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  • 权利要求
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    • 专利摘要:
    Methods for reducing the electrode impedance of implantable biosensors by coating the surface of the biosensor with a uniform hydrogel which allows unimpeded water movement around the sensor are provided. The surface coatings are compositions which are biocompatible and are capable of water uptake of at least 120% of their weight, more preferably at least 200% of their weight. Upon the uptake of water, the hydrogels used in the present invention will also swell and provide a layer of water around the electrodes to which the hydrogels are attached. The hydrogels can be prepared from (a) a diisocyanate, (b) a hydrophilic polymer which is a hydrophilic diol, a hydrophilic diamine, or a combination thereof, and optionally, (c) a chain extender.
    公开号:US20010008931A1
    申请号:US09/123,930
    申请日:1998-07-28
    公开日:2001-07-19
    发明作者:William Peter Van Antwerp；Christian C. Decker；John J. Mastrototaro
    申请人:William Peter Van Antwerp；Christian C. Decker；John J. Mastrototaro；
    IPC主号:A61B5-14865
    专利说明:
    [0001] This application is related to U.S. Ser. No. 08/721,262, filed Sep. 26, 1996 which is a Continuation-in-Part of U.S. Ser. No. 08/410,775, filed Mar. 27, 1995, the complete disclosures of each being incorporated herein by reference. [0001] FIELD OF THE INVENTION
    [0002] This invention lies in the field of polymer chemistry in which the polymers formed are suitable for coating biosensors. The coatings act to decrease the impedance at the sensor's electrode and thereby enhance the signal during in vivo placement of the sensor. [0002] BACKGROUND OF THE INVENTION
    [0003] Biosensors are small devices that use biological recognition properties for selective analysis of various analytes or biomolecules. Typically, the sensor will produce a signal that is quantitatively related to the concentration of the analyte. To achieve a quantitative signal, a recognition molecule or combination of molecules is often immobilized at a suitable transducer which converts the biological recognition event into a quantitative response. [0003]
    [0004] A variety of biosensors have been developed for use with numerous analytes. Electroenzymatic biosensors use enzymes to convert a concentration of analyte to an electrical signal. Immunological biosensors rely on molecular recognition of an analyte by, for example, antibodies. Chemoreceptor biosensors use chemoreceptor arrays such as those of the olfactory system or nerve fibers from the antennules of the blue crab [0004] Callinectes sapidus to detect the presence of amino acids in concentrations as low as 10−9 M. For a review of some of the operating principles of biosensors, see Bergveld, et al., ADVANCES IN BIOSENSORS, Supplement 1, p. 31-91, Turner ed., and Collison, et al., Anal. Chem. 62:425-437 (1990).
    [0005] Regardless of the type of biosensor, each must possess certain properties to function in vivo and provide an adequate signal. First, the elements of the biosensor must be compatible with the tissue to which it is attached and be adequately shielded from adjacent tissues such that allergic or toxic effects are not exerted. Further, the sensor should be shielded from the environment to control drift in the generated signal. Finally, the sensor should accurately measure the analyte in the presence of proteins, electrolytes and medications which may interfere. [0005]
    [0006] One of the problems with implantable biosensors occurs as a result of “road block” type interference. This problem is encountered when the outermost layer of the biosensor has some hydrophobic characteristics. These characteristics result in the accumulation of plasma proteins on the surface of the electrode after only short periods of direct contact with body fluids. The hydrophobic regions of the sensor surface are believed to denature the proteins resulting in large deposits of protein mass. The deposits then affect the sensor's performance through a physical interference in a “road block” type of effect. The protein deposition is a gradual process which creates a non-uniform, non-predictable diffusion path for the analyte to the sensor. Moreover, the effect on the sensor is a cascading type in which the protein deposits dissapate the normal voltages applied to the electrodes (i.e., the deposits increase the capacitance of the system). The resultant requirement for higher voltages to offset the increased capacitance increases the noise, ultimately compromising the validity of the sensor's output. [0006]
    [0007] Other problems are also associated with implantable sensors having hydrophobic regions at the sensor's surface. In particular, subcutaneous tissue contains substantial amounts of lipid vesicles. By implanting a biosensor directly into tissue, a portion of the sensor may be implanted directly into, or flush against a very hydrophobic lipid region. This also limits the aqueous environment which is required around the sensor's electrodes. [0007]
    [0008] What is needed in the art are new coatings for implantable sensors which are extremely hydrophilic and provide a substantial and uniform aqueous flow around the sensors. Quite surprisingly, the present invention provides such coatings and sensors equipped with those coatings. [0008] SUMMARY OF THE INVENTION
    [0009] The present invention provides methods for reducing the electrode impedance of implantable biosensors by coating the surface of the biosensor with a uniform hydrogel which allows unimpeded water movement around the sensor. The surface coatings are compositions which are biocompatible and are capable of water uptake of at least 120% of their weight, more preferably at least 200% of their weight. Upon the uptake of water, the hydrogels used in the present invention will also swell and provide a layer of water around the electrodes to which the hydrogels are attached. [0009]
    [0010] In one group of embodiments, the hydrogels can be prepared from: [0010]
    [0011] (a) a diisocyanate, [0011]
    [0012] (b) a hydrophilic polymer which is a hydrophilic diol, a hydrophilic diamine, or a combination thereof, and optionally, [0012]
    [0013] (c) a chain extender. [0013]
    [0014] The present invention further provides implantable biosensors for measuring a variety of analytes, the biosensor having a coating as described above. [0014] BRIEF DESCRIPTION OF THE DRAWINGS
    [0015] FIG. 1 illustrates polymerization reactions of a diisocyanate with a poly(alkylene) glycol or a diamino poly(alkylene oxide) which results in a polyurethane or polyurea, respectively. [0015]
    [0016] FIGS. 2 and 3 provide the structures of certain aliphatic and aromatic diisocyanates which are useful in forming the coatings described below. [0016]
    [0017] FIG. 4 provides the structures of a number of hydrophilic polymers including poly(alkylene) glycols and diamino poly(alkylene oxides) which are used in polymers described below. [0017]
    [0018] FIG. 5 provides the structures of some chain extenders which are useful in the present compositions. This include aliphatic diols, diamines and alkanolamines and further include some aromatic diols and diamines. [0018]
    [0019] FIG. 6 illustrates portions of a glucose sensor which can be coated with a hydrophilic swellable coating of the present invention. FIG. 6A is a schematic top view of a glucose sensor having electrodes covered with a polymer composition of the invention. FIG. 6B is a sectional side view of a working electrode of the sensor which is covered with layers of an enzyme, a glucose-limiting polymer and a hydrogel composition of the invention. [0019] DETAILED DESCRIPTION OF THE INVENTION
    [0020] The following abbreviations are used herein: dl, deciliter; DEG, diethylene glycol; DMF, dimethyl formamide; PBS, phosphate buffered saline; THF, tetrahydrofuran; DI, deionized; PEG, poly(ethylene)glycol; mv, millivolts. [0020]
    [0021] As used herein, the term “polyurethane/polyurea” refers to a polymer containing urethane linkages, urea linkages or combinations thereof. Typically, such polymers are formed by combining diisocyanates with alcohols and/or amines. For example, combining isophorone diisocyanate with PEG 600 and 1,4-diaminobutane under polymerizing conditions provides a polyurethane/polyurea composition having both urethane (carbamate) linkages and urea linkages (see FIG. 1). [0021]
    [0022] Methods for Reducing Electrode Impedance of Biosensors [0022]
    [0023] In one aspect, the present invention provides methods for reducing electrode impedance of biosensors by coating the biosensor with an extremely hydrophilic polymer such as a hydrogel or a cellulose acetate. Typically, the polymer is applied to the surface of the sensor by spin coating, dipping or spraying. Methods of spraying including traditional methods as well as microdeposition techniques with an ink-jet type of dispenser. Additionally, the polymer can be deposited on a sensor using photo-patterning to place the polymer on only specific portions of the sensor. This coating of the sensor provides a uniform water layer around the sensor which allows for improved diffusion of various analytes to the sensor. [0023]
    [0024] A hydrogel is a highly-interdependent, biphasic matrix consisting of a solid component (usually a polymer, and more commonly a highly cross-linked polymer) that has both hydrophilic and hydrophobic character. Additionally, the matrix has a liquid component (e.g., water) that is retained in the matrix by intermolecular forces. The hydrophobic character provides the matrix with a degree of water insolubility while the hydrophilic character affords water permeability. [0024]
    [0025] The polymer portion of the hydrogel will contain functionality which is suitable for hydrogen bonding (e.g., hydroxyl groups, amino groups, ether linkages, carboxylic acids and esters, and the like). Moreover, the affinity for water presented by the hydrogen bonding functionality must be of sufficient degree that the hydrated hydrogel will retain the water within its matrix even upon placement of the hydrogel in a hydrophobic medium such as an oil or lipid matrix. In addition to this binding of water within the hydrogel matrix, the hydrogel should allow water to flow through it when placed in an aqueous environment. A number of hydrogels have been developed for use as contact lenses. These hydrogels keep a layer of water at the surface of the eye to protect the eye from drying out. [0025]
    [0026] The hydrogels used in coating the biosensors will typically be a polyurea, a polyurethane or a polyurethane/polyurea combination. FIG. 1 illustrates some of the polymerization reactions which result in the compositions of the present invention. [0026]
    [0027] Hydrogel Components [0027]
    [0028] The hydrogels which are used in the present invention are prepared from the reaction of a diisocyanate and a hydrophilic polymer, and optionally, a chain extender. The hydrogels are extremely hydrophilic and will have a water pickup of from about 120% to about 400% by weight, more preferably from about 150% to about 400%. [0028]
    [0029] The diisocyanates which are useful in this aspect of the invention are those which are typically used in the preparation of biocompatible polyurethanes. Such diisocyanates are described in detail in Szycher, SEMINAR ON ADVANCES IN MEDICAL GRADE POLYURETHANES, Technomic Publishing, (1995) and include both aromatic and aliphatic diisocyanates (see FIGS. 2 and 3). Examples of suitable aromatic diisocyanates include toluene diisocyanate, 4,4′-diphenylmethane diisocyanate, 3,3′-dimethyl4,4′-biphenyl diisocyanate, naphthalene diisocyanate and paraphenylene diisocyanate. Suitable aliphatic diisocyanates include, for example, 1,6-hexamethylene diisocyanate (HDI), trimethylhexamethylene diisocyanate (TMDI), trans-1,4-cyclohexane diisocyanate (CHDI), 1,4-cyclohexane bis(methylene isocyanate) (BDI), 1,3-cyclohexane bis(methylene isocyanate) (II[0029] 6XDI), isophorone diisocyanate (IPDI) and 4,4′-methylenebis(cyclohexyl isocyanate) (H12MDI). In preferred embodiments, the diisocyanate is an aliphatic diisocyanate, more preferably isophorone diisocyanate, 1,6-hexamethylene diisocyanate, or 4,4′-methylenebis(cyclohexyl isocyanate). A number of these diisocyanates are available from commercial sources such as Aldrich Chemical Company (Milwaukee, Wis., USA) or can be readily prepared by standard synthetic methods using literature procedures.
