WO2001081890A2 - Biocapteur hydrogel et systeme d'alarme sanitaire fondee sur ce biocapteur - Google Patents

Biocapteur hydrogel et systeme d'alarme sanitaire fondee sur ce biocapteur Download PDF

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Publication number
WO2001081890A2
WO2001081890A2 PCT/US2001/012934 US0112934W WO0181890A2 WO 2001081890 A2 WO2001081890 A2 WO 2001081890A2 US 0112934 W US0112934 W US 0112934W WO 0181890 A2 WO0181890 A2 WO 0181890A2
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WIPO (PCT)
Prior art keywords
hydrogel
analyte
biosensor
concentration
pressure
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PCT/US2001/012934
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English (en)
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WO2001081890A3 (fr
Inventor
In Suk Han
Jules John Magda
Seok Lew
Young San Jean
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M-Biotech, Inc.
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Application filed by M-Biotech, Inc. filed Critical M-Biotech, Inc.
Priority to EP01957060A priority Critical patent/EP1309845A4/fr
Priority to JP2001578926A priority patent/JP2004507283A/ja
Priority to AU2001278840A priority patent/AU2001278840A1/en
Publication of WO2001081890A2 publication Critical patent/WO2001081890A2/fr
Publication of WO2001081890A3 publication Critical patent/WO2001081890A3/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/5302—Apparatus specially adapted for immunological test procedures
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase
    • A61B5/14865—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N13/00—Investigating surface or boundary effects, e.g. wetting power; Investigating diffusion effects; Analysing materials by determining surface, boundary, or diffusion effects
    • G01N13/04—Investigating osmotic effects
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/48785—Electrical and electronic details of measuring devices for physical analysis of liquid biological material not specific to a particular test method, e.g. user interface or power supply
    • G01N33/48792—Data management, e.g. communication with processing unit
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/66—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood sugars, e.g. galactose
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/02—Devices for withdrawing samples
    • G01N2001/021—Correlating sampling sites with geographical information, e.g. GPS

Definitions

  • This invention relates generally to biosensors utilizing hydrogels to measure the concentration of free analyte molecules in a fluid, particularly biosensors suitable for implantation in a patient to provide constant monitoring of a selected analyte.
  • the invention also relates to health alarm systems in which a biosensor is connected to apparatus which alerts a patient and/or patient caretakers to deleterious changes in the levels of analvte in the patient s bod ⁇ fluids oi to othei advei se changes in a patient s condition
  • amperomet ⁇ c sensors must overcome several hurdles before they will ever be useful for commercial in vivo monito ⁇ ng Current analyte sensor designs appear unlikely to solve these difficult problems in the near future.
  • the first hurdle a ⁇ ses from electrochemical interference.
  • the analyte (whether hydrogen peroxide or oxygen) must be the only species present which produces a current at the electrode.
  • an inner membrane must be used which is permeable to the analyte but impermeable to endogenous mterferents which may produce electrochemical effects.
  • hydrogels have also been used in devices developed to release insulin directly into a diabetic's bloodstream m response to high analyte levels
  • the hydrogel is constructed to have chemically immobilized pendant groups which are charged under physiological conditions (pH2 to pHIO) Molecules of glucose and of a glucose-specific binding molecule (abbi GBM, for example, concanavalin A) are also immobilized m the gel Within the hydrogel.
  • GBM glucose-specific binding molecule
  • hydrogel swelling increases the porosity and/or pore size between gel subunits
  • insulin a rather large molecule which does not diffuse readily through a closely-cross nked gel mat ⁇ x
  • hydrogel-based biosensors which the analyte -detecting process does not consume oxygen
  • the present invention compnses a hydrogel-based biosensor which measures the osmotic pressure within a hydrogel having pendant charged moieties, analyte molecules, and analyte binding partner molecules all immobilized with
  • the gel is confined in a ⁇ gid enclosure that has a semipermeable opening to permit osmotic contact between the test fluid (a patient's blood or other solution) and pressure detection means are operably associated with the hydrogel for detecting the osmotic pressure or swelling tendency of the hydrogel
  • the device uses a competition assay .
  • a biosensor of the invention compnses a polyme ⁇ c hydrogel having pendant moieties that are charged under physiological conditions, an analyte binding molecule immobilized m the hydrogel and capable of binding the free analyte, analyte molecules immobilized in the hydrogel.
