucose monitoring and control
US8303573B2 (en) 2007-10-17 2012-11-06 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
US8789536B2 (en) 2007-10-17 2014-07-29 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
US20090105561A1 (en) * 2007-10-17 2009-04-23 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Medical or veterinary digestive tract utilization systems and methods
US8808276B2 (en) * 2007-10-23 2014-08-19 The Invention Science Fund I, Llc Adaptive dispensation in a digestive tract
EP2056114A1 (en) * 2007-10-29 2009-05-06 Philips Electronics N.V. Automatic detection of infectious diseases
US8333754B2 (en) * 2007-10-31 2012-12-18 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
US8707964B2 (en) * 2007-10-31 2014-04-29 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
US8808271B2 (en) * 2007-10-31 2014-08-19 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
US20090163894A1 (en) * 2007-10-31 2009-06-25 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Medical or veterinary digestive tract utilization systems and methods
US8109920B2 (en) * 2007-10-31 2012-02-07 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
JP5311801B2 (ja) 2007-11-09 2013-10-09 キヤノン株式会社 浸透圧ポンプを用いた送液駆動機構および該送液駆動機構を有するマイクロチップ
US20090137866A1 (en) * 2007-11-28 2009-05-28 Searete Llc, A Limited Liability Corporation Of The State Delaware Medical or veterinary digestive tract utilization systems and methods
US20090149839A1 (en) * 2007-12-11 2009-06-11 Hyde Roderick A Treatment techniques using ingestible device
JP5461427B2 (ja) 2007-12-17 2014-04-02 ニューワールド ファーマシューティカルズ,エルエルシー 統合的な皮内送達、診断、及び、情報伝達システム
US9672471B2 (en) 2007-12-18 2017-06-06 Gearbox Llc Systems, devices, and methods for detecting occlusions in a biological subject including spectral learning
US9717896B2 (en) 2007-12-18 2017-08-01 Gearbox, Llc Treatment indications informed by a priori implant information
US20090287120A1 (en) 2007-12-18 2009-11-19 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Circulatory monitoring systems and methods
US8280484B2 (en) 2007-12-18 2012-10-02 The Invention Science Fund I, Llc System, devices, and methods for detecting occlusions in a biological subject
JP5806466B2 (ja) 2008-01-28 2015-11-10 バイオメット・3アイ・エルエルシー 親水性を向上させたインプラント表面
US20090198146A1 (en) * 2008-01-31 2009-08-06 Medtronic, Inc. Blanking infection monitoring during recharge
JP2011511665A (ja) * 2008-02-04 2011-04-14 バイエル・ヘルスケア・エルエルシーBayer HealthCare LLC 半導体を素材とする分析対象物センサー及び方法
CN102149812A (zh) * 2008-02-21 2011-08-10 埃凡特拉生物科技公司 基于液体流经阵列的分析
ES2369472T3 (es) * 2008-02-26 2011-12-01 Biostems Ltd. Dispositivo de investigación micro-invasiva en vivo que comprende una guía metálica.
CA2717862C (en) 2008-03-05 2016-11-22 Proteus Biomedical, Inc. Multi-mode communication ingestible event markers and systems, and methods of using the same
CN102187200A (zh) 2008-04-04 2011-09-14 高露洁-棕榄公司 药物沉积在其上的基体的分析
EP2982383A1 (en) 2008-04-10 2016-02-10 Abbott Diabetes Care, Inc. Method for sterilizing an analyte sensor
WO2009126900A1 (en) 2008-04-11 2009-10-15 Pelikan Technologies, Inc. Method and apparatus for analyte detecting device
US20100100036A1 (en) * 2008-04-24 2010-04-22 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational System and Method for Memory Modification
US20090312668A1 (en) * 2008-04-24 2009-12-17 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational system and method for memory modification
US8615407B2 (en) * 2008-04-24 2013-12-24 The Invention Science Fund I, Llc Methods and systems for detecting a bioactive agent effect
US9064036B2 (en) * 2008-04-24 2015-06-23 The Invention Science Fund I, Llc Methods and systems for monitoring bioactive agent use
US20090270694A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for monitoring and modifying a combination treatment
US9662391B2 (en) * 2008-04-24 2017-05-30 The Invention Science Fund I Llc Side effect ameliorating combination therapeutic products and systems
US9449150B2 (en) * 2008-04-24 2016-09-20 The Invention Science Fund I, Llc Combination treatment selection methods and systems
US20100280332A1 (en) * 2008-04-24 2010-11-04 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for monitoring bioactive agent use
US20090271375A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Combination treatment selection methods and systems
US20100076249A1 (en) * 2008-04-24 2010-03-25 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational system and method for memory modification
US20100130811A1 (en) * 2008-04-24 2010-05-27 Searete Llc Computational system and method for memory modification
US20090270688A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for presenting a combination treatment
US9649469B2 (en) 2008-04-24 2017-05-16 The Invention Science Fund I Llc Methods and systems for presenting a combination treatment
US20100041958A1 (en) * 2008-04-24 2010-02-18 Searete Llc Computational system and method for memory modification
US20090270687A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for modifying bioactive agent use
US9560967B2 (en) * 2008-04-24 2017-02-07 The Invention Science Fund I Llc Systems and apparatus for measuring a bioactive agent effect
US9026369B2 (en) * 2008-04-24 2015-05-05 The Invention Science Fund I, Llc Methods and systems for presenting a combination treatment
