Patent Application
20210212605
The present invention relates to methods and materials useful for implantable medical devices, such as glucose sensors used in the management of diabetes.
Patient responses to implanted foreign materials present challenges in the design of medical devices. These patient responses are typically characterized by the infiltration of inflammatory cells such as macrophages and their chronic activation, which can lead to the formation of a fibrous capsule at the site of implantation. This capsule typically functions to isolate the foreign body from the host immune system, and can be detrimental to the function of many medical devices including for example implanted biosensors as well as cardiovascular and orthopedic implants etc. The dense, collagen-rich tissue of a capsule may prevent diffusion of small molecules such as glucose to and from the implanted device. While efforts to reduce the immune response to implanted biomaterials have been somewhat successful, the conventional approaches have not been sufficient in addressing the effects of foreign body responses (FBR) on implanted device function.
The quantitative determination of analytes in humans and mammals is of great importance in the diagnosis and maintenance of a number of pathological conditions. For this reason, implantable analyte sensors are used to monitor a wide variety of compounds including in vivo analytes. The determination of glucose concentrations in body fluids is of particular importance to diabetic individuals, individuals who must frequently check glucose levels in their body fluids to regulate the glucose intake in their diets. The results of such tests can be crucial in determining what, if any, insulin and/or other medication need to be administered. Unfortunately, foreign body responses to implanted glucose sensors can inhibit the diffusion of glucose to and from the implanted glucose sensor, a phenomenon which can compromise the accuracy of sensor readings over time. In particular, glucose sensors become sensitive to in-vivo oxygen levels and respond more slowly over time due to encapsulation by the body's FBR. The film layer formed around the glucose sensor by FBR reduces glucose sensitivity, slows glucose response, and increases oxygen sensitivity. As the sensor consumes oxygen as part of its electrochemical reaction, oxygen levels can become very low within the isolated environment inside the FBR capsule.
Conventional solutions employed by artisans in this technology include depositing biocompatible films on implantable sensor surfaces to minimize FBR. While this can be an appropriate mitigation, coating deposition processes can damage the underlying sensor. Thus, there is a need in the art for new glucose sensor designs and configurations that can further avoid or minimize host immune responses with no damage to the sensor. Embodiments of the invention disclosed herein meet this as well as other needs.
The invention disclosed herein provides medical devices designed to include biocompatible sleeves adapted to contact an in vivo environment in order to provide the devices with enhanced functional and/or material properties, for example an ability to avoid or inhibit tissue inflammatory responses when implanted in vivo. The instant disclosure further provides methods for making and using such devices. As discussed in detail below, typical embodiments of the invention relate to the use of a biocompatible sleeve having selected material properties to envelop a sensor that measures a concentration of an aqueous analyte of interest or a substance indicative of the concentration or presence of the analyte in vivo. In illustrative embodiments, the sensor is an electrochemical analyte sensor used for continuous glucose monitoring in diabetic patients.
Glucose sensor sensitivity loss over time is believed to stem directly from the host immune response to the foreign sensor implant. In this context, embodiments of the invention disclosed herein address this problem by deploying the sensor inside a biocompatible hollow fiber membrane/sleeve. Typically, the biocompatible sleeve membranes useful with embodiments of the invention exhibit high permeability to small molecules such as glucose and O2, and exhibit very low or no permeability to large molecules. In this context, the biocompatible nature of the membrane sleeve material inhibits FBR encapsulation. Suitable membranes useful in embodiments of the invention include those commonly available for dialysis and filtration applications in the appropriate size range of, for example, ˜0.5 mm ID. In illustrative embodiments of the invention, the hollow fibers can be applied to a sensor or sensor element (e.g. a flex electrode element) by solvent swelling and subsequent shrink fitting, by using adhesive at the proximal end, or by heat staking to the flex at a “waist” area proximal to the electrodes. In embodiments of the invention, the tip of the sleeve can be sealed with adhesive, by heat staking, or may be left open if the gap between the flex and the sleeve is small enough to avoid FBR development inside.
The invention disclosed herein addresses significant problems in this technology because glucose sensor sensitivity loss caused by foreign body response is one of the leading factors in limiting sensor longevity. In this context, improving the longevity, stability, and accuracy of continuous glucose monitor sensors has numerous benefits to diabetic patients. These include lower patient cost (e.g. more days/sensor), improved therapy (e.g. greater accuracy), and improved reliability (e.g. less prone to errors because of stability). For example, with lessened sensitivity loss, a user does not need to replace a glucose sensor as often and can be comfortable knowing the sensor is performing accurately. In addition, by addressing the sensor sensitivity loss issue, sensor performance is more predictable over the lifetime of sensor wear, thereby enabling calibration-free continuous glucose monitoring.
The invention disclosed herein has a number of embodiments including implantable analyte sensors enveloped by a biocompatible sleeve that provides the sensors with enhanced functional and/or material properties. Illustrative embodiments of the invention include, for example, an electrochemical analyte sensor (e.g. a glucose sensor used by diabetic individuals) comprising a base layer, a conductive layer over the base layer, wherein the conductive layer includes a working electrode, an analyte sensing layer disposed on the conductive layer, wherein the analyte sensing layer includes a composition that can alter the electrical current at the working electrode in the conductive layer in the presence of an analyte (e.g. glucose oxidase, GOx), an analyte modulating layer disposed on the analyte sensing layer, and a biocompatible sleeve that envelops the electrochemical analyte sensor, wherein the biocompatible sleeve is permeable to glucose.
