Diffusion barriers and spacer membranes for enzymatic in-vivo sensors

Abstract

An electrode system is disclosed for measuring a concentration or presence of an analyte under in-vivo conditions, where the electrode system includes at least one electrode with immobilized enzyme molecules and an improved diffusion barrier that controls diffusion of the analyte from body fluid surrounding the electrode system to the enzyme molecules. The diffusion barrier includes a hydrophilic polyurethane or a block copolymer having at least one hydrophilic block and at least one hydrophobic block. The electrode system also can include a spacer membrane that includes a hydrophilic copolymer of acrylic and/or methacrylic monomers.

1 - 23 . (canceled) 
     
     
         24 . A method for determining the concentration or presence of an analyte in a body fluid and/or body tissue, comprising:
 implanting an in vivo electrode system beneath a patient's skin in operable contact with the body fluid and/or body tissue comprising the analyte, the in-vivo electrode system being suitable for use for the in-vivo measuring of the analyte,   the electrode system comprising:
 a working electrode, 
 a counter and/or reference electrode, 
 enzyme molecules immobilized directly on the working electrode, 
 an electronic system operably connected to the working electrode and the counter and/or reference electrode, and 
 a spacer membrane forming at least a portion of an outer layer of the electrode system and covering at least the working electrode, the spacer membrane being made of a hydrophilic copolymer of acrylic and/or methacrylic monomers comprising more than 50 mol-% hydrophilic monomers selected from the group consisting of hydrophilic (meth)acrylesters with a polar group, hydrophilic (meth)acrylamides, (meth)acrylic acid, and combinations thereof,
 the hydrophilic copolymer being a block copolymer comprising up to about 40 mol-% hydrophobic monomers selected from the group consisting of: methyl acrylate, methyl methacrylate (MMA), ethyl acrylate, ethyl methacrylate (EMA), n- or i-propyl acrylate, n- or i-propyl methacrylate, n-butyl acrylate, n-butyl methacrylate (BUMA), neopentyl acrylate, neopentyl methacrylate, and combinations thereof; 
 
   applying a voltage to the working and counter/reference electrode;   measuring the resulting current; and   determining the analyte in the body fluid and/or tissue from the measured current.   
     
     
         25 . The method of  claim 24 , wherein the spacer membrane is a hydrophilic copolymer comprising at least two acrylic and/or methacrylic monomers. 
     
     
         26 . The method of  claim 24 , wherein the hydrophilic monomers are selected from the group consisting: of 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate (HEMA), 2-methoxyethyl acrylate, 2-methoxyethyl methacrylate, 2-ethoxyethyl acrylate, 2-ethoxyethyl methacrylate, 2- or 3-hydroxypropyl acrylate, 2- or 3-hydroxypropyl methacrylate (2- or 3-HPMA), 2- or 3-methoxypropyl acrylate, 2- or 3-methoxypropyl methacrylate, 2- or 3-ethoxypropyl acrylate, 2- or 3-ethoxypropyl methacrylate, 1- or 2-glycerol acrylate, 1- or 2-glycerol methacrylate, acrylamide, methacrylamide, an N-alkyl- or N,N-dialkyl acrylamide, an N-alkyl- or N,N-dialkyl methylamide, wherein the alkyl comprises 1-3 C-atoms, acrylic acid, methacrylic acid, and combinations thereof. 
     
     
         27 . The method of  claim 26 , wherein the hydrophilic monomers are HEMA and/or 2-HPMA. 
     
     
         28 . The method of  claim 24 , wherein the hydrophilic copolymer comprises at least about 70 mol-% hydrophilic monomers and at most about 30 mol-% hydrophobic monomers. 
     
     
         29 . The method of  claim 24 , wherein the hydrophilic copolymer comprises up to about 30 mol-% hydrophobic monomers. 
     
     
         30 . The method of  claim 24 , wherein the hydrophobic monomers are MMA and/or BUMA. 
     
     
         31 . The method of  claim 24 , wherein the hydrophobic monomers are MMA or BUMA, and the hydrophilic monomers are HEMA and/or 2-HPMA. 
     
     
         32 . The method of  claim 24 , wherein the spacer membrane comprises BUMA, HEMA and 2-HPMA, and wherein the hydrophilic copolymer comprises 80 mol-% of HEMA monomers and at most 20 mol-% hydrophobic monomers. 
     
     
         33 . The method of  claim 24 , wherein the spacer membrane has a thickness that is less than about 20 μm. 
     
     
         34 . The method of  claim 33 , wherein the spacer membrane has a thickness that is less than 5 μm. 
     
     
         35 . The method of  claim 33 , wherein the spacer membrane has a thickness that is from 1 μm to 3 μm. 
     
     
         36 . The method of  claim 24 , wherein a relative water uptake of the hydrophilic copolymer does not exceed 50 wt-% based on the total weight of the copolymer. 
     
     
         37 . The method of  claim 36 , wherein a relative water uptake of the hydrophilic copolymer does not exceed 40 wt-% based on the total weight of the copolymer. 
     
     
         38 . The method of  claim 36 , wherein a relative water uptake of the hydrophilic copolymer does not exceed 30 wt-% based on the total weight of the copolymer. 
     
     
         39 . The method of  claim 24  in which the electrode system further comprises a diffusion barrier. 
     
     
         40 . The method of  claim 39 , wherein the analyte is glucose. 
     
     
         41 . The spacer membrane of  claim 40 , wherein the hydrophilic copolymer attenuates a foreign body reaction (FBR) against the electrode system when compared to an electrode system that lacks the spacer membrane. 
     
     
         42 . The spacer membrane of  claim 41  in which the hydrophilic copolymer attenuates the activation of immune cells and/or prevents hemolysis and complement activation.