Sensors for continuous analyte monitoring, and related methods

Abstract

To provide sensors for continuous analyte monitoring, and related methods.SOLUTION: Sensor devices including dissolvable tissue-piercing tips can be used in conjunction with dissolvable needles configured for inserting the sensor devices into a host. Hardening agents for strengthening membranes on the sensor devices are also provided. Methods of using and fabricating the sensor devices are also provided.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] Interactive Incorporation of Related Applications Any and all priority claims or any amendments thereto identified in the Application Data Sheet are incorporated herein by reference under 37 CFR 1.57. This application claims the benefit of U.S. Application No. 14 / 250,320, filed April 10, 2014, and U.S. Application No. 14 / 250,341, filed April 10, 2014. The foregoing applications are incorporated herein by reference in their entireties and expressly incorporated herein.

[0002] The present embodiments relate to systems and methods for determining the concentration of an analyte in a host. [Background technology]

[0003] Diabetes mellitus is a disorder in which the pancreas cannot produce enough insulin (type 1, or insulin-dependent), and / or insulin is ineffective (type 2, or non-insulin-dependent). In the diabetic state, sufferers suffer from hyperglycemia, which can lead to a range of physiological disorders (e.g., kidney failure, skin ulcers, or bleeding into the vitreous of the eye, associated with microvascular deterioration). A hypoglycemic reaction (hypoglycemia) can be caused by inadvertent overdose of insulin, or by extreme exercise or inadequate food intake after regular dosing with insulin or glucose-lowering drugs.

[0004] Traditionally, individuals with diabetes carry self-monitoring blood glucose (SMBG) monitors, which typically require an uncomfortable finger prick to obtain a blood sample for measurement. Due to the lack of comfort and convenience associated with finger pricks, individuals with diabetes typically measure their glucose levels only two to four times per day. Unfortunately, the intervals between measurements can be so far apart that individuals with diabetes may recognize a hyperglycemic or hypoglycemic state too late and sometimes suffer dangerous side effects. Not only do patients with diabetes tend not to obtain SMBG readings in a timely manner, patients also tend not to know whether their blood glucose levels are rising (getting higher) or falling (getting lower) based on traditional methods. Diabetic patients may therefore be hindered from making informed insulin therapy decisions.

[0005] Another device used by diabetics to monitor blood glucose is a continuous analyte sensor. Continuous analyte sensors typically include sensors that are placed subcutaneously, transdermally (e.g., transdermally), or intravascularly. The sensor measures the concentration of a given analyte in the body and generates a raw signal, which is transmitted to electronics associated with the sensor. The raw signal is converted into an output value, which is displayed on a display. The output value resulting from the conversion of the raw signal is typically expressed in a format that provides meaningful information to the user, for example, blood glucose expressed in mg / dL. Summary of the Invention [Means for solving the problem]

[0006] The various present embodiments have multiple features, none of which are solely responsible for their desirable attributes. Without limiting the scope of the present embodiments as set forth in the claims that follow, their more prominent features will now be discussed more briefly. After considering this discussion, and particularly after reading the section entitled "Detailed Description of the Invention," one will understand how the features of the present embodiments provide the advantages described herein.

[0007] One aspect of the present embodiments includes the recognition that a tack sensor includes a sharpened tip that remains embedded in tissue for the entire life of the sensor. Leaving the sharpened tip in vivo for an extended period of time can cause trauma to surrounding tissue, resulting in scarring and inhibited wound healing. Some of the present embodiments provide a solution to this problem.

[0008] In recognition of the aforementioned problems, in a first aspect, some of the present embodiments comprise a sensor device for measuring a concentration of an analyte in a host, the sensor device comprising: a sensor unit comprising a sensor body, at least one electrode, and a membrane covering at least a portion of the at least one electrode, wherein the sensor body has a smooth tip; a piercing element comprising a material that rapidly dissolves after insertion into the host, the piercing element abutting the sensor tip and capable of piercing tissue; and a mounting unit spaced from the sensor tip and configured to support the sensor device on an outer surface of the host's skin.

[0009] In an embodiment of the first aspect, the penetrating element is fixed to the sensor tip.

[0010] In some embodiments of the first aspect, the penetrating element is adhered to the sensor tip.

[0011] In some embodiments of the first aspect, the penetrating element is not fixed to the sensor tip, but is maintained in abutting contact with the sensor tip.

[0012] In some embodiments of the first aspect, the sleeve surrounding the sensor tip and the penetrating element maintain abutting contact.

[0013] In an embodiment of the first aspect, the penetrating element includes a coating that covers at least a portion of the sensor body, including the sensor tip.

[0014] In an embodiment of the first aspect, the coating comprises a sharp coating tip.

[0015] In an embodiment of the first aspect, the material of the penetration element comprises a wound control material.

[0016] In an embodiment of the first aspect, the material of the penetration element comprises a material that promotes rapid wound healing.

[0017] In an embodiment of the first aspect, the material of the penetration element comprises a material that induces osmotic or oncotic pressure.

[0018] In an embodiment of the first aspect, the material of the penetration element comprises one or more drugs.

[0019] In an embodiment of the first aspect, the material of the penetration element comprises vascular endothelial growth factor (VEGF).

[0020] In an embodiment of the first aspect, the material of the penetration element includes at least one of a salt, a metal salt, a sugar, a synthetic polymer, polylactic acid, polyglycolic acid, or a polyphosphazene.

[0021] In certain embodiments of the first aspect, the material of the penetration element biodegrades / dissolves within one day after insertion into the host.

[0022] In certain embodiments of the first aspect, the material of the penetration element biodegrades / dissolves within 3 hours after insertion into the host.

[0023] In certain embodiments of the first aspect, the penetrating element does not extend beyond the sensor tip in the direction of the mounting unit, or extends only a short distance in that direction.