  • the piessui e detection means is comp ⁇ sed of a diaphragm positioned such that changes in osmotic pi essure w ithin the gel cause changes in pressure exerted on the diaphragm, and a pressure transducer operably associated w ith the diaphragm for detecting these pressure changes
  • Biosensois of this invention can be designed to detect any analyte which can be immobilized within the hydiogel and for which an (immobilizable) binding partner with sufficient specificity and binding affinity can be found (see Table 1)
  • a further embodiment of the biosensor includes reporting means associated with the pressure detection means foi reporting the data signal, and computing means operably disposed to receive the data signal and constructed to compare it to a predetermined calibration curve and to produce an analyte data signal reflecting the measured analyte concentration
  • the reporting means is a battery powered telemeter which sends a radio data signal to a receiver operably attached to the computing means
  • the computing means is associated with an alarm system
  • the computing means may be a personal computer, but in a prefe ⁇ ed embodiment, the computing means is a microprocessoi
  • the computing means contains or is operably associated with alarm means for providing an alarm signal when the analyte concentration falls outside a pie-determined acceptable range
  • the biosensor includes reporting means associated with the pressure detection means foi reporting the data signal, and computing means operably disposed to receive the data signal and constructed to compare it to a predetermined calibration curve and to produce an analyte data signal reflecting the measured analyte concentration
  • the reporting means is a battery powered
  • the biosensoi of the system may be any sensor configured to detect a critical health-related biological determinant (such as, but not limited to, the concentiation of a selected analyte in the patient's body fluid)
  • the system may further include an automatic drug administration component which responds to the sensor by adm istenng an appropriate amount of a drug to ameliorate the adverse effects of the change m the biological determinant
  • the invention also encompasses a method of determining the concentration of free analyte m a solution
  • the method compnses steps of: providing a hydrogel having pendant charged moieties, analyte molecules, and analyte-specific binding molecules covalently immobilized therein, enclosing the hydrogel m a rigid structure which has at least one permeable portion available for contacting a test fluid with the hydrogel, the permeable portion constructed to permit free analyte to diffuse into the hydrogel; contacting the hydrogel sequentially with a se ⁇ es of calibration solutions having known concentrations of free analyte and measu ⁇ ng osmotic pressure in the hydrogel for each of the cahbration solutions to produce a calibration curve of osmotic pressure versus analyte concentration, contacting the hydrogel with the test fluid, and measu ⁇ ng a resulting osmotic pressure, and comparing the resulting osmotic pressure with the calibration curve to determine an
  • FIGURE 1 is an example of the competitive binding and swelling mechanism
  • FIGURE 2 is an example of a analyte binding molecule (ABM)-contammg copolymer
  • FIGURE 3 is a side, partial cross-sectional view and diagram of the preferred embodiment of the present invention, showing a biosensor that can be dipped in a sample and implanted under a patient's skin;
  • FIGURE 4 is a side partial cross-sectional view of an alternative embodiment thereof, showing a biosensor that is electronically attached to a computer;
  • FIGURE 5 is a side partial cross-sectional view of the preferred embodiment, showing analyte diffusing into the hydrogel, causing the hydrogel to swell and causing the pressure transducer to signal to a computer through a telemeter;
  • FIGURE 6 is side elevational sectional view of the pressure transducer
  • FIGURE 7 is side elevational sectional view of the pressure transducer including the prefened circuit board having miniature diodes which are part of a diode quad bndge circuit
  • FIGURE 8 is an electncal schematic showing the prefened diode quad bndge circuit
  • FIGURE 9 is a block diagram of one embodiment of an automatic alarm system in conjunction with wireless actuation of dialing.
  • FIGURE 10 is a schematic diagram of a power supply for the va ⁇ ous portions of the automatic alarm system of FIG 9.
  • FIGURE 11 is a schematic diagram of the signal conditioning circuit of the alarm system of FIG 9
  • FIGURE 12 is a schematic diagram of the comparatoi and control circuit of the alarm system of FIG 9.
  • FIGURE 13 is a schematic diagram of the transmitter and receiver of the alarm system of FIG 9,
  • FIGURE 14 is a schematic diagram of a dialing mechanism of the alarm system of FIG 9,
  • FIGURE 15 is a block diagram of an automatic alarm system of FIG 9 used in conjunction with an injection device for providing injections responsive to the alarm system.
  • FIGURE 16 is a block diagram of a highly preferred embodiment of an automatic health alarm system,
  • FIGURE 17 is a power supply circuit for the alarm system embodiment of FIG 16;
  • FIGURE 18 depicts a signal conditioning circuit for the alarm system of FIG 16
  • FIGURE 19 depicts a circuit for a micro-control unit of the alarm system of FIG
  • FIGURE 20 depicts circuits for the GPS and communications transmitters of the alarm system of FIG 16.
  • FIGURE 21 is a block diagram of a signal conditioner for the alarm system of FIG 16, and
  • FIGURE 22 is a block diagram of the micro-control unity for the alarm system of FIG 16
  • the biosensor 10 uses a special polymeric hydiogel 30 that changes its osmotic pressure in proportion to the concentration of free analyte, ABM immobilized in the hydrogel 30 the ABM competitiv ely binds with immobilized analyte and free analyte, thereby causing the hydrogel 30 to change its osmotic pressure, a means for measu ⁇ ng 40 the osmotic pressure of the hvdrogel 30, and a means for reporting 60 the concentration of analyte based on the measured osmotic pressure of the hydrogel 30
  • the biosensor 10 includes a ⁇ gid, biocompatible enclosure 20 having semipermeable membrane 26 cove ⁇ ng an open end
  • the enclosure 20 is designed to be dipped into a sample and implanted directly into the human body for monito ⁇ ng blood analyte levels
  • the biosensor 10 uses ABM immobilized in a hydrogel 30
  • the means for measunng 40 the osmotic piessure of the hydrogel 30 is preferably a pressure transducer 40 operably associated ith the flexible diaphragm 28
  • the means for reporting 60 analyte levels is preferably a battery 64 operated telemeter 60 that sends a radio data signal to a receivei operably attached to a computer 62
  • Alternative embodiments of this biosensor 10 can easily be adapted by those skilled in the art Rather than use of a telemeter 60 a direct elect ⁇ cal connection to a computer 62 can be used w hen the biosensor 10 is minimally invasive into a human bod ⁇ While the pressure transducei 40 is currently the prefe ⁇ e ⁇ tool for measuring changes the osmotic pressure of the hydrogel 30, those skilled in the art
  • the structure of the biosensor 10 is provided by an enclosure 20, preferably a cyhnd ⁇ cal enclosure 20 having an open end and a closed end The open end is sealed with a semipermeable membrane 26 A flexible diaphragm 28 is mounted between the semipermeable membrane 26 and the closed end The hydrogel 30, described below is enclosed between the semipermeable membrane 26 and the diaphragm 28
  • the enclosure 20 is preferably constructed of a ngid, impermeable, and biocompatible mate ⁇ al such as stainless steel, and the enclosure 20 is preferably conjugated with hepa ⁇ n to prevent blood clotting, and polyethylene glycol (PEG) to decrease the body's immune response against the enclosure 20
  • the enclosure 20 is preferably coating with a biocompatable mate ⁇ al such as a thin polymer
  • the enclosure 20 is preferably cyhnd ⁇ cal in shape to facilitate implantation, the cylinder being approximately 5 to 12 mm long and having a
  • the semipermeable membrane 26 is permeable to the passage of small analytes, however, it is impermeable to the passage of blood clots, cells, proteins, and the hydrogel
  • the semipermeable membrane 26 is preferably made of a mate ⁇ al ngid enough to sustain the pressure of a swollen analyte sensitive hydrogel 30 If the biosensoi 10 is to be implanted into the human body, the semipermeable membrane 26 is preferably an inert, nontoxic mate ⁇ al
  • a suitable semipermeable matenal can be selected from, but is not limited to, the following groups of polymers cellulose acetate, methyl cellulose.
