Optimized sensor geometry for an implantable glucose sensor
An implantable sensor for use in measuring a concentration of an analyte such as glucose in a bodily fluid, including a body with a sensing region adapted for transport of analytes between the sensor and the bodily fluid, wherein the sensing region is located on a curved portion of the body such that when a foreign body capsule forms around the sensor, a contractile force is exerted by the foreign body capsule toward the sensing region. The body is partially or entirely curved, partially or entirely covered with an anchoring material for supporting tissue ingrowth, and designed for subcutaneous tissue implantation. The geometric design, including curvature, shape, and other factors minimize chronic inflammatory response at the sensing region and contribute to improved performance of the sensor in vivo.
This application is a division of U.S. application Ser. No. 10/646,333 filed Aug. 22, 2003, which claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 60/460,825, filed Apr. 4, 2003, the contents of which are hereby incorporated by reference in their entirety.
FIELD OF THE INVENTIONThe present invention relates generally to implantable sensors that measure the concentration of an analyte in a biological fluid. The sensor geometry optimizes the healing at the sensor-tissue interface and is less amenable to accidental movement due to shear and rotational forces than other sensor configurations.
BACKGROUND OF THE INVENTIONImplantable analyte sensors that are placed in the subcutaneous tissue or other soft tissue sites must develop and sustain a stable biointerface that allows the continuous and timely transport of analytes across the interface between the tissue and the device. For example, in the case of a glucose sensor, glucose must be able to freely diffuse from surrounding blood vessels to a membrane of the sensor. Glucose sensors may be implanted in the subcutaneous tissue or other soft tissue. Such devices include glucose oxidase based amperometric sensors that sense glucose for weeks, months or longer after implantation.
While the utility of such devices for glucose sensing has been demonstrated, the consistency of function for such devices is not optimal. For a particular device, the sensor may, for example: 1) fail to function (namely, fail to track glucose effectively) in a stable manner during the first few weeks after implantation; 2) not work at all during the first few weeks, but subsequently begin to function in a stable manner; 3) function well during the first few weeks, lose function, then regain effectiveness or never recover function; or 4) work immediately, and continue to function with high accuracy throughout the course of a several month study.
Glucose sensors with improved acceptance within the host tissue and decreased variability of response are required for reliable functionality in vivo. Accordingly, the present invention discloses systems and methods for providing this improved functionality and consistency of analyte sensor in a host.
SUMMARY OF THE INVENTIONA sensor, especially a sensor suitable for implantation into soft tissue that provides accurate analyte measurements while offering consistency of function is highly desirable.
Accordingly, in a first embodiment an implantable sensor is provided for use in measuring a concentration of an analyte in a bodily fluid, the sensor including a body including a sensing region adapted for transport of analytes between the sensor and the bodily fluid, wherein the sensing region is located on a curved portion of the body such that when a foreign body capsule forms around the sensor, a contractile force is exerted by the foreign body capsule toward the sensing region.
In an aspect of the first embodiment, the sensor is a subcutaneous sensor.
In an aspect of the first embodiment, the sensor is an intramuscular sensor.
In an aspect of the first embodiment, the sensor is an intraperitoneal sensor.
In an aspect of the first embodiment, the sensor is an intrafascial sensor.
In an aspect of the first embodiment, the sensor is suitable for implantation in an axillary region.
In an aspect of the first embodiment, the sensor is suitable for implantation in a soft tissue of a body.
In an aspect of the first embodiment, the sensor is suitable for implantation at the interface between two tissue types.
In an aspect of the first embodiment, the sensor includes a plurality of sensor regions.
In an aspect of the first embodiment, the plurality of sensor regions are located on curved portions of the body.
In an aspect of the first embodiment, the body includes a first major surface and a second major surface, and wherein the sensing region is located on the first surface, and wherein the second surface is flat.
In an aspect of the first embodiment, the body includes a first major surface and a second major surface, and wherein the sensing region is located on the first major surface, and wherein the second major surface includes a curvature.
In an aspect of the first embodiment, the body includes a first major surface and a second major surface, and wherein the sensor region is situated at a position on the first major surface offset from a center point of the first major surface.
In an aspect of the first embodiment, the body includes a first major surface and a second major surface, and wherein the sensor region is situated on the first major surface approximately at a center point of the first major surface.
In an aspect of the first embodiment, the body includes a first surface and a second surface, and wherein the sensor region is situated approximately at an apex of the first surface.
In an aspect of the first embodiment, the body includes a first surface and a second surface, and wherein the first surface, when viewed from a direction perpendicular to a center of the first surface, has a substantially rectangular profile.
In an aspect of the first embodiment, the body includes a first surface and a second surface, and wherein the first surface, when viewed from a direction perpendicular to a center of the first surface, has a substantially rectangular profile with rounded corners.
In an aspect of the first embodiment, the body includes a first surface and a second surface, and wherein the first surface, when viewed from a direction perpendicular to a center of the first surface, has a substantially oval profile.
In an aspect of the first embodiment, the body includes a first surface and a second surface, and wherein the first surface, when viewed from a direction perpendicular to a center of the first surface, has a substantially circular profile.
In an aspect of the first embodiment, the body is substantially cuboidal defined by six faces, eight vertices, and twelve edges, wherein at least one of the faces includes the sensing region.
In an aspect of the first embodiment, at least two of the faces are substantially curved.
In an aspect of the first embodiment, at least four of the faces are substantially curved.
In an aspect of the first embodiment, all six of the faces are substantially curved.
In an aspect of the first embodiment, the edges are substantially rounded.
In an aspect of the first embodiment, the vertices are substantially rounded.
In an aspect of the first embodiment, the entire body is curved.
In an aspect of the first embodiment, the body is substantially cylindrical defined by a curved lateral surface and two ends, and wherein the sensor region is located on the lateral surface.
In an aspect of the first embodiment, the body is substantially cylindrical defined by a curved lateral surface and two ends, and wherein at least one of the ends includes the substantially curved portion on which the sensor region is located.
In an aspect of the first embodiment, the body is substantially spherical.
In an aspect of the first embodiment, the body is substantially ellipsoidal.
In an aspect of the first embodiment, the body includes a first surface on which the sensing region is located and a second surface, and wherein the first surface includes anchoring material thereon for supporting tissue ingrowth.
In an aspect of the first embodiment, the second surface is located opposite the first surface, and wherein the second surface includes anchoring material thereon for supporting tissue ingrowth.
In an aspect of the first embodiment, the second surface is located opposite the first surface, and wherein the second surface is substantially smooth and includes a biocompatible material that is non-adhesive to tissues.
In an aspect of the first embodiment, the second surface is curved.
In an aspect of the first embodiment, a mechanical anchoring mechanism is formed on the body.
In an aspect of the first embodiment, the curved portion includes a plurality of radii of curvature.
In an aspect of the first embodiment, the curved portion includes a radius of curvature between about 0.5 mm and about 10 cm.
In an aspect of the first embodiment, the curved portion includes a radius of curvature between about 1 cm and about 5 cm.
In an aspect of the first embodiment, the curved portion includes a radius of curvature between about 2 cm and about 3 cm.
In an aspect of the first embodiment, the curved portion includes a radius of curvature between about 2.5 cm and about 2.8 cm.
In an aspect of the first embodiment, the sensor includes a major surface and wherein the curved portion is located on at least a portion of the major surface.
In an aspect of the first embodiment, the body further includes a flat portion adjacent the curved portion.
In an aspect of the first embodiment, an interface between the flat portion and the curved portion includes a gradual transition.