In certain embodiments of the invention, the biocompatible sleeve is shrink wrapped on the electrochemical analyte sensor. Optionally, the biocompatible sleeve further comprises a composition selected to enhance biocompatibility, for example a hydrogel that includes hyaluronic acid. In typical embodiments of the invention, the biocompatible sleeve is formed from a material selected to provide defined permeability characteristics, for example a material that is permeable to glucose and impermeable to molecules larger than about 3,000 Daltons. In certain embodiments of the invention, the biocompatible sleeve is formed from a material designed to be absorbed in vivo, so that absorption of the sleeve provides a continually fresh surface over the life of the sensor. In some embodiments of the invention, the biocompatible sleeve is permselective such that the permeability of the material to oxygen is greater than permeability of the material to glucose. In typical embodiments of the invention, implanted electrochemical glucose sensors of the invention are observed to exhibit a decrease in implanted sensor signal decline over time as compared to an implanted control electrochemical glucose sensor that is identical to said electrochemical glucose sensor except that said control electrochemical glucose sensor does not comprise a biocompatible sleeve permeable to glucose.
Other embodiments of the invention involve methods of making an electrochemical analyte sensor. Such embodiments include, for example, a method of making an electrochemical analyte sensor comprising providing a base layer, forming a conductive layer over the base layer, wherein the conductive layer includes a working electrode, forming an analyte sensing layer over the conductive layer, wherein the analyte sensing layer includes a composition that can alter the electrical current at the working electrode in the conductive layer in the presence of an analyte, forming an analyte modulating layer over the analyte sensing layer, and then disposing the electrochemical analyte sensor within a biocompatible sleeve that envelops the electrochemical analyte sensor, wherein the biocompatible sleeve is permeable to glucose, so that the electrochemical analyte sensor is made. In illustrative embodiments of the invention, the biocompatible sleeve comprises a selected polymeric material such as cellulose and/or a polysulfone. Optionally the biocompatible sleeve with a composition selected to enhance biocompatibility, and/or a composition selected to modulate an immune response.
In certain methodological embodiments of the invention, the biocompatible sleeve comprises a tubular architecture having a first open end and a second open end, and the method comprises disposing the electrochemical analyte sensor within the biocompatible sleeve and then fitting the biocompatible sleeve on the electrochemical analyte sensor using an adhesive and/or heat staking. In some embodiments, the methods of making the analyte sensor comprise coupling the biocompatible sleeve to the electrochemical analyte sensor via a solvent swelling process. Optionally, these methods comprise shrink wrapping the biocompatible sleeve over the electrochemical analyte sensor. Some methodological embodiments of the invention further comprise disposing the electrochemical analyte sensor that is enveloped by the biocompatible sleeve within a piercing member. Optionally in such embodiments, the hollow fiber biocompatible sleeve can be modified (e.g. by trimming or folding portions of the sleeve) to fit inside the piercing member (e.g. a needle).
Other embodiments of the invention include methods of sensing an analyte within the body of a mammal. Typically, these methods comprise implanting an electrochemical analyte sensor enveloped by a biocompatible sleeve as disclosed herein in to the mammal; sensing an alteration in current at the working electrode in the presence of the analyte; and then correlating the alteration in current with the presence of the analyte, so that the analyte is sensed.
Other objects, features and advantages of the present invention will become apparent to those skilled in the art from the following detailed description. It is to be understood, however, that the detailed description and specific examples, while indicating some embodiments of the present invention are given by way of illustration and not limitation. Many changes and modifications within the scope of the present invention may be made without departing from the spirit thereof, and the invention includes all such modifications.
Unless otherwise defined, all terms of art, notations, and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings may be defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art. Many of the techniques and procedures described or referenced herein are well understood and commonly employed using conventional methodology by those skilled in the art. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer defined protocols and/or parameters unless otherwise noted. A number of terms are defined below.
All numbers recited in the specification and associated claims that refer to values that can be numerically characterized with a value other than a whole number (e.g. the diameter of a circular disc) are understood to be modified by the term “about”. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. Furthermore, all publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. Publications cited herein are cited for their disclosure prior to the filing date of the present application. Nothing here is to be construed as an admission that the inventors are not entitled to antedate the publications by virtue of an earlier priority date or prior date of invention. Further the actual publication dates may be different from those shown and require independent verification.
The term “analyte” as used herein is a broad term and is used in its ordinary sense, including, without limitation, to refer to a substance or chemical constituent in a fluid such as a biological fluid (for example, blood, interstitial fluid, cerebral spinal fluid, lymph fluid or urine) that can be analyzed. Analytes can include naturally occurring substances, artificial substances, metabolites, and/or reaction products. In common embodiments, the analyte is glucose. However, embodiments of the invention can be used with sensors designed for detecting a wide variety other analytes. Illustrative analytes include but are not limited to, lactate as well as salts, sugars, proteins fats, vitamins and hormones that naturally occur in vivo (e.g. in blood or interstitial fluids). The analyte can be naturally present in the biological fluid or endogenous; for example, a metabolic product, a hormone, an antigen, an antibody, and the like. Alternatively, the analyte can be introduced into the body or exogenous, for example, a contrast agent for imaging, a radioisotope, a chemical agent, a fluorocarbon-based synthetic blood, or a drug or pharmaceutical composition, including but not limited to insulin. The metabolic products of drugs and pharmaceutical compositions are also contemplated analytes.