    [0030] The quantity of diisocyanate used in the reaction mixture for the present compositions is typically about 50 mol % relative to the combination of the remaining reactants. More particularly, the quantity of diisocyanate employed in the preparation of the present compositions will be sufficient to provide at least about 100% of the —NCO groups necessary to react with the hydroxyl or amino groups of the remaining reactants. For example, a polymer which is prepared using x moles of diisocyanate, will use a moles of a hydrophilic polymer (diol, diamine or combination), and b moles of a chain extender, such that x=a+b, with the understanding that b can be zero. [0030]
    [0031] A second reactant used in the preparation of the swellable coatings described herein is a hydrophilic polymer. The hydrophilic polymer can be a hydrophilic diol, a hydrophilic diamine or a combination thereof. The hydrophilic diol can be a poly(alkylene)glycol, a polyester-based polyol, or a polycarbonate polyol (see FIG. 4). As used herein, the term “poly(alkylene)glycol” refers to polymers of lower alkylene glycols such as poly(ethylene)glycol, poly(propylene)glycol and polytetramethylene ether glycol (PTMEG). The term “polyester-based polyol” refers to a polymer as depicted in FIG. 4 in which the R group is a lower alkylene group such as ethylene, 1,3-propylene, 1,2-propylene, 1,4-butylene, 2,2-dimethyl-1,3-propylene, and the like. One of skill in the art will also understand that the diester portion of the polymer can also vary from the six-carbon diacid shown. For example, while FIG. 4 illustrates an adipic acid component, the present invention also contemplates the use of succinic acid esters, glutaric acid esters and the like. The term “polycarbonate polyol” refers those polymers having hydroxyl functionality at the chain termini and ether and carbonate functionality within the polymer chain (see FIG. 4). The alkyl portion of the polymer will typically be composed of C2 to C4 aliphatic radicals, or in some embodiments, longer chain aliphatic radicals, cycloaliphatic radicals or aromatic radicals. The term “hydrophilic diamines” refers to any of the above hydrophilic diols in which the terminal hydroxyl groups have been replaced by reactive amine groups or in which the terminal hydroxyl groups have been derivatized to produce an extended chain having terminal amine groups. For example, a preferred hydrophilic diamine is a “diamino poly(oxyalkylene)” which is poly(alkylene)glycol in which the terminal hydroxyl groups are replaced with amino groups. The term “diamino poly(oxyalkylene” also refers to poly(alkylene)glycols which have aminoalkyl ether groups at the chain termini. One example of a suitable diamino poly(oxyalkylene) is poly(propylene glycol) bis(2-aminopropyl ether). A number of diamino poly(oxyalkylenes) are available having different average molecular weights and are sold as Jeffamines® (for example, Jeffamine 230, Jeffamine 600, Jeffamine 900 and Jeffamine 2000). These polymers can be obtained from Aldrich Chemical Company. Alternatively, literature methods can be employed for their synthesis. [0031]
    [0032] The amount of hydrophilic polymer which is used in the present compositions will typically be about 10% to about 100% by mole relative to the diisocyanate which is used. Preferably, the amount is from about 50% to about 90% by mole relative to the diisocyanate. When amounts less than 100% of hydrophilic polymer are used, the remaining percentage (up to 100%) will be a chain extender. [0032]
    [0033] Thus, in one group of embodiments, the reaction mixture for the preparation of swellable coatings will also contain a chain extender which is an aliphatic or aromatic diol, an aliphatic or aromatic diamine, alkanolamine, or combinations thereof (see FIG. 8). Examples of suitable aliphatic chain extenders include ethylene glycol, propylene glycol, 1,4-butanediol, 1,6-hexanediol, ethanolamine, ethylene diamine, butane diamine and 1,4-cyclohexanedimethanol. Aromatic chain extenders include, for example, para-di(2-hydroxyethoxy)benzene, meta-di(2-hydroxyethoxy)benzene, Ethacure 100® (a mixture of two isomers of 2,4-diamino-3,5-diethyltoluene), Ethacure 300® (2,4-diamino-3,5-di(methylthio)toluene, 3,3 ′-dichloro-4,4′diaminodiphenylmethane, Polacure® 740 M (trimethylene glycol bis(para-aminobenzoate)ester), and methylenedianiline. Incorporation of one or more of the above chain extenders typically provides the resulting biocompatible membrane with additional physical strength, but does not substantially alter the hydrophilicity of the polymer. In particularly preferred compositions, the chain extender is butanediol, ethylenediamine, 1,6-hexamethylenediamine, 1,2-diaminocyclohexane or isophorone diamine. In one group of preferred embodiments, the chain extender is present an amount of from about 10% to 50% by mole relative to the diisocyanate. [0033]
    [0034] Coating Preparation [0034]
    [0035] Polymerization of the above reactants can be carried out in bulk or in a solvent system. Use of a catalyst is preferred, though not required. Suitable catalysts include dibutyltin bis(2-ethylhexanoate), dibutyltin diacetate, triethylamine and combinations thereof. Preferably dibutyltin bis(2-ethylhexanoate is used as the catalyst. Bulk polymerization is typically carried out at an initial temperature of about 25° C. (ambient temperature) to about 50° C., in order to insure adequate mixing of the reactants. Upon mixing of the reactants, an exotherm is typically observed, with the temperature rising to about 90-120° C. After the initial exotherm, the reaction flask can be heated at from 75° C. to 125° C., with 90° C. to 100° C. being a preferred temperature range. Heating is usually carried out for one to two hours. [0035]
    [0036] Solution polymerization can be carried out in a similar manner. Solvents which are suitable for solution polymerization include, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, halogenated solvents such as 1,2,3-trichloropropane, and ketones such as 4-methyl-2-pentanone. Preferably, THF is used as the solvent. When polymerization is carried out in a solvent, heating of the reaction mixture is typically carried out for at least three to four hours, and preferably at least 10-20 hours. At the end of this time period, the solution polymer is typically cooled to room temperature and poured into DI water. The precipitated polymer is collected, dried, washed with hot DI water to remove solvent and unreacted monomers, then re-dried. The dried polymer can be evaluated for water pickup as described in the Examples below. [0036]
    [0037] The hydrogels which are useful in the present invention will have a water pickup of at least 120%, preferably 150% to about 400%, and more preferably about 200% to about 400%. [0037]
    [0038] Polymers prepared by bulk polymerization are typically dissolved in dimethylformamide and precipitated from water. Polymers prepared in solvents such as THF can be poured into water at ambient temperatures, then filtered, dried, washed with boiling water and re-dried. [0038]
    [0039] Once the polymers have been prepared having suitable water pickup, the polymers can be solubilized in a solvent and used to coat a biosensor. [0039]
    [0040] Preparation of coated biosensors can be accomplished by dissolving the dried polymer in a suitable solvent and spin-coating the sensor, typically using, for example, a 5 wt % in 2-propanol solution of the polymer. The selection of other suitable solvents for coating the sensors will typically depend on the particular polymer as well as the volatility of the solvent. Other suitable solvents include THF, CHCl[0040] 3, CH2Cl2, DMF or combinations thereof. More preferably,. the solvent is THF or DMF/CH2Cl2 (2/98 volume %).