In an aspect of the first embodiment, the body includes a first major surface on which the sensing region is located and a second major surface, and wherein the first and second major surfaces together account for at least about 40% of the surface area of the device.
In an aspect of the first embodiment, the first and second major surfaces together account for at least about 50% of the surface area of the device.
In an aspect of the first embodiment, the body includes a first major surface on which the sensing region is located and a second major surface, wherein the first major surface has edges between which a width of the first major surface can be measured, and wherein the sensing region is spaced away from the edges by a distance that is at least about 10% of the width of the first major surface.
In an aspect of the first embodiment, the sensing region is spaced away from the edges by a distance that is at least about 15% of the width of the first major surface.
In an aspect of the first embodiment, the sensing region is spaced away from the edges by a distance that is at least about 20% of the width of the first major surface.
In an aspect of the first embodiment, the sensing region is spaced away from the edges by a distance that is at least about 25% of the width of the first major surface.
In an aspect of the first embodiment, the sensing region is spaced away from the edges by a distance that is at least about 30% of the width of the first major surface.
In an aspect of the first embodiment, the spacing of the sensing region from the edges is true for at least two width measurements, which measurements are taken generally transverse to each other.
In an aspect of the first embodiment, the body includes a first major surface on which the sensing region is located and a second major surface, wherein the first major surface is at least slightly convex.
In an aspect of the first embodiment, a reference plane may be defined that touches the first major surface at a point spaced in from edges of the first major surface, and is generally parallel to the first major surface, and is spaced away from opposite edges of the first major surface due to convexity of the first major surface, and wherein a location of an edge is the point at which a congruent line or a normal line is angled 45 degrees with respect to the reference plane.
In an aspect of the first embodiment, the reference plane is spaced from the edges a distance that is at least about 3% from the edges, and not more than 50% of the width.
In an aspect of the first embodiment, the reference plane is spaced from the edges a distance that is at least about 3% from the edges, and not more than 25% of the width.
In an aspect of the first embodiment, the reference plane is spaced from the edges a distance that is at least about 3% from the edges, and not more than 15% of the width.
In an aspect of the first embodiment, the body includes a first major surface on which the sensing region is located, and wherein edges of the first major surface are rounded and transition smoothly away from the first major surface.
In an aspect of the first embodiment, the body defines a surface area, and wherein between 10% and 100% of the surface area is convexly curved.
In an aspect of the first embodiment, the body defines a surface area, and wherein a substantial portion of the surface area is convexly curved.
In an aspect of the first embodiment, the body defines a surface area, and where at least about 90% of the surface area is convexly curved.
In an aspect of the first embodiment, the body includes plastic.
In an aspect of the first embodiment, the plastic is selected from the group consisting of thermoplastic and thermoset.
In an aspect of the first embodiment, the thermoset is epoxy.
In an aspect of the first embodiment, the thermoset is silicone.
In an aspect of the first embodiment, the thermoset is polyurethane.
In an aspect of the first embodiment, the plastic is selected from the group consisting of metal, ceramic, and glass.
In an aspect of the first embodiment, a porous biointerface material that covers at least a portion of the sensing region.
In an aspect of the first embodiment, the biointerface material includes interconnected cavities dimensioned and arranged to create contractile forces that counteract with the generally uniform downward fibrous tissue contracture caused by the foreign body capsule in vivo and thereby interfere with formation of occlusive cells.
In an aspect of the first embodiment, the sensor is a glucose sensor.
In a second embodiment, an implantable sensor is provided for use in measuring a concentration of an analyte in a bodily fluid, the sensor including: a body including a sensing region on a major surface of the body, wherein the major surface includes a continuous curvature substantially across the entire surface such that when a foreign body capsule forms around the sensor, a contractile force is exerted by the foreign body capsule toward the sensing region.
In a third embodiment, a wholly implantable sensor is provided to measure a concentration of an analyte in a bodily fluid, including: a wholly implantable body including a sensing region adapted for transport of analytes between the sensor and the bodily fluid, wherein the sensing region is located on a curved portion of a first surface of the body and wherein the first surface includes anchoring material thereon for supporting tissue ingrowth.
In a fourth embodiment, an implantable sensor is provided to measure a concentration of an analyte in a bodily fluid, including: a body having a first major surface and, opposite thereto, a second major surface, wherein the first major surface is generally planar, slightly convex, and has rounded edges, with a sensor region located on the first major surface that is spaced away from the rounded edges, wherein the first major surface is sufficiently convex that when a foreign body capsule forms around the sensor, contractile forces are exerted thereby generally uniformly towards the sensing region.
In a fifth embodiment, an implantable sensor is provided for use in measuring a concentration of an analyte in a bodily fluid, the sensor including: a body, the body including a sensing region adapted for transport of analytes between the sensor and the bodily fluid, wherein the sensing region is located on a curved portion of the body, and wherein a thermoset material substantially encapsulates the body outside the sensing region.
In a sixth embodiment, an implantable sensor for use in measuring a concentration of an analyte in a bodily fluid, the sensor including: sensing means for measuring a concentration of analyte in a bodily fluid; and housing means for supporting the sensing means, wherein the sensing means is located on a curved portion of housing means such that when a foreign body capsule forms around the housing means, a contractile force is exerted by the foreign body capsule toward the sensing means.
In a seventh embodiment, an implantable drug delivery device is provided that allows transport of analytes between the device and a bodily fluid, the device including: a body including an analyte transport region adapted for transport of analytes between the device and the bodily fluid, wherein the transport region is located on a curved portion of the body such that when a foreign body capsule forms around the device, a contractile force is exerted by the foreign body capsule toward the analyte transport region.
In an eighth embodiment, an implantable cell transplantation device is provided that allows transport of analytes between the device and a bodily fluid, the device including: a body including an analyte transport region adapted for transport of analytes between the device and the bodily fluid, wherein the transport region is located on a curved portion of the body such that when a foreign body capsule forms around the device, a contractile force is exerted by the foreign body capsule toward the analyte transport region.
BRIEF DESCRIPTION OF THE DRAWINGS
13B is a side schematic view of an analyte sensor with anchoring material on a first major surface on which the sensing region is located, and wherein a second major surface is substantially smooth.
The following description and examples illustrate some exemplary embodiments of the disclosed invention in detail. Those of skill in the art will recognize that there are numerous variations and modifications of this invention that are encompassed by its scope. Accordingly, the description of a certain exemplary embodiment should not be deemed to limit the scope of the present invention.
DefinitionsIn order to facilitate an understanding of the disclosed invention, a number of terms are defined below.
