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WO2001016575A1 - Biodétecteur de glucose - Google Patents

Biodétecteur de glucose Download PDF

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Publication number
WO2001016575A1
WO2001016575A1 PCT/US2000/023194 US0023194W WO0116575A1 WO 2001016575 A1 WO2001016575 A1 WO 2001016575A1 US 0023194 W US0023194 W US 0023194W WO 0116575 A1 WO0116575 A1 WO 0116575A1
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WO
WIPO (PCT)
Prior art keywords
hydrogel
biosensor
glucose
alarm
pressure
Prior art date
Application number
PCT/US2000/023194
Other languages
English (en)
Inventor
In Suk Han
You Han Bae
Dal Young Jung
Jules John Magda
Original Assignee
M-Biotech, Inc.
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
Application filed by M-Biotech, Inc. filed Critical M-Biotech, Inc.
Priority to AU69315/00A priority Critical patent/AU6931500A/en
Priority to JP2001520081A priority patent/JP2003517588A/ja
Priority to EP00957741A priority patent/EP1212601A4/fr
Publication of WO2001016575A1 publication Critical patent/WO2001016575A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/06—Investigating concentration of particle suspensions
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0002—Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network
    • A61B5/0031—Implanted circuitry
    • 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 or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/1468—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means
    • A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means using enzyme electrodes, e.g. with immobilised oxidase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis

Definitions

  • This invention generally relates to a biosensor for measuring the concentration of glucose molecules in a solution, and more particularly to an implantable glucose monitoring device using a pressure transducer and a glucose sensitive hydrogel having an immobilized glucose binding molecules (GBM), an immobilized charged pendant group, and an immobilized hexose saccharide, the device being proportionally responsive to increases in glucose levels in the physiological fluids such as blood when it is implanted.
  • GBM glucose binding molecules
  • immobilized charged pendant group an immobilized charged pendant group
  • immobilized hexose saccharide the device being proportionally responsive to increases in glucose levels in the physiological fluids such as blood when it is implanted.
  • Type II diabetes is one of the major diseases in the United States. In 1995, there were approximately sixteen million Americans suffering from diabetes, including those undiagnosed. It is estimated that 650,000 new cases are diagnosed each year. Diabetes was the seventh leading cause of the death listed on U.S. death certificates in 1993, according to the National Center for Health Statistics. There are two major types of diabetes: type I diabetes (10% of diabetes cases in the United States), and type II diabetes (90 % of diabetes cases in the United States). Type I diabetes is caused by an insulin deficiency due to the destruction of the pancreatic beta cells, and requires daily treatment with insulin to sustain life. Type II diabetes is caused by target organ insulin resistance resulting in a decreased responsiveness to both endogenous and exogenous insulin, and is usually managed by diet and exercise but may require treatment with insulin or other medication. Most people diagnosed with type II diabetes are over 40 years old.
  • Insulin is a critical hormone needed to keep glucose concentrations within very narrow physiological limits in normal people though high levels of carbohydrates may be consumed. Not only is insulin secreted by the beta cells of the pancreas, but also its levels are rapidly regulated by glucose concentrations in the blood. Insulin allows the passage of glucose into the targets cells, which contain receptors for uptake of glucose.
  • Diabetic patients with an elevated glucose level in the blood, hyperglycemia have either an insulin deficiency or a decreased responsiveness to insulin. Hyperglycemia adversely affects other physiological processes. For example, hyperglycemia causes severe water loss and dehydration.
  • Water loss can be so severe that it decreases blood pressure, and the reduced blood pressure may lead to brain damage.
  • patients of diabetes are often subject to destructive alterations of other physiological processes, causing blindness, heart attack, stroke, periodontal disease, neuropathy, nephropathy, and atherosclerosis resulting from hyperglycemia.
  • Tissue damage can be so extensive that amputations are required to save the patient.
  • hypoglycemic episodes can occur without the diabetic patient being aware of it. It is required to maintain a balance between insulin injection and glucose consumption to prevent hypoglycemia. However, the condition is not fatal if proper care is taken.
  • the aim is to tightly regulate the plasma glucose level within the normal physiological range (80 - 120 mg/dL), so that diabetic adverse effects can be avoided.
  • Self-monitoring of blood glucose levels using dry chemical strips with a single drop of blood is considered a major advance in diabetes management. This in vitro method of monitoring of blood glucose has two main disadvantages. The first is that sampling of blood is associated with the risk of infection, nerve and tissue damage, and discomfort to patients.
  • the second disadvantage is the practical limitation in self -monitoring which arises because the sampling frequency is not great enough for tight control of blood glucose levels close to normal ranges over a 24-hr period.
  • continuous monitoring of blood glucose concentrations in vivo has long been recognized as a major objective as a future tool in the fight against diabetes.