[0024] In some embodiments of the first aspect, the penetrating element extends beyond the sensor tip in the direction of the mounting unit but stops short of the electrodes.

[0025] In an embodiment of the first aspect, the mounting unit comprises a guiding portion configured to guide insertion of the sensor unit through the skin of the host and to support the column strength of the sensor body so that the sensor unit can be inserted through the skin of the host without substantial buckling.

[0026] In certain embodiments of the first aspect, the at least one electrode includes a working electrode and a reference electrode.

[0027] In an embodiment of the first aspect, the sensor body further comprises a support member configured to protect the membrane from damage during insertion of the sensor unit.

[0028] In an embodiment of the first aspect, at least one electrode is a support member.

[0029] In an embodiment of the first aspect, the support member is configured to support at least a portion of the at least one electrode.

[0030] In an embodiment of the first aspect, the support member is configured to substantially surround the at least one electrode.

[0031] In an embodiment of the first aspect, the mounting unit comprises a sensor electronics unit operably and removably connected to the sensor body.

[0032] In an embodiment of the first aspect, the sensor electronics unit is configured to be positioned over the sensor insertion site.

[0033] Further, in recognition of the aforementioned problems, in a second aspect, some of the present embodiments include a method of making a sensor device, the method including immersing a sensor tip in a liquid to form a coating of the liquid on the sensor tip, and withdrawing the sensor tip from the liquid while controlling withdrawal parameters such that the coating forms a sharp point extending from the sensor tip, the sharp point being capable of penetrating tissue.

[0034] In an embodiment of the second aspect, the parameters include at least one of a length (L) of the sensor submerged in the liquid, a viscosity of the liquid, and a rate of withdrawal.

[0035] In an embodiment of the second aspect, L is in the range of 0.1 to 4 mm.

[0036] In an embodiment of the second aspect, L is 2 to 3 mm.

[0037] In certain embodiments of the second aspect, the viscosity is less than 100 cP.

[0038] In one embodiment of the second aspect, the speed of withdrawal is 20 to 30 inches per second.

[0039] In certain embodiments of the second aspect, the method further comprises curing the coating.

[0040] In certain embodiments of the second aspect, curing comprises UV (or thermal) crosslinking, irradiation, drying, or heating.

[0041] In certain embodiments of the second aspect, the method further includes using a tip mold or draw-through fixture that clamps and cures in one step to form the sharp conical shape.

[0042] In certain embodiments of the second aspect, the method further comprises applying a voltage to the coating while the coating is curing.

[0043] In certain embodiments of the second aspect, the method further comprises heating the coating and stretching it like glass.

[0044] Another aspect of the present embodiments includes the recognition that in some current methods for sensor insertion, the sensor is received within the lumen of an insertion needle. The needle, which has a higher column strength than the sensor, withstands the frictional forces that occur during insertion. Once the sensor is positioned in the correct location in the tissue, the needle is removed. The need to remove the needle complicates the insertion process, including the need to electrically connect the sensor and sensor electronics after insertion. Some of the present embodiments provide a solution to this problem.

[0045] In recognition of the aforementioned problems, in a third aspect, some of the present embodiments comprise a sensor device for measuring a concentration of an analyte in a host, the sensor device comprising: a sensor unit comprising a sensor body, at least one electrode, and a membrane covering at least a portion of the at least one electrode; and a piercing element comprising a material that rapidly dissolves upon insertion into a host, the piercing element including a sharp tip capable of piercing tissue and a lumen that receives the sensor unit.

[0046] In an embodiment of the third aspect, the sensor body has a blunt tip.

[0047] In some embodiments of the third aspect, the sensor unit is not fixed to the penetrating element.

[0048] In an embodiment of the third aspect, the sensor unit is fixed to the penetrating element.

[0049] In an embodiment of the third aspect, the material of the penetration element comprises a wound control material.

[0050] In an embodiment of the third aspect, the material of the penetration element comprises a material that promotes rapid wound healing.

[0051] In an embodiment of the third aspect, the material of the penetration element comprises a material that induces osmotic or oncotic pressure.

[0052] In an embodiment of the third aspect, the material of the penetration element comprises one or more drugs.

[0053] In an embodiment of the third aspect, the material of the penetration element comprises vascular endothelial growth factor (VEGF).

[0054] In an embodiment of the third aspect, the material of the penetration element includes at least one of a salt, a metal salt, a sugar, a synthetic polymer, polylactic acid, polyglycolic acid, or a polyphosphazene.

[0055] In certain embodiments of the third aspect, the material of the penetration element biodegrades / dissolves within one day after insertion into the host.

[0056] In certain embodiments of the third aspect, the material of the penetration element biodegrades / dissolves within 3 hours after insertion into the host.

[0057] Another aspect of the present embodiments includes the recognition that the membrane material of the analyte sensor is soft and tends to peel off as the sensor is advanced through tissue. This problem is particularly acute in sensors formed by a process in which the sensor is first coated with a membrane and then the tip is sharpened. This process exposes the sensor body, leaving a thin membrane coating surrounding the sides of the tip of the sensor body. Some of the present embodiments provide a solution to this problem.

[0058] In recognition of the aforementioned problems, in a fourth aspect, some of the present embodiments comprise a sensor device for measuring a concentration of an analyte in a host, the sensor device comprising: a sensor unit comprising a sensor body, at least one electrode, and a membrane covering at least a portion of the at least one electrode; and a mounting unit spaced from the sensor tip and configured to support the sensor device on an outer surface of the host's skin, wherein the membrane comprises a stiffening agent that provides the sensor unit with increased column strength such that the sensor unit may be inserted through the host's skin without substantial buckling.

[0059] In certain embodiments of the fourth aspect, the stiffening agent is integrated into the membrane.