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 biological fluid (for example, blood, interstitial fluid, cerebral spinal fluid, lymph fluid or urine) that can be analyzed. Analytes may include naturally occurring substances, artificial substances, metabolites, and/or reaction products. In some embodiments, the analyte for measurement by the sensor heads, devices, and methods is glucose. However, other analytes are contemplated as well, including but not limited to acarboxyprothrombin; acylcarnitine; adenine phosphoribosyl transferase; adenosine deaminase; albumin; alpha-fetoprotein; amino acid profiles (arginine (Krebs cycle), histidine/urocanic acid, homocysteine, phenylalanine/tyrosine, tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers; arginase; benzoylecgonine (cocaine); biotinidase; biopterin; c-reactive protein; carbon dioxide; camitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase; conjugated 1-βhydroxy-cholic acid; cortisol; creatine kinase; creatine kinase MM isoenzyme; cyclosporin A; d-penicillamine; de-ethylchloroquine; dehydroepiandrosterone sulfate; DNA (acetylator polymorphism, alcohol dehydrogenase, alpha 1-antitrypsin, cystic fibrosis, Duchenne/Becker muscular dystrophy, glucose-6-phosphate dehydrogenase, hemoglobinopathies, A,S,C,E, D-Punjab, beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1, Leber hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax, sexual differentiation, 21-deoxycortisol); desbutylhalofantrine; dihydropteridine reductase; diptheria/tetanus antitoxin; erythrocyte arginase; erythrocyte protoporphyrin; esterase D; fatty acids/acylglycines; free 13-human chorionic gonadotropin; free erythrocyte porphyrin; free thyroxine (FT4); free tri-iodothyronine (FT3); fumarylacetoacetase; galactose/gal-1-phosphate; galactose-1-phosphate uridyltransferase; gentamicin; glucose-6-phosphate dehydrogenase; glutathione; glutathione perioxidase; glycocholic acid; glycosylated hemoglobin; halofantrine; hemoglobin variants; hexosaminidase A; human erythrocyte carbonic anhydrase I; 17 alpha-hydroxyprogesterone; hypoxanthine phosphoribosyl transferase; immunoreactive trypsin; lactate; lead; lipoproteins ((a), B/A-1, β); lysozyme; mefloquine; netilmicin; oxygen; phenobarbitone; phenytoin; phytanic/pristanic acid; progesterone; prolactin; prolidase; purine nucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3); selenium; serum pancreatic lipase; sissomicin; somatomedin C; specific antibodies (adenovirus, anti-nuclear antibody, anti-zeta antibody, arbovirus, Aujeszky's disease virus, dengue virus, Dracunculus medinensis, Echinococcus granulosus, Entamoeba histolytica, enterovirus, Giardia duodenalisa, Helicobacter pylori, hepatitis B virus, herpes virus, HIV-1, IgE (atopic disease), influenza virus, Leishmania donovani, leptospira, measles/mumps/rubella, Mycobacterium leprae, Mycoplasma pneumoniae, Myoglobin, Onchocerca volvulus, parainfluenza virus, Plasmodium falciparum, poliovirus, Pseudomonas aeruginosa, pH, respiratory syncytial virus, rickettsia (scrub typhus), Schistosoma mansoni, Toxoplasma gondii, Trepenoma pallidium, Trypanosoma cruzi/rangeli, vesicular stomatis virus, Wuchereria bancrofti, yellow fever virus); specific antigens (hepatitis B virus, HIV-1); succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH); thyroxine (T4); thyroxine-binding globulin; trace elements; transferrin; UDP-galactose-4-epimerase; urea; uroporphyrinogen I synthase; vitamin A; white blood cells; and zinc protoporphyrin. Salts, sugar, protein, fat, vitamins and hormones naturally occurring in blood or interstitial fluids may also constitute analytes in certain embodiments. The analyte may be naturally present in the biological fluid, for example, a metabolic product, a hormone, an antigen, an antibody, and the like. Alternatively, the analyte may be introduced into the body, 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; ethanol; cannabis (marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide, amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine (crack cocaine); stimulants (amphetamines, methamphetamines, Ritalin, Cylert, Preludin, Didrex, PreState, Voranil, Sandrex, Plegine); depressants (barbituates, methaqualone, tranquilizers such as Valium, Librium, Miltown, Serax, Equanil, Tranxene); hallucinogens (phencyclidine, lysergic acid, mescaline, peyote, psilocybin); narcotics (heroin, codeine, morphine, opium, meperidine, Percocet, Percodan, Tussionex, Fentanyl, Darvon, Talwin, Lomotil); designer drugs (analogs of fentanyl, meperidine, amphetamines, methamphetamines, and phencyclidine, for example, Ecstasy); anabolic steroids; and nicotine. The metabolic products of drugs and pharmaceutical compositions are also contemplated analytes. Analytes such as neurochemicals and other chemicals generated within the body may also be analyzed, such as, for example, ascorbic acid, uric acid, dopamine, noradrenaline, 3-methoxytyramine (3MT), 3,4-Dihydroxyphenylacetic acid (DOPAC), Homovanillic acid (HVA), 5-Hydroxytryptamine (5HT), and 5-Hydroxyindoleacetic acid (FHIAA).
By the terms “evaluated”, “monitored”, “analyzed”, and the like, it is meant that an analyte may be detected and/or measured.
The terms “sensor head” and “sensing region” as used herein are broad terms and are used in their ordinary sense, including, without limitation, the region of a monitoring device responsible for the detection of a particular analyte. In one embodiment, the sensing region generally comprises a non-conductive body, a working electrode (anode), a reference electrode, and a counter electrode (cathode) passing through and secured within the body forming an electrochemically reactive surface at one location on the body and an electronic connective means at another location on the body, and a multi-region membrane affixed to the body and covering the electrochemically reactive surface. The counter electrode generally has a greater electrochemically reactive surface area than the working electrode. During general operation of the sensor a biological sample (for example, blood or interstitial fluid) or a portion thereof contacts (directly or after passage through one or more membranes or domains) an enzyme (for example, glucose oxidase); the reaction of the biological sample (or portion thereof) results in the formation of reaction products that allow a determination of the analyte (e.g., glucose) level in the biological sample. In preferred embodiments, the multi-region membrane further comprises an enzyme domain and an electrolyte phase, namely, a free-flowing liquid phase comprising an electrolyte-containing fluid described further below. While the preferred embodiments are generally illustrated by a sensor as described above, other sensor head configurations are also contemplated. While electrochemical sensors (including coulometric, voltammetric, and/or amperometric sensors) for the analysis of glucose are generally contemplated, other sensing mechanisms, including but not limited to optochemical sensors, biochemical sensors, electrocatalytic sensors, optical sensors, piezoelectric sensors, thermoelectric sensors, and acoustic sensors may be used. A device may include one sensing region, or multiple sensing regions. Each sensing region can be employed to determine the same or different analytes. The sensor region may include the entire surface of the device, a substantial portion of the surface of the device, or only a small portion of the surface of the device. Different sensing mechanisms may be employed by different sensor regions on the same device, or a device may include one or more sensor regions and also one or more regions for drug delivery, immunoisolation, cell transplantation, and the like. It may be noted that the preferred embodiments, the “sensor head” is the part of the sensor that houses the electrodes, while the “sensing region” includes the sensor head and area that surrounds the sensor head, particularly the area in such proximity to the sensor head that effects of the foreign body capsule on the sensor head.
The term “foreign body capsule” or “FBC,” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, body's response to the introduction of a foreign object; there are three main layers of a FBC: 1) the innermost layer, adjacent to the object, is composed generally of macrophages, foreign body giant cells, and occlusive cell layers; 2) the intermediate FBC layer, lying distal to the first layer with respect to the object, is a wide zone (e.g., about 30-100 microns) composed primarily of fibroblasts, contractile fibrous tissue fibrous matrix; and 3) the outermost FBC layer is loose connective granular tissue containing new blood vessels. Over time, this FBC tissue becomes muscular in nature and contracts around the foreign object so that the object remains tightly encapsulated.
The term “subcutaneous,” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, under the skin.
The term “intramuscular,” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, within the substance of a muscle.
The term “intraperitoneal,” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, within the peritoneal cavity, which is the area that contains the abdominal organs.
The term “intrafascial,” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, within the fascia, which is a sheet or band of fibrous tissue such as lies deep to the skin or forms an investment for muscles and various other organs of the body.