  • the diaphragm 28 is pieferably be a flexible but conductive mate ⁇ al useful for use with a transducer 40 Such diaphragms are known in the art
  • the prefe ⁇ -ed diaphragm 28 is mode of an alloy sold under the trademarks KOVARTM or INVAR 36TM by Hamilton Technology, Inc., of Lancaster, Pennsylvania
  • the diaphragm 28 is preferably approximately 12.5 ⁇ m to achieve optimum spot welding and sensitivity.
  • Such a diaphragm is desc ⁇ bed in Baek SG Ph.D. Thesis. University of Utah, (1992)
  • the diaphragm 28 is preferably seal welded to the enclosure 20 between the semipermeable membrane 26 and the closed end 24 of the enclosure 20.
  • the hydrogel 30 fills the chamber withm the enclosure 20 between the semipermeable membrane 26 and the diaphragm 28.
  • the means for measu ⁇ ng 40 and the means for reporting 60, desc ⁇ bed below, are located the chamber withm the enclosure 20 between the diaphragm 28 and the closed end 24 of the enclosure 20.
  • Table I contains a list of analyte and analyte binding partners to which the method and biosensor of the invention can be applied.
  • the analyte binding partner molecule should bind the analyte with sufficiently high specificity and avidity.
  • an antibody (ABM) tightly bind with an antigen (analyte) with a high specificity.
  • hydi ogels contain, or can be modified to contain, diverse functional gioups
  • functional gioups can be used by those skilled in the ait to conjugate the ABM and analvte to hydrogel backbone
  • functional groups include but aie not limited to the following carboxyl, hydioxyl, alkyl, hydroxylalkyl, oxyalkyl, oxyhydroxyalkyl, saccha ⁇ de, carboxyl, caiboxyamidealkyl, aromatic ammo, phenolic hydroxyl, and polyethylene glycol Coupling reactions include but are not limited to the following diazo um coupling, iso
  • a p ⁇ marv, am o group in a peptide chain ABM and analyte can also be conjugated to hydrogel containing a functional group (such as thiol, hydroxyl, acyl chloride, sulfate, sulfonyl chlo ⁇ de, phosphate, phosphate chloride, and lmide) using coupling agents and or cross-linking agents such as benzyl carbamate, carbonate, N - succmimidyl 3-(2-py ⁇ dyld ⁇ th ⁇ o) propionate (SPDP), sulfo - LC - SPDP, succimmidv 1 4 - (N -maleimidomethyl) cyclohexane - 1 - carboxylate (SMCC), sulfo - SMCC.
  • a functional group such as thiol, hydroxyl, acyl chloride, sulfate, sulfonyl chlo ⁇ de,
  • SMPB succmimidyl 4 - (p - maleimidophenyl) butyrate
  • SMPB succmimidophen
  • analytes and ABM which have several pendant functional groups such as thiol, hydroxyl.
  • acyl chlonde, sulfate, sulfonyl chloride, phosphate, phosphate chlonde, and lmide can also be conjugated to hydrogel chain using the above coupling agents and crossing-linking agents.
  • a vinyl group is attached to an analyte and ABM containing a functional group such as amine and hydroxyl group through etherification reaction with allyl alcohol and/or nuclearphilic reaction with methacryloyl chloride.
  • Copolymerization an analyte and ABM with cross-linking agents and monomers such as acrylamide and hydroxylethyl methaacrylate (HEMA) preferably forms with a free radical reaction.
  • the polymer chain preferably contains chemically immobilized analyte and ABM as pendant groups.
  • the hydrogel is preferably porous. The porosity is preferably controlled with several methods such as bubbling or excessive addition of powdered salt to the copolyme ⁇ zation reaction.
  • the hydrogel preferably swells when free analyte is introduced in the hydrogel due to competitive binding to immobilized ABM on the hydrogel.
  • the swelling ratio is preferably proportional to free analyte concentrations in the solution.
  • the reaction ratio analyte and ABM, monomer. and cross-linking agents are preferably optimized to give a measurable pressure with a pressure transducer resulting in swelling and de-swelling of the hydrogel by changing free analyte concentrations.
  • a specific example of a biosensor of the invention is a glucose biosensor, desc ⁇ bed in the related application PCT /USOO/23194, pub. date Mar. 8, 2001, the contents of which are hereby incorporated by reference.