[0060] In an embodiment of the fourth aspect, the membrane covers the tip of the sensor body.

[0061] In certain embodiments of the fourth aspect, the tip of the sensor body is exposed through the membrane.

[0062] In certain embodiments of the fourth aspect, the exposed tip of the sensor body comprises a material that does not react with hydrogen peroxide.

[0063] In certain embodiments of the fourth aspect, the curing agent comprises a cyanoacrylate.

[0064] Further, in recognition of the aforementioned problems, in a fifth aspect, some of the present embodiments comprise a sensor device for measuring the concentration of an analyte in a host, the sensor device comprising: a sensor unit comprising a sensor body, at least one electrode, and a membrane covering at least a portion of the at least one electrode; and a mounting unit spaced from the sensor tip and configured to support the sensor device on an outer surface of the host's skin, wherein the membrane comprises a stiffening agent, which improves column strength of the sensor unit and enhances adhesion of the membrane to the at least one electrode, and wherein the membrane comprising the stiffening agent allows permeability of the analyte.

[0065] In certain embodiments of the fifth aspect, the curing agent is suspended in the matrix.

[0066] In an embodiment of the fifth aspect, the membrane covers the tip of the sensor.

[0067] In an embodiment of the fifth aspect, the tip of the sensor body is exposed through the membrane.

[0068] In an embodiment of the fifth aspect, the exposed tip of the sensor body comprises a material that does not react with hydrogen peroxide.

[0069] In an embodiment of the fifth aspect, the curing agent comprises a cyanoacrylate.

[0070] Further, in recognition of the aforementioned problems, in a sixth aspect, some of the present embodiments include a method of making a sensor device, the method including coating a wire with a film, cutting the coated wire to a desired length to form a sensor tip, and exposing the coated wire to a curing agent such that the film absorbs the curing agent.

[0071] In certain embodiments of the sixth aspect, exposing the coated wire comprises immersing at least the sensor tip in a curing agent.

[0072] In certain embodiments of the sixth aspect, some of the embodiments further include curing the film to cure the curing agent.

[0073] In certain embodiments of the sixth aspect, some of the embodiments further include sharpening the sensor tip to form a sharp point capable of penetrating tissue.

[0074] In an embodiment of the sixth aspect, the sensor tip comprises a material that does not react with hydrogen peroxide.

[0075] In certain embodiments of the sixth aspect, some of the embodiments further include applying a quenching agent to the sharpened sensor tip to quench all active surfaces exposed during the sharpening step.

[0076] In certain embodiments of the sixth aspect, the quenching agent comprises a cyanoacrylate or a silane.

[0077] In certain embodiments of the sixth aspect, the quenching agent is applied using vapor deposition.

[0078] In an embodiment of the sixth aspect, the curing agent comprises a cyanoacrylate.

[0079] Further recognizing the aforementioned problems, in a seventh aspect, some of the present embodiments include a method of making a sensor device, the method including cutting a wire to a desired length, thereby forming a sensor tip; sharpening the sensor tip to form a sharp point capable of penetrating tissue; coating the wire, including the sharpened sensor tip, with a film; and exposing the coated wire to a sclerosing agent such that the film absorbs the sclerosing agent.

[0080] In certain embodiments of the seventh aspect, exposing the coated wire comprises immersing at least the sensor tip in a curing agent.

[0081] In certain embodiments of the seventh aspect, some of the embodiments further comprise curing the film to cure the curing agent.

[0082] In an embodiment of the seventh aspect, the curing agent comprises a cyanoacrylate.

[0083] In recognition of any of the problems described herein, in an eighth aspect, some of the present embodiments include a sensor device for measuring the concentration of an analyte in a host. The sensor device is configured to be implanted into the host without the use of an inserter. The sensor device includes a sensor unit including a sensor body, at least one electrode, and a membrane covering at least a portion of the at least one electrode. The sensor device further includes a piercing element at a distal end of the sensor unit and configured to pierce the skin and / or tissue of the host. The sensor device further includes a mounting unit spaced from the sensor tip and configured to support the sensor device on an outer surface of the host's skin. The sensor body includes a stimuli-responsive material that changes at least one material property in response to a stimulus.

[0084] In certain embodiments of the eighth aspect, the at least one material property is at least one of hardness, shape, permeability, relative hydrophilicity, elastic modulus, or conformation of polymer orientation.

[0085] In an embodiment of the eighth aspect, the sensor body is rigid outside the body and soft inside the body.

[0086] In an embodiment of the eighth aspect, the stimulus that induces a change in the at least one material property is at least one of temperature, hydration, radiation, an electrical stimulus, or a magnetic field.

[0087] In an embodiment of the eighth aspect, the sensor body is a polymer.

[0088] In an embodiment of the eighth aspect, the sensor body is polyurethane, polyester, polyamide, polyacrylate, or polyether, or a copolymer thereof.

[0089] In an embodiment of the eighth aspect, the stimulus-responsive material is a shape memory metal.

[0090] In certain embodiments of the eighth aspect, the shape memory metal is copper-aluminum-nickel (Cu-Al-Ni), nickel-titanium (NiTi), iron-manganese-silicon (Fe-Mn-Si), or copper-zinc-aluminum (Cu-Zn-Al).

[0091] In an embodiment of the eighth aspect, the sensor body defines a first shape prior to insertion into the skin of the host.

[0092] In an embodiment of the eighth aspect, the sensor body defines a memorized shape, and the sensor body returns to the memorized shape after insertion into the skin of the host.

[0093] In an embodiment of the eighth aspect, the first shape is curvilinear or linear, and the memorized shape is curvilinear or linear.

[0094] In an embodiment of the eighth aspect, stored spring energy is released from the sensor body when the sensor body returns to the memorized shape.