    [0041] A number of different sensors can be used in the methods and compositions of the present invention. [0041]
    [0042] Membrane-Coated Biosensors [0042]
    [0043] Glucose sensors which utilize, for example, glucose oxidase to effect a reaction of glucose and oxygen are known in the art, and are within the skill in the art to fabricate. See, for example, U.S. Pat. Nos. 5,165,407, 4,890,620, 5,390,671 and 5,391,250, the disclosures of each being incorporated herein by reference. The present invention depends not on the configuration of the biosensor, but rather on the use of the inventive membranes to cover or encapsulate the sensor elements. [0043]
    [0044] In particular, the hydrogels described herein are particularly useful with a variety of biosensors for which it is advantageous to provide a surrounding water layer for the electrodes. Various such biosensors are well known in the art. For example, sensors for monitoring glucose concentration of diabetics are described in Shichiri, et al.,: “In Vivo Characteristics of Needle-Type Glucose Sensor-Measurements of Subcutaneous Glucose Concentrations in Human Volunteers,” [0044] Horm. Metab. Res., Suppl. Ser. 20:17-20 (1988); Bruckel, et al.,: “In Vivo Measurement of Subcutaneous Glucose Concentrations with an Enzymatic Glucose Sensor and a Wick Method,” Klin. Wochenschr. 67:491-495 (1989); and Pickup, et al.,: “In Vivo Molecular Sensing in Diabetes Mellitus: An Implantable Glucose Sensor with Direct Electron Transfer,” Diabetologia 32:213-217 (1989).
    [0045] Other sensors are described in, for example Reach, et al., in ADVANCES IN BIOSENSORS, A. Turner (ed.), JAI Press, London, Chap. 1, (1993), incorporated herein by reference. [0045]
    [0046] The following examples are offered by way of illustration and are not meant to limit the scope of the invention. [0046] EXAMPLES
    [0047] The materials used in the examples were obtained from the following sources: isophorone diisocyanate, 1,6-hexamethylenediisocyanate, PEG 600, butanediol, ethylene diamine, hexamethylenediamine, isophorone diamine and 1,2-diaminohexane (Aldrich Chemical Co., Milwaukee, Wis., USA); Jeffamine® D-230, ED-600, ED-900 and D-2000 were obtained from Aldrich. [0047]
    [0048] General Methods [0048]
    [0049] (a) Hydrogel Preparation [0049]
    [0050] Hydrogels suitable for use as biosensor coatings were prepared by combining a diisocyanate with an equivalent molar amount of a hydrophilic diol or diamine or with a combination of diol or diamine and chain extender such that the molar amount of the combination was equivalent to the diisocyanate. The polymerizations were carried out in a one-pot reaction using THF as solvent and a trace catalyst (tributyltin ethylhexanoate). The reactions were heated to reflux and held at this temperature overnight (about 16 hours). The resulting polymer solution was poured into a large volume of DI water at about 20° C. and then filtered, dried, and washed with boiling DI water. The resulting polymer was again dried then taken up in 2-propanol (as a 5 wt % solution) and used for spin coating. [0050]
    [0051] (b) Coating of Biosensors [0051]
    [0052] Coating of biosensors can be carried out using a commercial spin coating apparatus operating at between 1000 and 5000 rpm, depending on the viscosity of the polymer solution and the desired thickness of the hydrophilic coating. [0052]
    [0053] (c) Water Pickup [0053]
    [0054] Water pickup was determined gravimetrically at room temperature on polymers which had been dried to a constant weight at 50° C. in vacuo, then weighed, immersed in deionized water for 24 hours, removed and blotted with filter paper, and weighed. Percent water pickup was determined from the formula: [0054]
    [0055] where W[0055] w is the weight of the swollen film and Wd is the weight of the dry film.
    [0056] (d) Impedance Measurements [0056]
    [0057] Electrochemical impedance measurements were performed on finished sensors using a Bioanalytical Systems (BAS, Lafayette, Ind.) 100B Electrochemical Analyzer. Impedance was measured in a three electrode mode from 0.01 Hz to 1000 Hz. Linear extrapolation to DC impedance was used to obtain the final impedance figures. The final impedance is calculated as the sum of the real and imaginary parts of the impedance. The measurements were made in 100 mg/dl glucose solution in PBS, with a 600 mv applied potential and a 5 mv A.C. signal imposed on the applied potential. [0057] Example 1
    [0058] This example provides the formulations and properties of representative coatings. [0058]
    [0059] Table 1 provides ten formulations for representative polymers which were prepared by solution polymerization. [0059] TABLE 1 Representative Polymer Formulations Hydrophilic Polymer Diisocyanate diol or diamine Chain Extender 1 1,6-Hexamethylene Jeffamine 600 Butanediol (95%) (5%) 2 1,6-Hexamethylene Jeffamine 2000 None (100%) 3 1,6-Hexamethylene Jeffamine 2000 Butanediol (90%) (10%) 4 1,6-Hexamethylene PEG 2000 Butanediol (90%) (10%) 5 1,6-Hexamethylene Jeffamine 230 Ethylene diamine (30%) (70%) 6 1,6-Hexamethylene PEG 600 Ethylene diamine (75%) (25%) 7 Isophorone PEG 600 Butanediol (75%) (25%) 8 Isophorone Jeffamine 900 1,6-Diaminohexane (70%) (25%) 9 Isophorone Jeffamine 900 1,2-Diaminocyclo- (50%) hexane (50%) 10 Isophorone Jeffamine 900 Isophorone diamine (50%) (50%)
    [0060] Table 2 provides certain physical and chemical properties of the polymers above. [0060] TABLE 2 Physical Properties of Representative Polymers Impedance (Ohms) Polymer Water Pickup (%) (× 106) 1 250 2.3 2 160 1.7 3 240 1.4 4 400 6.1 5 110 3.3 6  45 6.9 7 280 1.1 8 240 0.7 9 220 0.5 10 184 0.8 Example 2
    [0061] This example illustrates the evaluation of a membrane-coated biosensor constructed according to the present invention. [0061]
    [0062] A membrane prepared from the polymer identified as [0062] 9 above was found to have excellent mechanical properties as well as appropriate water uptake and oxygen and glucose diffusivities. The membrane was evaluated using a prototype glucose sensor illustrated in FIG. 6A. According to FIG. 6A, a sensor 20 was constructed having a reference electrode 22, a working electrode 24, and a counter electrode 26 deposited on a polymeric sheet 29. A series of bonding pads 28 complete the sensor 20. As shown in FIG. 6B, the working electrode 24 was covered with a layer 30 of the enzyme glucose oxidase and the entire electrode array was coated with a first layer 32 of a glucose-limiting polymer prepared according to U.S. Ser. No. 08/721,262 (Attorney Docket No. 017898-000410, filed Sep. 26, 1996 and incorporated herein by reference) and a second layer 34 of the polymer 9 (see Example 1) by spin coating. The glucose limiting polymer was applied from a 7 wt % solution of the polymer in THF and the hydrophilic coating 34 was applied from a 5 wt % solution in 2-propanol. The sensor was connected to a commercial potentiostat (BAS Instruments, not shown) and operated with a potential of +0.6 volts between the working electrode and the reference electrode.
    [0063] The above description is illustrative and not restrictive. Many variations of the invention will become apparent to those of skill in the art upon review of this disclosure. Merely by way of example a variety of solvents, membrane formation methods, and other materials may be used without departing from the scope of the invention. The scope of the invention should, therefore, be determined not with reference to the above description, but instead should be determined with reference to the appended claims along with their full scope of equivalents. [0063]
    [0064] All publications, patents and patent applications mentioned in this specification are herein incorporated by reference into the specification to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. [0064]
    权利要求:
    Claims (15)
    [1" id="US-20010008931-A1-CLM-00001] 1. A method of reducing electrode impedance of an implantable biosensor comprising coating said biosensor with a hydrogel, wherein said hydrogel is formed from a reaction mixture of:
    (a) a diisocyanate, said diisocyanate comprising about 50 mol % of the reactants in said mixture;
    (b) a hydrophilic polymer which is a member selected from the group consisting of a hydrophilic polymer diol, a hydrophilic polymer diamine and combinations thereof; and optionally;
    (c) a chain extender,
    said hydrogel having a water pickup of from about 120% to about 400% by weight.
    [2" id="US-20010008931-A1-CLM-00002] 2. A method in accordance with
    claim 1 , wherein said coating is by spin coating, dipping or spraying.
    [3" id="US-20010008931-A1-CLM-00003] 3. A method in accordance with
    claim 1 , wherein said hydrophilic polymer is a poly(ethylene)glycol selected from the group consisting of PEG 600, PEG 2000, Jeffamine D-230, Jeffamine ED-600, Jeffamine ED-900 and Jeffamine D-2000.