  • glucose oxidase GOD
  • electrochemical transducers are the most highly developed, and this class of sensors can be further subdivided into potentiometric sensors, conductometric sensors, and amperometric sensors.
  • the local pH change due to production of gluconic acid in the GOD reaction can be measured with a pH-selective electrode or an ion selective field effect transistor (ISFET), which is the basis of the potentiometric method.
  • ISFET ion selective field effect transistor
  • the most advanced glucose sensors for in vivo monitoring are electrochemical sensors using the amperometric technique, possibly because they do offer the possibility for a linear calibration curve.
  • an electrode is used which produces a current proportional to the diffusional flux of hydrogen peroxide (H 2 O 2 ) to the electrode surface, or, alternatively, proportional to the diffusional flux of oxygen (O 2 ) to the electrode surface.
  • a membrane layer containing immobilized GOD surrounds the electrode.
  • the glucose reaction catalyzed by GOD produces hydrogen peroxide and consumes oxygen.
  • An increase in the surrounding glucose concentration should increase the diffusional flux of glucose into the membrane and increase the reaction rate within the membrane.
  • the increase in reaction rate in turn should increase the local hydrogen peroxide concentration and decrease the local oxygen concentration within the membrane.
  • Amperometric sensors must overcome several hurdles before they will ever be useful for commercial in vivo monitoring. Current glucose sensor designs appear unlikely to solve these difficult problems in the near future. The first hurdle arises from electrochemical interference. The analyte (whether hydrogen peroxide or oxygen) must be the only species present which produces a current at the electrode.
  • One approach is to use in a hydrogel a chemically immobilized pendant group which is charged at the physiological solution conditions (pH2 to pHIO), a chemically immobilized hexose saccharide such as glucose, galactose, and mannose in the hydrogel, and an immobilized glucose binding molecule (GBM) such as for example, glucokinase, GOD, xylose isomerase, boronic acids, or lectins including isolectin I and Concanabvalin A (Con A) in the hydrogel.
  • GBM glucose binding molecule
  • lectins including isolectin I and Concanabvalin A (Con A) in the hydrogel.
  • the hydrogel swells with increases in glucose concentration using essentially the same physical phenomenon that will be employed in the glucose biosensor, described below.
  • the amount of swelling in the insulin delivery devices was used to control insulin permeability through a hydrogel membrane.
  • the proposed biosensor infers changes in glucose concentration from changes in hydrogel crosslinking density, swelling tendency, and pressure exerted in the enclosure.
  • the decrease in hydrogel crosslinking density and the increase of the swelling tendency of the hydrogel is proportional to glucose concentration as a result of competitive binding between immobilized hexose saccharide and free glucose to the immobilized GBM in the polymer backbone which has high affinity to glucose.
  • the prior art does not teach the use of the glucose-induced swelling of the hydrogel as a method of measuring glucose concentrations.
  • the prior art specifically does not teach the use of a pressure transducer to measure hydrogel swelling in response to increases in glucose levels in the blood, the use of the pressure transducer providing a measurement tool that avoids the problems encountered by electrochemical methods of the prior art, described above.
  • the present invention avoids the problems of prior art biosensors such as interference, enzyme degradation, and oxygen deficit and provides further related advantages as described in the following summary.
  • the present invention teaches certain benefits in construction and use that will give rise to the objectives described below.
  • the present invention provides a biosensor for measuring the concentration of glucose in a solution.
  • the biosensor includes a hydrogel in a rigid and preferably biocompatible enclosure.
  • the hydrogel includes an immobilized hexose saccharide, such as a-D-mannopyranoside, and an immobilized GBM, such as concanavalin A (Con A), having high affinity to free glucose and the immobilized hexose saccharide (or a pendant glucose).
  • Con A concanavalin A
  • the GBM and hexose saccharide are chemically immobilized or physically immobilized on the backbone of the hydrogel.
  • the hydrogel is in a de-swelled form when there is no free glucose due to the tight binding between Con A and the immobilized glucose or hexose saccharide.
  • the hydrogel swells in a proportionto the concentration of free glucose due to competitive binding of the free glucose with the immobilized hexose saccharide to immobilized GBM such as Con A.
  • GBM such as Con A.
  • the free glucose binds to the GBM, this reduces hydrogel crosslinking density, thereby increasing hydrogel swelling tendency and increasing the pressure exerted by the swelling hydrogel in the enclosure.
  • a means for reporting the concentration of the glucose preferably a battery powered telemeter, is operably engaged with the means for measuring, and sends a radio data signal to a receiver operably attached to a computer with an alarm system.
  • a primary objective of the present invention is to provide a biosensor having advantages not taught by the prior art.
  • Another objective is to provide a biosensor that is extremely sensitive to the concentration of glucose, and also relatively free from interference, even when operating in complex media such as human blood.