[0095] In an embodiment of the eighth aspect, the released spring energy creates a whipping motion that facilitates penetration into the host's skin.

[0096] Another aspect of the present embodiments includes the recognition that the materials used to form the membrane of an analyte sensor are often soft and therefore prone to delamination (i.e., peeling, and sometimes peeling) as the sensor is advanced through skin and / or tissue. This problem is particularly acute in sensors formed by a process in which the sensor is first coated with a membrane and then the tip is sharpened. This process exposes the sensor body, leaving a thin membrane coating surrounding the sides of the tip of the sensor body. Some of the present embodiments provide solutions to this problem, including methods for forming the tip after applying the membrane without damaging the tip, while simultaneously maintaining the integrity of the tip.

[0097] In recognition of the foregoing problems, in a ninth aspect, some of the present embodiments include a method of making a sensor device configured for implantation into a host without the use of an inserter. The method includes forming a piercing tip on a sensor unit including a sensor body, at least one electrode, and a membrane covering at least a portion of the at least one electrode. The membrane is applied to the sensor unit prior to forming the piercing tip on the sensor unit.

[0098] In certain embodiments of the ninth aspect, the method further comprises applying a membrane to the sensor unit.

[0099] In an embodiment of the ninth aspect, forming the piercing tip comprises forming an annular channel around a circumference of the film-coated wire.

[0100] In an embodiment of the ninth aspect, the annular channel extends through the membrane and partially into the wire.

[0101] In certain embodiments of the ninth aspect, the method further comprises applying tension to the coated wire.

[0102] In an embodiment of the ninth aspect, the tension induces strain in the wire proximate to the annular channel, causing necking and breakage of the wire.

[0103] In an embodiment of the ninth aspect, the necking forms a piercing tip in the sensor body.

[0104] In an embodiment of the ninth aspect, the method further comprises coating the piercing tip with a protective outer layer.

[0105] In an embodiment of the ninth aspect, forming the piercing tip comprises selectively removing portions of the film coating from the wire stock.

[0106] In an embodiment of the ninth aspect, the wire stock is wound on a reel.

[0107] In certain embodiments of the ninth aspect, the method further comprises severing the wire stock at spaced locations to form a plurality of film-coated sensor wires.

[0108] In an embodiment of the ninth aspect, forming the piercing tip comprises exposing a distal end surface of the sensor body.

[0109] In an embodiment of the ninth aspect, the method further comprises applying a coating to the distal end of the sensor body.

[0110] In an embodiment of the ninth aspect, the coating renders the exposed distal end surface of the sensor body non-electroactive.

[0111] In an embodiment of the ninth aspect, forming the piercing tip comprises applying an end cap to a distal end of the membrane-coated sensor wire.

[0112] In an embodiment of the ninth aspect, the end cap comprises a piercing tip.

[0113] In an embodiment of the ninth aspect, forming the piercing tip comprises applying multiple layers of membrane to the sensor body.

[0114] In an embodiment of the ninth aspect, forming the piercing tip further comprises applying a rigid coating over the plurality of membrane layers at the distal end of the sensor body.

[0115] In certain embodiments of the ninth aspect, forming the piercing tip further comprises molding a rigid coating to provide the piercing tip.

[0116] In an embodiment of the ninth aspect, the method further comprises applying a membrane to the sensor body.

[0117] In an embodiment of the ninth aspect, the method further comprises applying a piercing tip to a distal end of the sensor body.

[0118] In an embodiment of the ninth aspect, the penetration tip is secured to the distal end of the sensor body by mechanical crimping, press fitting, welding, shrink tubing, or heating.

[0119] In an embodiment of the ninth aspect, the method further comprises applying a retractable introducer sheath around the sensor body.

[0120] In an embodiment of the ninth aspect, forming the piercing tip comprises applying a piercing tip to the distal end of the sensor body on the membrane.

[0121] In an embodiment of the ninth aspect, the piercing tip comprises a biodegradable and / or bioabsorbable material.

[0122] In an embodiment of the ninth aspect, the piercing tip material comprises polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), or maltose.

[0123] In an embodiment of the ninth aspect, applying a piercing tip to the distal end of the sensor body on the membrane comprises casting the piercing tip on the distal end of the sensor body and onto the membrane using a mold.

[0124] In an embodiment of the ninth aspect, applying the piercing tip to the distal end of the sensor body over the membrane comprises injection molding or insert molding.

[0125] In an embodiment of the ninth aspect, applying a piercing tip to the distal end of the sensor body on the membrane comprises inserting the distal end of the sensor body into the proximal end of the open piercing tip.

[0126] In an embodiment of the ninth aspect, the method further comprises crimping the proximal end of the penetration tip.

[0127] In an embodiment of the ninth aspect, applying a piercing tip to the distal end of the sensor body on the membrane comprises overmolding the piercing tip onto the distal end of the sensor body and onto the membrane.

[0128] Another aspect of the present embodiments includes the recognition that applying a film to a sharp sensor tip presents challenges. For example, a sharp tip can tear the film and / or cause it to delaminate, especially when the sensor is subjected to frictional forces during the sensor insertion process. Also, applying a film to a sharp sensor tip can dull the tip, making it less effective for direct pressure insertion of the sensor. Some of the present embodiments provide solutions to these problems, including methods for applying a film to a sharp tip without damaging the tip, while maintaining the integrity of the tip.

[0129] In recognition of the foregoing problems, in a tenth aspect, some of the present embodiments include a method of making a sensor device configured for implantation into a host without the use of an inserter. The method includes forming a piercing tip on a sensor unit including a sensor body, at least one electrode, and a membrane covering at least a portion of the at least one electrode. The piercing tip is formed on the sensor unit before applying the membrane to the sensor unit.

