Analyte measuring device

Abstract

An implantable analyte-measuring device including a membrane adapted to promote vascularization and/or interfere with barrier cell layer formation. The membrane includes any combination of materials, architecture, and bioactive agents that facilitate analyte transport to provide long-term in vivo performance of the implantable analyte-measuring device.

1 . A device for subcutaneous monitoring of glucose levels, comprising a housing and a sensor, the sensor comprising an angiogenic layer for promoting adequate microcirculatory delivery of glucose and oxygen to the sensor, wherein the angiogenic layer further comprises a bioactive agent.  
     
     
         2 . The device of  claim 1 , wherein the device is sized and configured for wholly subcutaneous implantation.  
     
     
         3 . The device of  claim 1 , wherein the angiogenic layer comprises a material selected from the group consisting of hydrophilic polyvinylidene fluoride, mixed cellulose esters, polyvinyl chloride, polyvinyl alcohol, polyethylene, polytetrafluoroethylene, cellulose acetate, cellulose nitrate, polycarbonate, nylon, polyester, mixed esters of cellulose polyvinylidene difluoride, silicone, polyacrylonitrile, polypropylene, polysulfone, polymethacrylate, and mixtures thereof.  
     
     
         4 . The device of  claim 3 , wherein the angiogenic layer comprises expanded polytetrafluoroethylene.  
     
     
         5 . The device of  claim 3 , wherein the angiogenic layer comprises silicone.  
     
     
         6 . The device of  claim 1 , wherein the bioactive agent is selected from the group consisting of anti-inflammatory agents, anti-infective agents, anesthetics, inflammatory agents, growth factors, immunosuppressive agents, antiplatelet agents, anticoagulants, ACE inhibitors, cytotoxic agents, anti-barrier cell compounds, vascularization-inducing compounds, anti-sense molecules, and mixtures thereof.  
     
     
         7 . The device of  claim 6 , wherein the bioactive agent is an anti-inflammatory agent selected from the group consisting of nonsteroidal anti-inflammatory drugs (NTHEs), aspirin, celecoxib, choline magnesium trisalicylate, diclofenac potasium, diclofenac sodium, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, melenamic acid, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, rofecoxib, salsalate, sulindac, tolmetin, corticosteroids, cortisone, hydrocortisone, methylprednisolone, prednisone, prednisolone, betamethesone, beclomethasone dipropionate, budesonide, dexamethasone sodium phosphate, flunisolide, fluticasone propionate, triamcinolone acetonide, betamethasone, fluocinolone, fluocinonide, betamethasone dipropionate, betamethasone valerate, desonide, desoximetasone, fluocinolone, triamcinolone, triamcinolone acetonide, clobetasol propionate, dexamethasone, and mixtures thereof.  
     
     
         8 . The device of  claim 6 , wherein the bioactive agent is an anti-infective agent selected from the group consisting of anthelmintics, mebendazole, antibiotics, aminoclycosides, gentamicin, neomycin, tobramycin, antifungal antibiotics, amphotericin b, fluconazole, griseofulvin, itraconazole, ketoconazole, nystatin, micatin, tolnaftate, cephalosporins, cefaclor, cefazolin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, cephalexin, beta-lactam antibiotics, cefotetan, meropenem, chloramphenicol, macrolides, azithromycin, clarithromycin, erythromycin, penicillins penicillin G sodium salt, amoxicillin, ampicillin, dicloxacillin, nafcillin, piperacillin, ticarcillin, tetracyclines, doxycycline, minocycline, tetracycline, bacitracin, clindamycin, colistimethate sodium, polymyxin b sulfate, vancomycin; antivirals including acyclovir, amantadine, didanosine, efavirenz, foscarnet, ganciclovir, indinavir, lamivudine, nelfinavir, ritonavir, saquinavir, stavudine, valacyclovir, valganciclovir, zidovudine, quinolones, ciprofloxacin, levofloxacin, sulfonamides, sulfadiazine, sulfisoxazole, sulfones, dapsone, furazolidone, metronidazole, pentamidine, sulfanilamidum crystallinum, gatifloxacin, sulfamethoxazole/trimethoprim, and mixtures thereof.  
     