  • the analyte binding partner is concanavalm A
  • the biosensoi includes a means for measuring 40 the pressure of the hydrogel This element is cntical A biosensor 10 that directly relies on change in free analyte concentration avoids an important source of outside interference. Free analyte itself is a controlled parameter than parameters measured directly by electrodes.
  • the means for measuiement is preferably a pressure transducer 40
  • Pressure transducei s are known m the art and those skilled in the field can construct a transducer optimized to the specific needs of the biosensor 10
  • An example of a transducer is disclosed Har ⁇ son DR, Dimeff J Rev Sci Instrum 44 1468-1472.
  • the biosensor 10 can also include a calibration hole 70 which receives a small brass tube 72, a solder stranded copper wire 74, a braided shield 76. insulators 78 and coaxial cables 80.
  • the means for measu ⁇ ng 40 is a capacitive pressure transducer 40 associated with the flexible diaphragm 28 described above
  • the prefened transducer 40 includes a first electrode 44 and a second electrode 46, the first and second electrodes 44 and 46 being separated by an insulator 48
  • the first and second electrodes 44 and 46. as well as the insulator 48 are coaxially aligned cylinders.
  • the flexible diaphragm 28 is preferably welded to the top of the first conductor 44, converting the diaphragm 28 into one of the electrodes of a capacitor portion of the transducer 40
  • the first electrode 44 is connected to the diaphragm 28, and the diaphragm 28 is separated from the second electrode 46 by an air gap 50.
  • the diaphragm 28 Since the diaphragm 28 is in mechanical contact with the hydrogel 30, the diaphragm 28 deflects in response to changes in the pressure of the hydrogel 30, thereby changing the size of the air gap 50 between the second electrode 46 and the diaphragm 28, thereby changing the value of the capacitance.
  • the value of the capacitance change is detected remotely, preferably using a diode quad bndge circuit 52
  • These pressure transducers 40 have been successfully used to measure pressure changes m flowing polymenc liquids as small as one Pascal.
  • transducers Examples of alternative transducers are desc ⁇ bed in Takaki, U.S. Pat. No. 5,711,291 and Fowler, U.S. Pat. No. 5,752.918, hereby incorporated by reference
  • a more detailed discussion of transducers can be found the following references, herebv incorporated by reference.
  • piefened pressure transducer 40 has been desc ⁇ bed, those stolled m the art can devise other means for measuring 40
  • Other alternative embodiments include a piezoelect ⁇ c transducer and piezoresistive pressure sensor
  • Other means for measu ⁇ ng pressure or increase m volume could also be used
  • the biosensor 10 includes a means for reporting 60 the concentration of the analyte molecule once it has been measured This element will vary greatly depending upon the specific use of the biosensor 10 as well as the needs of the user
  • the transducer 40 is simply connected electronically to a computer means, generally a personal computer
  • the computer compares the data from the transducer 40 to a calibration curve to generate usable data for export through a reporting means
  • the computer sounds an alarm if the concentration of the analyte molecule exceeds a certain level
  • the computer outputs data onto a reporting outlet such as a computer monitor
  • the computer controls a feedback loop to change a process is response to va ⁇ ation in the concentration of the analyte molecule
  • the biosensor 10 is a biosensor 10 that can be implanted into the human bodv
  • the means for reporting 60 is preferably a battery powered telemeter 60 that transmits
  • the invention further includes a method for using a biosensor 10 to measure the concentration of analyte in a solution
  • the method includes the following steps First providing a biosensor 10 as described above ABM is chemically or physically immobilized the hydrogel 30, preferably using chemical conjugation The biosensoi 10 is preferably first immersed on a buffer and inserted into a control solution.
  • the data generated is then compared to a calibration curve to calibrate the biosensor 10
  • the biosensor 10 is inserted into the solution
  • the analyte molecules are allowed to diffuse into the polyme ⁇ c hydrogel 30, causing the competitively binding of free analyte with immobilized analyte to ABM
  • the competitive binding between free analyte and immobilized analyte to ABM causes the hydrogel 30 to increase in osmotic pressure and swell, as shown m FIG.
  • the means for measunng 40 is preferably a pressure transducer 40
  • the pressure transducer 40 is used to measure the osmotic pressure of the hydrogel 30, which is proportional to the concentration of the free analyte level in the hydrogel 30
  • Data from the transducer 40 regarding this measurement is then sent to a means for reporting 60
  • a battery powered telemetei 60 is used to transmit the data to a computer This can be then reported to the user through a computer monitor, an audible alarm, or a feedback system Throughout use, the system can be recalibrated by taking blood samples and compa ⁇ ng the analyte readings to those reported by the biosensor 10
  • the computer actuated means of calibration can then be adjusted to correct for any enors
  • FIG 9 shows a diagram of a working model for giving an alarm to diabetics and a signal to caretakers using automatic dialing and sending of a prerecorded message when blood glucose levels drop to the level of hypoglycemia
  • an automatic alarm device the major elements of an automatic alarm device are a power supply 100, a sensor (such as biosensor 10 or other sensor foi monitonng a physiological condition), a signal conditioning circuit 104, a comparator circuit 108, a transmitter/receiver 112a and 112b, a dial actuator 116, and a control circuit
  • the power supply 100 preterably provides electric energy to all the elements of the device requi ⁇ ng power Conside ⁇ ng portability of the device, a dry-cell battery is the preferred choice for supplying power
  • a dry-cell battery is the preferred choice for supplying power
  • compatibility of the cell with power requirements of all the elements will be somewhat determinative of the type used As presently perceived, a large capacity 9-volt battery is believed to be the best choice
  • a bipolar power supply using 2 batte ⁇ es makes the circuit design much easier
  • a low-battery indicator should be an essential part
  • the need for the signal conditioning circuit 104 depends on the quality of the signal from the sensor If the sensor signal comes along with a great deal of environmental noise, the signal conditioning circuit 104(FIG 11) is necessary to operate the device in a reliable manner.