[0130] In certain embodiments of the tenth aspect, forming the piercing tip comprises immersing the sensor body in a membrane solution to form a membrane on the sensor body.

[0131] In certain embodiments of the tenth aspect, forming the piercing tip further comprises removing a portion of the membrane at the distal end of the sensor body after the membrane solution has dried to expose the distal end of the sensor body.

[0132] In an embodiment of the tenth aspect, removing the portion of the membrane at the distal end of the sensor body comprises laser ablation, electropolishing, bead blasting, dry ice blasting, or baking.

[0133] In an embodiment of the tenth aspect, the method further comprises applying a protective layer to the distal end of the sensor body.

[0134] In an embodiment of the tenth aspect, forming the piercing tip includes removing a portion of the membrane solution at the distal end of the sensor body before the membrane solution dries.

[0135] In certain embodiments of the tenth aspect, removing the portion of the membrane solution comprises wiping or wiping the distal end of the sensor body.

[0136] In an embodiment of the tenth aspect, the method further comprises applying a membrane to the sensor body and the penetration tip.

[0137] In an embodiment of the tenth aspect, the method further comprises applying a coating to the piercing tip.

[0138] In an embodiment of the tenth aspect, the method further comprises applying a retractable introducer sheath around the sensor body.

[0139] In an embodiment of the tenth aspect, the outer diameter of the introducer sheath is substantially the same as or smaller than the diameter of the penetration tip at its proximal end.

[0140] In an embodiment of the tenth aspect, the sensor body comprises a core and an outer layer.

[0141] In certain embodiments of the tenth aspect, the membrane is applied over the outer layer but not over the core.

[0142] In certain embodiments of the tenth aspect, the core and outer layer comprise different materials.

[0143] In an embodiment of the tenth aspect, the core comprises a membrane-repellent material.

[0144] In an embodiment of the tenth aspect, the material of the core has a low surface energy.

[0145] In an embodiment of the tenth aspect, the material of the core is non-wettable.

[0146] In an embodiment of the tenth aspect, forming the piercing tip comprises electrochemical grinding.

[0147] In an embodiment of the tenth aspect, the membrane comprises multiple layers.

[0148] In certain embodiments of the tenth aspect, the thickness of each layer is in the range of about 0.5 microns to about 10 microns.

[0149] In an embodiment of the tenth aspect, a thickness of at least one of the layers is less than a thickness of at least another of the layers.

[0150] In an embodiment of the tenth aspect, the method further comprises applying a membrane to the sensor body and the penetration tip.

[0151] In an embodiment of the tenth aspect, the method includes removing the membrane from the penetration tip but not from the sensor body.

[0152] In an embodiment of the tenth aspect, removing the membrane from the piercing tip comprises chemical etching, laser ablation, or mechanical cutting.

[0153] In certain embodiments of the tenth aspect, the method further comprises applying a membrane to the sensor body and the penetration tip by immersion in a membrane solution.

[0154] In an embodiment of the tenth aspect, the method comprises immersing the piercing tip in a solvent to dissolve and substantially remove the membrane from the piercing tip.

[0155] In some embodiments of the tenth aspect, the method further comprises immersing the piercing tip in a release agent that prevents the membrane from adhering to the piercing tip.

[0156] In an embodiment of the tenth aspect, forming the piercing tip comprises coating the piercing tip with a sacrificial material.

[0157] In an embodiment of the tenth aspect, the method further comprises applying a membrane to the sensor body and the penetration tip.

[0158] In an embodiment of the tenth aspect, the method includes treating the piercing tip to disrupt the sacrificial layer and remove the membrane from the piercing tip.

[0159] In certain embodiments of the tenth aspect, the sacrificial material is light-sensitive, heat-sensitive, or soluble, and treating the penetration tip comprises applying light, applying heat, or applying a solvent.

[0160] In certain embodiments of the tenth aspect, the method further includes applying a membrane to the piercing tip by immersing the piercing tip in a membrane solution with the piercing tip facing downwards, and then, before the solution dries, inverting the sensor unit so that the piercing tip faces upwards.

[0161] In an embodiment of the tenth aspect, the method further includes applying a membrane to the sensor body by immersing the piercing tip in the membrane solution with the piercing tip facing upwards, such that the sensor body is only partially submerged in the membrane solution and the membrane solution never contacts the piercing tip.

[0162] In an embodiment of the tenth aspect, the method further includes removing an annular band of material from the sensor body immediately proximal to the penetration tip to form an annular channel, wherein a distal end of the channel defines an edge.

[0163] In an embodiment of the tenth aspect, the method further comprises immersing the sensor body and the penetration tip in a membrane solution.

[0164] In certain embodiments of the tenth aspect, the edge provides for breaking of the liquid meniscus of the membrane solution, thereby leaving the piercing tip uncoated with the membrane.

[0165] In an embodiment of the tenth aspect, the sensor body comprises a core and an outer layer.

[0166] In certain embodiments of the tenth aspect, the method further comprises removing the first portion of the outer layer and the second portion of the outer layer to expose the core.

[0167] In an embodiment of the tenth aspect, the first portion of the outer layer is located adjacent to the piercing tip and the second portion of the outer layer is located proximal to the piercing tip.

[0168] In an embodiment of the tenth aspect, the method further comprises removing a portion of the core to form a piercing tip.

[0169] In an embodiment of the tenth aspect, the method further comprises attaching a cap to the piercing tip.

[0170] In an embodiment of the tenth aspect, the attached cap comprises a sharpened distal end.

[0171] In an embodiment of the tenth aspect, the attached cap comprises an absorbent material such that the cap is absorbed into the host's body after the sensor body is inserted into the host's skin and / or tissue.

[0172] In an embodiment of the tenth aspect, the sensor body includes a planar flexible printed circuit board (PCB) embedded in the outer core.