    [4" id="US-20010008931-A1-CLM-00004] 4. A method in accordance with
    claim 1 , wherein said diisocyanate is a member selected from the group consisting of isophorone diisocyanate, 1,6-hexamethylene diisocyanate and 4,4′-methylenebis(cyclohexyl isocyanate).
    [5" id="US-20010008931-A1-CLM-00005] 5. A method in accordance with
    claim 1 , wherein said chain extender is selected from the group consisting of an alkylene diol, an alkylene diamine, an aminoalkanol and combinations thereof.
    [6" id="US-20010008931-A1-CLM-00006] 6. A method in accordance with
    claim 1 , wherein said chain extender is selected from the group consisting of butanediol, ethylenediamine, hexamethylenediamine, 1,2-diaminocyclohexane and isophoronediamine.
    [7" id="US-20010008931-A1-CLM-00007] 7. A method in accordance with
    claim 1 , wherein said diisocyanate is 1,6-hexamethylene diisocyanate and said hydrophilic polymer is selected from the group consisting of Jeffamine ED-600, Jeffamine D-2000 and PEG 2000 and is present in an amount of about 40 to about 50 mol %.
    [8" id="US-20010008931-A1-CLM-00008] 8. A method in accordance with
    claim 1 , wherein said diisocyanate is 1,6-hexamethylene diisocyanate, said hydrophilic polymer is selected from the group consisting of Jeffamine ED-600, Jeffamine D-2000 and PEG 2000 and is present in an amount of about 40 to about 50 mol % and said chain extender is butanediol and is present in an amount of about 2.5 to about 10 mol %.
    [9" id="US-20010008931-A1-CLM-00009] 9. An implantable biosensor having a hydrogel coating, said coating prepared from a reaction mixture of:
    (a) a diisocyanate, said diisocyanate comprising about 50 mol % of the reactants in said mixture;
    (b) a hydrophilic polymer which is a member selected from the group consisting of a hydrophilic polymer diol, a hydrophilic polymer diamine and combinations thereof; and optionally;
    (c) a chain extender;
    wherein said coating has a water pickup of from about 120% to about 400% by weight.
    [10" id="US-20010008931-A1-CLM-00010] 10. An implantable biosensor in accordance with
    claim 9 , wherein said hydrophilic polymer is a poly(ethylene)glycol selected from the group consisting of PEG 600, IPEG 2000, Jeffamine D-230, Jeffamine ED-600, Jeffamine ED-900 and Jeffamine D-2000.
    [11" id="US-20010008931-A1-CLM-00011] 11. An implantable biosensor in accordance with
    claim 9 , wherein said diisocyanate is a member selected from the group consisting of isophorone diisocyanate, 1,6-hexamethylene diisocyanate and 4,4′-methylenebis(cyclohexyl isocyanate).
    [12" id="US-20010008931-A1-CLM-00012] 12. An implantable biosensor in accordance with
    claim 9 , wherein said chain extender is selected from the group consisting of an alkylene diol, an alkylene diamine, an aminoalkanol and combinations thereof.
    [13" id="US-20010008931-A1-CLM-00013] 13. An implantable biosensor in accordance with
    claim 9 , wherein said chain extender is selected from the group consisting of butanediol, ethylenediamine, hexamethylenediamine, 1,2-diaminocyclohexane and isophoronediamine.
    [14" id="US-20010008931-A1-CLM-00014] 14. An implantable biosensor in accordance with
    claim 9 , wherein said diisocyanate is 1,6-hexamethylene diisocyanate and said hydrophilic polymer is selected from the group consisting of Jeffamine ED-600, Jeffamine D-2000 and PEG 2000 and is present in an amount of about 40 to about 50 mol %.
    [15" id="US-20010008931-A1-CLM-00015] 15. An implantable biosensor in accordance with
    claim 9 , wherein said diisocyanate is 1,6-hexamethylene diisocyanate, said hydrophilic polymer is selected from the group consisting of Jeffamine ED-600, Jeffamine D-2000 and PEG 2000 and is present in an amount of about 40 to about 50 mol % and said chain extender is butanediol and is present in an amount of about 2.5 to about 10 mol %.
    类似技术:
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    同族专利:
    公开号 | 公开日
    DK0876604T3|2006-09-11|
    CA2238648C|2007-03-13|
    CA2238648A1|1998-04-30|
    US5786439A|1998-07-28|
    EP0876604B1|2006-05-24|
    EP0876604A1|1998-11-11|
    AT327504T|2006-06-15|
    DE69735932D1|2006-06-29|
    US20030069383A1|2003-04-10|
    WO1998017995A1|1998-04-30|
    JP3852712B2|2006-12-06|
    AU5092198A|1998-05-15|
    US6784274B2|2004-08-31|
    US6462162B2|2002-10-08|
    JP2000502280A|2000-02-29|
    DE69735932T2|2007-01-04|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO2011084651A1|2009-12-21|2011-07-14|Medtronic Minimed, Inc.|Analyte sensors comprising blended membrane compositions and methods for making and using them|
    WO2016025407A1|2014-08-11|2016-02-18|Cardiac Pacemakers, Inc.|Implantable medical device coating for wetting and microbial resistance|
    US9399076B2|2004-05-19|2016-07-26|Medtronic Minimed, Inc.|Optical sensor for in vivo detection of analyte|
    WO2019118483A1|2017-12-11|2019-06-20|Innovative Surface Technologies, Inc.|Polyurea copolymer coating compositions and methods|
    US10335513B2|2016-06-16|2019-07-02|Cardiac Pacemakers, Inc.|Hydrophilization and antifouling of enhanced metal surfaces|
    US10342899B2|2015-12-19|2019-07-09|Cardiac Pacemakers, Inc.|Biologically inert coating for implantable medical devices|
    US10842912B2|2016-08-09|2020-11-24|Cardiac Pacemakers, Inc.|Functionalized PEG for implantable medical devices|US4484987A|1983-05-19|1984-11-27|The Regents Of The University Of California|Method and membrane applicable to implantable sensor|
    CA1283872C|1985-02-19|1991-05-07|Steven D. Aust|Process for the degradation of environmentally persistent organic compounds|
    US4890620A|1985-09-20|1990-01-02|The Regents Of The University Of California|Two-dimensional diffusion glucose substrate sensing electrode|
    US4909908A|1986-04-24|1990-03-20|Pepi Ross|Electrochemical cncentration detector method|
    US5214119A|1986-06-20|1993-05-25|Minnesota Mining And Manufacturing Company|Block copolymer, method of making the same, dimaine precursors of the same, method of making such diamines and end products comprising the block copolymer|
    GB2194843A|1986-09-08|1988-03-16|Cambridge Life Sciences|Enzyme electrode membrane and method of making same|
    US4759828A|1987-04-09|1988-07-26|Nova Biomedical Corporation|Glucose electrode and method of determining glucose|
    US4816130A|1987-07-02|1989-03-28|Becton, Dickinson And Company|Blood electrolyte sensors including crosslinked polyetherurethane membranes|
    US5128408A|1987-11-16|1992-07-07|Toyo Boseki Kabushiki Kaisha|Gas-permeable material with excellent compatibility with blood|
    US5334691A|1990-07-24|1994-08-02|Tyndale Plains-Hunter Ltd.|Hydrophilic polyurethanes of improved strength|
    US5000955A|1988-07-29|1991-03-19|Tyndale Plains-Hunter Ltd.|Thermally reversible polyurethane hydrogels and cosmetic, biological and medical uses|
    JPH02298855A|1989-03-20|1990-12-11|Assoc Univ Inc|Electrochemical biosensor using immobilized enzyme and redox polymer|
    US5320725A|1989-08-02|1994-06-14|E. Heller & Company|Electrode and method for the detection of hydrogen peroxide|
    GB8918589D0|1989-08-15|1989-09-27|Graham Neil B|Polymeric compositions|
    US5108819A|1990-02-14|1992-04-28|Eli Lilly And Company|Thin film electrical component|
    US5165407A|1990-04-19|1992-11-24|The University Of Kansas|Implantable glucose sensor|
    US5160790A|1990-11-01|1992-11-03|C. R. Bard, Inc.|Lubricious hydrogel coatings|
    EP0643833A1|1991-06-04|1995-03-22|FISONS plc|Analytical device|
    US5322063A|1991-10-04|1994-06-21|Eli Lilly And Company|Hydrophilic polyurethane membranes for electrochemical glucose sensors|
    US5238732A|1992-07-16|1993-08-24|Surface Coatings, Inc.|Waterproof breathable polyurethane membranes and porous substrates protected therewith|