The term “sensor” for example in “analyte sensor,” is used in its ordinary sense, including, without limitation, means used to detect a compound such as an analyte. A “sensor” includes, for example, elements, structures and architectures (e.g. specific 3-dimensional constellations of elements) designed to facilitate sensor use and function. Sensors can include, for example, compositions such as those having selected material properties, as well as electronic components such as elements and devices used in signal detection and analysis (e.g. current detectors, monitors, processors and the like).
Embodiments of the invention disclosed herein provide sensors of the type used, for example, in subcutaneous or transcutaneous monitoring of blood glucose levels in a diabetic patient. A variety of implantable, electrochemical biosensors have been developed for the treatment of diabetes and other life-threatening diseases. Many existing sensor designs use some form of immobilized enzyme to achieve their bio-specificity. Embodiments of the invention described herein can be adapted and implemented with a wide variety of known electrochemical sensors, including for example, U.S. Patent Application No. 20050115832, U.S. Pat. Nos. 6,001,067, 6,702,857, 6,212,416, 6,119,028, 6,400,974, 6,595,919, 6,141,573, 6,122,536, 6,512,939 5,605,152, 4,431,004, 4,703,756, 6,514,718, 5,985,129, 5,390,691, 5,391, 250, 5,482,473, 5,299,571, 5,568,806, 5,494,562, 6,120,676, 6,542,765, 7,033,336 as well as PCT International Publication Numbers WO 01/58348, WO 04/021877, WO 03/034902, WO 03/035117, WO 03/035891, WO 03/023388, WO 03/022128, WO 03/022352, WO 03/023708, WO 03/036255, WO03/036310 WO 08/042,625, and WO 03/074107, and European Patent Application EP 1153571, the contents of each of which are incorporated herein by reference.
Embodiments of the invention disclosed herein provide medical devices designed to comprise a biocompatible sleeve that provides the devices with enhanced functional and/or material properties, for example an ability to avoid or inhibit tissue inflammatory responses when implanted in vivo. The disclosure further provides methods for making and using such devices. In some embodiments, the implantable device is a subcutaneous, intramuscular, intraperitoneal, intravascular or transdermal device. As discussed in detail below, some embodiments of the invention relate to the use of a sensor device that is implanted to measure a concentration of an aqueous analyte of interest or a substance indicative of the concentration or presence of the analyte in vivo. Typically, the sensor can be used for continuous glucose monitoring.
Embodiments of the invention include, for example, an electrochemical analyte sensor (e.g. a glucose sensor used by diabetic individuals) comprising a base layer, a conductive layer over the base layer, wherein the conductive layer includes a working electrode, an analyte sensing layer disposed on the conductive layer, wherein the analyte sensing layer includes a composition that can alter the electrical current at the working electrode in the conductive layer in the presence of an analyte (e.g. glucose oxidase), an analyte modulating layer disposed on the analyte sensing layer, and a biocompatible sleeve that envelops the electrochemical analyte sensor, wherein the biocompatible sleeve is permeable to glucose.
In certain embodiments of the invention, the biocompatible sleeve is shrink wrapped on the electrochemical analyte sensor via a conventional methodology (see, e.g. Kohler et al., Phys Rev Lett. 2006 7(18); and U.S. Patent Publications 20050196563). Optionally, the biocompatible sleeve comprises a composition selected to enhance biocompatibility, for example a hydrogel that comprises a hyaluronic acid, a steroid (e.g. dexamethasone or a betamethasone), a heparin, a rapamycin or the like. Optionally the composition selected to enhance biocompatibility is coated on the biocompatible sleeve or is disposed within the biocompatible sleeve or is otherwise coupled to the biocompatible sleeve via conventional methods in the art. In typical embodiments of the invention, the biocompatible sleeve is formed from a material selected to provide defined permeability characteristics, for example a material that is permeable to glucose and impermeable to molecules larger than about 1,000, 3,000, 5,000 or 10,000 Daltons In some embodiments of the invention, the biocompatible sleeve is permselective such that the permeability of the material to oxygen is greater than permeability of the material to glucose.
In certain embodiments of the invention, the biocompatible sleeve comprises a microporous membrane formed from a bioabsorbable material, or the biocompatible sleeve is coated with, or otherwise coupled to a bioabsorbable material. A variety of bioabsorbable materials that can be used with such embodiments of the invention include, for example, a PLA (polylactic acid or polylactide) material, a PGA (polyglycolic acid) material, a PLGA (poly(lactic-co-glycolic acid) material, a PCL (polycaprolactone) material or the like. In certain embodiments of the invention, the material of the biocompatible sleeve is selected to have a specific bioabsorption profile, for example one where, following implantation, at least 75% (or at least 90%) of the material is bioabsorbed by day 1, or by day 3, or by day 7 or by day 10 etc.