  • a further objective is to provide a biosensor that directly measures changes in free glucose, rather than the indirect parameters measured by electrodes. This is especially critical in implantable biosensors because this frees the present invention from potential sources of interference as well as alleviates the need for oxygen that is essentially required for the GOD reaction.
  • FIGURE 1 is an example of the competitive binding and swelling mechanism
  • FIGURE 2 is an example of a glucose-containing 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 implanted under a diabetic'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 glucose 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 preferred circuit board having miniature diodes, which are part of a diode quad bridge circuit;
  • FIGURE 8 is an electrical schematic showing the preferred diode quad bridge circuit
  • FIGURE 9 is a block diagram of an automatic alarm system in conjunction with wireless actuation of dialing
  • FIGURE 10 is a schematic diagram of a power supply for the various portions of the automatic alarm system
  • FIGURE 10 is a schematic diagram of a power supply for the various portions of the automatic alarm system
  • FIGURE 11 is a schematic diagram of the signal conditioning circuit
  • FIGURE 12 is a schematic diagram of the comparator and control circuit
  • FIGURE 13 is a schematic diagram of the transmitter and receiver
  • FIGURE 14 is a schematic diagram of dialing mechanism
  • FIGURE 15 is a block diagram of an automatic alarm system used in conjunction with an injection device for providing injections responsive to the alarm system.
  • Con A or other GBM is immobilized in the hydrogel 30, and free glucose competitively binds with an immobilized hexose saccharide such as glucose to Con A, reducing hydrogel crosslinks and thereby causing the hydrogel 30 to swell and increasing the pressure of the hydrogel in its enclosure.
  • the biosensor 10 has a means for measuring 40 the pressure of the hydrogel 30, and a means for reporting 60 the concentration of glucose based on the measured pressure of the hydrogel 30.
  • the biosensor 10 includes a rigid, biocompatible enclosure 20 having semipermeable membrane 26 covering an open end 22, a flexible diaphragm 28 between the semipermeable membrane 26 and the closed end 24, and a polymeric hydrogel 30 enclosed therebetween, the hydrogel 30 including moieties that cause the hydrogel 30 to swell in proportion to the free glucose diffusing into the hydrogel 30.
  • the enclosure 20 is designed to be implanted directly into the human body for monitoring blood glucose levels of diabetics.
  • the biosensor 10 uses Con A immobilized in a hydrogel 30.
  • the means for measuring 40 the pressure of the hydrogel 30 is preferably a pressure transducer 40 operably associated with the flexible diaphragm 28.
  • the means for reporting 60 glucose levels is preferably a battery 64 operated telemeter 60 that sends a radio data signal to a receiver operably attached to a computer 62.
  • Alternative embodiments of this biosensor 10 can easily be adapted by those skilled in the art.
  • the biosensor 10 can measure free glucose by replacing Con A with an appropriate GBM having specifically high affinity to glucose such as GOD, glucokinase, xylose isomerase, boronic acids, and isolectin I.
  • a direct electrical connection to a computer 62 can be used when the biosensor 10 is a minimally invasive implant into a human body.
  • pressure transducer 40 is currently the preferred tool for measuring changes in the pressure of the hydrogel 30, those skilled in the art can devise alternative means of measuring and reporting changes in the pressure of the hydrogel 30.
  • One alternative method is to use a piezoresistive sensor in place of the pressure transducer 40.
  • the structure of the biosensor 10 is provided by an enclosure 20, preferably a cylindrical 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 rigid, impermeable, and biocompatible material such as stainless steel; and the enclosure 20 is preferably conjugated with heparin to prevent blood clotting, and polyethylene glycol (PEG) to decrease the body's immune response against the enclosure 20.
  • PEG polyethylene glycol
  • the enclosure 20 is preferably coated with a biocompatable material such as a thin polymer.
  • the enclosure 20 is preferably cylindrical in shape to facilitate implantation, the cylinder being approximately 5 to 12 mm long and having a diameter of approximately 0.1 to 3 mm. If the enclosure 20 will not be implanted, any rigid and impermeable material such as fiber, plastic or metal can be used.
  • the semipermeable membrane 26 is permeable to the passage of glucose, and gluconic acid; however, it is impermeable to the passage of blood clots, cells, proteins,lectins, and the hydrogel 30.
  • the semipermeable membrane 26 is preferably made of a material rigid enough to sustain the pressure of a swollen glucose sensitive hydrogel 30. If the biosensor 10 is to be implanted into the human body, the semipermeable membrane 26 is preferably an inert, nontoxic material.
  • a suitable semipermeable material can be selected from, but is not limited to, the following groups of polymers: cellulose acetate, methyl cellulose, polyvinyl alcohol, and polyurethane.
  • the semipermeable materials are also preferably conjugated with heparin and polyethlyene glycol (PEG) to decrease immunogenic response, blood clotting and cell attachment on the surface.