    US5239037A|1992-07-16|1993-08-24|Surface Coatings, Inc.|Waterproof breathable polyurethane membranes and porous substrates protected therewith|
    US5208313A|1992-07-16|1993-05-04|Surface Coatings, Inc.|Waterproof breathable polyurethane membranes and porous substrates protected therewith|
    CA2121660A1|1993-05-10|1994-11-11|Gregory J. Mann|Biostable polyurethane and medical article therefrom|
    US5484818A|1993-07-22|1996-01-16|Imperial Chemical Industries Plc|Organic aerogels|
    WO1995015352A1|1993-12-01|1995-06-08|Universite Du Quebec A Montreal|Albumin based hydrogel|
    US5674275A|1994-04-06|1997-10-07|Graphic Controls Corporation|Polyacrylate and polymethacrylate ester based hydrogel adhesives|
    US5614586A|1994-04-06|1997-03-25|Graphic Controls Corporation|Polyacrylate and Polymethacrylate ester based hydrogel adhesives|
    US5863972A|1994-11-14|1999-01-26|Chiron Diagnostics Corporation|Randomly segmented thermoplastic polyurethanes as matrix for electrochemical analysis of Ca++ ions|
    US5882494A|1995-03-27|1999-03-16|Minimed, Inc.|Polyurethane/polyurea compositions containing silicone for biosensor membranes|
    US5665222A|1995-10-11|1997-09-09|E. Heller & Company|Soybean peroxidase electrochemical sensor|
    US5786439A|1996-10-24|1998-07-28|Minimed Inc.|Hydrophilic, swellable coatings for biosensors|AU5446098A|1996-11-21|1998-06-10|Lawrence Livermore National Laboratory|Detection of biological molecules using boronate-based chemical amplification and optical sensors|
    US5786439A|1996-10-24|1998-07-28|Minimed Inc.|Hydrophilic, swellable coatings for biosensors|
    US6001067A|1997-03-04|1999-12-14|Shults; Mark C.|Device and method for determining analyte levels|
    US8527026B2|1997-03-04|2013-09-03|Dexcom, Inc.|Device and method for determining analyte levels|
    US6036924A|1997-12-04|2000-03-14|Hewlett-Packard Company|Cassette of lancet cartridges for sampling blood|
    US6331163B1|1998-01-08|2001-12-18|Microsense Cardiovascular SystemsLtd.|Protective coating for bodily sensor|
    US6391005B1|1998-03-30|2002-05-21|Agilent Technologies, Inc.|Apparatus and method for penetration with shaft having a sensor for sensing penetration depth|
    US6060023A|1998-03-31|2000-05-09|Motorola, Inc.|Molecular sensing apparatus|
    US8688188B2|1998-04-30|2014-04-01|Abbott Diabetes Care Inc.|Analyte monitoring device and methods of use|
    US6175752B1|1998-04-30|2001-01-16|Therasense, Inc.|Analyte monitoring device and methods of use|
    US9066695B2|1998-04-30|2015-06-30|Abbott Diabetes Care Inc.|Analyte monitoring device and methods of use|
    US8480580B2|1998-04-30|2013-07-09|Abbott Diabetes Care Inc.|Analyte monitoring device and methods of use|
    US8974386B2|1998-04-30|2015-03-10|Abbott Diabetes Care Inc.|Analyte monitoring device and methods of use|
    US8465425B2|1998-04-30|2013-06-18|Abbott Diabetes Care Inc.|Analyte monitoring device and methods of use|
    US8346337B2|1998-04-30|2013-01-01|Abbott Diabetes Care Inc.|Analyte monitoring device and methods of use|
    US6485703B1|1998-07-31|2002-11-26|The Texas A&M University System|Compositions and methods for analyte detection|
    US6605294B2|1998-08-14|2003-08-12|Incept Llc|Methods of using in situ hydration of hydrogel articles for sealing or augmentation of tissue or vessels|
    US6602678B2|1998-09-04|2003-08-05|Powderject Research Limited|Non- or minimally invasive monitoring methods|
    EP1413245B1|1998-10-08|2011-06-29|Medtronic MiniMed, Inc.|Telemetered characteristic monitor system|
    US20060202859A1|1998-10-08|2006-09-14|Mastrototaro John J|Telemetered characteristic monitor system and method of using the same|
    US6424847B1|1999-02-25|2002-07-23|Medtronic Minimed, Inc.|Glucose monitor calibration methods|
    US7890295B2|2000-02-23|2011-02-15|Medtronic Minimed, Inc.|Real time self-adjusting calibration algorithm|
    CA2368247A1|1999-04-27|2000-11-09|Ciphergen Biosystems, Inc.|Probes for a gas phase ion spectrometer|
    US6342071B1|1999-07-08|2002-01-29|Benjamin David Pless|Ambulatory blood pump|
    WO2001012746A1|1999-08-17|2001-02-22|Porex Technologies Corporation|Self-sealing materials and devices comprising same|
    US7045054B1|1999-09-20|2006-05-16|Roche Diagnostics Corporation|Small volume biosensor for continuous analyte monitoring|
    US6589778B1|1999-12-15|2003-07-08|Amersham Biosciences Ab|Method and apparatus for performing biological reactions on a substrate surface|
    US7003336B2|2000-02-10|2006-02-21|Medtronic Minimed, Inc.|Analyte sensor method of making the same|
    US6484045B1|2000-02-10|2002-11-19|Medtronic Minimed, Inc.|Analyte sensor and method of making the same|
    AU6013001A|2000-03-17|2001-09-24|Roche Diagnostics Gmbh|Implantable analyte sensor|
    US6405066B1|2000-03-17|2002-06-11|The Regents Of The University Of California|Implantable analyte sensor|
    US7527821B2|2000-05-02|2009-05-05|Smiths Detection Inc.|Sensor fabricating method|
    US6340421B1|2000-05-16|2002-01-22|Minimed Inc.|Microelectrogravimetric method for plating a biosensor|
    US8285382B2|2000-08-21|2012-10-09|Cochlear Limited|Determining stimulation signals for neural stimulation|
    US9008786B2|2000-08-21|2015-04-14|Cochlear Limited|Determining stimulation signals for neural stimulation|
    AUPQ952800A0|2000-08-21|2000-09-14|Cochlear Limited|Power efficient electrical stimulation|
    US8641644B2|2000-11-21|2014-02-04|Sanofi-Aventis Deutschland Gmbh|Blood testing apparatus having a rotatable cartridge with multiple lancing elements and testing means|
    US6653141B2|2000-12-05|2003-11-25|The Regents Of The University Of California|Polyhydroxyl-substituted organic molecule sensing method and device|
    US6627177B2|2000-12-05|2003-09-30|The Regents Of The University Of California|Polyhydroxyl-substituted organic molecule sensing optical in vivo method utilizing a boronic acid adduct and the device thereof|
    US7470420B2|2000-12-05|2008-12-30|The Regents Of The University Of California|Optical determination of glucose utilizing boronic acid adducts|
    US6642015B2|2000-12-29|2003-11-04|Minimed Inc.|Hydrophilic polymeric material for coating biosensors|
    US6560471B1|2001-01-02|2003-05-06|Therasense, Inc.|Analyte monitoring device and methods of use|
    US7892183B2|2002-04-19|2011-02-22|Pelikan Technologies, Inc.|Method and apparatus for body fluid sampling and analyte sensing|
    US8372016B2|2002-04-19|2013-02-12|Sanofi-Aventis Deutschland Gmbh|Method and apparatus for body fluid sampling and analyte sensing|
    EP1397068A2|2001-04-02|2004-03-17|Therasense, Inc.|Blood glucose tracking apparatus and methods|
    US6932894B2|2001-05-15|2005-08-23|Therasense, Inc.|Biosensor membranes composed of polymers containing heterocyclic nitrogens|
    US7232451B2|2002-04-19|2007-06-19|Pelikan Technologies, Inc.|Method and apparatus for penetrating tissue|
    US7648468B2|2002-04-19|2010-01-19|Pelikon Technologies, Inc.|Method and apparatus for penetrating tissue|
    US7674232B2|2002-04-19|2010-03-09|Pelikan Technologies, Inc.|Method and apparatus for penetrating tissue|
    US8360992B2|2002-04-19|2013-01-29|Sanofi-Aventis Deutschland Gmbh|Method and apparatus for penetrating tissue|
    US8579831B2|2002-04-19|2013-11-12|Sanofi-Aventis Deutschland Gmbh|Method and apparatus for penetrating tissue|
    US7175642B2|2002-04-19|2007-02-13|Pelikan Technologies, Inc.|Methods and apparatus for lancet actuation|
    US8337419B2|2002-04-19|2012-12-25|Sanofi-Aventis Deutschland Gmbh|Tissue penetration device|
    US7909778B2|2002-04-19|2011-03-22|Pelikan Technologies, Inc.|Method and apparatus for penetrating tissue|
    DE60239132D1|2001-06-12|2011-03-24|Pelikan Technologies Inc|APPARATUS FOR INCREASING THE SUCCESS RATE IN RESPECT OF BLOOD EXPLOITATION OBTAINED BY A FINGERSTICK|