In illustrative embodiments, a sensor or sensor element (e.g. a sensor flex element) can be enveloped by biocompatible sleeve which is absorbable in vivo, thereby providing a slowly dissolving and continually fresh surface (e.g. a surface which contacts in vivo tissues) over the life of the sensor. As is known in the art, materials for the biocompatible sleeve can be selected to have specific bioabsorption profiles in order to, for example, make them useful for different applications. In one such embodiment, a sensor or sensor element (e.g. a sensor flex element) can be enveloped by biocompatible sleeve which is designed to be absorbed in vivo after a certain given period of time (e.g. 1, 3- or 7-days post implantation), thereby exposing the sensor flex directly to the in vivo environment. In an illustrative embodiment of this, a sensor is designed to include 2 sensor flexes where, following implantation, both sensor flexes reside in the interstitial fluid simultaneously. In this embodiment, the first sensor flex is operational immediately (e.g. embodiments where this first sensor flex does not comprise a biocompatible sleeve) and the second sensor flex is fully enveloped by the bioabsorbable sleeve, and is then operational following absorption of the bioabsorbable sleeve (e.g. at day 7+). In such embodiments, while the first sensor flex is operational (i.e. days 1-7), simultaneously, the bioabsorbable sleeve on the second sensor flex is being absorbed by the body. Once the sleeve on the second flex is fully absorbed (after a known given period of time, e.g. 7 days) by the body, the second sensor flex can then be used to generate sensor glucose values (e.g. and the microprocessor can then be controlled to no longer power the first sensor flex). Using such embodiments, artisans can extend the life of the sensor, for example beyond 10 or 15 days.
In typical embodiments of the invention, implanted electrochemical glucose sensors of the invention comprising the biocompatible sleeve that is permeable to glucose are observed to exhibit a decrease in implanted sensor signal decline over time (e.g. over 1, 2, 3 or 4 weeks post implantation) as compared to an implanted control electrochemical glucose sensor that is identical to said electrochemical glucose sensor except that said control electrochemical glucose sensor does not comprise a biocompatible sleeve permeable to glucose.
Other embodiments of the invention involve methods of making an electrochemical analyte sensor. Such embodiments include, for example, a method of making an electrochemical analyte sensor comprising providing a base layer, forming a conductive layer over the base layer, wherein the conductive layer includes a working electrode, forming an analyte sensing layer over the conductive layer, wherein the analyte sensing layer includes a composition that can alter the electrical current at the working electrode in the conductive layer in the presence of an analyte, forming an analyte modulating layer over the analyte sensing layer, and then disposing the electrochemical analyte sensor within a biocompatible sleeve that envelops the electrochemical analyte sensor, wherein the biocompatible sleeve is permeable to glucose, so that the electrochemical analyte sensor is made. In illustrative embodiments of the invention, the biocompatible sleeve comprises a polymeric material useful in in vivo applications such as a cellulose, a polysulfone or the like (see, e.g. Khan M A, Hussain A (2019) Haemodialysis Membranes: A Review. J Membr Sci Technol 9:199; and Klinkmann et al., Nephrol Dial Transplant. 1995; 10 Suppl 3:39-45). Optionally the biocompatible sleeve comprises a composition selected to enhance biocompatibility, and/or a composition selected to modulate an immune response.
In certain embodiments, these methods of making the analyte sensor comprise coupling the biocompatible sleeve to the electrochemical analyte sensor. Optionally, these methods comprise shrink wrapping the biocompatible sleeve over the electrochemical analyte sensor. In certain methodological embodiments of the invention, the biocompatible sleeve comprises a tubular architecture having a first open end and a second open end, and the method comprises disposing the electrochemical analyte sensor within the biocompatible sleeve and then fitting the biocompatible sleeve on the electrochemical analyte sensor using an adhesive and/or heat staking. Some methodological embodiments of the invention further comprise disposing the electrochemical analyte sensor that is enveloped by the biocompatible sleeve within a piercing member (e.g. a needle).
Other embodiments of the invention include methods of sensing an analyte within the body of a mammal. Typically, these methods comprise implanting an electrochemical analyte sensor enveloped by a biocompatible sleeve as disclosed herein in to the mammal; sensing an alteration in current at the working electrode in the presence of the analyte; and then correlating the alteration in current with the presence of the analyte, so that the analyte is sensed.
While the biocompatible sleeve elements of the invention can be adapted for use with a wide variety of implantable devices, the illustrative embodiments focused on in this disclosure are analyte sensors, typically electrochemical sensors that measure a concentration of an analyte of interest or a substance indicative of the concentration or presence of the analyte in fluid (e.g. glucose). The biocompatible sleeve disclosed herein can be used in a wide variety of other medical devices, including devices implanted long term (e.g. devices implanted more than one month) such as orthopedics device, dental implants, stents, pacemakers, catheters and the like as well as devices implanted short term (e.g. devices implanted less than one month) such as catheters, CGM sensors, tubing for infusion sets and the like.
In typical embodiments of the invention, the implantable device comprising a biocompatible sleeve that contacts an in vivo tissue is a glucose sensor. In certain embodiments, the glucose sensor comprises a base layer, a working electrode, a reference electrode, and a counter electrode disposed on the base layer, an analyte sensing layer disposed over the working electrode, wherein the analyte sensing layer comprises glucose oxidase, and an analyte modulating layer disposed over the analyte sensing layer, wherein the analyte modulating layer modulates the diffusion of glucose therethrough. Optionally, the glucose sensor further comprises at least one of an interference rejection layer disposed over the working electrode, an adhesion promoting layer disposed between the analyte sensing layer and the analyte modulating layer, a protein layer disposed on the analyte sensing layer; or a cover layer disposed over the analyte modulating layer.