US20100022820A1 (en) * 2008-04-24 2010-01-28 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational system and method for memory modification
US7974787B2 (en) * 2008-04-24 2011-07-05 The Invention Science Fund I, Llc Combination treatment alteration methods and systems
US20090271122A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for monitoring and modifying a combination treatment
US20100125561A1 (en) * 2008-04-24 2010-05-20 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational system and method for memory modification
US20100081861A1 (en) * 2008-04-24 2010-04-01 Searete Llc Computational System and Method for Memory Modification
US20100063368A1 (en) * 2008-04-24 2010-03-11 Searete Llc, A Limited Liability Corporation Computational system and method for memory modification
US8682687B2 (en) 2008-04-24 2014-03-25 The Invention Science Fund I, Llc Methods and systems for presenting a combination treatment
US8930208B2 (en) * 2008-04-24 2015-01-06 The Invention Science Fund I, Llc Methods and systems for detecting a bioactive agent effect
US20090271009A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Combination treatment modification methods and systems
US20100081860A1 (en) * 2008-04-24 2010-04-01 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational System and Method for Memory Modification
US20100069724A1 (en) * 2008-04-24 2010-03-18 Searete Llc Computational system and method for memory modification
US20100042578A1 (en) * 2008-04-24 2010-02-18 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational system and method for memory modification
US20090312595A1 (en) * 2008-04-24 2009-12-17 Searete Llc, A Limited Liability Corporation Of The State Of Delaware System and method for memory modification
US8876688B2 (en) * 2008-04-24 2014-11-04 The Invention Science Fund I, Llc Combination treatment modification methods and systems
US20100041964A1 (en) * 2008-04-24 2010-02-18 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for monitoring and modifying a combination treatment
US20100004762A1 (en) * 2008-04-24 2010-01-07 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational system and method for memory modification
US20100015583A1 (en) * 2008-04-24 2010-01-21 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational System and method for memory modification
US7801686B2 (en) * 2008-04-24 2010-09-21 The Invention Science Fund I, Llc Combination treatment alteration methods and systems
US20090269329A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Combination Therapeutic products and systems
US9282927B2 (en) * 2008-04-24 2016-03-15 Invention Science Fund I, Llc Methods and systems for modifying bioactive agent use
US20100030089A1 (en) * 2008-04-24 2010-02-04 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for monitoring and modifying a combination treatment
US8606592B2 (en) * 2008-04-24 2013-12-10 The Invention Science Fund I, Llc Methods and systems for monitoring bioactive agent use
US20100017001A1 (en) * 2008-04-24 2010-01-21 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational system and method for memory modification
US9239906B2 (en) * 2008-04-24 2016-01-19 The Invention Science Fund I, Llc Combination treatment selection methods and systems
WO2009135197A3 (en) * 2008-05-02 2010-02-04 Sri International Optical microneedle-based spectrometer
US8636670B2 (en) 2008-05-13 2014-01-28 The Invention Science Fund I, Llc Circulatory monitoring systems and methods
JP5654988B2 (ja) 2008-07-08 2015-01-14 プロテウス デジタル ヘルス, インコーポレイテッド 摂取型事象マーカデータフレームワーク
WO2010009172A1 (en) 2008-07-14 2010-01-21 Abbott Diabetes Care Inc. Closed loop control system interface and methods
US8540633B2 (en) 2008-08-13 2013-09-24 Proteus Digital Health, Inc. Identifier circuits for generating unique identifiable indicators and techniques for producing same
WO2010022252A3 (en) * 2008-08-21 2010-04-22 Third Rock Ventures Device and method for drug evaluation and local treatment
US20100063462A1 (en) * 2008-09-09 2010-03-11 Postel Olivier B Methods and Apparatus for Charging and Evacuating a Diffusion Dressing
US8417311B2 (en) 2008-09-12 2013-04-09 Optiscan Biomedical Corporation Fluid component analysis system and method for glucose monitoring and control
EP2341828A4 (en) * 2008-09-19 2012-11-21 Bayer Healthcare Llc Lancet analyte sensors and methods of manufacturing
CA2735675C (en) 2008-09-19 2017-02-14 Bayer Healthcare Llc Electrochemical devices with enhanced electrochemical activity and manufacturing methods thereof
US9173597B2 (en) * 2008-09-19 2015-11-03 Bayer Healthcare Llc Analyte sensors, systems, testing apparatus and manufacturing methods
US8788212B2 (en) 2008-10-31 2014-07-22 The Invention Science Fund I, Llc Compositions and methods for biological remodeling with frozen particle compositions
US9050070B2 (en) 2008-10-31 2015-06-09 The Invention Science Fund I, Llc Compositions and methods for surface abrasion with frozen particles
US8545857B2 (en) 2008-10-31 2013-10-01 The Invention Science Fund I, Llc Compositions and methods for administering compartmentalized frozen particles
US20100111857A1 (en) 2008-10-31 2010-05-06 Boyden Edward S Compositions and methods for surface abrasion with frozen particles
US8545855B2 (en) 2008-10-31 2013-10-01 The Invention Science Fund I, Llc Compositions and methods for surface abrasion with frozen particles