[0173] In an embodiment of the tenth aspect, the method further comprises removing a portion of the outer core proximal to the penetration tip to form a window.

[0174] In an embodiment of the tenth aspect, removing the fraction of the outer core comprises laser ablation.

[0175] In an embodiment of the tenth aspect, the outer surface of the PCB in the region of the window comprises a platinum layer that is resistant to laser ablation.

[0176] In certain embodiments of the tenth aspect, the method further comprises immersing the sensor body in a membrane solution to form a membrane on the inside of the window.

[0177] In an embodiment of the tenth aspect, the sensor body comprises a thin, flat micro-electromechanical systems (MEMS) substrate.

[0178] In an embodiment of the tenth aspect, the substrate comprises a piercing tip.

[0179] In certain embodiments of the tenth aspect, the method further comprises forming a film on a substrate.

[0180] Another aspect of the present embodiments includes the recognition that forming a sharp distal tip on a sensor presents challenges, such as membrane surface contamination and / or membrane damage, which can prevent the membrane from functioning properly. Membrane contamination can alter membrane properties, such as diffusion. For example, contamination can reduce the membrane's permeability properties (e.g., permselectivity). Damage to the membrane can also affect sensor functionality. For example, if membrane removal extends beyond the distal tip into portions intended to cover the electroactive surfaces forming the electrodes, the sensor's diffusion properties can be substantially altered and uncontrollable, rendering the sensor defective. On the other hand, if excess membrane material is present at the sensor's distal tip, the sensor's distal tip can become blunt and less effective at penetrating skin and / or tissue. Some of the present embodiments include solutions to these problems, including methods of forming a sharp distal tip by removing material from the tip and methods of forming a sharp distal tip by adding material to the tip. Another aspect of this embodiment includes the recognition that the piercing tip may be formed on the sensor during the step of separating the sensor wire into individual sensors. For example, the separation process may include, without limitation, mechanical pressing, hot pressing, laser ablation, extrusion, cutting, etc. By forming the piercing tip during separation, a sharp distal tip may be formed before applying the membrane to the sensor, thereby avoiding cross-contamination and damage to the delicate membrane from subsequent tip formation steps.

[0181] In recognition of the aforementioned problems, in an eleventh aspect, some of the present embodiments include a method of making a sensor device configured for implantation into a host without the use of an inserter. The method includes forming a piercing tip on a sensor unit including a sensor body, at least one electrode, and a membrane covering at least a portion of the at least one electrode. Forming the piercing tip includes removing material from the sensor body.

[0182] In an embodiment of the eleventh aspect, forming the piercing tip comprises severing the wire stock while exposing the wire stock to cyanoacrylate vapor.

[0183] In an embodiment of the eleventh aspect, the method includes reel-to-reel continuous processing.

[0184] In an embodiment of the eleventh aspect, forming the piercing tip comprises dipping the distal end of the sensor body.

[0185] In an embodiment of the eleventh aspect, immersing the distal end of the sensor body comprises immersing in an etching or polishing solution.

[0186] In an embodiment of the eleventh aspect, forming the piercing tip comprises electropolishing.

[0187] In an embodiment of the eleventh aspect, forming the piercing tip comprises moving the sensor body relative to the polishing surface with the sensor body forming an angle Θ with respect to the polishing surface.

[0188] In certain embodiments of the eleventh aspect, Θ is between 0° and 90°.

[0189] In certain embodiments of the eleventh aspect, Θ is about 5°, or about 10°, or about 15°.

[0190] In an embodiment of the eleventh aspect, the sensor body is held in a support fixture that is moved relative to the polishing surface.

[0191] In certain embodiments of the eleventh aspect, the sensor body includes an inner core and an outer layer, and forming the penetration tip includes removing a portion of the outer layer at a distal end of the sensor body to expose a portion of the inner core.

[0192] In certain embodiments of the eleventh aspect, removing the portion of the outer layer comprises mechanical cutting, laser ablation, bead blasting, polishing, or chemical etching.

[0193] In an embodiment of the eleventh aspect, forming the piercing tip comprises applying tension to the sensor along a longitudinal axis of the sensor wire.

[0194] In an embodiment of the eleventh aspect, the applied tension causes the sensor wire to neck at the mid-region.

[0195] In an embodiment of the eleventh aspect, the applied tension further causes the sensor wire to break at the mid-region.

[0196] In an embodiment of the eleventh aspect, the method further comprises applying heat to an intermediate portion of the sensor wire, wherein the heat is applied simultaneously with the tension.

[0197] In an embodiment of the eleventh aspect, the heat is applied using a resistive heating element.

[0198] In an embodiment of the eleventh aspect, forming the piercing tip comprises placing the sensor wire between opposing cutting blades and severing the sensor wire into at least two pieces.

[0199] In certain embodiments of the eleventh aspect, a cutting edge defined by a converging surface of one of the cutting blades defines an angle between 30 degrees and 145 degrees.

[0200] In certain embodiments of the eleventh aspect, the angle is not a right angle.

[0201] Further, in recognition of the aforementioned problems, in a twelfth aspect, some of the present embodiments include a method of making a sensor device configured for implantation into a host without the use of an inserter. The method includes forming a piercing tip on a sensor unit including a sensor body, at least one electrode, and a membrane covering at least a portion of the at least one electrode. Forming the piercing tip includes adding material to the sensor body.

[0202] In an embodiment of the twelfth aspect, forming the penetration tip comprises immersing the sensor body in a bath of polymeric material.

[0203] In an embodiment of the twelfth aspect, the method further includes removing the sensor body from the bath and applying a voltage across the polymer material, thereby elongating the polymer material to form a piercing tip.

[0204] In an embodiment of the twelfth aspect, the method comprises electrospinning.