In typical glucose sensor embodiments of the invention, electrochemical glucose sensors are operatively coupled to a sensor input capable of receiving signals from the electrochemical sensor; and a processor coupled to the sensor input, wherein the processor is capable of characterizing one or more signals received from the electrochemical sensor. In certain embodiments of the invention, the electrical conduit of the electrode is coupled to a potentiostat. Optionally, a pulsed voltage is used to obtain a signal from an electrode. In certain embodiments of the invention, the processor is capable of comparing a first signal received from a working electrode in response to a first working potential with a second signal received from a working electrode in response to a second working potential. Optionally, the electrode is coupled to a processor adapted to convert data obtained from observing fluctuations in electrical current from a first format into a second format. Such embodiments include, for example, processors designed to convert a sensor current Input Signal (e.g. ISIG measured in nA) to a blood glucose concentration.
In embodiments of the invention, the sensors can comprise one or more biocompatible polymer regions adapted to be implanted in vivo and directly contact the in vivo environment. In embodiments of the invention, the biocompatible region can comprise any polymer surface that contacts an in vivo tissue. In this way, sensors used in the systems of the invention can be used to sense a wide variety of analytes in different aqueous environments. In some embodiments, the sensor comprises a discreet probe that pierces an in vivo environment. In some embodiments of the invention, the electrode is coupled to a piercing member (e.g. a needle) adapted to be implanted in vivo. While sensor embodiments of the invention can comprise one or two piercing members, optionally such sensor apparatuses can include 3 or 4 or 5 or more piercing members that are coupled to and extend from a base element and are operatively coupled to 3 or 4 or 5 or more electrochemical sensors (e.g. microneedle arrays, embodiments of which are disclosed for example in U.S. Pat. Nos. 7,291,497 and 7,027,478, and U.S. patent Application No. 20080015494, the contents of which are incorporated by reference).
As noted above, embodiments of the invention include analyte sensor apparatus including a base on which electrically conductive members are disposed and configured to form a working electrode. In some embodiments of the invention, an array of electrically conductive members is coupled to a common electrical conduit (e.g. so that the conductive members of the array are not separately wired, and are instead electrically linked as a group). Optionally, the electrical conduit is coupled to a power source adapted to sense fluctuations in electrical current of the array of the working electrode. Typically, the apparatus includes a reference electrode; and a counter electrode. Optionally one or more of these electrodes also comprises a plurality of electrically conductive members disposed on the base in an array. In some embodiments, each of the electrically conductive members of the electrode (e.g. the counter electrode) comprises an electroactive surface adapted to sense fluctuations in electrical current at the electroactive surface; and the group of electrically conductive members are coupled to a power source (e.g. a potentiostat or the like).
In some embodiments of the invention, the apparatus comprises a plurality of working electrodes, counter electrodes and reference electrodes. In some sensor embodiments, electrodes are organized/disposed within a flex-circuit assembly (i.e. a circuitry assembly that utilizes flexible rather than rigid materials). Such flex-circuit assembly embodiments provide an interconnected assembly of elements (e.g. electrodes, electrical conduits, contact pads and the like) configured to facilitate wearer comfort (for example by reducing pad stiffness and wearer discomfort).
In some embodiments of the invention, an analyte sensing layer is disposed over electrically conductive members, and includes an agent that is selected for its ability to detectably alter the electrical current at the working electrode in the presence of an analyte. In the working embodiments of the invention that are disclosed herein, the agent is glucose oxidase, a protein that undergoes a chemical reaction in the presence of glucose that results in an alteration in the electrical current at the working electrode. These working embodiments further include an analyte modulating layer disposed over the analyte sensing layer, wherein the analyte modulating layer modulates the diffusion of glucose as it migrates from an in vivo environment to the analyte sensing layer. In certain embodiments of the invention, the analyte modulating layer comprises a hydrophilic comb-copolymer having a central chain and a plurality of side chains coupled to the central chain, wherein at least one side chain comprises a silicone moiety. In certain embodiments of the invention, the analyte modulating layer comprises a blended mixture of: a linear polyurethane/polyurea polymer, and a branched acrylate polymer; and the linear polyurethane/polyurea polymer and the branched acrylate polymer are blended at a ratio of between 1:1 and 1:20 (e.g. 1:2) by weight %. In working embodiments of the present invention, the signal strength and O2 response of the microarray sensor electrode can be increased with the use of a 2× permselective GLM (glucose limiting membrane). Typically, this analyte modulating layer composition comprises a first polymer formed from a mixture comprising a diisocyanate; at least one hydrophilic diol or hydrophilic diamine; and a siloxane; that is blended with a second polymer formed from a mixture comprising: a 2-(dimethylamino)ethyl methacrylate; a methyl methacrylate; a polydimethyl siloxane monomethacryloxypropyl; a poly(ethylene oxide) methyl ether methacrylate; and a 2-hydroxyethyl methacrylate. Additional material layers can be included in such apparatuses. For example, in some embodiments of the invention, the apparatus comprises an adhesion promoting layer disposed between the analyte sensing layer and the analyte modulating layer.