    US7901362B2|2002-04-19|2011-03-08|Pelikan Technologies, Inc.|Method and apparatus for penetrating tissue|
    CA2448902C|2001-06-12|2010-09-07|Pelikan Technologies, Inc.|Self optimizing lancing device with adaptation means to temporal variations in cutaneous properties|
    US7331931B2|2002-04-19|2008-02-19|Pelikan Technologies, Inc.|Method and apparatus for penetrating tissue|
    US7371247B2|2002-04-19|2008-05-13|Pelikan Technologies, Inc|Method and apparatus for penetrating tissue|
    US7198606B2|2002-04-19|2007-04-03|Pelikan Technologies, Inc.|Method and apparatus for a multi-use body fluid sampling device with analyte sensing|
    CA2448905C|2001-06-12|2010-09-07|Pelikan Technologies, Inc.|Blood sampling apparatus and method|
    US9314194B2|2002-04-19|2016-04-19|Sanofi-Aventis Deutschland Gmbh|Tissue penetration device|
    US7717863B2|2002-04-19|2010-05-18|Pelikan Technologies, Inc.|Method and apparatus for penetrating tissue|
    US7976476B2|2002-04-19|2011-07-12|Pelikan Technologies, Inc.|Device and method for variable speed lancet|
    US7041068B2|2001-06-12|2006-05-09|Pelikan Technologies, Inc.|Sampling module device and method|
    US7547287B2|2002-04-19|2009-06-16|Pelikan Technologies, Inc.|Method and apparatus for penetrating tissue|
    US9248267B2|2002-04-19|2016-02-02|Sanofi-Aventis Deustchland Gmbh|Tissue penetration device|
    US7291117B2|2002-04-19|2007-11-06|Pelikan Technologies, Inc.|Method and apparatus for penetrating tissue|
    US8267870B2|2002-04-19|2012-09-18|Sanofi-Aventis Deutschland Gmbh|Method and apparatus for body fluid sampling with hybrid actuation|
    AU2002348683A1|2001-06-12|2002-12-23|Pelikan Technologies, Inc.|Method and apparatus for lancet launching device integrated onto a blood-sampling cartridge|
    US7229458B2|2002-04-19|2007-06-12|Pelikan Technologies, Inc.|Method and apparatus for penetrating tissue|
    US7491178B2|2002-04-19|2009-02-17|Pelikan Technologies, Inc.|Method and apparatus for penetrating tissue|
    US9226699B2|2002-04-19|2016-01-05|Sanofi-Aventis Deutschland Gmbh|Body fluid sampling module with a continuous compression tissue interface surface|
    US7297122B2|2002-04-19|2007-11-20|Pelikan Technologies, Inc.|Method and apparatus for penetrating tissue|
    US9795334B2|2002-04-19|2017-10-24|Sanofi-Aventis Deutschland Gmbh|Method and apparatus for penetrating tissue|
    US7981056B2|2002-04-19|2011-07-19|Pelikan Technologies, Inc.|Methods and apparatus for lancet actuation|
    US8221334B2|2002-04-19|2012-07-17|Sanofi-Aventis Deutschland Gmbh|Method and apparatus for penetrating tissue|
    DE60238119D1|2001-06-12|2010-12-09|Pelikan Technologies Inc|ELECTRIC ACTUATOR ELEMENT FOR A LANZETTE|
    US8784335B2|2002-04-19|2014-07-22|Sanofi-Aventis Deutschland Gmbh|Body fluid sampling device with a capacitive sensor|
    US9427532B2|2001-06-12|2016-08-30|Sanofi-Aventis Deutschland Gmbh|Tissue penetration device|
    AUPR604801A0|2001-06-29|2001-07-26|Cochlear Limited|Multi-electrode cochlear implant system with distributed electronics|
    US20030032874A1|2001-07-27|2003-02-13|Dexcom, Inc.|Sensor head for use with implantable devices|
    US20030153026A1|2002-01-04|2003-08-14|Javier Alarcon|Entrapped binding protein as biosensors|
    US20050239155A1|2002-01-04|2005-10-27|Javier Alarcon|Entrapped binding protein as biosensors|
    US7247162B1|2002-01-14|2007-07-24|Edwards Lifesciences Corporation|Direct access atherectomy devices|
    US8702624B2|2006-09-29|2014-04-22|Sanofi-Aventis Deutschland Gmbh|Analyte measurement device with a single shot actuator|
    US7153265B2|2002-04-22|2006-12-26|Medtronic Minimed, Inc.|Anti-inflammatory biosensor for reduced biofouling and enhanced sensor performance|
    US9492111B2|2002-04-22|2016-11-15|Medtronic Minimed, Inc.|Methods and materials for stabilizing analyte sensors|
    DE10221047A1|2002-05-10|2003-11-27|Degussa|Process for the solvent-free, continuous production of polyureas|
    US7226978B2|2002-05-22|2007-06-05|Dexcom, Inc.|Techniques to improve polyurethane membranes for implantable glucose sensors|
    WO2007120442A2|2003-07-25|2007-10-25|Dexcom, Inc.|Dual electrode system for a continuous analyte sensor|
    US7613491B2|2002-05-22|2009-11-03|Dexcom, Inc.|Silicone based membranes for use in implantable glucose sensors|
    US9763609B2|2003-07-25|2017-09-19|Dexcom, Inc.|Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise|
    US7828728B2|2003-07-25|2010-11-09|Dexcom, Inc.|Analyte sensor|
    US8364229B2|2003-07-25|2013-01-29|Dexcom, Inc.|Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise|
    US20040068230A1|2002-07-24|2004-04-08|Medtronic Minimed, Inc.|System for providing blood glucose measurements to an infusion device|
    US7278983B2|2002-07-24|2007-10-09|Medtronic Minimed, Inc.|Physiological monitoring device for controlling a medication infusion device|
    US20050008828A1|2002-07-25|2005-01-13|Trustees Of Stevens Institute Of Technology|Patterned polymer microgel and method of forming same|
    US20060014003A1|2003-07-24|2006-01-19|Libera Matthew R|Functional nano-scale gels|
    US20040061232A1|2002-09-27|2004-04-01|Medtronic Minimed, Inc.|Multilayer substrate|
    US8003513B2|2002-09-27|2011-08-23|Medtronic Minimed, Inc.|Multilayer circuit devices and manufacturing methods using electroplated sacrificial structures|
    US6770729B2|2002-09-30|2004-08-03|Medtronic Minimed, Inc.|Polymer compositions containing bioactive agents and methods for their use|
    EP2290238A1|2002-10-09|2011-03-02|Abbott Diabetes Care Inc.|Plunger pump actuated by a shape memory element|
    US7727181B2|2002-10-09|2010-06-01|Abbott Diabetes Care Inc.|Fluid delivery device with autocalibration|
    US7993108B2|2002-10-09|2011-08-09|Abbott Diabetes Care Inc.|Variable volume, shape memory actuated insulin dispensing pump|
    US9237865B2|2002-10-18|2016-01-19|Medtronic Minimed, Inc.|Analyte sensors and methods for making and using them|
    US20040074785A1|2002-10-18|2004-04-22|Holker James D.|Analyte sensors and methods for making them|
    AU2003287735A1|2002-11-12|2004-06-03|Argose, Inc.|Non-invasive measurement of analytes|
    US20040106163A1|2002-11-12|2004-06-03|Workman Jerome James|Non-invasive measurement of analytes|
    US20030134410A1|2002-11-14|2003-07-17|Silva Robin M.|Compositions and methods for performing biological reactions|
    US20040122353A1|2002-12-19|2004-06-24|Medtronic Minimed, Inc.|Relay device for transferring information between a sensor system and a fluid delivery system|
    US8574895B2|2002-12-30|2013-11-05|Sanofi-Aventis Deutschland Gmbh|Method and apparatus using optical techniques to measure analyte levels|
    AU2003303597A1|2002-12-31|2004-07-29|Therasense, Inc.|Continuous glucose monitoring system and methods of use|
    US20040126831A1|2002-12-31|2004-07-01|Medtronic Minimed, Inc.|Functionalization of immobilized proteins|
    AU2003297503A1|2002-12-31|2004-07-29|Medtronic Minimed, Inc.|Hydrophilic cross-linking agents for use in enzymatic sensors|
    US6949816B2|2003-04-21|2005-09-27|Motorola, Inc.|Semiconductor component having first surface area for electrically coupling to a semiconductor chip and second surface area for electrically coupling to a substrate, and method of manufacturing same|
    JP4565193B2|2003-04-23|2010-10-20|バレリタス，インコーポレイテッド|Hydraulically operated pump for long duration pharmaceutical administration|
    US7679407B2|2003-04-28|2010-03-16|Abbott Diabetes Care Inc.|Method and apparatus for providing peak detection circuitry for data communication systems|
    EP2238892A3|2003-05-30|2011-02-09|Pelikan Technologies Inc.|Apparatus for body fluid sampling|
    WO2004107964A2|2003-06-06|2004-12-16|Pelikan Technologies, Inc.|Blood harvesting device with electronic control|