[0205] In certain embodiments of the twelfth aspect, forming the piercing tip comprises immersing the sensor body in a bath and withdrawing the sensor body from the bath, wherein upon withdrawal of the sensor body, a dip coating on the sensor body hardens to form the piercing tip.

[0206] In recognition of any of the problems described herein, in a thirteenth aspect, some of the present embodiments include a sensor device for measuring a concentration of an analyte in a host, the sensor device being configured to be implanted into the host without the use of an inserter. The sensor device includes a conductive core wire. The sensor device further includes a non-conductive jacket disposed over at least a portion of the core wire. The sensor device further includes at least one electrode disposed over the jacket and in electrical communication with the core wire. The at least one electrode is formed by printing.

[0207] In an embodiment of the thirteenth aspect, the at least one electrode comprises a first electrode, a second electrode, and a third electrode, the electrodes being axially spaced apart along the sensor device.

[0208] In an embodiment of the thirteenth aspect, the second electrode does not extend around the entire circumference of the jacket.

[0209] In an embodiment of the thirteenth aspect, the sensor device further comprises a conductive trace extending along the jacket between the first electrode and the third electrode.

[0210] In an embodiment of the thirteenth aspect, the sensor device further comprises an insulating material overlying at least a portion of the conductive traces.

[0211] In an embodiment of the thirteenth aspect, the distal end of the sensor device comprises a piercing tip.

[0212] In an embodiment of the thirteenth aspect, the distal end of the sensor device is non-electroactive.

[0213] In recognition of any of the problems described herein, in a fourteenth aspect, some of the present embodiments include a sensor device for measuring a concentration of an analyte in a host, the sensor device being configured to be implanted into the host without the use of an inserter. The sensor device includes a non-conductive core wire. The sensor device further includes at least one electrode disposed on the core wire. The sensor device further includes at least one conductive trace extending from the at least one electrode along the core wire. The at least one electrode is formed by printing.

[0214] In an embodiment of the fourteenth aspect, the at least one electrode comprises a first electrode, a second electrode, and a third electrode, the electrodes being axially spaced apart along the sensor device.

[0215] In an embodiment of the fourteenth aspect, the first and second electrodes do not extend around the entire circumference of the core wire.

[0216] In an embodiment of the fourteenth aspect, the distal end of the sensor device comprises a piercing tip.

[0217] Fourteenth Aspect In some embodiments, at least one electrode is printed onto the core wire using platinum paste.

[0218] In recognition of any of the problems described herein, in a fifteenth aspect, some of the present embodiments include a sensor device for measuring a concentration of an analyte in a host, the sensor device being configured for implantation into the host without the use of an inserter, the sensor device comprising a sensor body shaped as a flat plate that is rolled into a cylindrical shape.

[0219] In an embodiment of the fifteenth aspect, the cylinder includes an overlap region where opposing edges of the plate converge.

[0220] In an embodiment of the fifteenth aspect, the overlapping portions of the opposing edges are secured to one another.

[0221] In an embodiment of the fifteenth aspect, the overlapping portions are secured to one another with an adhesive.

[0222] In an embodiment of the fifteenth aspect, the adhesive dissolves after the sensor device is implanted in the host.

[0223] In an embodiment of the fifteenth aspect, when the adhesive dissolves, the curled sensor body unfolds and resumes its planar shape.

[0224] In recognition of any of the problems described herein, in a sixteenth aspect, some of the present embodiments include a sensor device for measuring a concentration of an analyte in a host, the sensor device being configured to be implanted into the host without the use of an inserter. The sensor device includes a sensor unit including a sensor body, at least one electrode, and a membrane covering at least a portion of the at least one electrode. The sensor device further includes a piercing element at a distal end of the sensor unit and configured to pierce the skin and / or tissue of the host. The sensor device further includes a mounting unit spaced from the sensor tip and configured to support the sensor device on an outer surface of the host's skin. The sensor device further includes a retractable introducer sheath configured to cover at least a portion of the membrane during insertion of the sensor device.

[0225] In an embodiment of the sixteenth aspect, the proximal end of the tissue-piercing element has a diameter greater than a diameter of the sensor body.

[0226] In an embodiment of the sixteenth aspect, the diameter of the introducer sheath is substantially the same as or smaller than the diameter of the proximal end of the tissue-piercing element.

[0227] In recognition of any of the problems described herein, in a seventeenth aspect, some of the present embodiments include a sensor device for measuring a concentration of an analyte in a host, the sensor device being configured to be implanted into the host without the use of an inserter. The sensor device includes a sensor unit including a sensor body, at least one electrode, and a membrane covering at least a portion of the at least one electrode. The sensor device further includes a piercing element at a distal end of the sensor unit and configured to pierce the skin and / or tissue of the host. The sensor device further includes a mounting unit spaced from the sensor tip and configured to support the sensor device on an outer surface of the host's skin. The sensor body includes a cross-section defining at least one trough extending along the length of the sensor body.

[0228] In an embodiment of the seventeenth aspect, a cross-section of the sensor body defines a plus sign shape having four equally spaced troughs.

[0229] In an embodiment of the seventeenth aspect, a cross-section of the sensor body defines a circle having a single trough.

[0230] In an embodiment of the seventeenth aspect, the at least one electrode is located in the at least one trough.

[0231] In certain embodiments of the seventeenth aspect, the at least one electrode and the at least one membrane are flush with or recessed below the periphery of the sensor body.

[0232] In recognition of any of the problems described herein, in an eighteenth aspect, some of the present embodiments include a sensor device for measuring a concentration of an analyte in a host, the sensor device being configured to be implanted into the host without the use of an inserter. The sensor device includes a sensor unit including a sensor body, at least one electrode, and a membrane covering at least a portion of the at least one electrode. The sensor device further includes a piercing element at a distal end of the sensor unit and configured to pierce the skin and / or tissue of the host. The sensor device further includes a mounting unit spaced from the sensor tip and configured to support the sensor device on an outer surface of the host's skin. The sensor device further includes a retractable introducer sheath configured to cover at least a portion of the membrane during insertion of the sensor device.