US9072799B2 (en) 2008-10-31 2015-07-07 The Invention Science Fund I, Llc Compositions and methods for surface abrasion with frozen particles
US8788211B2 (en) 2008-10-31 2014-07-22 The Invention Science Fund I, Llc Method and system for comparing tissue ablation or abrasion data to data related to administration of a frozen particle composition
US8858912B2 (en) 2008-10-31 2014-10-14 The Invention Science Fund I, Llc Frozen compositions and methods for piercing a substrate
US9060926B2 (en) 2008-10-31 2015-06-23 The Invention Science Fund I, Llc Compositions and methods for therapeutic delivery with frozen particles
US9060934B2 (en) 2008-10-31 2015-06-23 The Invention Science Fund I, Llc Compositions and methods for surface abrasion with frozen particles
US8731840B2 (en) 2008-10-31 2014-05-20 The Invention Science Fund I, Llc Compositions and methods for therapeutic delivery with frozen particles
US8762067B2 (en) 2008-10-31 2014-06-24 The Invention Science Fund I, Llc Methods and systems for ablation or abrasion with frozen particles and comparing tissue surface ablation or abrasion data to clinical outcome data
US9050317B2 (en) 2008-10-31 2015-06-09 The Invention Science Fund I, Llc Compositions and methods for therapeutic delivery with frozen particles
US8256233B2 (en) 2008-10-31 2012-09-04 The Invention Science Fund I, Llc Systems, devices, and methods for making or administering frozen particles
US9072688B2 (en) 2008-10-31 2015-07-07 The Invention Science Fund I, Llc Compositions and methods for therapeutic delivery with frozen particles
US8603494B2 (en) 2008-10-31 2013-12-10 The Invention Science Fund I, Llc Compositions and methods for administering compartmentalized frozen particles
US8409376B2 (en) 2008-10-31 2013-04-02 The Invention Science Fund I, Llc Compositions and methods for surface abrasion with frozen particles
US8793075B2 (en) 2008-10-31 2014-07-29 The Invention Science Fund I, Llc Compositions and methods for therapeutic delivery with frozen particles
US9056047B2 (en) 2008-10-31 2015-06-16 The Invention Science Fund I, Llc Compositions and methods for delivery of frozen particle adhesives
US8731841B2 (en) 2008-10-31 2014-05-20 The Invention Science Fund I, Llc Compositions and methods for therapeutic delivery with frozen particles
US8725420B2 (en) 2008-10-31 2014-05-13 The Invention Science Fund I, Llc Compositions and methods for surface abrasion with frozen particles
US8603495B2 (en) 2008-10-31 2013-12-10 The Invention Science Fund I, Llc Compositions and methods for biological remodeling with frozen particle compositions
US8721583B2 (en) 2008-10-31 2014-05-13 The Invention Science Fund I, Llc Compositions and methods for surface abrasion with frozen particles
US8551505B2 (en) 2008-10-31 2013-10-08 The Invention Science Fund I, Llc Compositions and methods for therapeutic delivery with frozen particles
US9060931B2 (en) 2008-10-31 2015-06-23 The Invention Science Fund I, Llc Compositions and methods for delivery of frozen particle adhesives
US8036748B2 (en) 2008-11-13 2011-10-11 Proteus Biomedical, Inc. Ingestible therapy activator system and method
EP2358270A4 (en) 2008-12-11 2014-08-13 Proteus Digital Health Inc Evaluation of gastrointestinal function using portable electroviscerography systems and methods of using the same
US9439566B2 (en) 2008-12-15 2016-09-13 Proteus Digital Health, Inc. Re-wearable wireless device
CA2792224A1 (en) 2008-12-15 2010-07-01 Proteus Digital Health, Inc. Body-associated receiver and method
US9659423B2 (en) 2008-12-15 2017-05-23 Proteus Digital Health, Inc. Personal authentication apparatus system and method
CN102365084B (zh) 2009-01-06 2014-04-30 普罗秋斯数字健康公司 药剂递送系统
CA2750158A1 (en) 2009-01-06 2010-07-15 Proteus Biomedical, Inc. Ingestion-related biofeedback and personalized medical therapy method and system
US8130904B2 (en) 2009-01-29 2012-03-06 The Invention Science Fund I, Llc Diagnostic delivery service
US8254524B2 (en) 2009-01-29 2012-08-28 The Invention Science Fund I, Llc Diagnostic delivery service
US9375169B2 (en) 2009-01-30 2016-06-28 Sanofi-Aventis Deutschland Gmbh Cam drive for managing disposable penetrating member actions with a single motor and motor and control system
CN104434136A (zh) * 2009-03-02 2015-03-25 第七感生物系统有限公司 用于抽出血液的装置
DE102009013594A1 (de) * 2009-03-17 2010-10-14 Siemens Aktiengesellschaft Verfahren für eine in vivo Messung mit einer in einen Patienten implantierten Vorrichtung und entsprechende Vorrichtung
US8540664B2 (en) 2009-03-25 2013-09-24 Proteus Digital Health, Inc. Probablistic pharmacokinetic and pharmacodynamic modeling
US8545402B2 (en) 2009-04-28 2013-10-01 Proteus Digital Health, Inc. Highly reliable ingestible event markers and methods for using the same
CN102414561A (zh) * 2009-04-28 2012-04-11 创新实验室技术公司 侧流式免疫层析测定设备
WO2010129375A1 (en) 2009-04-28 2010-11-11 Abbott Diabetes Care Inc. Closed loop blood glucose control algorithm analysis
EP2432458A4 (en) 2009-05-12 2014-02-12 Proteus Digital Health Inc Ingestible event markers comprising an ingestible component
US8790916B2 (en) * 2009-05-14 2014-07-29 Genestream, Inc. Microfluidic method and system for isolating particles from biological fluid
KR101136739B1 (ko) * 2009-06-15 2012-04-19 주식회사 라파스 다기능 하이브리드 마이크로구조체 및 그의 제조방법
US20100331833A1 (en) * 2009-06-26 2010-12-30 Michael Maschke In-vitro device monitoring during minimally invasive ablation therapy