  • PEG polyethlyene glycol
  • the diaphragm 28 is preferably a flexible but conductive material useful for use with a transducer 40. Such diaphragms are known in the art.
  • the preferred diaphragm 28 is made of an alloy sold under the trademarks KOVARTM or INVAR 36TM by Hamilton Technology, Inc., of Lancaster, Pennsylvania.
  • the diaphragm 28 thickness is preferably approximately 12.5 mm to achieve optimum spot welding and sensitivity. Such a diaphragm is described 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 within the enclosure 20 between the semipermeable membrane 26 and the diaphragm 28.
  • the means for measuring 40 and the means for reporting 60 are located in the chamber within the enclosure 20 between the diaphragm 28 and the closed end 24 of the enclosure 20.
  • Con A has been shown to have significant biological properties such as binding of specific saccharides with high affinity.
  • Con A containing 238 amino acid residues and having a molecular weight of 27,000, exists as dimers in solution at pH below 6 and as tetramers at physiologic pH.
  • the metal ions usually Mn+2 or Ca+2, play an essential role in stabilizing the formation of the specific saccharide binding site.
  • the binding properties of Con A to specific saccharides are changed by various conditions such as ionic strength, temperature, and pH.
  • Con A shows maximum binding activity to saccharide at pH between 6 to 7.
  • Con A alters its binding activity at high pH, above pH 9, due to its conformational changes.
  • Tetrameric forms are favored to bind with specific saccharides.
  • Con A forms tetramers.
  • increasing the temperature 4 °C to 37 °C significantly enhances precipitation of dextran by Con A.
  • Con A is denatured above 50 °C like most proteins.
  • Con A exists as dimers at lower ionic strength.
  • a minimal configurational structure of saccharides such as unmodified hydroxyl groups on the C-3, C-4, and C-6 position in a hexose is essential for binding to Con A with high affinity.
  • the binding affinity of a hexose saccharide is dependent upon the configurational factor at C2 hydroxyl group, since mannose with the axial position at C2 hydroxyl group has 40 times higher binding affinity than mannose with the equatorial position at C2 hydroxyl group.
  • a vinyl group is preferably attached to C 1 of glucose (allyl glucose; AG) and Con A through etherification reaction of glucose with allyl alcohol and nucleophilic reaction of Con A with metaacryloyl chloride.
  • C3, C4, and C6 hydroxyl groups of AG are preferably not modified as described (Obaidat, AA., and Park, K. Pharmaceutical Research 13: 989-995, 1996).
  • Copolymerization of AG and modified Con A with cross-linking agents and monomers such as acrylamide and hydroxylethyl methacrylate (HEMA) preferably occurs by a free radical reaction.
  • the polymer chain preferably contains glucose and Con A as pendant groups.
  • the hydrogel thus formed is preferably porous.
  • the porosity is preferably controlled with several methods such as bubbling or excessive addition of powdered salt to the copolymerization reaction.
  • the hydrogel preferably swells when free glucose is introduced into the hydrogel due to competitive binding between free glucose with immobilized glucose to immobilized Con A in the hydrogel.
  • the swelling ratio is preferably proportional to free glucose concentrations in the solution.
  • the reaction ratios of AG and modified Con A, monomer, and cross-linking agents are preferably optimized to give a measurable pressure with a pressure transducer resulting from swelling and de-swelling of the hydrogel due to changing free glucose concentrations.
  • p-nitrophenyl-a-D-mannopyranoside and p- nitrophenyl-a-D-glucopyranoside can be used for immobilization on the polymer instead of glucose.
  • other GBMs such as GOD, glucokinase, xylose isomerase, boronic acids, and isolactin I can be physically or chemically immobilized on the polymer instead of Con A.
  • the biosensor includes a means for measuring 40 the pressure of the hydrogel. This element is critical. While prior art biosensors rely on direct measurement of the GOD catalyzed chemical reaction with an electrode, measurement of the increase in hydrogel pressure and free glucose induced swelling has never been used in the prior art. A biosensor 10 that directly relies on changes in free glucose concentration avoids an important source of outside interference.
  • the means for measurement is preferably a pressure transducer 40.
  • Pressure transducers are known in the art and those skilled in the field can construct a transducer optimized to the specific needs of the biosensor 10.
  • 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 measuring 40 is a capaciti ve pressure transducer 40 associated with the flexible diaphragm 28 described above.
  • the preferred 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 bridge circuit 52.
  • These pressure transducers 40 have been successfully used to measure pressure changes in flowing polymeric liquids as small as one Pascal. Examples of alternative transducers are described in Takaki, U.S. Pat. No.
  • the biosensor 10 includes a means for reporting 60 the concentration of the organic 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 organic 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 in response to variation in the concentration of the organic molecule.
  • the biosensor 10 is a glucose biosensor 10 that can be implanted into the human body.