One sensor embodiment shown in
Embodiments of the invention also provide articles of manufacture and kits for observing a concentration of an analyte. In an illustrative embodiment, the kit includes a sensor comprising biocompatible sleeve as discussed herein. In typical embodiments, the sensors are disposed in the kit within a sealed sterile dry package. Optionally the kit comprises an insertion device that facilitates insertion of the sensor. The kit and/or sensor set typically comprises a container, a label and an analyte sensor as described above. Suitable containers include, for example, an easy to open package made from a material such as a metal foil, bottles, vials, syringes, and test tubes. The containers may be formed from a variety of materials such as metals (e.g. foils) paper products, glass or plastic. The label on, or associated with, the container indicates that the sensor is used for assaying the analyte of choice. The kit and/or sensor set may include other materials desirable from a commercial and user standpoint, including buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.
Specific aspects of embodiments of the invention are discussed in detail in the following sections.
The embodiment shown in
As discussed in detail below, the base layer 402 and/or conductive layer 404 can be generated using many known techniques and materials. In certain embodiments of the invention, the electrical circuit of the sensor is defined by etching the disposed conductive layer 404 into a desired pattern of conductive paths. A typical electrical circuit for the sensor 400 comprises two or more adjacent conductive paths with regions at a proximal end to form contact pads and regions at a distal end to form sensor electrodes. An electrically insulating cover layer 406 such as a polymer coating can be disposed on portions of the sensor 400. Acceptable polymer coatings for use as the insulating protective cover layer 406 can include but are not limited to polymers having the constellation of features disclosed herein, non-toxic biocompatible polymers such as silicone compounds, polyimides, biocompatible solder masks, epoxy acrylate copolymers, or the like. In the sensors of the present invention, one or more exposed regions or apertures 408 can be made through the cover layer 406 to open the layers to the external environment and to, for example, allow an analyte such as glucose to permeate the layers of the sensor and be sensed by the sensing elements. Apertures 408 can be formed by a number of techniques, including laser ablation, tape masking, chemical milling or etching or photolithographic development or the like. In certain embodiments of the invention, during manufacture, a secondary photoresist can also be applied to the protective layer 406 to define the regions of the protective layer to be removed to form the aperture(s) 408. The exposed electrodes and/or contact pads can also undergo secondary processing (e.g. through the apertures 408), such as additional plating processing, to prepare the surfaces and/or strengthen the conductive regions.
In the sensor configuration shown in
In embodiments of the invention, the analyte sensing layer 410 can be applied over portions of the conductive layer or over the entire region of the conductive layer. Typically, the analyte sensing layer 410 is disposed on the working electrode which can be the anode or the cathode. Optionally, the analyte sensing layer 410 is also disposed on a counter and/or reference electrode. Methods for generating a thin analyte sensing layer 410 include brushing the layer onto a substrate (e.g. the reactive surface of a platinum black electrode), as well as spin coating processes, dip and dry processes, low shear spraying processes, ink-jet printing processes, silk screen processes and the like. In certain embodiments of the invention, brushing is used to: (1) allow for a precise localization of the layer; and (2) push the layer deep into the architecture of the reactive surface of an electrode (e.g. platinum black produced by an electrodeposition process).
Typically, the analyte sensing layer 410 is coated and or disposed next to one or more additional layers. Optionally, the one or more additional layers includes a protein layer 416 disposed upon the analyte sensing layer 410. Typically, the protein layer 416 comprises a protein such as human serum albumin, bovine serum albumin or the like. Typically, the protein layer 416 comprises human serum albumin. In some embodiments of the invention, an additional layer includes an analyte modulating layer 412 that is disposed above the analyte sensing layer 410 to regulate analyte contact with the analyte sensing layer 410. For example, the analyte modulating membrane layer 412 can comprise a glucose limiting membrane, which regulates the amount of glucose that contacts an enzyme such as glucose oxidase that is present in the analyte sensing layer. Such glucose limiting membranes can be made from a wide variety of materials known to be suitable for such purposes, e.g., silicone compounds such as polydimethyl siloxanes, polyurethanes, polyurea cellulose acetates, Nafion, polyester sulfonic acids (e.g. Kodak AQ), hydrogels or any other suitable hydrophilic membranes known to those skilled in the art.
In typical embodiments of the invention, an adhesion promoter layer 414 is disposed between the analyte modulating layer 412 and the analyte sensing layer 410 as shown in
The following disclosure provides examples of typical elements/constituents used in sensor embodiments of the invention. While these elements can be described as discreet units (e.g. layers), those of skill in the art understand that sensors can be designed to contain elements having a combination of some or all of the material properties and/or functions of the elements/constituents discussed below (e.g. an element that serves both as a supporting base constituent and/or a conductive constituent and/or a matrix for the analyte sensing constituent and which further functions as an electrode in the sensor). Those in the art understand that these thin film analyte sensors can be adapted for use in a number of sensor systems such as those described below.