CN104799866A (zh) 2009-07-23 2015-07-29 雅培糖尿病护理公司 分析物监测装置
US8641671B2 (en) 2009-07-30 2014-02-04 Tandem Diabetes Care, Inc. Infusion pump system with disposable cartridge having pressure venting and pressure feedback
EP2467707A4 (en) 2009-08-21 2014-12-17 Proteus Digital Health Inc Apparatus and method for measuring biochemical parameters
US8062568B2 (en) * 2009-08-27 2011-11-22 Korea University Research And Business Foundation Nano pattern writer
CN102713914B (zh) 2009-10-19 2016-03-30 提拉诺斯公司 集成的健康数据采集和分析系统
CN102667834B (zh) 2009-11-04 2016-08-31 普罗秋斯数字健康公司 供应链管理系统
WO2011065972A3 (en) * 2009-11-24 2011-09-22 Seventh Sense Biosystems, Inc. Patient-enacted sampling technique
CN103405341A (zh) 2009-12-02 2013-11-27 普罗秋斯数字健康公司 与药物制品整合的可摄入的事件标记系统
WO2011094573A1 (en) 2010-01-28 2011-08-04 Seventh Sense Biosystems, Inc. Monitoring or feedback systems and methods
WO2011094606A3 (en) 2010-02-01 2011-10-20 Proteus Biomedical, Inc. Data gathering system
US8641418B2 (en) 2010-03-29 2014-02-04 Biomet 3I, Llc Titanium nano-scale etching on an implant surface
KR20130045261A (ko) 2010-04-07 2013-05-03 프로테우스 디지털 헬스, 인코포레이티드 소형의 섭취가능한 장치
DE102010014703A1 (de) * 2010-04-12 2011-10-13 Mbr Optical Systems Gmbh & Co. Kg Medizinisches Gerätesystem
US8965476B2 (en) 2010-04-16 2015-02-24 Sanofi-Aventis Deutschland Gmbh Tissue penetration device
US9795747B2 (en) 2010-06-02 2017-10-24 Sanofi-Aventis Deutschland Gmbh Methods and apparatus for lancet actuation
WO2011163347A3 (en) 2010-06-23 2012-03-29 Seventh Sense Biosystems, Inc. Sampling devices involving relatively little pain
JP2013538069A (ja) 2010-07-16 2013-10-10 セブンス センス バイオシステムズ,インコーポレーテッド 流体移動デバイスのための低圧環境
JP6063382B2 (ja) 2010-08-05 2017-01-18 フォーサイト・ビジョン フォー・インコーポレーテッド 治療薬を眼の埋め込み体へと注入するためのシステム
CN103282764A (zh) * 2010-10-29 2013-09-04 尼尔科学公司 用于分析物检测的方法和装置
EP2992827B1 (en) 2010-11-09 2017-04-19 Seventh Sense Biosystems, Inc. Systems and interfaces for blood sampling
EP2452624A1 (de) * 2010-11-12 2012-05-16 BIOTRONIK SE & Co. KG Implantierbarer theranostischer Artikel
WO2012071280A3 (en) 2010-11-22 2012-07-26 Proteus Biomedical, Inc. Ingestible device with pharmaceutical product
DK2646070T3 (da) * 2010-11-29 2015-05-04 Sanofi Aventis Deutschland Pumpeplaster med flere reservoirer
CN106290159A (zh) 2011-01-21 2017-01-04 提拉诺斯公司 样品使用最大化的系统和方法
US20120209090A1 (en) * 2011-02-14 2012-08-16 Searete Llc, A Limited Liability Corporation Of The Sate Of Delaware Systems, devices, and methods including implantable devices with anti-microbial properties
CN107019515A (zh) 2011-02-28 2017-08-08 雅培糖尿病护理公司 显示传感器读数的方法与分析物监测装置及其操作方法
EP2683291A4 (en) 2011-03-11 2014-09-03 Proteus Digital Health Inc Wearable personal body associated device with various physical configurations
US20120238032A1 (en) 2011-03-18 2012-09-20 International Business Machines Corporation Lab on a chip
CN102250751B (zh) * 2011-03-22 2013-05-22 博奥生物有限公司 一种用于生物芯片的接口装置
US8464076B2 (en) 2011-03-24 2013-06-11 International Business Machines Corporation Born encrypted optical data
US9581552B2 (en) * 2011-04-06 2017-02-28 Klein Medical Limited Spectroscopic analyser
US20120270331A1 (en) * 2011-04-20 2012-10-25 Achal Singh Achrol Microfluidic system and method for automated processing of particles from biological fluid
JP2014516644A (ja) 2011-04-29 2014-07-17 セブンス センス バイオシステムズ,インコーポレーテッド 血斑または他の体液の収集および/または操作のためのデバイスおよび方法
ES2597081T3 (es) 2011-04-29 2017-01-13 Seventh Sense Biosystems, Inc. Entrega y/o recepción de fluidos
EP3106092A3 (en) 2011-04-29 2017-03-08 Seventh Sense Biosystems, Inc. Systems and methods for collecting fluid from a subject
WO2012156432A1 (en) * 2011-05-17 2012-11-22 Academisch Medisch Centrum Bij De Universiteit Van Amsterdam Device and probe for detection of infection
US20140221941A1 (en) 2011-06-28 2014-08-07 Forsight Vision4, Inc. Diagnostic methods and apparatus
KR101323891B1 (ko) * 2011-07-08 2013-10-30 엘지전자 주식회사 정수기
US9443061B2 (en) 2011-08-16 2016-09-13 Elwha Llc Devices and methods for recording information on a subject's body
US9286615B2 (en) * 2011-08-16 2016-03-15 Elwha Llc Devices and methods for recording information on a subject's body
US9772270B2 (en) 2011-08-16 2017-09-26 Elwha Llc Devices and methods for recording information on a subject's body
EP2755600A4 (en) 2011-09-16 2015-09-16 Forsight Vision4 Inc Fluid exchange apparatus and methods
US9619627B2 (en) 2011-09-25 2017-04-11 Theranos, Inc. Systems and methods for collecting and transmitting assay results
US8475739B2 (en) 2011-09-25 2013-07-02 Theranos, Inc. Systems and methods for fluid handling
US8380541B1 (en) 2011-09-25 2013-02-19 Theranos, Inc. Systems and methods for collecting and transmitting assay results
US9250229B2 (en) 2011-09-25 2016-02-02 Theranos, Inc. Systems and methods for multi-analysis
US8840838B2 (en) 2011-09-25 2014-09-23 Theranos, Inc. Centrifuge configurations
US9664702B2 (en) 2011-09-25 2017-05-30 Theranos, Inc. Fluid handling apparatus and configurations
US9268915B2 (en) 2011-09-25 2016-02-23 Theranos, Inc. Systems and methods for diagnosis or treatment
US9632102B2 (en) 2011-09-25 2017-04-25 Theranos, Inc. Systems and methods for multi-purpose analysis
JP2014236758A (ja) * 2011-09-30 2014-12-18 テルモ株式会社 センサ
WO2013066873A1 (en) 2011-10-31 2013-05-10 Abbott Diabetes Care Inc. Electronic devices having integrated reset systems and methods thereof