  • a high input-impedance differential amplifier works for any kind of sensor.
  • a prepackaged circuit, the so-called “instrumentation amplifier” is commercially available.
  • a quad-op amp IC e.g., LM 384 from National Semiconductors
  • a differential amplifier is excellent m removing common mode noise. The gain of the differential amplifier can be adjusted to provide signals of a good linear range.
  • a low - pass filter after differential amplification will further decrease high frequency noise.
  • a comparator always compares the monitored signal (here, from the output of the signal conditioning circuit) with the preset value.
  • the threshold value will be adjusted using a potentiometer. If the monitored signal goes over the threshold value, the output of the comparator changes its status from '0' to T or from 'off to OnM This change of status is utilized to actuate a following digital circuit.
  • the simplest circuit will be driving an electromechanical switch to 'on' position, by which a transmitter circuit is connected to the power supply; LM311 type comparator should best fit the purpose.
  • the comparator circuit 108 must be with extra control circuits 130 (FIG. 12)
  • the extra controls are for deactivating the device and resetting the device in the case when alarms are sent mistakenly or by device malfunction.
  • an extra switch should be there to actuate dialing in any case at the discretion of the device user. All these factors can be achieved by using a digital D-flip-flop IC(C7474)
  • the comparator circuit 108 can be used for determining if the sensor 10 operates normally as well as for alarming. If sensor output goes beyond an expected operating range including an alert level, the comparator 108 will indicate malfunction of the sensor 10.
  • a transmitter/receiver 112a and 112b is necessary in order to operate a phone 114 at a distance from the device-earner (FIG. 13). Wireless activation of the phone 114 can be achieved using a typical FM method
  • a transmitter consists of a car ⁇ ei wave generatoi 140 a signal generatoi 144 a modulatoi 148 to mix signal to ca ⁇ iei wave a pow ei boostei 152 and a radiatoi 156
  • the earner wave frequency may be the range of se eral tens to several hundreds megahertz
  • the signal must be unique that the receiver picks up to avoid mistaken dialing due to environmental noises from other electronic devices
  • a leceivei 112b operates m a reversed manner to that of a transmitter 112a
  • a transmitter/receiver, 1 12a l 12b must be custom designed eventually, it can be adapted from a minimally modified transmitter/receiver used in kids' remote control toys (In light
  • Dialing to a remote alarm signal can be achieved in a number of ways that will be well known to those skilled in the art A schematic of such a system is shown in FIG 14 and those familiar with remote telephone interactions will be familiar with numerous ways of implementing this and other configurations
  • the alarm system can also function as a system for treating hypoglycemia in a diabetic
  • FIG 15 there is shown a schematic of an alarm system similar to that shown in FIG 9
  • the system further includes, however, an injection mechanism 150 that dispenses glucose another sugar, or a drug into the blood stream of the patient in response to the alarm
  • the injection device 150 may provide predetermined dose, or may inject varying quantities in response to the physiological condition detected by the sensor 10
  • the injection device 150 may be hard wired to the system, or may be controlled by the transmitter 112a In addition to the injection mechanism 150.
  • the system can also include a global positioning system 160 associated with the telephone 114 or some other position of the alaim system
  • the global positioning system 160 enables lapid location of the individual in the event that medical treatment is necessary
  • Such a system is particularly beneficial for individuals who have diabetes but still w hich to engage in activities such as c ⁇ chng hunting and fishing
  • FIG 16 A highly prefened embodiment of the automatic alarm system is depicted FIG 16, and circuits useful in this embodiment are shown in FIGS 17-23 As seen in FIG 16, the major elements are a sensor (such as biosensor 10 or other sensors for monito ⁇ ng physiological condition), a power supply 200, a signal conditioning unit 204, a global positioning system (GPS) receiver 260, a MCU circuit unit 270, and a data transmitter 214.
  • a sensor such as biosensor 10 or other sensors for monito ⁇ ng physiological condition
  • GPS global positioning system
  • the power supply 200 preferably provides electric energy to all the elements of the device requi ⁇ ng power Conside ⁇ ng portability of the device, a battery is the preferred choice for supplying power
  • a battery is the preferred choice for supplying power
  • compatibility of the cell with power requirements of all the elements (voltage and capacity) will be somewhat determined of the type used As presently perceived, a +3 3-volt (+3 3V) rechargeable battery and a charging system aie preferably used to supply power as a whole
  • SMPS Switching Mode Power Supply
  • charging circuit 200b charges the rechargeable battery accoiding to the battery capacity and remaining battery level
  • Li-ion, Ni-ca, and Ni-H are preferably used for the rechargeable battery 200c
  • a low battery indicator and a charging status indicator should be an essential part
  • the rechargeable battery can be charged up to +3.3V, which is supplied to the circuit as a whole except the LCD and the transmitter and micro controller unit (MCU) Additional +5V is needed to operate LCD and transmitter, and this voltage is preferably acquired from the battery by using of a conventional DC-DC converter 200d.
  • the need for the signal conditioning unit 204 depends on the quality of the signal from a sensor. If the sensor signal comes along with a great deal of environmental noise and/or a low voltage input, the signal conditioning circuit 204 (FIG. 11) is necessary to operate the device in a reliable manner.
  • a signal-conditioning unit 204 is designed for a noise reduction and amplification for an input signal from a sensor.