The term “axillary region,” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, the pyramidal region between the upper thoracic wall and the arm, its base formed by the skin and apex bounded by the approximation of the clavicle, coracoid process, and first rib; it contains axillary vessels, the brachial plexus of nerves, many lymph nodes and vessels, and loose areolar tissue.
The term “apex,” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, the uppermost point; for example the outermost point of a convexly curved portion.
The term “cuboidal,” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, a polyhedron composed of six faces, eight vertices, and twelve edges, wherein the faces.
The term “convex,” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, outwardly protuberant; that is, an object is convex if for any pair of points within the object, any point on the line that joins them is also within the object. A convex portion is a portion of an object that is convex in that portion of the object. For example, a solid cube is convex, but anything that is hollow or has a dent in it is not convex.
The term “curvature,” “curved portion,” and “curved,” as used herein, are broad terms and is used in their ordinary sense, including, without limitation, one or more arcs defined by one or more radii.
The term “cylindrical,” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, a solid of circular or elliptical cross section in which the centers of the circles or ellipses all lie on a single line. A cylinder defines a lateral surface and two ends.
The term “ellipsoidal,” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, closed surface of which all plane sections are either ellipses or circles. An ellipsoid is symmetrical about three mutually perpendicular axes that intersect at the center.
The term “spherical,” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, a solid that is bounded by a surface consisting of all points at a given distance from a point constituting its center.
The term “anchoring material,” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, biocompatible material that is non-smooth, and particularly comprises an architecture that supports tissue ingrowth in order to facilitate anchoring of the material into bodily tissue in vivo. Some examples of anchoring materials include polyester, polypropylene cloth, polytetrafluoroethylene felts, expanded polytetrafluoroethylene, and porous silicone, for example.
The term “mechanical anchoring mechanism,” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, mechanical mechanisms (e.g., prongs, spines, barbs, wings, hooks, helical surface topography, gradually changing diameter, or the like), which aids in immobilizing the sensor in the subcutaneous space, particularly prior to formation of a mature foreign body capsule
The term “biocompatible,” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, compatibility with living tissue or a living system by not being toxic.
The term “non-adhesive to tissue,” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, a material or surface of a material to which cells and/or cell processes do not adhere at the molecular level, and/or to which cells and/or cell processes do not adhere to the surface of the material.
The term “plastic,” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, polymeric materials that have the capability of being molded or shaped, usually by the application of heat and pressure. Polymers that are classified as plastics can be divided into two major categories: thermoplastic and thermoset.
The term “thermoplastic,” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, polymeric materials such as polyethylene and polystyrene that are capable of being molded and remolded repeatedly. The polymer structure associated with thermoplastics is that of individual molecules that are separate from one another and flow past one another.
The term “thermoset,” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, polymeric materials such as epoxy, silicone, and polyurethane that cannot be reprocessed upon reheating. During their initial processing, thermosetting resins undergo a chemical reaction that results in an infusible, insoluble network. Essentially, the entire heated, finished article becomes one large molecule. For example, the epoxy polymer undergoes a cross-linking reaction when it is molded at a high temperature. Subsequent application of heat does not soften the material to the point where it can be reworked and indeed may serve only to break it down.
The term “substantially,” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, refers to an amount greater than 50 percent, preferably greater than 75 percent and, most preferably, greater than 90 percent.
The term “host,” as used herein is a broad term and is used in its ordinary sense, including, without limitation, both humans and animals.
The term “R-value,” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, one conventional way of summarizing the correlation of data; that is, a statement of what residuals (e.g., root mean square deviations) are to be expected if the data are fitted to a straight line by the a regression.
Overview
In a preferred embodiment, the sensor heads, devices, and methods of the preferred embodiments may be used to determine the level of glucose or other analytes in a host. The level of glucose is a particularly important measurement for individuals having diabetes in that effective treatment depends on the accuracy of this measurement.
Although the description that follows is primarily directed at implantable glucose sensors, the methods of the preferred embodiments are not limited to either electrochemical sensing or glucose measurement. Rather, the methods may be applied to any implantable sensor that detects and quantifies an analyte present in biological fluids (including, but not limited to, amino acids and lactate), including those analytes that are substrates for oxidase enzymes (see, e.g., U.S. Pat. No. 4,703,756 to Gough et al., hereby incorporated by reference), as well as to implantable sensors that detect and quantify analytes present in biological fluids by analytical methods other than electrochemical methods, as described above. The methods may also offer benefits and be suitable for use with implantable devices, other than sensors, that are concerned with the transport of analytes, for example, drug delivery devices, cell transplantation devices, tracking devices, or any other foreign body implanted subcutaneously or in other soft tissue of the body, for example, intramuscular, intraperitoneal, intrafascial, or in the axial region.
Methods and devices that may be suitable for use in conjunction with aspects of the preferred embodiments are disclosed in copending applications including U.S. application Ser. No. 09/916,386 filed Jul. 27, 2001 and entitled “MEMBRANE FOR USE WITH IMPLANTABLE DEVICES”; U.S. application Ser. No. 09/916,711 filed Jul. 27, 2001 and entitled “SENSOR HEAD FOR USE WITH IMPLANTABLE DEVICE”; U.S. application Ser. No. 09/447,227 filed Nov. 22, 1999 and entitled “DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS”; U.S. application Ser. No. 10/153,356 filed May 22, 2002 and entitled “TECHNIQUES TO IMPROVE POLYURETHANE MEMBRANES FOR IMPLANTABLE GLUCOSE SENSORS”; U.S. application Ser. No. 09/489,588 filed Jan. 21, 2000 and entitled “DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS”; U.S. application Ser. No. 09/636,369 filed Aug. 11, 2000 and entitled “SYSTEMS AND METHODS FOR REMOTE MONITORING AND MODULATION OF MEDICAL DEVICES”; and U.S. application Ser. No. 09/916,858 filed Jul. 27, 2001 and entitled “DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS,” as well as issued patents including U.S. Pat. No. 6,001,067 issued Dec. 14, 1999 and entitled “DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS”; U.S. Pat. No. 4,994,167 issued Feb. 19, 1991 and entitled “BIOLOGICAL FLUID MEASURING DEVICE”; and U.S. Pat. No. 4,757,022 filed Jul. 12, 1988 and entitled “BIOLOGICAL FLUID MEASURING DEVICE.” All of the above patents and patent applications are incorporated in their entirety herein by reference.
Such medical devices, including implanted analyte sensors, drug delivery devices and cell transplantation devices require close vascularization and transport of solutes across the device-tissue interface for proper function. These devices generally include a biointerface membrane, which encases the device or a portion of the device to prevent access by host inflammatory cells, immune cells, or soluble factors to sensitive regions of the device.
Nature of the Foreign Body Capsule
Biointerface membranes stimulate a local inflammatory response, called the foreign body response (FBR) that has long been recognized as limiting the function of implanted devices that require solute transport. The FBR has been well described in the literature.
Sensor Geometry
It has been observed that the variability of function observed in implanted sensors may sometimes occur in several different devices implanted within the same host (e.g., human or animal). Accordingly, this observation suggests that individual variability of hosts may not be a significant factor in the observed variability. Data suggest that a major factor in the variability is the individual nature of how the surrounding tissue heals around each device. Accordingly, the present invention discloses methods and systems for selecting an appropriate geometry for a device that requires transport of analytes in vivo, such that the healing of the host tissue around the device is optimized. Optimizing the host response includes minimizing variability, increasing transport of analytes, and controlling motion artifact in vivo, for example.