     
         9 . The device of  claim 6 , wherein the bioactive agent is an anesthetic selected from the group consisting of ethanol, bupivacaine, chloroprocaine, levobupivacaine, lidocaine, mepivacaine, procaine, ropivacaine, tetracaine, desflurane, isoflurane, ketamine, propofol, sevoflurane, codeine, fentanyl, hydromorphone, marcaine, meperidine, methadone, morphine, oxycodone, remifentanil, sufentanil, butorphanol, nalbuphine, tramadol, benzocaine, dibucaine, ethyl chloride, xylocaine, phenazopyridine, and mixtures thereof.  
     
     
         10 . The device of  claim 1 , wherein the bioactive agent is selected from the group. consisting of S1P, monobutyrin, Cyclosporin A, Anti-thrombospondin-2, Rapamycin, Dexamethasone, Super Oxide Dismutase (SOD) Mimetic Compounds, Lipopolysaccharide, angiogenic lipid product of adipocytes, Sphingosine-1-Phosphate, Thrombospondin-2 antisense, and mixtures thereof.  
     
     
         11 . The device of  claim 1 , wherein the bioactive agent is incorporated within the angiogenic layer by absorption into the angiogenic layer.  
     
     
         12 . The device of  claim 1 , wherein the bioactive agent is incorporated within the angiogenic layer during formation of the angiogenic layer.  
     
     
         13 . The device of  claim 1 , wherein the bioactive agent is incorporated within the angiogenic layer using a microcapsule agent.  
     
     
         14 . The device of  claim 1 , wherein the bioactive agent is incorporated within the angiogenic layer using a carrier agent.  
     
     
         15 . The device of  claim 1 , wherein the bioactive agent is incorporated in the angiogenic layer using at least one substance selected from the group consisting of an ionic surfactant, a nonionic surfactant, a detergent, an emulsifier, a demulsifier, a stabilizer, an aqueous carrier, an oleaginous carrier, a solvent, a preservative, an antioxidant, a buffering agent, and mixtures thereof.  
     
     
         16 . The device of  claim 1 , wherein the angiogenic layer comprises a plurality of pores and wherein the bioactive agent is contained within the pores of the angiogenic layer.  
     
     
         17 . The device of  claim 1 , the sensor further comprising a membrane impregnated with an oxidase.  
     
     
         18 . The device of  claim 17 , wherein the oxidase impregnated membrane comprises a resistance layer, an enzyme layer, an interference layer, and an electrolyte layer.  
     
     
         19 . The device of  claim 17 , wherein the oxidase impregnated membrane comprises a single homogeneous structure.  
     
     
         20 . The device of  claim 18 , wherein the resistance layer restricts transport of glucose therethrough.  
     
     
         21 . The device of  claim 18 , wherein the resistance layer comprises a polymer membrane with an oxygen-to-glucose permeability ratio of at least about 100:1.  
     
     
         22 . The device of  claim 18 , wherein the interference layer comprises a hydrophobic membrane substantially permeable to hydrogen peroxide.  
     
     
         23 . The device of  claim 18 , wherein the interference layer comprises a hydrophobic membrane substantially impermeable to at least one substance having a molecular weight substantially greater than hydrogen peroxide.  
     
     
         24 . The device of  claim 18 , wherein the electrolyte layer comprises a semipermeable hydrophilic coating.  
     
     
         25 . The device of  claim 18 , wherein the electrolyte layer comprises a curable copolymer of a urethane polymer and a hydrophilic film-forming polymer.  
     
     
         26 . The device of  claim 18 , wherein the enzyme layer comprises glucose oxidase.  
     
     
         27 . The device of  claim 1 , wherein the housing comprises an electronic circuit and at least two electrodes operatively connected to the electronic circuit, and wherein the sensor is operably connected to the electrodes of the housing.  
     