  • a prepackaged multi-step amplification circuit, the so-called "instrumentation amplifier” is commercially available.
  • a chopper-op amp IC e.g. MAX 420 or MAX421 from Maxim
  • a quad-op amp IC e.g..
  • LM 384 from National Semiconductors
  • a differential amplifier is excellent in removing common mode noise.
  • a low-pass filter after differential amplification will further decrease high frequency noise.
  • An RC time constant of 0.1 to 1 seconds is approp ⁇ ate. For example, an RC time constant of 1 second can be obtained using 100 kohm and 10 mF.
  • a chopper-stabilized amp IC (Al, A2, A3, A4, A5, and A6 signal conditioning circuit 204) preferably use for a prototype device in signal conditioning circuit.
  • the op- amps are a monolithic chopper op-amp having precise input characte ⁇ stics.
  • a high mput-impedance differential amplifier as a buffer circuit such as Al and A2 in amplification circuit 204a works for any k d of sensor to adjust zero crossing with an available resistor like VR1 (a variable resistor) in amplification circuit 204a.
  • Al and A2 preferably have voltage-regulating capability with condensers such as C3, C4, C5.
  • the first amplification circuit (A3) 204a consists of a low pass filter for reduction of noise and an amphfiei
  • the low pass filter reduces a level of noise before amplification A3 204a as a chopper stabilized operational amplifier amplifies the filtered sensoi signal
  • the operational amplifier A3 preferably has a low input offset voltage of l ⁇ Vtyp and a low d ⁇ ft offset of 0.02 ⁇ V/Ctyp
  • the final segment of the signal condition circuit 204c preferably provides a function of offset compensation (VR2 and VR3) and third amplification (A6 in circuit 204c)
  • a condenser C17 is preferably selected to make a loop response c ⁇ tically damped When the signal overshoot and a noise level are greater than input voltage V cc , the input voltage V cc is preferably bypassed m the forward direction of a diode D4 When the signal overshoot and a noise level are less than ground voltage, input voltage V cc is preferably bypassed in the backward direction of diode D5
  • control unit The functions of the control unit are to compare the input sensor signal with the pre assigned reference signal, to determine the alarm status, to store new value of sensor signal, to retneve the stored values m memory, to engage with data transmitter for emergency contact to activate injection device, to initiate alarming buzzer, and to respond key input from patients
  • an 8 -bit microprocessor is preferably used for every transaction of the automatic alarm system
  • An assembler and/or a computer language like C language preferably code the transaction, which is compiled for the implementation of microprocessor in hand Alarm status, GPS location code, and signal itself from a sensor can be stored in the memory semiconductor such as flash memory. SRAM, DRAM, or EEPROM. 8K byte of EEPROM 172a is preferably selected for the purpose.
  • the pnmary function of the microprocessor is to establish real-time monito ⁇ ng and automatic alarm informing system.
  • An 8-bit microprocessor having low power consumption can supervise the real-time monito ⁇ ng activity and the automatic alarm system.
  • TMP87CH48 of TOSHIBA 270a is preferably selected for the purpose
  • Patients can manually operate the automatic alarm device by pushing the key such as reset, signal value display, location code display, and other assigned user functions
  • the control unit recognizes and interprets key input of a voltage level depending on which key users hit to accomplish the function in hand
  • the display with a displaying capacity of 20 characters and 2 lines is preferably TN type of LCD or RCM2072R of ROHM 273a
  • the extra control functions are the deactivation of the device and the reset 270b of the device in a case when alarms are sent mistakenly or by device malfunctions
  • the control unit has the facility to provide output pulse signal 275a to initiate an injection device, and activates an alarming buzzer 271a
  • the injection device is activated when the microprocessor turns on analog output circuit from 'high' to 'low' or 'low' to 'high' as a function '0 ' and T.
  • patient ' s information is preferably continuously transfe ⁇ ed to data transmitter case of emergency
  • the patient's information preferably includes patient's code of identification, alarm status,
  • a transmitter 214a is necessary in order to operate a communication device 214
  • the candidate for data transmitter 214a can be a communication devices 214 such as a phone including a portable wireless communication device, which can accommodate external data port for exchanging data with the automatic alarm system and inform alarm status and data automatically to a pre-determmed devices in remote location.
  • Cable and connector can preferably make the connection between data transmitter and automatic alarm system The selection of cable and connector depends on the wireless data communication device concern
  • a wireless connection protocol like Bluetooth can accomplish the data transfer between the devices
  • Alarm status, location information, and other essential information from the automatic alarm system can be transmitted in the form of voice message or text message depending on devices in remote
  • the wireless communication device is preferably a wireless personal phone supporting CDMA, TDMA, GSM, and other wireless communication standards in operation PDA (Personal Digital Assistance) with remote Internet service can prefeiably be other form of wireless portable communication device
  • a transmitter 214a consists of a earner wave generator, a signal generator, a modulator to mix signal to carrier wave, a power booster, and a radiator.