Particularly,
A wide variability in the healing of the tissue adjacent to the sensor dome of the device is observed. Particularly, the foreign body capsule is thickest in the area 42 adjacent to the discontinuous surface (e.g., O-ring and sensor head-sensor body interface). This thickest portion is a result of tissue contracture that occurs during the foreign body response, resulting in forces being applied to the portion of the device interfacing with the tissue. Notably, because the device of
The tissue response resulting in the growth of occlusive cells as described above tends to occur due to the contraction of the surrounding wound tissue. It is therefore desirable to ensure stable wound healing that does not change after the initial healing. As illustrated by the photomicrograph of
Consequently, contractile forces 54 pull laterally and outwardly along the flat surfaces, including the sensing region, which is the area proximal to the electrodes 52, as the FBC tightens around the device. Lateral contractile forces 54 caused by the FBC 50 along the flat surfaces are believed increase motion artifact and tissue damage due to shear forces 56 between the device 52 and the tissue. In other words, rather than firmly holding the tissue adjacent the sensing region with a downward force against the sensing region (such as will be shown with the geometry of the present invention), a lateral movement (indicated by arrow 56) is seen in the tissue adjacent to the sensing region, causing trauma-induced wounding mechanisms that may lead to improper healing and the growth of occlusive cells at the biointerface. This is especially harmful in the sensing region, which requires substantially consistent transport of analytes, because it is known that thickening of the FBC from chronic inflammation and occlusive cells decreases or blocks analyte transport to the device.
It may be noted that some prior art devices attempt to minimize tissue trauma by rounding edges and corners, however the effects of tissue trauma will still be seen in the flat surfaces (e.g., sensing region) of the device such as described above, thereby at least partially precluding function of a device requiring analyte transport. Similarly, placement of the sensing region, or a plurality of sensing regions, away from the center of the device (such as seen in some prior art devices) would not significantly improve the effects of the lateral contractile forces along the flat surface of the sensing region(s), because it is the flat surface, whether at the center and/or off center, that causes in the occlusive tissue trauma in vivo.
It may be noted that the thickness of the FBC appears to increase around the central portion of the device and be thinner around the ends. It is believed that this phenomenon is due to the loose and counteracting lateral contractile forces near the center of the device, while a tighter contractile force near the ends of the device indicates tighter control of the FBC.
In contrast to the prior art, a preferred embodiment of the present invention provides a sensor geometry that includes a sensing region adapted for transport of analytes between the sensor and the bodily fluid, wherein the sensing region is located on a curved portion of the sensor body such that when a foreign body capsule forms around the sensor, a contractile force is exerted by the foreign body capsule toward the sensing region. This contractile force provides sufficient support to maintain the foreign body capsule in close proximity to the sensing region without substantial motion artifact or shearing forces, thereby minimizing inflammatory trauma, minimizing the thickness of the foreign body capsule, and maximizing the transport of analytes through the foreign body capsule. Additionally, the overall design described herein ensures more stable wound healing, and therefore better acceptance in the body.
It may be noted that the disadvantageous outward forces (e.g., forces 40 as described with reference to
In this embodiment, the analyte sensor 80 includes the sensing region 82 located on a curved portion of the sensor body, and including no abrupt edge or discontinuous surface in the proximity of the sensing region. Additionally, the overall curvature of the surface on which the sensing region is located, including rounded edges, invokes a generally uniform FBC around that surface, decreasing inflammatory response and increasing analyte transport at the device-tissue interface 84.
In one aspect of this embodiment, the sensor geometry particularly suited for healing at the device-tissue interface 84 when the sensor is implanted between two tissue planes. That is, the geometry includes a thin, substantially oval sensor, wherein the sensor head is positioned on one of the major surfaces of the sensor rather than at the tip, as illustrated in
Perpendicular forces 88, depicted in
It may be noted that any curved surface can be deconvoluted to a series of radii, as is appreciated by one skilled in the art. It is generally preferred to have a radius of curvature in the lateral, longitudinal or other direction of from about 0.5 mm or less to about 10 cm or more. More preferably the radius of curvature is from about 1, 2, 3, 4, 5, 6, 7, 8, or 9 mm to about 5, 6, 7, 8, or 9 cm, even more preferably the radius of curvature is from about 1, 1.25, 1.5, 1.75, 2 or 2.25 cm to about 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, or 4.75 cm, and most preferably the radius of curvature is from about 2.5 or 2.6 cm to about 2.7, 2.8, or 2.9 cm. Radii of curvature in the longitudinal direction are generally preferred to be larger than those in the lateral direction. However, in certain embodiments the radii of curvature may be approximately the same, or smaller in the longitudinal direction.
In one embodiment, the preferred shape of the device can be defined in the context of a reference plane. In such an embodiment, the device has a first major surface and a second major surface opposite the first major surface, where the first major surface includes a sensor. The first and second major surfaces together preferably account for at least about 40% or 50% of the surface area of the device. The first major surface has edges between which a width of the first major surface can be measured, and the sensor is preferably spaced away from the edges by a distance that is at least about 10% of the width, and preferably at least about 15%, 20%, 25%, or 30% of the width of the first major surface. It is understood that the first major surface may have multiple edges and that multiple widths can be measured, and in the context of the foregoing, a width should be configured to run from one edge to an opposite edge. Preferably, spacing of the sensor from the edges specified above is true for at least two width measurements, which measurements are taken generally transverse to each other.
With the sensor situated on the first major surface of the device, a reference plane can be imagined that is congruent to the first major surface, which first major surface is preferably at least slightly convex. This plane, which would then touch the first major surface at a point spaced in from the edges of the first major surface, would be generally parallel to the first major surface and would additionally be spaced away from opposite edges of the first major surface due to the convex nature of the first major surface. In preferred embodiments, the reference plane would be spaced from the edges a distance that is at least about 3%, 4%, or 5% of the width between those edges, and more preferably 6%, 7%, 8% or more from the edges, but at the same time the distance is preferably not more than 50%, 40%, or 30% of the width, and may well be not more than 25%, 20%, or 15% of the width between the edges. In preferred embodiments, the edges of the first major surface are rounded, so that they transition smoothly away from the first major surface. In this situation, the location of the edge can be configured to be the point at which a congruent line and/or a normal line would be angled 45 degrees with respect to the reference plane.
In preferred embodiments, the sensor body defines a surface area, and wherein between 10% and 100% of the surface area is convexly curved. In some preferred embodiments a substantial portion of the surface area is convexly curved. In one preferred embodiment, at least about 90% of the surface area is convexly curved. In other preferred embodiments, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% of the surface area is curved.
As a first noted advantage, the cylindrical geometry of the sensor body 120 allows for discreet placement within or between tissue types when the overall surface area-to-volume ratio can be optimized to provide a maximal surface area with a minimal volume. That is, although the volume of a sensor often depends on the necessary electronics within the sensor body, the evolution of smaller batteries and circuit boards sanctions the design and manufacture of a cylindrical sensor with minimal volume; simultaneously, the surface area inherent in a cylindrical geometry allows for maximal tissue anchoring in vivo (e.g., as compared to a substantially rectangular or oval structure). In one exemplary embodiment, an application specific integrated circuit (ASIC) may be designed to fit within the geometric design of any of the embodiments disclosed herein to maximize the electronic capabilities while minimizing volume requirements as compared to conventional circuit boards. Sensor electronics requirements vary depend on the sensor type, however one example of electronics for a glucose sensor is described in more detail with reference to copending U.S. patent application Ser. No. 10/633,367 filed on Aug. 1, 2003 and entitled “SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR DATA,” which is incorporated by reference herein in its entirety.
