Tissue implantable sensor with hermetically sealed housing

Abstract

A tissue-implantable sensor for measurement of solutes in fluids and gases, such as oxygen and glucose, is provided. The sensor includes: i) a detector array including at least one detector; ii) a telemetry transmission portal; iii) an electrical power source; and iv) circuitry electrically connected to the detector array including signal processing means for determining an analyte level, such as glucose level, in a body fluid contacting the detectors. The sensor components are disposed in a hermetically sealed housing having a size and shape suitable for comfortable, safe, and unobtrusive subcutaneous implantation allowing for in vivo detection and long term monitoring of tissue glucose concentrations by wireless telemetry.

1 .- 100 . (canceled) 
     
     
         101 . An implantable analyte sensor configured for implantation within tissues of a body, the implantable analyte sensor comprising:
 a substrate;   a detector array disposed on at least an outer surface of the substrate and comprising at least one detector and one or more membrane layers, the one or more membrane layers comprising:
 an enzymatic material; 
 a membrane structure comprising (i) a cavity, the enzymatic material disposed within the cavity, (ii) a top wall on an exterior surface of the membrane structure, (iii) at least one side wall connected to a perimeter of the top wall, at least the top wall and the at least one side wall defining the cavity, and (iv) an aperture disposed in the top wall and in communication with the cavity; and 
 a non-enzymatic coating membrane disposed within the aperture; and 
   circuitry operatively connected to the detector array and configured to process at least a portion of signals generated by the at least one detector for generation of processed detector signals related to a physiologic analyte concentration.   
     
     
         102 . The implantable analyte sensor of  claim 101 , wherein the one or more membrane layers comprise a three-dimensional portion of the detector array which extends outwardly from the outer surface of the substrate. 
     
     
         103 . The implantable analyte sensor of  claim 102 , wherein the at least one detector comprises a plurality of detectors, the respective three-dimensional portions of each of the plurality of detectors configured to promote interlock with the tissues of the body and limit slippage of the implantable analyte sensor when the implantable analyte sensor is implanted subcutaneously. 
     
     
         104 . The implantable analyte sensor of  claim 101 , wherein the detector array further comprises at least one electrolyte layer and an inner membrane, the inner membrane comprising a bottom wall of the cavity, at least a portion of the at least one electrolyte layer disposed between at least one detector and the inner membrane. 
     
     
         105 . The implantable analyte sensor of  claim 101 , wherein:
 the enzymatic material comprises a crosslinked protein material having at least glucose oxidase immobilized therein; and   the non-enzymatic coating membrane is formed on at least a portion of a top surface of the crosslinked protein material having at least glucose oxidase immobilized therein.   
     
     
         106 . The implantable analyte sensor of  claim 105 , wherein the non-enzymatic coating membrane is configured to limit contact between the enzymatic material and the tissues of the body when the implantable analyte sensor is implanted subcutaneously, and thereby limit immune response by the tissues to the glucose oxidase. 
     
     
         107 . The implantable analyte sensor of  claim 101 , wherein the non-enzymatic coating membrane comprises a non-enzymatic cross-linked protein material configured to occlude the aperture. 
     
     
         108 . An implantable analyte sensor, comprising:
 a substrate;   a detector array disposed on at least an outer surface of the substrate and comprising at least one detector and one or more membrane layers, the one or more membrane layers comprising:
 an enzymatic material; 
 a membrane structure comprising at least a cavity and an aperture, the aperture in communication with the cavity, the enzymatic material disposed within the cavity; 
 a non-enzymatic cross-linked protein material disposed within the aperture, the membrane structure and the non-enzymatic cross-linked protein material configured to enclose the enzymatic material within the cavity; and 
 an electrolyte layer disposed between the at least one detector and the membrane structure; and 
   circuitry operatively connected to the detector array and configured to process at least a portion of signals generated by the at least one detector for generation of processed detector signals related to a physiologic analyte concentration when the implantable analyte sensor is implanted subcutaneously.   
     
     
         109 . The implantable analyte sensor of  claim 108 , wherein the enzymatic material comprises a cross-linked protein material having glucose oxidase and catalase co-immobilized therein, and the implantable analyte sensor is configured for detection of blood glucose. 
     
