Sensors with thromboresistant coating

Abstract

Embodiments of the present invention relate to analyte sensors comprising a heparin benzalkonium antithrombogenic coating, and methods of coating analyte sensors.

1 . An analyte sensor, comprising:
 an elongate member;   an analyte-responsive indicator disposed along a distal portion of the elongate member, wherein said indicator is capable of generating a signal related to a concentration of analyte in the blood vessel;   a porous membrane covering at least the indicator along the distal portion of the elongate member; and   a coating comprising heparin and benzalkonium stably associated with at least a portion of the porous membrane.   
     
     
         2 . The analyte sensor of  claim 1 , wherein the elongate member comprises an optical fiber comprising a light path. 
     
     
         3 . The analyte sensor of  claim 2 , wherein the analyte-responsive indicator comprises a fluorophore operably coupled to an analyte binding moiety, wherein analyte binding causes a change in the emission intensity of the fluorophore, and wherein the analyte responsive indictor is disposed within the light path of the optical fiber. 
     
     
         4 . The analyte sensor of  claim 3 , wherein the fluorophore is HPTS-triCysMA and the binding moiety is 3,3′-oBBV. 
     
     
         5 . The analyte sensor of  claim 1 , wherein the porous membrane is a microporous membrane. 
     
     
         6 . The analyte sensor of  claim 5 , wherein the microporous membrane comprises one or more polymers selected from a group consisting of the polyolefins, the fluoropolymers, the polycarbonates, and the polysulfones. 
     
     
         7 . The analyte sensor of  claim 6 , wherein the microporous membrane comprises at least one fluoropolymer. 
     
     
         8 . The analyte sensor of  claim 7 , wherein the at least one fluoropolymer is selected from the group consisting of polytetrafluoroethylene, perfluoroalkoxy polymer, fluorinated ethylene-propylene, polyethylenetetrafluoroethylene, polyvinylfluoride, polyethylenechlorotrifluoroethylene, polyvinylidene fluoride, polychlorotrifluoroethylene, perfluoropolyether, perfluoroelastomer, and fluoroelastomer. 
     
     
         9 . The analyte sensor of  claim 5 , wherein the microporous membrane comprises at least one polyolefin. 
     
     
         10 . The analyte sensor of  claim 9 , wherein the at least one polyolefin is polyethylene. 
     
     
         11 . The analyte sensor of  claim 3 , wherein the analyte-responsive indicator is immobilized within a hydrogel that comprises heparin. 
     
     
         12 . An equilibrium intravascular analyte sensor, comprising:
 an optical fiber configured for positioning within a blood vessel and comprising a light path and an outer surface;   a chemical indicator system comprising a fluorophore operably coupled to an analyte binding moiety, wherein the fluorophore and analyte binding moiety are immobilized within a water-insoluble organic polymer, and wherein the chemical indicator system is disposed within the light path along a distal portion of the optical fiber; and   an antithrombogenic, analyte-permeable coating on at least a portion of the outer surface of the optical fiber and overlying the chemical indicator system disposed therein, wherein the coating comprises heparin covalently cross-linked to the outer surface.   
     
     
         13 . The analyte sensor of  claim 12 , wherein the fluorophore is HPTS-triCysMA and the binding moiety is 3,3′-oBBV. 
     
     
         14 . The analyte sensor of  claim 12 , further comprising a porous, analyte-permeable membrane disposed between the chemical indicator system and the antithrombogenic coating. 
     
     
         15 . A method for reducing the thrombogenicity of an analyte sensor, comprising:
 providing the analyte sensor comprising an elongate optical fiber defining a light path, an equilibrium fluorescent chemical indicator system immobilized within a hydrogel and disposed along a distal region of the optical fiber within the light path, and an analyte-permeable porous membrane, which forms an outer layer of at least a portion of the distal region, wherein the indicator system is covered by the porous membrane;   contacting the analyte sensor with a single solution comprising a mixture of heparin and benzalkonium, or with separate first and second solutions, wherein the first solution comprises heparin and the second solution comprises benzalkonium; and   drying the analyte sensor.   
     
     
         16 . The method of  claim 15 , wherein the contacting and drying steps are repeated between 2 and 10 times. 
     
     
         17 . The method of  claim 15 , further comprising a step of soaking the analyte sensor in a solution comprising heparin for a time sufficient to allow the heparin to saturate the hydrogel. 
     
     
         18 . The method of  claim 15 , wherein the equilibrium fluorescent chemical indicator system comprises a fluorophore and an analyte binding moiety. 
     
     
         19 . The method of  claim 18 , wherein the fluorophore is HPTS-triCysMA, the binding moiety is 3,3′-oBBV, and the hydrogel is a DMAA (N,N-dimethylacrylamide) hydrogel matrix. 
     
     
         20 . The method of  claim 15 , wherein the porous membrane comprises microporous polyethylene. 
     
     
         21 . A method for reducing the thrombogenicity of an analyte sensor, comprising:
 providing the analyte sensor comprising an elongate optical fiber defining a light path, an equilibrium fluorescent chemical indicator system disposed along a distal region of the optical fiber within the light path, and an analyte-permeable porous membrane, which forms an outer surface over at least a portion of the distal region, wherein the indicator system is covered by the porous membrane;   providing a photoactivatable chemical linking agent and an antithrombogenic molecule, wherein the linking agent is capable, upon activation, of covalent attachment to the outer surface and the antithrombogenic molecule, wherein the linking agent comprises a charged, nonpolymeric di- or higher functional photoactivatable compound comprising two or more photoreactive groups and one or more charged groups; and   activating the two or more photoreactive groups, thereby cross-linking the antithrombogenic molecule to the outer surface.   
     
     
         22 . The method of  claim 21 , wherein the equilibrium fluorescent chemical indicator system comprises a fluorophore and an analyte binding moiety, immobilized within a water-insoluble organic polymer. 
     
     
         23 . The method of  claim 22 , wherein the fluorophore is HPTS-triCysMA, the binding moiety is 3,3′-oBBV, and the water-insoluble organic polymer is a DMAA (N,N-dimethylacrylamide) hydrogel matrix. 
     
     
         24 . The method of  claim 21 , wherein the porous membrane comprises microporous polyethylene.