As a second noted advantage, the curved lateral surface 122 of the cylindrical structure lends itself to a plurality of sensing regions 124 (e.g., electrodes) and allows the sensor to sense a variety of different constituents (e.g., glucose, oxygen, interferants (e.g., ascorbate, urate, etc.)) using one compact sensor body.
As a third noted advantage, when the plurality of sensing regions 124 are configured to sense the same constituent (e.g., glucose) such as shown in
As a fourth noted advantage, the FBC that forms around the lateral curved surface 122 will create generally uniform forces 126 toward the sensing region 124 and around the entire lateral surface. Furthermore, when the ends 128 of the cylindrical sensor body 120 are designed with a curvature such as shown in the embodiment of
As a first noted advantage, a spherical geometry defines an optimal surface-to-volume ratio when compared to other geometries of devices with a comparable volume (e.g., rectangular, oval, and cylindrical). That is, when volume is a constant, the spherical geometry will provide an optimal surface area for tissue ingrowth in vivo in combination with an optimal curvature for uniform contractile forces from a FBC in vivo as compared to other geometries.
As a second noted advantage, entirely curved surface area of the spherical geometry lends itself to a plurality of sensing regions (e.g., electrodes) 132a and allows the sensor to sense a variety of different constituents (e.g., glucose, oxygen, interferants (e.g., ascorbate, urate, etc.)) using one compact sensor body 130a.
As a third noted advantage, when a plurality of sensing regions 132a that sense the same constituent (e.g., glucose) are spread apart, the likelihood of finding an area of the FBC that is optimized for transport of analytes is increased by the amount of increase of the area of the sensing regions.
As a fourth noted advantage, the FBC that forms around the spherical sensor body will create uniform forces 134a toward the entire surface area, including the sensing regions 132a, which may therefore be located anywhere on the sensor body. Consequently in vivo, a sensor body with a curvature such as shown in the embodiment of
The separation of at least some of the electronics between the sensing body which houses the electrodes, from the rod which may house, for example a cylindrical battery, allows for optimization of the sensing body design by minimizing the volume and/or mass requirements of the sensing body 130b due electronics. The geometric design of the sphere and rod as shown in
The sensor 140 includes a sensing body 144 on which the sensing region 145 is located and an electronics body 146 in which the sensor electronics are located such as described with reference to
In these embodiments wherein the sensing body 152 is tethered to the electronics body 156, the sensing body 152 can be easily optimized for surface area, shape, size, geometry, mass, density, volume, surface area-to-volume, surface area-to-density, and surface area-to-mass as desired. That is, without the mass, size, and volume constraints normally imposed by the electronics portion of a sensor, the sensing body can be optimally designed for a particular implantation site, function, or other parameter. Additionally, the electronics body can be formed from any biocompatible material (e.g., metal, ceramic, or plastic) known in the art. Additionally, it may be hermetically sealed to protect the electronic components. The tether 158 may be formed from a polymeric material or other biocompatible material and encases a conductive wire (e.g., copper) that connects the electronics within the electronics body 156 to the electronics portion of the sensing body 152 (e.g. to electrodes on the sensing region 153).
This tethered sensor design of these embodiments advantageously allows for an optimal design of the sensing body without concern for the effects of the foreign body response caused by the electronics body. The tether can be design shorter or longer, and stiffer or more flexible, in order to optimize the isolation, strain relief, and/or implantation issues.
In practice, the electronics body 168 may be implanted in the subcutaneous tissue without particular concern for the design (e.g., anchoring material, curvature, etc) and its effect on the formation of a FBC. After the FBC has healed around the electronics body 168, the sensing bodies 162 can be individually inserted in a minimally invasive manner (e.g., guide wire introduced with needle and sheath) as needed. Advantageously, each sensing body 162 functions up to about one year or more in vivo. Accordingly, when a sensing body fails to function as needed, another sensing body 162 may be inserted into another port 166 of the electronics body 168.
It may be noted that the sensors of preferred embodiments may be rigid or flexible, and of any suitable shape, including but not limited to rectangular, cylindrical, square, elliptical, oval, spherical, circular, ellipsoidal, ovoid, hourglass, bullet-shaped, porpoise-nosed, flat sheet, accordion, or any other suitable symmetrical or irregular shape. Corners may range from sharp to slightly round, to substantially round. While the sensors of preferred embodiments are preferably employed to determine the presence of an analyte, devices of preferred geometries may also be constructed for drug delivery, immunoisolation, cell transplantation, and the like. For example, the preferred device configurations can be suitable for use in fabricating an artificial pancreas.
In addition to a simple circular curvature, the curvature can also be elliptical or parabolic. The curvature can be perfectly symmetrical about the sensor head, or can possess some degree of asymmetry. While a true curvature is generally preferred, in certain embodiments a triangular profile or other polygonal profile with rounded edges may also be employed. While a smooth surface is generally preferred, in certain embodiments it may be desired to incorporate local features, such as bumps, dimples, ridges, and the like, while maintaining an overall curvature. It is generally preferred that each surface is convex, or less preferably flat but not concave. However, in certain embodiments a slightly concave or recessed surface may be acceptable presuming it is located sufficiently far from the sensing region that any chronic inflammatory response will not translate to the area adjacent the sensor head. The sensor head preferably protrudes above the radius of curvature or is flush with the radius of curvature. A recessed sensor head is generally not preferred. However, in certain embodiments such a configuration may be acceptable.
The sensor head may be positioned on any convenient location of on the device. Particularly preferred locations are the geometric center of a surface of the device, or offset to one side. In certain embodiments it may be desirable to incorporate multiple sensor heads on a single device. Such sensor heads may be spaced apart so as to maximize the distance between the sensor heads, or grouped together at one location on the device.
Manufacture of Sensor Body
In a preferred embodiment, the sensor is formed by substantially entirely epoxy encapsulating the sensor electronics; that is, the sensor body, outside the sensor head, is comprises an epoxy resin body. During the manufacture of the sensor body of the preferred embodiment, the sensitive electronic parts (e.g. battery, antenna, and circuit board, such as described in copending U.S. patent application Ser. No. 10/633,367 filed on Aug. 1, 2003 and entitled “SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR DATA”) are substantially entirely encapsulated in epoxy, with the exception of the sensor head. In some molding processes, the epoxy body may be formed with a curvature on a portion thereof. After the epoxy has completely cured, additional curvature may be machined, milled, laser-etched, or otherwise processed into the epoxy body to form the final geometric shape. In alternative embodiments, a light epoxy coating may be applied to the sensitive electronic parts, after which injection molding or reaction injection molding (RIM) may be used to form the final shape of the epoxy body. While a preferred sensor is constructed of epoxy resin, a non-conductive metal, ceramic or other suitable material may be used.
Anchoring Material & Implantation
In one embodiment, the entire surface of the sensor is covered with an anchoring material to provide for strong attachment to the tissues. In another embodiment, only the sensor head side of the sensor incorporates anchoring material, with the other sides of the sensor lacking fibers or porous anchoring structures and instead presenting a very smooth, non-reactive biomaterial surface to prevent attachment to tissue and to support the formation of a thicker capsule. The anchoring material may be selected from the group consisting of: polyester, polypropylene cloth, polytetrafluoroethylene felts, expanded polytetrafluoroethylene, and porous silicone.