  • the means for reporting 60 is preferably a battery powered telemeter 60 that transmits a data signal to a receiver operably connected to the computer.
  • the computer also compares the data signal to a calibration curve and reports the concentration through a reporting means.
  • the reporting means is preferably an audible alarm to warn diabetics if glucose levels get too high or too low.
  • the computer also controls an insulin pump to correct the blood glucose level of the diabetic.
  • the biosensor 10 would be used on conjunction with an implanted glucose pump and would functionally replace the pancreas in controlling blood glucose levels, allowing diabetics to lead nearly normal lives.
  • the invention further includes a method for using a biosensor 10 to measure the concentration of glucose in a solution.
  • the method includes the following steps: First, providing a biosensor 10 as described above. Con A is chemically or physically immobilized in the hydrogel 30, preferably using chemical conjugation.
  • the biosensor 10 is preferably first immersed in a buffer and inserted into a control solution. The data generated is then compared to a calibration curve to calibrate the biosensor 10. Once the biosensor 10 is removed and rinsed in another buffer, the biosensor 10 is inserted into the solution. The glucose molecules are allowed to diffuse into the polymeric hydrogel 30, causing competitive binding of free glucose with immobilized glucose to Con A.
  • the competitive binding between free glucose and immobilized glucose to Con A reduces hydrogel crosslinking, which causes the hydrogel 30 to swell and exert a pressure on the diaphragm 28, as shown in Fig. 5.
  • This swelling is measured with the means for measuring 40.
  • the means for measuring 40 is preferably a pressure transducer 40.
  • the pressure transducer 40 is used to measure the pressure of the hydrogel 30, which is proportional to the concentration of the free glucose 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 telemeter 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 such as an automatic insulin pump (as described above) or glucagon injection pump.
  • a feedback system such as an automatic insulin pump (as described above) or glucagon injection pump.
  • the system can be recalibrated by taking blood samples and comparing the glucose readings to those reported by the biosensor 10.
  • the computer actuated means of calibration can then be adjusted to correct for any errors.
  • the output of a sensor is always monitored and compared with a preset value (or threshold value). If the sensor output is out of the preset range, an alarm signal is generated. This alarm signal can be further utilized to actuate a certain alarm protocol such as automatic dialing and send a prerecorded message corresponding to the condition detected.
  • a preset value or threshold value
  • the block diagram in Figure 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.
  • the major elements of an automatic alarm device are a power supply 100, a sensor (such as biosensor 10 or other sensor for monitoring 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 preferably provides electric energy to all the elements of the device requiring power. Considering portability of the device, a dry-cell battery is the preferred choice for supplying power. However, compatibility of the cell with power requirements of all the elements (voltage and capacity) 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 batteries 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( Figure 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 in 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.
  • An RC time constant of 0.1 to 1 seconds is appropriate. For example, an RC time constant of 1 second can be obtained using 100 kohm and lOmF Comparator and Control Circuit.
  • 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 '1' or from 'off to 'on'. 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 ( Figure
  • the extra controls are for deactivating the device and resetting the device in the case when alarms are sent mistakenly or by device malfunction. Furthermore, 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-carrier ( Figure 13). Wireless activation of the phone 114 can be achieved using a typical FM method.
  • a transmitter consists of a carrier wave generator 140, a signal generator 144, a modulator 148 to mix signal to carrier wave, a power booster 152, and a radiator 156.
  • the carrier wave frequency may be in the range of several 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 receiver 112b operates in a reversed manner to that of a transmitter 112a. Although a transmitter/receiver, 112a/l 12b must be custom designed eventually, it can be adapted from a minimally modified transmitter/receiver used in kids' remote control toys.
  • 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.

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Abstract

Cette invention concerne un biodétecteur (10) comportant un hydrogel (30) dans une enveloppe (20) rigide et de préférence biocompatible. L'hydrogel (30) comprend une protéine de liaison au glucose (GBM) tel que la concanavaline A (Con A) et un saccharide d'hexose immobilisé du type mannopyranoside-D. Le saccharide d'hexose immobilisé se lie concurremment avec le glucose libre à la GBM, ce qui a pour effet de modifier le nombre de ponts dans l'hydrogel (30) ainsi que la tendance au gonflement dudit hydrogel et sa pression dans son espace de confinement, ceci en proportion de la concentration de glucose libre. A partir du changement de pression de l'hydrogel mesuré au moyen d'un transducteur de pression (40), le biodétecteur (10) est en mesure de déterminer avec précision la concentration de la molécule de glucose libre, sans les problèmes de limitations d'oxygène et d'interférence inhérents aux biodétecteurs existant à ce jour. Un télémètre (60) alimenté par pile et relié fonctionnel au transducteur de pression (40) envoie un signal radio à un récepteur (66) assorti d'un système d'alarme relié à un ordinateur (62). L'invention porte en outre sur un système d'alarme comportant un tel détecteur qui prévient automatiquement la personne lorsque son taux de glycémie sort d'une plage prédéterminée et/ou injecte automatiquement un agent tel que du glucose ou du glycogène pour faire remonter le taux de glycémie.