     
         110 . The implantable analyte sensor of  claim 109 , wherein the glucose oxidase is immobilized within the crosslinked protein material at a first concentration, and the catalase is immobilized within the cross-linked protein material at a second concentration, the first concentration selected for a specified detector response time characteristic, the second concentration selected to be in excess relative to the first concentration in order to limit degradation of the glucose oxidase caused by exposure to a hydrogen peroxide byproduct, the hydrogen peroxide byproduct produced during a reaction between the glucose oxidase and the blood glucose when the implantable analyte sensor is implanted subcutaneously. 
     
     
         111 . The implantable analyte sensor of  claim 108 , wherein the non-enzymatic cross-linked protein material is configured to limit contact between the enzymatic material and the tissues of the body when the implantable analyte sensor is implanted subcutaneously, and thereby limit immune response by the tissues to the enzymatic material. 
     
     
         112 . The implantable analyte sensor of  claim 108 , wherein a thickness of the non-enzymatic crosslinked protein material is selected for a specified analyte permeability characteristic. 
     
     
         113 . The implantable analyte sensor of  claim 108 , wherein a thickness of the non-enzymatic crosslinked protein material is selected for a specified detector response time characteristic. 
     
     
         114 . An analyte detector apparatus configured for use with an implantable analyte sensor, the implantable analyte sensor configured for implantation within tissues of a body, the analyte detector apparatus comprising:
 at least one detector, the at least one detector configured to be operatively coupled to circuitry of the implantable analyte sensor for processing at least a portion of signals generated by the at least one detector for generation of processed detector signals related to a physiologic analyte concentration when the implantable analyte sensor is implanted subcutaneously; and   one or more membrane layers associated with the at least one detector, the one or more membrane layers comprising at least:
 an enzymatic material; and 
 a membrane structure comprising:
 a cavity, the enzymatic material disposed within the cavity; and 
 an aperture in communication with the cavity, the aperture having a non-enzymatic coating membrane disposed therein; 
 
   wherein the non-enzymatic coating membrane configured to occlude the aperture and enable diffusion of analyte from the tissues of the body into the cavity for reaction with the enzymatic material when the implantable analyte sensor is implanted subcutaneously.   
     
     
         115 . The analyte detector apparatus of  claim 115 , wherein a thickness of the non-enzymatic coating membrane is selected for a specified analyte permeability characteristic. 
     
     
         116 . The analyte detector apparatus of  claim 115 , wherein a thickness of the non-enzymatic coating membrane is selected for a specified detector response time characteristic. 
     
     
         117 . The analyte detector apparatus of  claim 115 , wherein:
 the enzymatic material comprises a crosslinked protein material having at least glucose oxidase immobilized therein; and   the non-enzymatic coating membrane is formed on a top surface of the crosslinked protein material having at least glucose oxidase immobilized therein.   
     
     
         118 . The analyte detector apparatus of  claim 115 , wherein the membrane structure further comprises: (i) a bottom wall, (ii) a top wall opposing the bottom wall, (iii) at least one side wall connected to each of the bottom wall and the top wall, the bottom wall, the top wall and the at least one side wall defining the cavity, the aperture disposed in the top wall. 
     
     
         119 . The analyte detector apparatus of  claim 115 , wherein:
 the implantable analyte sensor is configured for detection of blood glucose; and   the enzymatic material comprises a crosslinked protein material having at least two types of enzyme co-immobilized therein, the at least two types of enzyme comprising at least glucose oxidase and catalase, the glucose oxidase immobilized within the crosslinked protein material at a first concentration, and the catalase immobilized within the cross-linked protein material at a second concentration, the first concentration selected for a specified glucose detection characteristic, the second concentration selected to be in excess relative to the first concentration in order to limit peroxide-mediated inactivation of the glucose oxidase.   
     
     
         120 . The analyte detector apparatus of  claim 115 , wherein the non-enzymatic coating membrane further configured to limit contact between the enzymatic material and the tissues of the body when the implantable analyte sensor is implanted subcutaneously, and thereby limit immune response by the tissues to the enzymatic material.