While these configurations of anchoring materials are particularly preferred, other configurations may also be suitable for use in certain embodiments, including configurations with different degrees of surface coverage. For example, from less than about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% to more than about 55, 60, 65, 70, 75, 80, 85, 90, or 95% of the surface of the device may be covered with anchoring material. The anchoring material may cover one side, two sides, three sides, four sides, five sides, or six sides. The anchoring material may cover only a portion of one or more sides, for example, strips, dots, weaves, fibers, meshes, and other configurations or shapes of anchoring material may cover one or more sides. Likewise, while silicone and polyester fibers are particularly preferred, any biocompatible material capable of facilitating anchoring of tissue to the device may be employed.
It may be noted that the optimum amount of anchoring material that may be used for any particular sensor is dependent upon one or more of the following parameters: implantation site (e.g., location in the host), surface area, shape, size, geometry, mass, density, volume, surface area-to-volume, surface area-to-density, and surface area-to-mass. For example, a device with a greater mass as compared to a device with a lesser mass may require more anchoring material to support the greater mass differential.
In preferred embodiments, the sensor of the described geometry is implanted at the interface between two kinds of tissue, and is preferably anchored to the more robust tissue type. For example, the sensor may be placed adjacent to an organ (for example, a kidney, the liver, or the peritoneal wall), or adjacent to the fascia below adipose tissue. When implanted in such a fashion, the sensor geometry minimizes force transference, permitting non-anchored tissue to move over the smooth surface of the sensor, thereby minimizing the force transferred to the underlying tissue to which the sensor is anchored. While it is generally preferred to anchor the sensor to the more robust tissue type, in certain embodiments it may be preferred to anchor the sensor to the less robust tissue type, permitting the more robust tissue to move over the smooth surface of the sensor. While the sensor geometries of preferred embodiments are particularly preferred for use at tissue interfaces, such sensors are also suitable for use when implanted into a single type of tissue, for example, muscle tissue or adipose tissue. In such embodiments, however, the sensor geometry may not confer any benefit, or only a minimal benefit, in terms of force transference. Other benefits may be observed, however. In another embodiment, the sensor may be suspended, with or without sutures, in a single tissue type, or be placed between two tissue types, and anchoring material covering substantially the entire surface of the device may be employed.
In some alternative embodiments, a mechanical anchoring mechanism, such as prongs, spines, barbs, wings, hooks, helical surface topography, gradually changing diameter, or the like, may be used instead of or in combination with anchoring material such as described herein. For example when an oblong or cylindrical type sensor is implanted within the subcutaneous tissue, it may tend to slip along the pocket that was formed during implantation, particularly if some additional space exists within the pocket. This slippage can lead to increased inflammatory response and/or movement of the sensor prior to or during tissue ingrowth. Accordingly, a mechanical mechanism can aid in immobilizing the sensor in place, particularly prior to formation of a mature foreign body capsule. One example of mechanical anchoring means is shown on
An anchoring material covering the sensor may also make it difficult to remove the sensor for maintenance, repair, or permanent removal if its function is no longer necessary. It is generally difficult to cut down through the surrounding tissue to the surface of the sensor without also cutting into the anchoring material and leaving some of it behind in the patient's tissues. Leaving a portion of the sensor free of anchoring material enables the sensor to be more easily removed by locating the smooth surface, grasping the sensor with a holding tool, and then cutting along the plane of the anchoring material to fully remove the sensor. In certain embodiments, however, it may be desirable for the entire surface of the sensor, or a substantial portion thereof, to be covered with an anchoring material. For example, when implanted into a single tissue type (subcutaneous adipose tissue, or muscle tissue), it may be desirable to have anchoring over all or substantially the entire surface of the sensor. In still other embodiments, no anchoring at all may be preferred, for example, in sensors having very small dimensions. One contiguous sheet of anchoring material can be employed, or two or more different sheets may be employed, for example, an array of dots, stripes, mesh, or other suitable configuration of anchoring material.
In other words, in
It may be noted that the smoothness of the surface of the device can be measured by any suitable method, for example, by profilometry as described in U.S. Pat. No. 6,517,571, the contents of which is hereby incorporated by reference in its entirety. Measurements are preferably taken from representative areas (for example, square areas of 500 microns length on each side) of the smooth surface of the device. A surface is generally considered “smooth” if it has a smoothness of less than 1.80 microns RMS. Surfaces with a smoothness greater than or equal to 1.80 microns RMS are generally considered “rough.” In certain embodiments, however, the cut-off between “rough” and “smooth” may be higher or lower than 1.80 microns RMS.
Profilometry measurements can be performed with a Tencor Profiler Model P-10, measuring samples of square areas of 500-micron length per side. Surface data measurements can be made using the Tencor Profiler Model P-10 with a MicroHead or Exchangeable Measurement Head (stylus tip radius of 2.0 microns with an angle of 60°). Preferred menu recipe settings for the profilometer are as follows:
Cursors can be set at each end of the length of each area to be sampled, for example, at 0 microns and at 500 microns. Scans can be performed in the longitudinal direction of tubular samples, or in any convenient direction for samples of other shapes. A parameter correlating to roughness of surfaces of the devices of preferred embodiments is Rq, which is the Root-Mean-Square (RMS) roughness, defined as the geometric average of the roughness profile from the mean line measured in the sampling length, expressed in units of microns RMS.
The use of an alternative (finer) waviness filter during profilometry allows for materials that include gross surface non-uniformities, such as corrugated surfaces made from microscopically smooth materials.
In certain embodiments it is preferred that the smooth surfaces of the device are smooth in their entirety, namely, along the entire length of the surface. For surfaces of relatively uniform smoothness along their entire length, surface measurements are preferably made at three points along the length of the surface, specifically at points beginning at one fourth, one half and three fourths of the length of the surface as measured from one end of device to the other. For surfaces of non-uniform surface character along their entire length, five samples equally spaced along the length are preferably considered. The measurements from these 3-5 sample areas are then averaged to obtain the surface value for the smooth surface. In other embodiments, however, other methods of obtaining measurements may be employed.
An article entitled “Atomic force microscopy for characterization of the biomaterial interface” describes the use of AFM for consideration of surface smoothness (Siedlecki and Marchant, Biomaterials 19 (1998), pp. 441-454). AFM may be usefully employed for the smoothness evaluation of device surfaces where the resolution of profilometry is marginally adequate for extremely smooth surfaces. However, for purposes of the preferred embodiments, profilometry measurements made using the above-described Tencor profilometer are generally adequate for determining the smoothness of the device surface
EXAMPLES Weekly infusion studies were conducted for four-weeks to investigate the effects of sensor geometries of preferred embodiments on the functional performance of glucose sensors. A first group of sensors (n=5) included a cylindrical geometry similar to that described with reference to
The implantation entailed making a 1-inch incision, then forming a pocket lateral to the incision by blunt dissection. After placement of the device with the sensing region facing towards the fascia, a suture was placed by pulling the connective tissue together at the end of the device proximal to the incision. It is believed that the sutures held effectively during wound healing and device integration with tissues.