PCT/US2000/023194 1999-08-27 2000-08-23 Biodétecteur de glucose WO2001016575A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU69315/00A AU6931500A (en) 1999-08-27 2000-08-23 Glucose biosensor
JP2001520081A JP2003517588A (ja) 1999-08-27 2000-08-23 グルコースバイオセンサ
EP00957741A EP1212601A4 (fr) 1999-08-27 2000-08-23 Biod tecteur de glucose

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US15103499P 1999-08-27 1999-08-27
US60/151,034 1999-08-27

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JP (1) JP2003517588A (fr)
KR (1) KR100771711B1 (fr)
AU (1) AU6931500A (fr)
WO (1) WO2001016575A1 (fr)

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WO2003006993A3 (fr) * 2001-07-10 2003-09-25 Univ Montfort Compositions de gel
US6923764B2 (en) 2000-06-27 2005-08-02 Rosedale Medical, Inc. Analyte monitor
EP1309845A4 (fr) * 2000-04-22 2005-10-12 Biotech Inc M Biocapteur hydrogel et systeme d'alarme sanitaire fondee sur ce biocapteur
WO2005124348A1 (fr) * 2004-06-09 2005-12-29 Becton, Dickinson And Company Detecteur d'analytes multiples
US7004928B2 (en) 2002-02-08 2006-02-28 Rosedale Medical, Inc. Autonomous, ambulatory analyte monitor or drug delivery device
GB2426333A (en) * 2005-01-20 2006-11-22 Mark Christopher Turpin Sensor device for the measurement of concentration in liquid mixtures
EP1977687A1 (fr) * 2007-04-05 2008-10-08 Koninklijke Philips Electronics N.V. Dispositif à base d'hydrogel pour détecter l'état de l'environnement
WO2010047799A1 (fr) * 2008-10-22 2010-04-29 Surmodics, Inc. Matrices polymères biodégradables et gonflables et procédés
KR101135624B1 (ko) 2009-01-15 2012-04-17 한양대학교 산학협력단 수명연장을 위한 전기감응성 고분자층이 부착된 바이오센서
WO2012080258A1 (fr) * 2010-12-17 2012-06-21 Eyesense Ag Utilisation d'hydrogels pour des biocapteurs à sensibilité accrue
US20130066264A1 (en) * 2010-05-26 2013-03-14 National Institute For Materials Science Sugar-responsive gel and medicine administering device
US8919605B2 (en) 2009-11-30 2014-12-30 Intuity Medical, Inc. Calibration material delivery devices and methods
DE102013212539A1 (de) * 2013-06-27 2015-01-15 Carl Von Ossietzky Universität Oldenburg Verfahren zur Analyse
US8969097B2 (en) 2005-06-13 2015-03-03 Intuity Medical, Inc. Analyte detection devices and methods with hematocrit-volume correction and feedback control
US9060723B2 (en) 2005-09-30 2015-06-23 Intuity Medical, Inc. Body fluid sampling arrangements
US9095292B2 (en) 2003-03-24 2015-08-04 Intuity Medical, Inc. Analyte concentration detection devices and methods
US9127651B2 (en) 2006-12-04 2015-09-08 Universite Joseph Fourier Method and device for changing the pH of a solution
US9636051B2 (en) 2008-06-06 2017-05-02 Intuity Medical, Inc. Detection meter and mode of operation
CN107029245A (zh) * 2011-03-02 2017-08-11 森苏林公司 囊泡组合物
US9782114B2 (en) 2011-08-03 2017-10-10 Intuity Medical, Inc. Devices and methods for body fluid sampling and analysis
US9833183B2 (en) 2008-05-30 2017-12-05 Intuity Medical, Inc. Body fluid sampling device—sampling site interface
WO2019118231A1 (fr) * 2017-12-11 2019-06-20 Microoptx Inc. Dispositifs et procédés pour un capteur de glucose oculaire implantable
US10330667B2 (en) 2010-06-25 2019-06-25 Intuity Medical, Inc. Analyte monitoring methods and systems
US10383556B2 (en) 2008-06-06 2019-08-20 Intuity Medical, Inc. Medical diagnostic devices and methods
US10433780B2 (en) 2005-09-30 2019-10-08 Intuity Medical, Inc. Devices and methods for facilitating fluid transport
US10441202B2 (en) 2013-05-23 2019-10-15 Iphenotype Llc Methods and systems for assisting persons, product providers and/or service providers
US10729386B2 (en) 2013-06-21 2020-08-04 Intuity Medical, Inc. Analyte monitoring system with audible feedback
WO2025021960A1 (fr) 2023-07-25 2025-01-30 Glucoset As Biocapteurs pour mesurer la concentration de glucose et polymères de détection de glucose