     
         28 . The device of  claim 27 , wherein the housing comprises a data transmitting apparatus operatively connected to the electronic circuit for transmitting data to a location external to the device.  
     
     
         29 . The device of  claim 28 , wherein the data transmitting apparatus comprises radiotelemetry.  
     
     
         30 . The device of  claim 1 , wherein the sensor is located at an apex of the housing.  
     
     
         31 . The device of  claim 1 , wherein the sensor comprises a dome configuration on at least a portion thereof.  
     
     
         32 . A device for subcutaneous monitoring of a glucose level, comprising a housing and a sensor, the sensor comprising a first domain, a second domain, and a bioactive agent; wherein the first domain supports tissue ingrowth and is positioned more distal to the housing than the second domain; wherein the second domain is substantially impermeable to macrophages and is situated between the first domain and the housing, and wherein the bioactive agent is incorporated within at least one of the first domain, the second domain, and the sensor.  
     
     
         33 . The device of  claim 32 , wherein the device is sized and configured for wholly subcutaneous implantation.  
     
     
         34 . The device of  claim 32 , wherein the first domain comprises a material selected from the group consisting of hydrophilic polyvinylidene fluoride, mixed cellulose esters, polyvinyl chloride, polyethylene, polyvinyl alcohol, polytetrafluoroethylene, expanded polytetrafluoroethylene, cellulose acetate, cellulose nitrate, polycarbonate, nylon, polyester, mixed esters of cellulose polyvinylidene difluoride, silicone, polyacrylonitrile, polypropylene, polysulfone, polymethacrylate, and mixtures thereof.  
     
     
         35 . The device of  claim 32 , wherein the bioactive agent is selected from the group consisting of anti-inflammatory agents, anti-infective agents, anesthetics, inflammatory agents, growth factors, immunosuppressive agents, antiplatelet agents, anticoagulants, ACE inhibitors, cytotoxic agents, anti-barrier cell compounds, vascularization-inducing compounds, anti-sense molecules, and mixtures thereof.  
     
     
         36 . The device of  claim 35 , wherein the bioactive agent is an anti-inflammatory agent selected from the group consisting of nonsteroidal anti-inflammatory drugs (NTHEs), aspirin, celecoxib, choline magnesium trisalicylate, diclofenac potasium, diclofenac sodium, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, melenamic acid, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, rofecoxib, salsalate, sulindac, tolmetin, corticosteroids, cortisone, hydrocortisone, methylprednisolone, prednisone, prednisolone, betamethesone, beclomethasone dipropionate, budesonide, dexamethasone sodium phosphate, flunisolide, fluticasone propionate, triamcinolone acetonide, betamethasone, fluocinolone, fluocinonide, betamethasone dipropionate, betamethasone valerate, desonide, desoximetasone, fluocinolone, triamcinolone, triamcinolone acetonide, clobetasol propionate, dexamethasone, and mixtures thereof.  
     
     
         37 . The device of  claim 35 , wherein the bioactive agent is an anti-infective agent selected from the group consisting of anthelmintics, mebendazole, antibiotics, aminoclycosides, gentamicin, neomycin, tobramycin, antifungal antibiotics, amphotericin b, fluconazole, griseofulvin, itraconazole, ketoconazole, nystatin, micatin, tolnaftate, cephalosporins, cefaclor, cefazolin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, cephalexin, beta-lactam antibiotics, cefotetan, meropenem, chloramphenicol, macrolides, azithromycin, clarithromycin, erythromycin, penicillins penicillin G sodium salt, amoxicillin, ampicillin, dicloxacillin, nafcillin, piperacillin, ticarcillin, tetracyclines, doxycycline, minocycline, tetracycline, bacitracin, clindamycin, colistimethate sodium, polymyxin b sulfate, vancomycin; antivirals including acyclovir, amantadine, didanosine, efavirenz, foscarnet, ganciclovir, indinavir, lamivudine, nelfinavir, ritonavir, saquinavir, stavudine, valacyclovir, valganciclovir, zidovudine; quinolones, ciprofloxacin, levofloxacin, sulfonamides, sulfadiazine, sulfisoxazole, sulfones, dapsone, furazolidone, metronidazole, pentamidine, sulfanilamidum crystallinum, gatifloxacin, and sulfamethoxazole/trimethoprim.  
     