The delayed start-up of the cylindrical group as compared to the thin, oblong group is believed to be due to delayed ingrowth of tissues or lack of ingrowth of tissues, which effects device function through lack of glucose sensitivity, compromised function after start-up, low sensitivity, and long time lags. One cause for this delay of or lack of tissue ingrowth in the cylindrical group is believed to be the placement of the sensing region on the device. Particularly, when a sensor is implanted in the subcutaneous space between two tissue types, such as the adipose subcutaneous tissue and the fascia, optimal tissue ingrowth may occur when the sensor is directly adjacent and fully engaged with the fascia, such as described with reference in
Some additional observations may be directly related to the delayed sensor function in the cylindrical sensors of this study. For example, the thin, oblong geometry as compared to the cylindrical geometry does not protrude from the host as much and is less amenable to accidental bumping or movement, and less available for patient “fiddling.” Thus, it may be inferred that overall dimensions may effect sensor geometry such that by increasing the discreetness of the geometry (e.g., mass, shape, dimensions), sensor functionality may improve. As another example, the thin, oblong geometry as compared to the cylindrical geometry is less susceptible to torsion and/or rotational forces, which may create motion artifact and therefore chronic inflammatory response at the device-tissue interface. In other words, with the sensor head oriented down towards the fascia, and nearer to the center of the sensor, downward pressure on either end is not transferred as shear force to the sensor head; even if the sensor is moved, the sensor head more likely remains adjacent to the tissue so that it may heal in a favorable fashion, unlike the sensors wherein the tip is positioned on an end of the sensor body, which can leave a space after lateral movement. From this observation, it may be hypothesized that surface area-to-volume ratio may effect the function of the sensor. Particularly, an increased surface area-to-volume ratio, particularly as a consequence of reducing the volume of the sensor, may decrease the effects of forces (e.g., torsion, rotational, and shearing) caused by behavioral and environment movement. Similarly, optimization of surface area-to-mass and surface area-to-density ratios may impact healing.
It may be observed that both geometry groups performed with sufficient accuracy by week three (e.g., greater than 0.79 R-value constitutes sufficient accuracy in one example). It may also be observed that the sensors of the thin, oblong group increased in accuracy and were more consistent than the sensors of the cylindrical group. It is believed that the slightly improved performance of the thin, oblong group as compared to the cylindrical group may be due to a variety of factors, including those described with reference to
From the observations of the above described study, optimization of the sensor geometry may additionally include: 1) density optimization to better correspond to the density of tissue (e.g., fascia or adipose), 2) surface area-to-volume optimization by increasing the surface area-to-volume ratio of the sensor, 3) size optimization by decreasing the overall size, mass, and/or volume of the sensor, and 4) surface area-to-mass optimization by increasing the surface area-to-mass ratio of the sensor, for example.
Table 1 illustrates additional analysis from the above described infusion study, including a comparison of average R-value at week 4 and standard deviation at week 4 for the two groups of sensors.
As described above with reference to
The above description discloses several methods and materials of the present invention. This invention is susceptible to modifications in the methods and materials, as well as alterations in the fabrication methods and equipment. Such modifications will become apparent to those skilled in the art from a consideration of this disclosure or practice of the invention disclosed herein. Consequently, it is not intended that this invention be limited to the specific embodiments disclosed herein, but that it cover all modifications and alternatives coming within the true scope and spirit of the invention as embodied in the attached claims. All patents, applications, and other references cited herein are hereby incorporated by reference in their entirety.
Claims
1. An implantable sensor for use in measuring a concentration of an analyte in a bodily fluid, the sensor comprising:
- a body comprising a sensing region adapted for transport of analytes between the sensor and the bodily fluid, wherein the sensing region is located on a curved portion of the body such that when a foreign body capsule forms around the sensor, a contractile force is exerted by the foreign body capsule toward the sensing region, wherein the body comprises a first surface and a second surface, wherein the sensor region is situated at a position on said first surface offset from a center point of said first surface, and wherein the sensor is a subcutaneous sensor suitable for implantation in a soft tissue of a body.
2. The sensor of claim 1, wherein the sensor comprises a plurality of sensor regions.
3. The sensor of claim 1, wherein said second surface is flat.
4. The sensor of claim 1, wherein said second surface comprises a curvature.
5. The sensor of claim 1, wherein t wherein said first surface, when viewed from a direction perpendicular to a center of said first surface, has a substantially oval profile.
6. The sensor of claim 1, wherein said first surface, when viewed from a direction perpendicular to a center of said first surface, has a substantially circular profile.
7. The sensor of claim 1, wherein the body is substantially cylindrical defined by a curved lateral surface and two ends.
8. The sensor of claim 1, wherein the body is substantially cylindrical defined by a curved lateral surface and two ends, and wherein at least one of said ends comprises the substantially curved portion on which the sensor region is located.
9. The sensor of claim 1, wherein the second surface comprises anchoring material thereon for supporting tissue ingrowth.
10. The sensor of claim 1, further comprising a mechanical anchoring mechanism formed on the body.
11. The sensor of claim 1, wherein said curved portion comprises a plurality of radii of curvature.
12. The sensor of claim 1, wherein said curved portion comprises a radius of curvature between about 0.5 mm and about 10 cm.
13. The sensor of claim 1, wherein the body comprises a first major surface on which said sensing region is located and a second major surface, and wherein the first and second major surfaces together account for at least about 40% of the surface area of the device.
14. The sensor of claim 1, wherein the body comprises a first major surface on which said sensing region is located and a second major surface, wherein the first major surface has edges between which a width of the first major surface can be measured, and wherein the sensing region is spaced away from the edges by a distance that is at least about 10% of the width of the first major surface.
15. The sensor of claim 1, and wherein edges of the first major surface are rounded and transition smoothly away from the first major surface.
16. The sensor of claim 1, wherein the body defines a surface area, and wherein between 10% and 100% of the surface area is convexly curved.
17. The sensor of claim 1, wherein the body comprises plastic.
18. The sensor of claim 17, wherein the plastic is selected from the group consisting of thermoplastic and thermoset.
19. The sensor of claim 18, wherein the thermoset is selected from the group consisting of epoxy, silicone, and polyurethane.
20. The sensor of claim 1, wherein the body comprises a material selected from the group consisting of metal, ceramic, and glass.
21. The sensor of claim 1, further comprising a porous biointerface material that covers at least a portion of the sensing region.
22. The sensor of claim 21, wherein the biointerface material comprises interconnected cavities dimensioned and arranged to interfere with formation of occlusive cells.
23. The sensor of claim 1, wherein the sensor is a glucose sensor.
24. A wholly implantable sensor adapted to measure a concentration of an analyte in a bodily fluid, comprising:
- a wholly implantable body comprising a sensing region adapted for transport of analytes between the sensor and the bodily fluid, wherein the sensing region is located on a curved portion of a first major surface of said body, wherein the body further comprises a second major surface, wherein the sensing region is situated at a position on said first major surface offset from a center point of said first major surface, wherein the sensor is a subcutaneous sensor suitable for implantation in a soft tissue of a body, and wherein said first surface comprises a porous material thereon for supporting tissue ingrowth.
25. An implantable sensor adapted to measure a concentration of an analyte in a bodily fluid, comprising:
- a body having a first major surface and, opposite thereto, a second major surface, wherein the first major surface is generally planar, slightly convex, and has rounded edges, with a sensor region located on the first major surface that is spaced away from the rounded edges and offset from a center point of said first major surface, wherein the first major surface is sufficiently convex that when a foreign body capsule forms around the sensor, contractile forces are exerted thereby generally uniformly towards the sensing region, and wherein the sensor is a subcutaneous sensor suitable for implantation in a soft tissue of a body.
Type: Application
Filed: May 2, 2006
Publication Date: Oct 5, 2006
Inventors: James Brauker (San Diego, CA), Victoria Carr-Brendel (San Diego, CA), Paul Neale (San Diego, CA), Laura Martinson (La Mesa, CA)
Application Number: 11/416,346
International Classification: A61M 31/00 (20060101); A61K 9/22 (20060101);