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KR101783695B1 (ko) * 2015-10-02 2017-10-11 주식회사 엔게인 폴리히드록시에틸메타크릴레이트계 수화겔, 이의 제조방법 및 이를 포함하는 글루코스 센서
KR102679692B1 (ko) 2022-04-18 2024-07-01 서울과학기술대학교 산학협력단 효소 기반 자가전력 인공 포도당 조절기 및 이를 이용한 포도당 조절 방법
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EP1309845A4 (fr) * 2000-04-22 2005-10-12 Biotech Inc M Biocapteur hydrogel et systeme d'alarme sanitaire fondee sur ce biocapteur
US6923764B2 (en) 2000-06-27 2005-08-02 Rosedale Medical, Inc. Analyte monitor
US7585278B2 (en) 2000-06-27 2009-09-08 Intuity Medical, Inc. Analyte monitor
WO2003006993A3 (fr) * 2001-07-10 2003-09-25 Univ Montfort Compositions de gel
JP2004534103A (ja) * 2001-07-10 2004-11-11 デ・モントフォート・ユニバーシティ ゲル組成物
US8247391B2 (en) 2001-07-10 2012-08-21 De Montfort University Gel compositions
US7556934B2 (en) 2001-10-05 2009-07-07 Clive Lindsay Ragless Concentration measurement by sensing hydrogel pressure
WO2003031945A1 (fr) * 2001-10-05 2003-04-17 Clive Lindsay Ragless Mesure d'une concentration par detection de la pression d'hydrogel
AU2002333046B2 (en) * 2001-10-05 2008-02-28 Ragless, Clive Lindsay MR Concentration measurement by sensing hydrogel pressure
US7004928B2 (en) 2002-02-08 2006-02-28 Rosedale Medical, Inc. Autonomous, ambulatory analyte monitor or drug delivery device
US10772550B2 (en) 2002-02-08 2020-09-15 Intuity Medical, Inc. Autonomous, ambulatory analyte monitor or drug delivery device
US9603562B2 (en) 2002-02-08 2017-03-28 Intuity Medical, Inc. Autonomous, ambulatory analyte monitor or drug delivery device
US9095292B2 (en) 2003-03-24 2015-08-04 Intuity Medical, Inc. Analyte concentration detection devices and methods
WO2005124348A1 (fr) * 2004-06-09 2005-12-29 Becton, Dickinson And Company Detecteur d'analytes multiples
US7951605B2 (en) 2004-06-09 2011-05-31 Becton, Dickinson And Company Multianalyte sensor
GB2426333A (en) * 2005-01-20 2006-11-22 Mark Christopher Turpin Sensor device for the measurement of concentration in liquid mixtures
US10226208B2 (en) 2005-06-13 2019-03-12 Intuity Medical, Inc. Analyte detection devices and methods with hematocrit/volume correction and feedback control
US11419532B2 (en) 2005-06-13 2022-08-23 Intuity Medical, Inc. Analyte detection devices and methods with hematocrit/volume correction and feedback control
US9366636B2 (en) 2005-06-13 2016-06-14 Intuity Medical, Inc. Analyte detection devices and methods with hematocrit/volume correction and feedback control
US8969097B2 (en) 2005-06-13 2015-03-03 Intuity Medical, Inc. Analyte detection devices and methods with hematocrit-volume correction and feedback control
US10441205B2 (en) 2005-09-30 2019-10-15 Intuity Medical, Inc. Multi-site body fluid sampling and analysis cartridge
US9380974B2 (en) 2005-09-30 2016-07-05 Intuity Medical, Inc. Multi-site body fluid sampling and analysis cartridge
US10842427B2 (en) 2005-09-30 2020-11-24 Intuity Medical, Inc. Body fluid sampling arrangements
US10433780B2 (en) 2005-09-30 2019-10-08 Intuity Medical, Inc. Devices and methods for facilitating fluid transport
US9060723B2 (en) 2005-09-30 2015-06-23 Intuity Medical, Inc. Body fluid sampling arrangements
US11986298B2 (en) 2005-09-30 2024-05-21 Intuity Medical, Inc. Devices and methods for facilitating fluid transport
US9839384B2 (en) 2005-09-30 2017-12-12 Intuity Medical, Inc. Body fluid sampling arrangements
US9127651B2 (en) 2006-12-04 2015-09-08 Universite Joseph Fourier Method and device for changing the pH of a solution
EP1977687A1 (fr) * 2007-04-05 2008-10-08 Koninklijke Philips Electronics N.V. Dispositif à base d'hydrogel pour détecter l'état de l'environnement
WO2008122926A1 (fr) 2007-04-05 2008-10-16 Koninklijke Philips Electronics N.V. Dispositif a base d'hydrogel permettant de detecter un etat environnemental