    US8066639B2|2003-06-10|2011-11-29|Abbott Diabetes Care Inc.|Glucose measuring device for use in personal area network|
    US20200037875A1|2007-05-18|2020-02-06|Dexcom, Inc.|Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise|
    JP2007500336A|2003-07-25|2007-01-11|デックスコム・インコーポレーテッド|Electrode system for electrochemical sensors|
    JP4708342B2|2003-07-25|2011-06-22|デックスコム・インコーポレーテッド|Oxygen augmentation membrane system for use in implantable devices|
    US20190357827A1|2003-08-01|2019-11-28|Dexcom, Inc.|Analyte sensor|
    US7857760B2|2004-07-13|2010-12-28|Dexcom, Inc.|Analyte sensor|
    US8282576B2|2003-09-29|2012-10-09|Sanofi-Aventis Deutschland Gmbh|Method and apparatus for an improved sample capture device|
    WO2005032512A2|2003-10-02|2005-04-14|Trustees Of Stevens Institute Of Technology|Capsules of multilayered neutral polymer films associated by hydrogen bonding|
    US9351680B2|2003-10-14|2016-05-31|Sanofi-Aventis Deutschland Gmbh|Method and apparatus for a variable user interface|
    JP2007512859A|2003-11-03|2007-05-24|マイクロチップス・インコーポレーテッド|Medical device for sensing glucose|
    DE602004029092D1|2003-12-05|2010-10-21|Dexcom Inc|CALIBRATION METHODS FOR A CONTINUOUSLY WORKING ANALYTIC SENSOR|
    US8668656B2|2003-12-31|2014-03-11|Sanofi-Aventis Deutschland Gmbh|Method and apparatus for improving fluidic flow and sample capture|
    WO2005089103A2|2004-02-17|2005-09-29|Therasense, Inc.|Method and system for providing data communication in continuous glucose monitoring and management system|
    US20070184222A1|2004-04-20|2007-08-09|University Of Rochester|Hydrogel-supported porous semiconductor devices|
    US8277713B2|2004-05-03|2012-10-02|Dexcom, Inc.|Implantable analyte sensor|
    US8792955B2|2004-05-03|2014-07-29|Dexcom, Inc.|Transcutaneous analyte sensor|
    WO2006011062A2|2004-05-20|2006-02-02|Albatros Technologies Gmbh & Co. Kg|Printable hydrogel for biosensors|
    US9775553B2|2004-06-03|2017-10-03|Sanofi-Aventis Deutschland Gmbh|Method and apparatus for a fluid sampling device|
    EP1765194A4|2004-06-03|2010-09-29|Pelikan Technologies Inc|Method and apparatus for a fluid sampling device|
    US20050272989A1|2004-06-04|2005-12-08|Medtronic Minimed, Inc.|Analyte sensors and methods for making and using them|
    WO2005124348A1|2004-06-09|2005-12-29|Becton, Dickinson And Company|Multianalyte sensor|
    CN100409909C|2004-06-11|2008-08-13|文贵华|Biological affinitic electrode stimulating device|
    WO2006001797A1|2004-06-14|2006-01-05|Pelikan Technologies, Inc.|Low pain penetrating|
    US7519435B2|2004-06-23|2009-04-14|Cochlear Limited|Methods for maintaining low impedance of electrodes|
    US9089636B2|2004-07-02|2015-07-28|Valeritas, Inc.|Methods and devices for delivering GLP-1 and uses thereof|
    US10022078B2|2004-07-13|2018-07-17|Dexcom, Inc.|Analyte sensor|
    US9247900B2|2004-07-13|2016-02-02|Dexcom, Inc.|Analyte sensor|
    US8515516B2|2004-07-13|2013-08-20|Dexcom, Inc.|Transcutaneous analyte sensor|
    BRPI0517066A|2004-11-05|2008-09-30|Basf Ag|microcapsule dispersion, process for preparing a microcapsule dispersion, and microcapsules|
    US8652831B2|2004-12-30|2014-02-18|Sanofi-Aventis Deutschland Gmbh|Method and apparatus for analyte measurement test time|
    US7822454B1|2005-01-03|2010-10-26|Pelikan Technologies, Inc.|Fluid sampling device with improved analyte detecting member configuration|
    US7920906B2|2005-03-10|2011-04-05|Dexcom, Inc.|System and methods for processing analyte sensor data for sensor calibration|
    CA2601441A1|2005-03-21|2006-09-28|Abbott Diabetes Care Inc.|Method and system for providing integrated medication infusion and analyte monitoring system|
    US8112240B2|2005-04-29|2012-02-07|Abbott Diabetes Care Inc.|Method and apparatus for providing leak detection in data monitoring and management systems|
    US8744546B2|2005-05-05|2014-06-03|Dexcom, Inc.|Cellulosic-based resistance domain for an analyte sensor|
    US7768408B2|2005-05-17|2010-08-03|Abbott Diabetes Care Inc.|Method and system for providing data management in data monitoring system|
    US7620437B2|2005-06-03|2009-11-17|Abbott Diabetes Care Inc.|Method and apparatus for providing rechargeable power in data monitoring and management systems|
    WO2007024649A2|2005-08-19|2007-03-01|X-Cell Medical Incorporated|Methods of treating and preventing acute myocardial infarction|
    US7756561B2|2005-09-30|2010-07-13|Abbott Diabetes Care Inc.|Method and apparatus for providing rechargeable power in data monitoring and management systems|
    US7583190B2|2005-10-31|2009-09-01|Abbott Diabetes Care Inc.|Method and apparatus for providing data communication in data monitoring and management systems|
    US7766829B2|2005-11-04|2010-08-03|Abbott Diabetes Care Inc.|Method and system for providing basal profile modification in analyte monitoring and management systems|
    US20070127745A1|2005-12-07|2007-06-07|Cochlear Limited|Prevention of static bonding between medical device components|
    US7813780B2|2005-12-13|2010-10-12|Medtronic Minimed, Inc.|Biosensors and methods for making and using them|
    US8344966B2|2006-01-31|2013-01-01|Abbott Diabetes Care Inc.|Method and system for providing a fault tolerant display unit in an electronic device|
    CN101460216B|2006-03-30|2013-06-19|瓦莱里塔斯公司|Multi-cartridge fluid delivery device|
    US8226891B2|2006-03-31|2012-07-24|Abbott Diabetes Care Inc.|Analyte monitoring devices and methods therefor|
    US7620438B2|2006-03-31|2009-11-17|Abbott Diabetes Care Inc.|Method and system for powering an electronic device|
    US20070227907A1|2006-04-04|2007-10-04|Rajiv Shah|Methods and materials for controlling the electrochemistry of analyte sensors|
    WO2007143225A2|2006-06-07|2007-12-13|Abbott Diabetes Care, Inc.|Analyte monitoring system and method|
    CN101528824B|2006-08-18|2012-05-09|珀雷克斯公司|Sintered polymeric materials and applications thereof|
    EP1892877B1|2006-08-25|2008-12-03|Alcatel Lucent|Digital signal receiver with Q-monitor|
    US8579853B2|2006-10-31|2013-11-12|Abbott Diabetes Care Inc.|Infusion devices and methods|
    US8930203B2|2007-02-18|2015-01-06|Abbott Diabetes Care Inc.|Multi-function analyte test device and methods therefor|
    US8732188B2|2007-02-18|2014-05-20|Abbott Diabetes Care Inc.|Method and system for providing contextual based medication dosage determination|
    US8123686B2|2007-03-01|2012-02-28|Abbott Diabetes Care Inc.|Method and apparatus for providing rolling data in communication systems|
    US8093039B2|2007-04-10|2012-01-10|The Trustees Of The Stevens Institute Of Technology|Surfaces differentially adhesive to eukaryotic cells and non-eukaryotic cells|
    US8456301B2|2007-05-08|2013-06-04|Abbott Diabetes Care Inc.|Analyte monitoring system and methods|
    US8461985B2|2007-05-08|2013-06-11|Abbott Diabetes Care Inc.|Analyte monitoring system and methods|
    US7928850B2|2007-05-08|2011-04-19|Abbott Diabetes Care Inc.|Analyte monitoring system and methods|
    US8665091B2|2007-05-08|2014-03-04|Abbott Diabetes Care Inc.|Method and device for determining elapsed sensor life|
    EP2540225B1|2007-05-30|2015-07-08|Bayer HealthCare LLC|Method of making a multi-layer pad|
    US20090030145A1|2007-07-26|2009-01-29|Bayer Materialscience Llc|Hydrophilic sealants|
    US20120046533A1|2007-08-29|2012-02-23|Medtronic Minimed, Inc.|Combined sensor and infusion sets|
    US9968742B2|2007-08-29|2018-05-15|Medtronic Minimed, Inc.|Combined sensor and infusion set using separated sites|
    KR20100076962A|2007-09-07|2010-07-06|도레이 카부시키가이샤|Sheet for developing liquid|
    US20090088723A1|2007-09-28|2009-04-02|Accessclosure, Inc.|Apparatus and methods for treating pseudoaneurysms|
    US8000918B2|2007-10-23|2011-08-16|Edwards Lifesciences Corporation|Monitoring and compensating for temperature-related error in an electrochemical sensor|