  • the carnei wave frequency may be in the range of several tens to several hundreds megahertz (MHz)
  • the signal picked up from a receiver must be unique to avoid mistaken transmittal due to enviionmental noises from other electronic devices
  • Either AM oi FM wireless communication can be applied in the automatic alarm system, employing the approp ⁇ ate communication protocol, and matching an AM or FM receiver also designed to receive the data from the tiansmitter 214a
  • the pnmary function of the GPS unit is to provide location data to the rec ⁇ p ⁇ ent(s) of the alarm the event that the patient carrying the automatic alarm device either does not know his/her location or is unconscious or otherwise unable to describe his location
  • a GPS receiver 260a supporting NMEA protocol is preferably used in the automatic alarm system
  • the receiver gives a location coordinate of X, Y, Z in a binary form, and the code is transferred to control unit by a conventional RS232C se ⁇ al communication
  • the GPS receiver is normally in a standby mode, and automatically activated to inform the caretakers of his/her cunent location when a patient is in a cntical condition
  • FIGURES 21, 22 and 23 are block diagrams of three major components of the automatic alarm system for a prototype device
  • FIG 21 shows a switch mode power supply (SMPS) and charger
  • FIG 22 shows a signal conditioning circuit
  • FIG 23 depicts the overall control unit
  • SMPS switch mode power supply
  • FIG 21 which is a block diagram of a free voltage input S M P.S circuit and charger block
  • AC power noise is filtered in an AC input filter 290 before bridge circuit 291 m which AC power (AC 85V to 265V) is converted to all wave RC filter circuit 292 converts the all wave into DC power at the same time DC power noise is filtered Nevertheless, the converted DC power has spark noise and can be preferably removed by using of snubber circuit 293
  • the level of converted DC voltage can be preferably adjusted in a adjustment circuit 294 between 4 5V and 5V. which is usually a little higher than the voltage capacity of battei y to be charged
  • the converted DC power voltage is preferably filtered by LC filter 296 to reduce the noise generated during the adjustment of DC voltage level
  • the battery charging circuit 295 controls the charging cunent and voltage, depending on how much the rechargeable battery is being charged
  • a block diagram of the signal conditioner is presented m FIG 22
  • the signal level from a sensor is very low and vulnerable to environmental noise Before amplification the low level signal is preferably filtered by a RC filter, low pass filter 1 (LPF1). 280 Otherwise, both signal and noise are amplified and the signal cannot be distinguished from the noise.
  • the filtered signal is preferably amplified with a ga of approximately 10
  • the higher amplification ga for the low levels of signal possibly deteriorates the signal and is unable to restore the signal from the noise.
  • the amplified signal is filtered by conventional RC filter (LPF2) 284 to reduce noises again
  • an approximate gam of 100 is preferably engaged to give an enough dynamic range of the A/D converter in the control unit, and the noise filter, LPF3 286 is also used for reducing noises.
  • a va ⁇ able resistor should be preferably adjusted in the amplifier adjustment circuit 287
  • the total amplification ga can be adjusted by an initial input signal from a sensor
  • a surge filter 288 is included to prevent damage from voltage surges As shown in the block diagram of FIG.
  • a microprocessor control unit (MCU) 270 preferably controls all devices of a GPS receiver 260, a wireless communication device 214, a signal conditioner 204, a buzzer and recorded voice 271, a memory 272, a display 273, a key in 274, an auto injection device 275 and a reset 276. It operates under the designated speed, which can be determined by a crystal 277. MCU 270 can access to memory for sto ⁇ ng and retrieving data, which are needed to operate the automatic alarm system. The user can initialize MCU 270 by engaging reset switch 276. Reset 276 will make MCU 270 along with the whole system return to the initial condition, as if the system is turned off and turned on again.
  • the MCU can preferably display information in the automatic alarm system on the LCD (Liquid Clear Display) 273. Users can command
  • MCU 270 by the pre assigned key inputs 274, which are preferably detected by voltage level.
  • the signals bearing location code from GPS satellites 261 are preferably firsthand filtered by BPF(Band Path Filter) 260a with the 20MHz of bandwidth and 1575.42MHz of center frequency, which is a nominal frequency band of GPS. Since the signals from the satellites 261 are received as a form of coded data, they should be decoded in GPS controller module 260b. The decoded coordinate data of X/Y/Z directions are then transfened to MCU 270 by RS232C serial communication.
  • the analog signal from signal conditioner 204 is converted to digital signal by MCU 270, which has the A/D converter inside.
  • the digital signal is utilized for comparing pre-determined threshold to monitor patient's condition.
  • the output signal of MCU 270 to activate alarming buzzer 271 preferably passes a current drive 271a to control sound level. Along with alarming sound, when critical condition is detected, MCU 271 pi ov ides an activated signal to an automatic inaction divice 275 in concern
  • a wireless communication device 214 is preferably used for an automatic alarm informing system
  • the health alarm system of the invention is herein desc ⁇ bed p ⁇ ma ⁇ ly in terms of a hydrogel biosensor m which changes m osmotic pressure reflect changes a blood analyte level
  • the health alarm system may instead use an entirely different type of biosensor, for example one which detects cardiac rhythm, blood coagulation factors, or any other desired health determinant, or which uses a method other than measurement of osmotic pressure to determine the blood analyte level, or measures a blood analyte unrelated to diabetes
  • the delivery of an alarm to concerned individuals not on the same premises as the patient, and the further potential offered by including a GPS unit to provide patient location data to those concerned individuals m the event of an emergency, are potentially of benefit to patients suffenng from diverse conditions who nevertheless wish to travel, hike. fish, etc

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Abstract

La présente invention concerne un biocapteur (10) qui possède un hydrogel (30) dans une enceinte (20) rigide et de préférence biocompatible. Cet hydrogel (30) comprend une molécule de liaison d'analyte immobilisé (ABM) et un analyte immobilisé. Cet analyte immobilisé se lie de façon concurrentielle avec un analyte libre à cette ABM, modifiant ainsi le nombre de réticulations dans cet hydrogel (30), ce qui modifie la tendance au gonflement de l'hydrogel (et par la même la pression osmotique) dans son espace confiné proportionnellement à la concentration de l'analyte libre. Par la mesure du changement de pression de l'hydrogel avec un transducteur (40) de pression, ce biocapteur (10) peut mesurer précisément la concentration de molécule d'analyte libre sans rencontrer le problème des limitations d'oxygène et d'interférence qui se posait avec les biocapteurs utilisés jusqu'à présent. Un télémètre (60) alimenté par batterie en contact opérationnel avec le transducteur de pression (40) envoie un signal de donnée radio à un récepteur (66) doté d'un système d'alarme fixé opérationnel à un ordinateur (62). Par ailleurs, un système d'alarme utilise un tel capteur pour prévenir automatiquement une personne que le niveau d'analyte est en dehors des paramètres prédéterminés souhaités, et/ou pour injecter automatiquement un agent de façon à contrebalancer les niveaux d'analyte défavorables.