US8840839B2 (en) 2007-04-05 2014-09-23 Koninklijke Philips N.V. Hydrogel based device for detecting an environmental state
US11045125B2 (en) 2008-05-30 2021-06-29 Intuity Medical, Inc. Body fluid sampling device-sampling site interface
US9833183B2 (en) 2008-05-30 2017-12-05 Intuity Medical, Inc. Body fluid sampling device—sampling site interface
US10383556B2 (en) 2008-06-06 2019-08-20 Intuity Medical, Inc. Medical diagnostic devices and methods
US11399744B2 (en) 2008-06-06 2022-08-02 Intuity Medical, Inc. Detection meter and mode of operation
US9636051B2 (en) 2008-06-06 2017-05-02 Intuity Medical, Inc. Detection meter and mode of operation
US11553860B2 (en) 2008-06-06 2023-01-17 Intuity Medical, Inc. Medical diagnostic devices and methods
US11986293B2 (en) 2008-06-06 2024-05-21 Intuity Medical, Inc. Medical diagnostic devices and methods
WO2010047799A1 (fr) * 2008-10-22 2010-04-29 Surmodics, Inc. Matrices polymères biodégradables et gonflables et procédés
KR101135624B1 (ko) 2009-01-15 2012-04-17 한양대학교 산학협력단 수명연장을 위한 전기감응성 고분자층이 부착된 바이오센서
US11933789B2 (en) 2009-11-30 2024-03-19 Intuity Medical, Inc. Calibration material delivery devices and methods
US9897610B2 (en) 2009-11-30 2018-02-20 Intuity Medical, Inc. Calibration material delivery devices and methods
US8919605B2 (en) 2009-11-30 2014-12-30 Intuity Medical, Inc. Calibration material delivery devices and methods
US11002743B2 (en) 2009-11-30 2021-05-11 Intuity Medical, Inc. Calibration material delivery devices and methods
US20130066264A1 (en) * 2010-05-26 2013-03-14 National Institute For Materials Science Sugar-responsive gel and medicine administering device
US10330667B2 (en) 2010-06-25 2019-06-25 Intuity Medical, Inc. Analyte monitoring methods and systems
WO2012080258A1 (fr) * 2010-12-17 2012-06-21 Eyesense Ag Utilisation d'hydrogels pour des biocapteurs à sensibilité accrue
CN103370623A (zh) * 2010-12-17 2013-10-23 视觉股份公司 水凝胶在具有提高的灵敏度的生物传感器中的用途
US9244064B2 (en) 2010-12-17 2016-01-26 Eyesense Ag Use of hydrogels for biosensors having elevated sensitivity
CN107029245A (zh) * 2011-03-02 2017-08-11 森苏林公司 囊泡组合物
US9782114B2 (en) 2011-08-03 2017-10-10 Intuity Medical, Inc. Devices and methods for body fluid sampling and analysis
US11382544B2 (en) 2011-08-03 2022-07-12 Intuity Medical, Inc. Devices and methods for body fluid sampling and analysis
US11051734B2 (en) 2011-08-03 2021-07-06 Intuity Medical, Inc. Devices and methods for body fluid sampling and analysis
US11672452B2 (en) 2011-08-03 2023-06-13 Intuity Medical, Inc. Devices and methods for body fluid sampling and analysis
US10441202B2 (en) 2013-05-23 2019-10-15 Iphenotype Llc Methods and systems for assisting persons, product providers and/or service providers
US10729386B2 (en) 2013-06-21 2020-08-04 Intuity Medical, Inc. Analyte monitoring system with audible feedback
DE102013212539B4 (de) * 2013-06-27 2015-07-23 Carl Von Ossietzky Universität Oldenburg Verfahren und Vorrichtung zur Analyse
DE102013212539A1 (de) * 2013-06-27 2015-01-15 Carl Von Ossietzky Universität Oldenburg Verfahren zur Analyse
US11291391B2 (en) 2017-12-11 2022-04-05 Microoptx Inc. Implantable ocular glucose sensor devices and methods
WO2019118231A1 (fr) * 2017-12-11 2019-06-20 Microoptx Inc. Dispositifs et procédés pour un capteur de glucose oculaire implantable
WO2025021960A1 (fr) 2023-07-25 2025-01-30 Glucoset As Biocapteurs pour mesurer la concentration de glucose et polymères de détection de glucose

Also Published As

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JP2003517588A (ja) 2003-05-27
EP1212601A4 (fr) 2006-03-29
KR20020035583A (ko) 2002-05-11
EP1212601A1 (fr) 2002-06-12
AU6931500A (en) 2001-03-26
KR100771711B1 (ko) 2007-10-30

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