US9235683B2 (en) 2011-11-09 2016-01-12 Proteus Digital Health, Inc. Apparatus, system, and method for managing adherence to a regimen
WO2013101908A1 (en) * 2011-12-27 2013-07-04 Massachusetts Institute Of Technology Microneedle devices and uses thereof
US9131995B2 (en) 2012-03-20 2015-09-15 Biomet 3I, Llc Surface treatment for an implant surface
US9103502B2 (en) * 2012-04-19 2015-08-11 Wisconsin Alumni Research Foundation Method and device for controlled laminar flow patterning within a channel
US20130309713A1 (en) * 2012-05-16 2013-11-21 David Ribble Pathogen detection systems and methods
US20130310663A1 (en) * 2012-05-21 2013-11-21 International Business Machines Corporation Dispensing drugs from a companion diagnostic linked smart pill
WO2013186628A1 (en) * 2012-06-15 2013-12-19 Delta Instruments S.R.L. Transdemal device for the fluorometric detection of an analyte in a biological fluid and analysis apparatus associated with said transdermal device
US9789206B2 (en) 2013-07-10 2017-10-17 The General Hospital Corporation Compounds, systems, and methods for monitoring and treating a surface of a subject
JP2015530888A (ja) * 2012-07-10 2015-10-29 ザ ジェネラル ホスピタル コーポレイション 対象のモニタリングと表面処理のためのシステムおよび方法
US9500639B2 (en) 2012-07-18 2016-11-22 Theranos, Inc. Low-volume coagulation assay
RU2015105699A (ru) 2012-07-23 2016-09-10 Протеус Диджитал Хелс, Инк. Способы получения проглатываемых маркеров событий, содержащих проглатываемый компонент
KR101565013B1 (ko) 2012-10-18 2015-11-02 프로테우스 디지털 헬스, 인코포레이티드 통신 디바이스를 위한 전원에서 전력 소비 및 브로드캐스트 전력을 적응적으로 최적화시키는 장치, 시스템 및 방법
WO2014078374A3 (en) * 2012-11-13 2014-07-17 Presage Biosciences, Inc. Methods for multiplexed drug evaluation
US20140163346A1 (en) 2012-12-06 2014-06-12 Medtronic Minimed, Inc. Microarray electrodes useful with analyte sensors and methods for making and using them
US9456780B2 (en) 2013-02-07 2016-10-04 Hill-Rom Services, Inc. Dynamic therapy delivery system
GB201302774D0 (en) * 2013-02-18 2013-04-03 Sphere Medical Ltd Analyte extraction apparatus and method
US9810704B2 (en) 2013-02-18 2017-11-07 Theranos, Inc. Systems and methods for multi-analysis
US9623409B2 (en) 2013-03-11 2017-04-18 Cue Inc. Cartridges, kits, and methods for enhanced mixing for detection and quantification of analytes
CA2904135A1 (en) 2013-03-11 2014-10-09 Cue Inc. Systems and methods for detection and quantification of analytes
US20140309553A1 (en) * 2013-04-11 2014-10-16 Rarecyte, Inc. Kits and methods for separating a target analyte from a suspension
EP2991552A4 (en) * 2013-04-30 2017-01-11 Abbott Diabetes Care Inc Systems, devices, and methods for energy efficient electrical device activation
EP2991719A4 (en) * 2013-05-02 2017-01-11 Elwha Llc Implantable device for manipulating immune cells
US9796576B2 (en) 2013-08-30 2017-10-24 Proteus Digital Health, Inc. Container with electronically controlled interlock
WO2015035256A3 (en) 2013-09-06 2015-07-16 Theranos, Inc. Devices, systems, methods and kits for receiving a swab
WO2015035260A1 (en) 2013-09-06 2015-03-12 Theranos, Inc. Systems and methods for detecting infectious diseases
DE102013217959A1 (de) * 2013-09-09 2015-03-12 Efficient Robotics Gmbh Mikrofluidikanalyse-Bauelement und Herstellungsverfahren
WO2015042411A1 (en) 2013-09-20 2015-03-26 Proteus Digital Health, Inc. Methods, devices and systems for receiving and decoding a signal in the presence of noise using slices and warping
WO2015044722A1 (en) 2013-09-24 2015-04-02 Proteus Digital Health, Inc. Method and apparatus for use with received electromagnetic signal at a frequency not known exactly in advance
GB201318195D0 (en) * 2013-10-14 2013-11-27 Scott Phillipa K Protein monitor and correcting device
DE102013222123A1 (de) * 2013-10-30 2015-04-30 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Mobile Überwachungsvorrichtung
US20150122647A1 (en) 2013-11-07 2015-05-07 Medtronic Minimed, Inc. Enzyme matrices for use with ethylene oxide sterilization
US9681864B1 (en) 2014-01-03 2017-06-20 Harpoon Medical, Inc. Method and apparatus for transapical procedures on a mitral valve
KR101562865B1 (ko) * 2014-01-24 2015-10-26 한국과학기술연구원 신경 영양인자를 감지하기 위한 초소형 센서 시스템
US9079002B1 (en) 2014-02-07 2015-07-14 Texas Instruments Incorporated Ceramic nanochannel drug delivery device and method of formation
CN103908306A (zh) * 2014-04-17 2014-07-09 山东师范大学 基于留置针的循环肿瘤细胞在体捕获装置及方法
USD745423S1 (en) 2014-05-12 2015-12-15 Cue Inc. Automated analyzer test cartridge and sample collection device for analyte detection
US20170095233A1 (en) * 2014-05-28 2017-04-06 University Of Cincinnati Devices with reduced sweat volumes between sensors and sweat glands
US9820690B1 (en) * 2014-07-16 2017-11-21 Verily Life Sciences Llc Analyte detection system
WO2017015172A1 (en) 2015-07-17 2017-01-26 Cue Inc. Systems and methods for enhanced detection and quantification of analytes
WO2017054006A1 (en) * 2015-09-25 2017-03-30 Sanmina Corporation System and method for a drug delivery and biosensor patch
US9636457B2 (en) 2015-07-19 2017-05-02 Sanmina Corporation System and method for a drug delivery and biosensor patch
US9643181B1 (en) 2016-02-08 2017-05-09 International Business Machines Corporation Integrated microfluidics system
WO2017164982A1 (en) * 2016-03-21 2017-09-28 The Regents Of The University Of California Real-time and continuous measurement in vivo using aptamer-based biosensors