PCT/US2001/012934 2000-04-22 2001-04-20 Biocapteur hydrogel et systeme d'alarme sanitaire fondee sur ce biocapteur WO2001081890A2 (fr)

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EP01957060A EP1309845A4 (fr) 2000-04-22 2001-04-20 Biocapteur hydrogel et systeme d'alarme sanitaire fondee sur ce biocapteur
JP2001578926A JP2004507283A (ja) 2000-04-22 2001-04-20 ヒドロゲルのバイオセンサとバイオセンサに基づいた健康のアラームシステム（ｈｙｄｒｏｇｅｌｂｉｏｓｅｎｓｏｒａｎｄｂｉｏｓｅｎｓｏｒ−ｂａｓｅｄｈｅａｌｔｈａｌａｒｍｓｙｓｔｅｍ）
AU2001278840A AU2001278840A1 (en) 2000-04-22 2001-04-20 Hydrogel biosensor and biosensor-based health alarm system

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WO2004083828A1 (fr) * 2003-03-17 2004-09-30 Disetronic Licensing Ag Osmometre a membrane sensoriel et procede de mesure osmotique pour determination quantitative de ligands d'affinite de faible poids moleculaire
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US7556934B2 (en) 2001-10-05 2009-07-07 Clive Lindsay Ragless Concentration measurement by sensing hydrogel pressure
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WO2004083828A1 (fr) * 2003-03-17 2004-09-30 Disetronic Licensing Ag Osmometre a membrane sensoriel et procede de mesure osmotique pour determination quantitative de ligands d'affinite de faible poids moleculaire
WO2004083829A1 (fr) * 2003-03-17 2004-09-30 Disetronic Licensing Ag Osmometre a membrane et procede de determination selective d'analytes specifiques
EP2160973A1 (fr) * 2008-09-05 2010-03-10 Visgeneer, Inc. Biocapteur rechargeable
KR101135624B1 (ko) * 2009-01-15 2012-04-17 한양대학교 산학협력단 수명연장을 위한 전기감응성 고분자층이 부착된 바이오센서
CN102175863A (zh) * 2011-02-23 2011-09-07 谭森 一种军团菌预警系统和方法
US9279792B2 (en) 2011-04-13 2016-03-08 3M Innovative Properties Company Method of using an absorptive sensor element
US9506888B2 (en) 2011-04-13 2016-11-29 3M Innovative Properties Company Vapor sensor including sensor element with integral heating
US9429537B2 (en) 2011-04-13 2016-08-30 3M Innovative Properties Company Method of detecting volatile organic compounds
US9658198B2 (en) 2011-12-13 2017-05-23 3M Innovative Properties Company Method for identification and quantitative determination of an unknown organic compound in a gaseous medium
WO2013169924A1 (fr) * 2012-05-08 2013-11-14 Health Line International Corp. Administration à base d'hydrogel et capteur
CN104271191A (zh) * 2012-05-08 2015-01-07 美国昊朗国际公司 基于水凝胶的传送和传感器
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EP4152003A1 (fr) * 2012-11-02 2023-03-22 Roche Diabetes Care GmbH Systèmes et procédés d'analyse d'analytes multiples
CN104737022B (zh) * 2012-11-02 2017-06-13 霍夫曼-拉罗奇有限公司 用于多种分析物分析的系统和方法
WO2014068024A1 (fr) * 2012-11-02 2014-05-08 Roche Diagnostics Gmbh Systèmes et procédés pour l'analyse d'analytes multiples
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CN103977776A (zh) * 2014-04-21 2014-08-13 苏州康磁医疗科技有限公司 一种基于金表面的糖敏智能水凝胶及其合成方法
RU2670653C9 (ru) * 2017-05-03 2018-12-11 Федеральное государственное бюджетное учреждение науки Институт высокомолекулярных соединений Российской академии наук Устройство для доставки физически активного или лекарственного препарата на основе электроуправляемого композиционного полимерного материала
RU2670653C1 (ru) * 2017-05-03 2018-10-24 Федеральное государственное бюджетное учреждение науки Институт высокомолекулярных соединений Российской академии наук Устройство для доставки физически активного или лекарственного препарата на основе электроуправляемого композиционного полимерного материала
CN114343651A (zh) * 2021-12-09 2022-04-15 中国科学院深圳先进技术研究院 一种具有梯度孔隙率的柔性触头及其包含该柔性触头的凝胶半干电极和脑电帽
CN115219262A (zh) * 2022-09-19 2022-10-21 吉林大学 水凝胶太阳能蒸发器净水效率测试装置及测试方法
CN115219262B (zh) * 2022-09-19 2022-11-29 吉林大学 水凝胶太阳能蒸发器净水效率测试装置及测试方法

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EP1309845A4 (fr) 2005-10-12
AU2001278840A1 (en) 2001-11-07
EP1309845A2 (fr) 2003-05-14

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