    US20090247984A1|2007-10-24|2009-10-01|Masimo Laboratories, Inc.|Use of microneedles for small molecule metabolite reporter delivery|
    US8417312B2|2007-10-25|2013-04-09|Dexcom, Inc.|Systems and methods for processing sensor data|
    US7783442B2|2007-10-31|2010-08-24|Medtronic Minimed, Inc.|System and methods for calibrating physiological characteristic sensors|
    US20090118604A1|2007-11-02|2009-05-07|Edwards Lifesciences Corporation|Analyte monitoring system having back-up power source for use in either transport of the system or primary power loss|
    US8512731B2|2007-11-13|2013-08-20|Medtronic Minimed, Inc.|Antimicrobial coatings for medical devices and methods for making and using them|
    US20090188811A1|2007-11-28|2009-07-30|Edwards Lifesciences Corporation|Preparation and maintenance of sensors|
    US9839395B2|2007-12-17|2017-12-12|Dexcom, Inc.|Systems and methods for processing sensor data|
    US9135402B2|2007-12-17|2015-09-15|Dexcom, Inc.|Systems and methods for processing sensor data|
    EP2257794B1|2008-03-28|2018-05-09|Dexcom, Inc.|Polymer membranes for continuous analyte sensors|
    US8682408B2|2008-03-28|2014-03-25|Dexcom, Inc.|Polymer membranes for continuous analyte sensors|
    US8583204B2|2008-03-28|2013-11-12|Dexcom, Inc.|Polymer membranes for continuous analyte sensors|
    WO2009126900A1|2008-04-11|2009-10-15|Pelikan Technologies, Inc.|Method and apparatus for analyte detecting device|
    US20090294302A1|2008-05-28|2009-12-03|John Pasqua|Use of Alginate to Reduce Hematocrit Bias in Biosensors|
    EP2154167A1|2008-07-30|2010-02-17|Bayer MaterialScience AG|Electromechanical converter with a polymer element on a polyisocyanate basis|
    US8900431B2|2008-08-27|2014-12-02|Edwards Lifesciences Corporation|Analyte sensor|
    EP3795987A1|2008-09-19|2021-03-24|Dexcom, Inc.|Particle-containing membrane and particulate electrode for analyte sensors|
    US20100160756A1|2008-12-24|2010-06-24|Edwards Lifesciences Corporation|Membrane Layer for Electrochemical Biosensor and Method of Accommodating Electromagnetic and Radiofrequency Fields|
    US8103456B2|2009-01-29|2012-01-24|Abbott Diabetes Care Inc.|Method and device for early signal attenuation detection using blood glucose measurements|
    US9375169B2|2009-01-30|2016-06-28|Sanofi-Aventis Deutschland Gmbh|Cam drive for managing disposable penetrating member actions with a single motor and motor and control system|
    US8560082B2|2009-01-30|2013-10-15|Abbott Diabetes Care Inc.|Computerized determination of insulin pump therapy parameters using real time and retrospective data processing|
    US8467972B2|2009-04-28|2013-06-18|Abbott Diabetes Care Inc.|Closed loop blood glucose control algorithm analysis|
    WO2010127050A1|2009-04-28|2010-11-04|Abbott Diabetes Care Inc.|Error detection in critical repeating data in a wireless sensor system|
    US20100278738A1|2009-05-04|2010-11-04|Sitzman Thomas J|Method to detect and monitor ischemia in transplanted organs and tissues|
    US8798934B2|2009-07-23|2014-08-05|Abbott Diabetes Care Inc.|Real time management of data relating to physiological control of glucose levels|
    EP2280034A1|2009-07-31|2011-02-02|Bayer MaterialScience AG|Electromechanical converter with a polymer element on the basis of a mixture of polyisocyanate and isocyanate-functional prepolymer and a connection with at least two isocyanate reactive hydroxyl groups|
    WO2011026148A1|2009-08-31|2011-03-03|Abbott Diabetes Care Inc.|Analyte monitoring system and methods for managing power and noise|
    US9314195B2|2009-08-31|2016-04-19|Abbott Diabetes Care Inc.|Analyte signal processing device and methods|
    WO2011041469A1|2009-09-29|2011-04-07|Abbott Diabetes Care Inc.|Method and apparatus for providing notification function in analyte monitoring systems|
    US20110082356A1|2009-10-01|2011-04-07|Medtronic Minimed, Inc.|Analyte sensor apparatuses having interference rejection membranes and methods for making and using them|
    WO2011051690A2|2009-11-02|2011-05-05|Ocutec Limited|Polymers for contact lenses|
    GB0919411D0|2009-11-05|2009-12-23|Ocutec Ltd|Polymer for contact lenses|
    GB0919459D0|2009-11-06|2009-12-23|Ocutec Ltd|Polymer for contact lenses|
    US20110288388A1|2009-11-20|2011-11-24|Medtronic Minimed, Inc.|Multi-conductor lead configurations useful with medical device systems and methods for making and using them|
    US10448872B2|2010-03-16|2019-10-22|Medtronic Minimed, Inc.|Analyte sensor apparatuses having improved electrode configurations and methods for making and using them|
    US8965476B2|2010-04-16|2015-02-24|Sanofi-Aventis Deutschland Gmbh|Tissue penetration device|
    US9795747B2|2010-06-02|2017-10-24|Sanofi-Aventis Deutschland Gmbh|Methods and apparatus for lancet actuation|
    US9215995B2|2010-06-23|2015-12-22|Medtronic Minimed, Inc.|Sensor systems having multiple probes and electrode arrays|
    US8515540B2|2011-02-24|2013-08-20|Cochlear Limited|Feedthrough having a non-linear conductor|
    DK3575796T3|2011-04-15|2021-01-18|Dexcom Inc|ADVANCED ANALYZE SENSOR CALIBRATION AND ERROR DETECTION|
    US9008744B2|2011-05-06|2015-04-14|Medtronic Minimed, Inc.|Method and apparatus for continuous analyte monitoring|
    WO2012173812A1|2011-06-15|2012-12-20|Porex Corporation|Sintered porous plastic liquid barrier media and applications thereof|
    EP2775918B1|2011-11-07|2020-02-12|Abbott Diabetes Care Inc.|Analyte monitoring device and methods|
    WO2013103514A1|2012-01-04|2013-07-11|The Trustees Of The Stevens Institute Of Technology|Clay-containing thin films as carriers of absorbed molecules|
    EP2863990B1|2012-06-21|2017-08-09|Neuronano AB|Medical microelectrode|
    US20140012115A1|2012-07-03|2014-01-09|Medtronic Minimed, Inc.|Plasma deposited adhesion promoter layers for use with analyte sensors|
    US9968306B2|2012-09-17|2018-05-15|Abbott Diabetes Care Inc.|Methods and apparatuses for providing adverse condition notification with enhanced wireless communication range in analyte monitoring systems|
    RU2637417C2|2013-03-15|2017-12-04|Микротек Медикал Текнолоджис Лтд.|Implantable device with jumper|
    AU2014315246B2|2013-09-06|2016-09-22|Med-El Elektromedizinische Geraete Gmbh|Electrode contact with hydrogel covering|
    CN105658272B|2013-09-06|2017-09-12|Med-El电气医疗器械有限公司|Cochlear implant electrode with liquid metal alloy|
    CN104761697B|2014-01-02|2017-12-26|上海移宇科技股份有限公司|The film layer and preparation method of a kind of biology sensor|
    WO2016053340A1|2014-10-02|2016-04-07|Halliburton Energy Services, Inc.|Three-dimensional waveguide sensors for sample analysis|
    US10324058B2|2016-04-28|2019-06-18|Medtronic Minimed, Inc.|In-situ chemistry stack for continuous glucose sensors|
    US11179078B2|2016-06-06|2021-11-23|Medtronic Minimed, Inc.|Polycarbonate urea/urethane polymers for use with analyte sensors|
    CN112088217A|2018-05-16|2020-12-15|美敦力泌力美公司|Thermostable glucose limiting membrane for glucose sensors|
    US20200259159A1|2017-10-04|2020-08-13|Hercules Llc|Elastic and stretchable gel polymer electrolyte|
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    优先权:
    申请号 | 申请日 | 专利标题
    US41077595A| true| 1995-03-27|1995-03-27||
    US08/721,262|US5777060A|1995-03-27|1996-09-26|Silicon-containing biocompatible membranes|
    US08/749,754|US5786439A|1996-10-24|1996-10-24|Hydrophilic, swellable coatings for biosensors|
    US09/123,930|US6462162B2|1995-03-27|1998-07-28|Hydrophilic, swellable coatings for biosensors|US09/123,930| US6462162B2|1995-03-27|1998-07-28|Hydrophilic, swellable coatings for biosensors|
    US10/213,265| US6784274B2|1995-03-27|2002-08-06|Hydrophilic, swellable coatings for biosensors|
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