Sensors of the invention typically include a base constituent (see, e.g. element 402 in
The electrochemical sensors of the invention typically include a conductive constituent disposed upon the base constituent that includes at least one electrode for contacting an analyte or its byproduct (e.g. oxygen and/or hydrogen peroxide) to be assayed (see, e.g. element 404 in
In addition to the working electrode, the analyte sensors of the invention typically include a reference electrode or a combined reference and counter electrode (also termed a quasi-reference electrode or a counter/reference electrode). If the sensor does not have a counter/reference electrode then it may include a separate counter electrode, which may be made from the same or different materials as the working electrode. Typical sensors of the present invention have one or more working electrodes and one or more counter, reference, and/or counter/reference electrodes. One embodiment of the sensor of the present invention has two, three or four or more working electrodes. These working electrodes in the sensor may be integrally connected or they may be kept separate. Optionally, the electrodes can be disposed on a single surface or side of the sensor structure. Alternatively, the electrodes can be disposed on a multiple surfaces or sides of the sensor structure (and can for example be connected by vias through the sensor material(s) to the surfaces on which the electrodes are disposed). In certain embodiments of the invention, the reactive surfaces of the electrodes are of different relative areas/sizes, for example a 1× reference electrode, a 2.6× working electrode and a 3.6× counter electrode.
The electrochemical sensors of the invention optionally include an interference rejection constituent disposed between the surface of the electrode and the environment to be assayed. In particular, certain sensor embodiments rely on the oxidation and/or reduction of hydrogen peroxide generated by enzymatic reactions on the surface of a working electrode at a constant potential applied. Because amperometric detection based on direct oxidation of hydrogen peroxide requires a relatively high oxidation potential, sensors employing this detection scheme may suffer interference from oxidizable species that are present in biological fluids such as ascorbic acid, uric acid and acetaminophen. In this context, the term “interference rejection constituent” is used herein according to art accepted terminology and refers to a coating or membrane in the sensor that functions to inhibit spurious signals generated by such oxidizable species which interfere with the detection of the signal generated by the analyte to be sensed. Certain interference rejection constituents function via size exclusion (e.g. by excluding interfering species of a specific size). Examples of interference rejection constituents include one or more layers or coatings of compounds such as hydrophilic polyurethanes, cellulose acetate (including cellulose acetate incorporating agents such as poly(ethylene glycol), polyethersulfones, polytetra-fluoroethylenes, the perfluoronated ionomer Nafion™, polyphenylenediamine, epoxy and the like.
The electrochemical sensors of the invention include an analyte sensing constituent disposed on the electrodes of the sensor (see, e.g. element 410 in
Typical sensor embodiments of this element of the invention utilize an enzyme (e.g. glucose oxidase) that has been combined with a second protein (e.g. albumin) in a fixed ratio (e.g. one that is typically optimized for glucose oxidase stabilizing properties) and then applied on the surface of an electrode to form a thin enzyme constituent. In a typical embodiment, the analyte sensing constituent comprises a GOx and HSA mixture. In a typical embodiment of an analyte sensing constituent having GOx, the GOx reacts with glucose present in the sensing environment (e.g. the body of a mammal) and generates hydrogen peroxide.
As noted above, the enzyme and the second protein (e.g. an albumin) are typically treated to form a crosslinked matrix (e.g. by adding a cross-linking agent to the protein mixture). As is known in the art, crosslinking conditions may be manipulated to modulate factors such as the retained biological activity of the enzyme, its mechanical and/or operational stability. Illustrative crosslinking procedures are described in U.S. patent application Ser. No. 10/335,506 and PCT publication WO 03/035891 which are incorporated herein by reference. For example, an amine cross-linking reagent, such as, but not limited to, glutaraldehyde, can be added to the protein mixture. The addition of a cross-linking reagent to the protein mixture creates a protein paste. The concentration of the cross-linking reagent to be added may vary according to the concentration of the protein mixture. While glutaraldehyde is an illustrative crosslinking reagent, other cross-linking reagents may also be used or may be used in place of glutaraldehyde. Other suitable cross-linkers also may be used, as will be evident to those skilled in the art.
As noted above, in some embodiments of the invention, the analyte sensing constituent includes an agent (e.g. glucose oxidase) capable of producing a signal (e.g. a change in oxygen and/or hydrogen peroxide concentrations) that can be sensed by the electrically conductive elements (e.g. electrodes which sense changes in oxygen and/or hydrogen peroxide concentrations). However, other useful analyte sensing constituents can be formed from any composition that is capable of producing a detectable signal that can be sensed by the electrically conductive elements after interacting with a target analyte whose presence is to be detected. In some embodiments, the composition comprises an enzyme that modulates hydrogen peroxide concentrations upon reaction with an analyte to be sensed. Alternatively, the composition comprises an enzyme that modulates oxygen concentrations upon reaction with an analyte to be sensed. In this context, a wide variety of enzymes that either use or produce hydrogen peroxide and/or oxygen in a reaction with a physiological analyte are known in the art and these enzymes can be readily incorporated into the analyte sensing constituent composition. A variety of other enzymes known in the art can produce and/or utilize compounds whose modulation can be detected by electrically conductive elements such as the electrodes that are incorporated into the sensor designs described herein. Such enzymes include for example, enzymes specifically described in Table 1, pages 15-29 and/or Table 18, pages 111-112 of Protein Immobilization: Fundamentals and Applications (Bioprocess Technology, Vol 14) by Richard F. Taylor (Editor) Publisher: Marcel Dekker; Jan. 7, 1991) the entire contents of which are incorporated herein by reference.