     
         38 . The device of  claim 35 , wherein the bioactive agent is an anesthetic selected from the group consisting of ethanol, bupivacaine, chloroprocaine, levobupivacaine, lidocaine, mepivacaine, procaine, ropivacaine, tetracaine, desflurane, isoflurane, ketamine, propofol, sevoflurane, codeine, fentanyl, hydromorphone, marcaine, meperidine, methadone, morphine, oxycodone, remifentanil, sufentanil, butorphanol, nalbuphine, tramadol, benzocaine, dibucaine, ethyl chloride, xylocaine, phenazopyridine, and mixtures thereof.  
     
     
         39 . The device of  claim 32 , wherein the bioactive agent is selected from the group consisting of S1P, monobutyrin, Cyclosporin A, Anti-thrombospondin-2, Rapamycin, Dexamethasone, Super Oxide Dismutase (SOD) Mimetic Compounds, Lipopolysaccharide, angiogenic lipid product of adipocytes, Sphingosine-1-Phosphate, Thrombospondin-2 antisense, and mixtures thereof.  
     
     
         40 . The device of  claim 32 , wherein the bioactive agent is incorporated within the first domain by absorption.  
     
     
         41 . The device of  claim 32 , wherein the bioactive agent is incorporated within the second domain by absorption.  
     
     
         42 . The device of  claim 32 , wherein the bioactive agent is loaded into at least one of the first domain, the second domain, and the sensor using a microcapsule agent.  
     
     
         43 . The device of  claim 32 , wherein the bioactive agent is loaded is loaded into at least one of the first domain, the second domain, and the sensor using a carrier agent.  
     
     
         44 . The device of  claim 32 , wherein the bioactive agent is incorporated into the vascular promotion layer using at least one substance selected from the group consisting of an ionic surfactant, a nonionic surfactant, a detergent, an emulsifier, a demulsifier, a stabilizer, an aqueous carrier, an oleaginous carrier, a solvent, a preservative, an antioxidant, a buffering agent, and mixtures thereof.  
     
     
         45 . The device of  claim 32 , wherein the first domain comprises a plurality of pores and wherein the vascular promotion layer comprises the bioactive agent contained within the pores of the angiogenic layer.  
     
     
         46 . The device of  claim 32 , the sensor further comprising a membrane impregnated with an oxidase.  
     
     
         47 . The device of  claim 46 , wherein the oxidase impregnated membrane comprises a resistance layer, an enzyme layer, an interference layer, and an electrolyte layer.  
     
     
         48 . The device of  claim 46 , wherein the oxidase impregnated membrane comprises a single homogeneous structure.  
     
     
         49 . The device of  claim 47 , wherein the resistance layer restricts transport of glucose therethrough.  
     
     
         50 . The device of  claim 47 , wherein the resistance layer comprises a polymer membrane with an oxygen-to-glucose permeability ratio of at least about 100:1.  
     
     
         51 . The device of  claim 47 , wherein the interference layer comprises a hydrophobic membrane substantially permeable to hydrogen peroxide.  
     
     
         52 . The device of  claim 47 , wherein the interference layer comprises a hydrophobic membrane substantially impermeable to substances having a molecular weight substantially greater than hydrogen peroxide.  
     
     
         53 . The device of  claim 47 , wherein the electrolyte layer comprises a semipermeable hydrophilic coating.  
     
     
         54 . The device of  claim 47 , wnerein the electrolyte layer comprises a curable copolymer of a urethane polymer and a hydrophilic film-forming polymer.  
     
     
         55 . The device of  claim 47 , wherein the enzyme layer comprises glucose oxidase.  
     