WO2018013579A1 (en) * 2016-07-11 2018-01-18 cARIZONA BOARD OF REGENTS ON BEHALF OF ARIZONA STATE UNIVERSITY Sweat as a biofluid for analysis and disease identification

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5716852A (en) 1996-03-29 1998-02-10 University Of Washington Microfabricated diffusion-based chemical sensor
CN1181720A (zh) 1995-04-25 1998-05-13 伊萝莉公司 可远程编程的存储器材料及其应用
US5807375A (en) 1994-11-04 1998-09-15 Elan Medical Technologies Limited Analyte-controlled liquid delivery device and analyte monitor
US5848991A (en) 1990-12-13 1998-12-15 Elan Medical Technologies Limited Athlone, Co. Intradermal drug delivery device and method for intradermal delivery of drugs
GB2374149A (en) 2000-11-08 2002-10-09 Hewlett Packard Co A swallowable internal drug dispensing capsule with memory

Family Cites Families (77)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4003379A (en) * 1974-04-23 1977-01-18 Ellinwood Jr Everett H Apparatus and method for implanted self-powered medication dispensing
US4146029A (en) * 1974-04-23 1979-03-27 Ellinwood Jr Everett H Self-powered implanted programmable medication system and method
GB8422876D0 (en) * 1984-09-11 1984-10-17 Secr Defence Silicon implant devices
US5279607A (en) * 1991-05-30 1994-01-18 The State University Of New York Telemetry capsule and process
US5318557A (en) 1992-07-13 1994-06-07 Elan Medical Technologies Limited Medication administering device
US5624850A (en) * 1994-06-06 1997-04-29 Idetek, Inc. Immunoassays in capillaries
US5976896A (en) 1994-06-06 1999-11-02 Idexx Laboratories, Inc. Immunoassays in capillary tubes
US6340588B1 (en) * 1995-04-25 2002-01-22 Discovery Partners International, Inc. Matrices with memories
US5874214A (en) * 1995-04-25 1999-02-23 Irori Remotely programmable matrices with memories
US6352854B1 (en) * 1995-04-25 2002-03-05 Discovery Partners International, Inc. Remotely programmable matrices with memories
US6319668B1 (en) * 1995-04-25 2001-11-20 Discovery Partners International Method for tagging and screening molecules
US5961923A (en) * 1995-04-25 1999-10-05 Irori Matrices with memories and uses thereof
US5832296A (en) 1995-04-26 1998-11-03 Interval Research Corp. Wearable context sensitive user interface for interacting with plurality of electronic devices of interest to the user
DE19601487C2 (de) * 1996-01-17 2001-09-13 Micronas Gmbh Vorrichtung zum Behandeln von malignen Gewebsveränderungen
US5801057A (en) * 1996-03-22 1998-09-01 Smart; Wilson H. Microsampling device and method of construction
US5797898A (en) * 1996-07-02 1998-08-25 Massachusetts Institute Of Technology Microchip drug delivery devices
DE19717023C2 (de) * 1997-04-23 2003-02-06 Micronas Gmbh Vorrichtung zum Behandeln von malignen, tumorösen Gewebebereichen
US6406845B1 (en) * 1997-05-05 2002-06-18 Trustees Of Tuft College Fiber optic biosensor for selectively detecting oligonucleotide species in a mixed fluid sample
JP2001518624A (ja) * 1997-09-26 2001-10-16 ユニバーシティ・オブ・ワシントン 同時の粒子分離および化学反応
US6117643A (en) * 1997-11-25 2000-09-12 Ut Battelle, Llc Bioluminescent bioreporter integrated circuit
US6200814B1 (en) * 1998-01-20 2001-03-13 Biacore Ab Method and device for laminar flow on a sensing surface
US6287765B1 (en) * 1998-05-20 2001-09-11 Molecular Machines, Inc. Methods for detecting and identifying single molecules
US6503231B1 (en) 1998-06-10 2003-01-07 Georgia Tech Research Corporation Microneedle device for transport of molecules across tissue
US7799521B2 (en) * 1998-06-24 2010-09-21 Chen & Chen, Llc Thermal cycling
US6344333B2 (en) * 1998-09-08 2002-02-05 Synectig Corporation Reagent-free immunoassay monitoring electrode assembly
US6542717B1 (en) * 1999-01-20 2003-04-01 International Business Machines Corporation System and method for optimizing personal area network (PAN) electrostatic communication
US8636648B2 (en) * 1999-03-01 2014-01-28 West View Research, Llc Endoscopic smart probe
US6464687B1 (en) * 1999-03-09 2002-10-15 Ball Semiconductor, Inc. Implantable drug delivery system
US6544732B1 (en) 1999-05-20 2003-04-08 Illumina, Inc. Encoding and decoding of array sensors utilizing nanocrystals
US6649358B1 (en) * 1999-06-01 2003-11-18 Caliper Technologies Corp. Microscale assays and microfluidic devices for transporter, gradient induced, and binding activities
US6256533B1 (en) * 1999-06-09 2001-07-03 The Procter & Gamble Company Apparatus and method for using an intracutaneous microneedle array
US7195670B2 (en) * 2000-06-27 2007-03-27 California Institute Of Technology High throughput screening of crystallization of materials
US6514769B2 (en) * 1999-07-29 2003-02-04 Jin Po Lee Multiple analyte assay device with sample integrity monitoring system
DE60018582T2 (de) * 1999-08-18 2006-01-19 Microchips, Inc., Bedford Thermisch aktivierbarer microchip als abgabevorrichtung für chemikalien
US6368275B1 (en) * 1999-10-07 2002-04-09 Acuson Corporation Method and apparatus for diagnostic medical information gathering, hyperthermia treatment, or directed gene therapy
US20050009101A1 (en) * 2001-05-17 2005-01-13 Motorola, Inc. Microfluidic devices comprising biochannels
ES2332869T3 (es) * 1999-11-17 2010-02-15 Boston Scientific Limited Dispositivos microfabricados para la entrega de moleculas en fluidos portadores.