The electrochemical sensors of the invention optionally include a protein constituent disposed between the analyte sensing constituent and the analyte modulating constituent (see, e.g. element 416 in
The electrochemical sensors of the invention can include one or more adhesion promoting (AP) constituents (see, e.g. element 414 in
The electrochemical sensors of the invention can include one or more high-density amine constituent layers (see, e.g.
The electrochemical sensors of the invention can include an analyte modulating constituent disposed on the sensor (see, e.g. element 412 in
With respect to glucose sensors, in known enzyme electrodes, glucose and oxygen from blood, as well as some interferants, such as ascorbic acid and uric acid, diffuse through a primary membrane of the sensor. As the glucose, oxygen and interferants reach the analyte sensing constituent, an enzyme, such as glucose oxidase, catalyzes the conversion of glucose to hydrogen peroxide and gluconolactone. The hydrogen peroxide may diffuse back through the analyte modulating constituent, or it may diffuse to an electrode where it can be reacted to form oxygen and a proton to produce a current that is proportional to the glucose concentration. The analyte modulating sensor membrane assembly serves several functions, including selectively allowing the passage of glucose therethrough (see, e.g. U.S. Patent Application No. 2011-0152654).
The electrochemical sensors of the invention include one or more biocompatible sleeve constituents (see, e.g.
Embodiments of the sensor elements and sensors can be operatively coupled to a variety of other system elements typically used with analyte sensors (e.g. structural elements such as piercing members, insertion sets and the like as well as electronic components such as processors, monitors, medication infusion pumps and the like), for example to adapt them for use in various contexts (e.g. implantation within a mammal). One embodiment of the invention includes a method of monitoring a physiological characteristic of a user using an embodiment of the invention that includes an input element capable of receiving a signal from a sensor that is based on a sensed physiological characteristic value of the user, and a processor for analyzing the received signal. In typical embodiments of the invention, the processor determines a dynamic behavior of the physiological characteristic value and provides an observable indicator based upon the dynamic behavior of the physiological characteristic value so determined. In some embodiments, the physiological characteristic value is a measure of the concentration of blood glucose in the user. In other embodiments, the process of analyzing the received signal and determining a dynamic behavior includes repeatedly measuring the physiological characteristic value to obtain a series of physiological characteristic values in order to, for example, incorporate comparative redundancies into a sensor apparatus in a manner designed to provide confirmatory information on sensor function, analyte concentration measurements, the presence of interferences and the like.
Embodiments of the invention include devices which process display data from measurements of a sensed physiological characteristic (e.g. blood glucose concentrations) in a manner and format tailored to allow a user of the device to easily monitor and, if necessary, modulate the physiological status of that characteristic (e.g. modulation of blood glucose concentrations via insulin administration). An illustrative embodiment of the invention is a device comprising a sensor input capable of receiving a signal from a sensor, the signal being based on a sensed physiological characteristic value of a user; a memory for storing a plurality of measurements of the sensed physiological characteristic value of the user from the received signal from the sensor; and a display for presenting a text and/or graphical representation of the plurality of measurements of the sensed physiological characteristic value (e.g. text, a line graph or the like, a bar graph or the like, a grid pattern or the like or a combination thereof). Typically, the graphical representation displays real time measurements of the sensed physiological characteristic value. Such devices can be used in a variety of contexts, for example in combination with other medical apparatuses. In some embodiments of the invention, the device is used in combination with at least one other medical device (e.g. a glucose sensor).
An illustrative system embodiment consists of a glucose sensor, a transmitter and pump receiver and a glucose meter. In this system, radio signals from the transmitter can be sent to the pump receiver every 5 minutes to provide providing real-time sensor glucose (SG) values. Values/graphs are displayed on a monitor of the pump receiver so that a user can self monitor blood glucose and deliver insulin using their own insulin pump. Typically, an embodiment of device disclosed herein communicates with a second medical device via a wired or wireless connection. Wireless communication can include for example the reception of emitted radiation signals as occurs with the transmission of signals via RF telemetry, infrared transmissions, optical transmission, sonic and ultrasonic transmissions and the like. Optionally, the device is an integral part of a medication infusion pump (e.g. an insulin pump). Typically, in such devices, the physiological characteristic values include a plurality of measurements of blood glucose.
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While the analyte sensor and sensor systems disclosed herein are typically designed to be implantable within the body of a mammal, the inventions disclosed herein are not limited to any particular environment and can instead be used in a wide variety of contexts, for example for the analysis of most in vivo and in vitro liquid samples including biological fluids such as interstitial fluids, whole-blood, lymph, plasma, serum, saliva, urine, stool, perspiration, mucus, tears, cerebrospinal fluid, nasal secretion, cervical or vaginal secretion, semen, pleural fluid, amniotic fluid, peritoneal fluid, middle ear fluid, joint fluid, gastric aspirate or the like. In addition, solid or desiccated samples may be dissolved in an appropriate solvent to provide a liquid mixture suitable for analysis.
It is to be understood that this invention is not limited to the particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims. In the description of the preferred embodiment, reference is made to the accompanying drawings which form a part hereof, and in which is shown by way of illustration a specific embodiment in which the invention may be practiced. It is to be understood that other embodiments may be utilized, and structural changes may be made without departing from the scope of the present invention.