     
         56 . The device of  claim 32 , wherein the housing comprises an electronic circuit and at least two electrodes operatively connected to the electronic circuit, and wherein the sensor is operably connected to the electrodes of the housing.  
     
     
         57 . The device of  claim 56 , wherein the housing comprises a data transmitting apparatus operatively connected to the electronic circuit for transmitting data to a location external to the device.  
     
     
         58 . The device of  claim 57 , wherein the data transmitting apparatus comprises radiotelemetry.  
     
     
         59 . The device of  claim 32 , wherein the sensor is located at an apex of the housing.  
     
     
         60 . The device of  claim 32 , wherein the sensor comprises a dome configuration on at least a portion thereof.  
     
     
         61 . A device for subcutaneous monitoring of glucose levels, comprising a housing, a sensor, and an an angiogenic layer for promoting adequate microcirculatory delivery of glucose and oxygen to the sensor, wherein the angiogenic layer is configured to promote vascularization in or around the angiogenic layer so as to maintain sufficient blood flow to the sensor for glucose measurement thereby.  
     
     
         62 . The device of  claim 61 , wherein the device is sized and configured for wholly subcutaneous implantation.  
     
     
         63 . The device of  claim 61 , wherein the angiogenic layer comprises a material selected from the group consisting of hydrophilic polyvinylidene fluoride, mixed cellulose esters, polyvinyl chloride, polyvinyl alcohol, polyethylene, polytetrafluoroethylene, cellulose acetate, cellulose nitrate, polycarbonate, nylon, polyester, mixed esters of cellulose polyvinylidene difluoride, silicone, polyacrylonitrile, polypropylene, polysulfone, polymethacrylate, and mixtures thereof.  
     
     
         64 . The device of  claim 63 , wherein the angiogenic layer comprises expanded polytetrafluoroethylene.  
     
     
         65 . The device of  claim 63 , wherein the angiogenic layer comprises silicone.  
     
     
         66 . The device of  claim 61 , the sensor further comprising a membrane impregnated with an oxidase.  
     
     
         67 . The device of  claim 66 , wherein the oxidase impregnated membrane comprises a resistance layer, an enzyme layer, an interference layer, and an electrolyte layer.  
     
     
         68 . The device of  claim 66 , wherein the oxidase impregnated membrane comprises a single homogeneous structure.  
     
     
         69 . The device of  claim 67 , wherein the resistance layer restricts transport of glucose therethrough.  
     
     
         70 . The device of  claim 67 , wherein the resistance layer comprises a polymer membrane with an oxygen-to-glucose permeability ratio of at least about 100:1.  
     
     
         71 . The device of  claim 67 , wherein the interference layer comprises a hydrophobic membrane substantially permeable to hydrogen peroxide.  
     
     
         72 . The device of  claim 67 , wherein the interference layer comprises a hydrophobic membrane substantially impermeable to at least one substance having a molecular weight substantially greater than hydrogen peroxide.  
     
     
         73 . The device of  claim 67 , wherein the electrolyte layer comprises a semipermeable hydrophilic coating.  
     
     
         74 . The device of  claim 67 , wherein the electrolyte layer comprises a curable copolymer of a urethane polymer and a hydrophilic film-forming polymer.  
     
     
         75 . The device of  claim 67 , wherein the enzyme layer comprises glucose oxidase.  
     
     
         76 . The device of  claim 61 , wherein the housing comprises an electronic circuit and at least two electrodes operatively connected to the electronic circuit, and wherein the sensor is operably connected to the electrodes of the housing.  
     
     
         77 . The device of  claim 76 , wherein the housing comprises a data transmitting apparatus operatively connected to the electronic circuit for transmitting data to a location external to the device.  
     
     
         78 . The device of  claim 77 , wherein the data transmitting apparatus comprises radiotelemetry.  
     
     
         79 . The device of  claim 61 , wherein the sensor is located at an apex of the housing.  
     
     
         80 . The device of  claim 61 , wherein the sensor comprises a dome configuration on at least a portion thereof.