GB9930000D0 (en) * 1999-12-21 2000-02-09 Phaeton Research Ltd An ingestible device
EP1350103B1 (en) * 2000-01-19 2010-01-06 Given Imaging Ltd. A system for detecting substances
EP1255980B1 (en) * 2000-01-31 2008-07-30 Board Of Regents The University Of Texas System Portable sensor array system
US7039453B2 (en) * 2000-02-08 2006-05-02 Tarun Mullick Miniature ingestible capsule
KR100542386B1 (ko) 2000-02-15 2006-01-10 주식회사 신한은행 기업간 대금결제 관리 시스템 및 이를 이용한 기업간대금결제 관리 방법
CA2399842C (en) * 2000-03-02 2006-11-14 Microchips, Inc. Microfabricated devices for the storage and selective exposure of chemicals and devices
EP1304959A1 (en) * 2000-07-24 2003-05-02 Motorola, Inc. Ingestible electronic capsule
US20040005582A1 (en) * 2000-08-10 2004-01-08 Nanobiodynamics, Incorporated Biospecific desorption microflow systems and methods for studying biospecific interactions and their modulators
CN1471413A (zh) * 2000-09-08 2004-01-28 茵斯莱特有限公司 用于患者注射的装置、系统和方法
WO2002046766A3 (de) 2000-12-06 2002-11-07 Ecole Polytech Bioanalytisches reagens verfahren zu dessen herstellung und sensorplattformen sowie nachweisverfahren beruhend auf der verwendung des bioanalytischen reagens
GB0030929D0 (en) * 2000-12-19 2001-01-31 Inverness Medical Ltd Analyte measurement
US6560471B1 (en) * 2001-01-02 2003-05-06 Therasense, Inc. Analyte monitoring device and methods of use
CA2435205A1 (en) * 2001-01-22 2002-08-01 V-Target Technologies Ltd. Ingestible device
JP2002282219A (ja) * 2001-03-22 2002-10-02 Toshio Chiba 体内カプセル
US7563255B2 (en) * 2001-05-03 2009-07-21 Massachusetts Eye And Ear Infirmary Implantable drug delivery device and use thereof
US20030117491A1 (en) 2001-07-26 2003-06-26 Dov Avni Apparatus and method for controlling illumination in an in-vivo imaging device
JP4744026B2 (ja) * 2001-07-30 2011-08-10 オリンパス株式会社 カプセル内視鏡およびカプセル内視鏡システム
JP4643089B2 (ja) * 2001-09-27 2011-03-02 オリンパス株式会社 カプセル型医療装置
US7807197B2 (en) * 2002-09-28 2010-10-05 Mcneil-Ppc, Inc. Composite dosage forms having an inlaid portion
US6966880B2 (en) 2001-10-16 2005-11-22 Agilent Technologies, Inc. Universal diagnostic platform
EP1468281A1 (en) * 2001-12-17 2004-10-20 Powderject Research Limited Diagnostic sensing apparatus
US20030143551A1 (en) * 2002-01-30 2003-07-31 Cattell Herbert F. Reading multiple chemical arrays
CA2474530A1 (en) * 2002-02-07 2003-08-14 Eastern Virginia Medical School Of The Medical College Of Hampton Roads Diagnostic microarray and method of use thereof
US7004928B2 (en) * 2002-02-08 2006-02-28 Rosedale Medical, Inc. Autonomous, ambulatory analyte monitor or drug delivery device
US7797033B2 (en) * 2002-04-08 2010-09-14 Smart Pill Corporation Method of using, and determining location of, an ingestible capsule
US6832296B2 (en) * 2002-04-09 2004-12-14 Ip-First, Llc Microprocessor with repeat prefetch instruction
US7112444B2 (en) * 2002-04-24 2006-09-26 Wisconsin Alumni Research Foundation Method of performing gradient-based assays in a microfluidic device
US7125510B2 (en) * 2002-05-15 2006-10-24 Zhili Huang Microstructure fabrication and microsystem integration
EP1376131A1 (en) * 2002-06-27 2004-01-02 Inverness Medical Switzerland GmbH Assay device for liquid sample
DE60332944D1 (de) * 2002-08-13 2010-07-22 Given Imaging Ltd System für die probenahme und analyse in vivo
CN2559986Y (zh) 2002-08-23 2003-07-09 上海博昇微晶科技有限公司 集成微流体和微阵列探针的微芯片
US7415299B2 (en) * 2003-04-18 2008-08-19 The Regents Of The University Of California Monitoring method and/or apparatus
US7611480B2 (en) * 2003-04-24 2009-11-03 Levy Mark M Gastrointestinal bioreactor
JP4399455B2 (ja) 2003-06-10 2010-01-13 ライフケア エイエス 浸透変化の生体内測定センサ
CA2852974C (en) * 2003-09-11 2017-06-27 Theranos, Inc. Medical device for analyte monitoring and drug delivery
US7887750B2 (en) * 2004-05-05 2011-02-15 Bayer Healthcare Llc Analytical systems, devices, and cartridges therefor
US8071051B2 (en) * 2004-05-14 2011-12-06 Honeywell International Inc. Portable sample analyzer cartridge
US7641856B2 (en) 2004-05-14 2010-01-05 Honeywell International Inc. Portable sample analyzer with removable cartridge
EP3121601A1 (en) 2005-12-22 2017-01-25 Honeywell International Inc. Portable sample analyzer system
DK1766400T3 (da) 2004-06-03 2009-07-20 Meso Scale Technologies Llc Fremgangsmåde til at udföre fuldblodsanalyser

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5848991A (en) 1990-12-13 1998-12-15 Elan Medical Technologies Limited Athlone, Co. Intradermal drug delivery device and method for intradermal delivery of drugs
US5807375A (en) 1994-11-04 1998-09-15 Elan Medical Technologies Limited Analyte-controlled liquid delivery device and analyte monitor
CN1181720A (zh) 1995-04-25 1998-05-13 伊萝莉公司 可远程编程的存储器材料及其应用
US5716852A (en) 1996-03-29 1998-02-10 University Of Washington Microfabricated diffusion-based chemical sensor
GB2374149A (en) 2000-11-08 2002-10-09 Hewlett Packard Co A swallowable internal drug dispensing capsule with memory

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Claudia Preininger et al..Polymer-coated optical fibres for application in adirectevanescent wave immunoassay.Analytica Chimica Acta403 1-2.2000,403(1-2),第70页第2栏倒数第3行至第72页第1栏第6行、附图3.

Also Published As

Publication number Publication date Type
KR101496392B1 (ko) 2015-02-27 grant
US20160058323A1 (en) 2016-03-03 application
JP4603547B2 (ja) 2010-12-22 grant
KR20120041270A (ko) 2012-04-30 application
KR20070020374A (ko) 2007-02-21 application
US8101402B2 (en) 2012-01-24 grant
EP2319403A3 (en) 2012-04-04 application
US20110166553A1 (en) 2011-07-07 application
EP2319403A2 (en) 2011-05-11 application
DK1662987T3 (da) 2012-02-27 grant
CA2538038A1 (en) 2005-03-24 application
WO2005025413A3 (en) 2005-09-15 application
CA2852974C (en) 2017-06-27 grant
JP2013046759A (ja) 2013-03-07 application
ES2374563T3 (es) 2012-02-17 grant
JP6139616B2 (ja) 2017-05-31 grant
US7291497B2 (en) 2007-11-06 grant
JP6117733B2 (ja) 2017-04-19 grant
US8202697B2 (en) 2012-06-19 grant
KR101761235B1 (ko) 2017-07-25 grant
EP1662987B1 (en) 2011-11-09 grant
KR20130006539A (ko) 2013-01-16 application
WO2005025413A2 (en) 2005-03-24 application
KR20150117711A (ko) 2015-10-20 application
KR20120101181A (ko) 2012-09-12 application
JP2007504905A (ja) 2007-03-08 application
KR20140134338A (ko) 2014-11-21 application
US9131884B2 (en) 2015-09-15 grant
KR101556457B1 (ko) 2015-10-01 grant
CA2896407A1 (en) 2005-03-24 application
CN1905835A (zh) 2007-01-31 application
JP2010221042A (ja) 2010-10-07 application
JP5635041B2 (ja) 2014-12-03 grant
US20060062852A1 (en) 2006-03-23 application
JP5255594B2 (ja) 2013-08-07 grant
JP2016027866A (ja) 2016-02-25 application
KR101330431B1 (ko) 2013-11-20 grant
CA2852974A1 (en) 2005-03-24 application
EP1662987A2 (en) 2006-06-07 application
US20060182738A1 (en) 2006-08-17 application
US20050100937A1 (en) 2005-05-12 application
CA2538038C (en) 2015-10-27 grant
KR20140002090A (ko) 2014-01-07 application
KR101328849B1 (ko) 2013-11-13 grant
KR20170086705A (ko) 2017-07-26 application
KR101471731B1 (ko) 2014-12-15 grant
JP2014221197A (ja) 2014-11-27 application

Similar Documents

Publication Publication Date Title
Huh et al. Surface enhanced Raman spectroscopy and its application to molecular and cellular analysis
US6704587B1 (en) Dual function assay device
US6572566B2 (en) System for determining analyte concentrations in body fluids
US7964390B2 (en) Sensor system
US20060264783A1 (en) Systems and methods for monitoring pharmacological parameters
Jokerst et al. Affibody‐functionalized gold–silica nanoparticles for Raman molecular imaging of the epidermal growth factor receptor
US20070264629A1 (en) Real-Time Detection of Influenza Virus
Razzacki et al. Integrated microsystems for controlled drug delivery
US8158430B1 (en) Systems and methods of fluidic sample processing
Wang et al. Minimally invasive extraction of dermal interstitial fluid for glucose monitoring using microneedles
Matzeu et al. Advances in wearable chemical sensor design for monitoring biological fluids
US20050106713A1 (en) Personal diagnostic devices and related methods
Ma et al. In vivo, transcutaneous glucose sensing using surface-enhanced spatially offset Raman spectroscopy: multiple rats, improved hypoglycemic accuracy, low incident power, and continuous monitoring for greater than 17 days
US20040180391A1 (en) Sliver type autonomous biosensors
Retterer et al. Model neural prostheses with integrated microfluidics: a potential intervention strategy for controlling reactive cell and tissue responses
US20080154179A1 (en) Agent delivery system
US20090291508A1 (en) Nanoparticles in diagnostic tests
US20040186359A1 (en) Afinity biosensor for monitoring biological process
US20050209518A1 (en) Self-calibrating body analyte monitoring system
US20050267326A1 (en) Percutaneous chemical sensor based on fluorescence resonant energy transfer (FRET)
US20030171666A1 (en) Internal biochemical sensing device
US20080166720A1 (en) Method and apparatus for rapid nucleic acid analysis
EP0992287A2 (de) Vorrichtung zur Aufnahme und Aufbewahrung einer Substanz für eine Analyse
US20050064529A1 (en) Diagnostic sensing apparatus
US8778665B2 (en) Detection and quantification of analytes in bodily fluids

Legal Events

Date Code Title Description
C06 Publication
C10 Entry into substantive examination
C14 Grant of patent or utility model
TR01