[0233] In recognition of any of the problems described herein, in a nineteenth aspect, some of the present embodiments include a sensor device for measuring a concentration of an analyte in a host, the sensor device being configured to be implanted into the host without the use of an inserter. The sensor device includes a sensor unit including a sensor body, at least one electrode, and a membrane covering at least a portion of the at least one electrode. The sensor device further includes a piercing element at a distal end of the sensor unit and configured to pierce the skin and / or tissue of the host. The sensor device further includes a mounting unit spaced from the sensor tip and configured to support the sensor device on an outer surface of the host's skin. The sensor device further includes at least one through-hole extending through the sensor body.

[0234] In an embodiment of the nineteenth aspect, the membrane is disposed within the at least one through-hole.

[0235] In recognition of any of the problems described herein, in a twentieth aspect, some of the present embodiments include a sensor device for measuring a concentration of an analyte in a host, the sensor device being configured to be implanted into the host without the use of an inserter. The sensor device includes a sensor unit including a sensor body, at least one electrode, and a membrane covering at least a portion of the at least one electrode. The sensor device further includes a piercing element at a distal end of the sensor unit and configured to pierce the skin and / or tissue of the host. The sensor device further includes a mounting unit spaced from the sensor tip and configured to support the sensor device on an outer surface of the host's skin. The sensor body includes a plurality of indentations.

[0236] In an embodiment of the twentieth aspect, the membrane is disposed within at least one of the recesses.

[0237] In certain embodiments of the twentieth aspect, the membrane is flush with or recessed below the outer surface of the sensor body.

[0238] In certain embodiments of the twentieth aspect, the depressions are randomly arranged.

[0239] In recognition of any of the problems described herein, in a twenty-first aspect, some of the present embodiments include a sensor device for measuring a concentration of an analyte in a host, the sensor device being configured to be implanted into the host without the use of an inserter. The sensor device includes a sensor unit including a sensor body, at least one electrode, and a membrane covering at least a portion of the at least one electrode. The sensor device further includes a piercing element at a distal end of the sensor unit and configured to pierce the skin and / or tissue of the host. The sensor device further includes a mounting unit spaced apart from the sensor tip and configured to support the sensor device on an outer surface of the host's skin. The sensor device further includes a plurality of axially spaced recesses in the sensor body.

[0240] In certain embodiments of the twenty-first aspect, the membrane is disposed within the depression.

[0241] In an embodiment of the twenty-first aspect, the sensor device further comprises an outer layer of material that is permeable to one or more selected analytes.

[0242] In recognition of any of the problems described herein, in a twenty-second aspect, some of the present embodiments include a sensor device for measuring a concentration of an analyte in a host, the sensor device being configured to be implanted into the host without the use of an inserter. The sensor device includes a sensor unit including a sensor body, at least one electrode, and a membrane covering at least a portion of the at least one electrode. The sensor device further includes a piercing element at a distal end of the sensor unit and configured to pierce the skin and / or tissue of the host. The sensor device further includes a mounting unit spaced from the sensor tip and configured to support the sensor device on an outer surface of the host's skin. The sensor device further includes a protective outer layer disposed over the sensor body and the membrane.

[0243] In an embodiment of the twenty-second aspect, the protective outer layer comprises a material that dissolves upon insertion into the skin and / or tissue of a host.

[0244] In an embodiment of the twenty-second aspect, the material of the protective outer layer comprises polyvinyl-pyrrolidone (PVP).

[0245] In recognition of any of the problems described herein, in a twenty-third aspect, some of the present embodiments include a sensor device for measuring a concentration of an analyte in a host, the sensor device being configured to be implanted into the host without the use of an inserter. The sensor device includes a sensor unit including a sensor body, at least one electrode, and a membrane covering at least a portion of the at least one electrode. The sensor device further includes a piercing element at a distal end of the sensor unit and configured to pierce the skin and / or tissue of the host. The sensor device further includes a mounting unit spaced from the sensor tip and configured to support the sensor device on an outer surface of the host's skin. The sensor device further includes an outer layer made of a rigid material.

[0246] In certain embodiments of the twenty-third aspect, the outer layer covers substantially all of the sensor body but includes at least one window.

[0247] In an embodiment of the twenty-third aspect, the window is positioned over the at least one electrode such that the at least one electrode is exposed to contact with tissue and / or bodily fluids of the host.

[0248] In an embodiment of the twenty-third aspect, the outer layer comprises a cyanoacrylate.

[0249] In recognition of any of the problems described herein, in a twenty-fourth aspect, some of the present embodiments include a sensor device for measuring a concentration of an analyte in a host, the sensor device being configured to be implanted into the host without the use of an inserter. The sensor device includes a sensor unit including a sensor body, at least one electrode, and a membrane covering at least a portion of the at least one electrode. The sensor device further includes a piercing element at a distal end of the sensor unit and configured to pierce the skin and / or tissue of the host. The sensor device further includes a mounting unit spaced from the sensor tip and configured to support the sensor device on an outer surface of the host's skin. The sensor body includes a conductive wire and an outer coating disposed on the wire, the outer coating having a thickness greater than that of the wire.

[0250] In an embodiment of the twenty-fourth aspect, the outer coating comprises at least one window corresponding to the location of the at least one electrode.

[0251] In an embodiment of the twenty-fourth aspect, the membrane is disposed within the window.

[0252] In certain embodiments of the twenty-fourth aspect, the membrane is recessed below an outer surface of the outer coating.

[0253] In an embodiment of the twenty-fourth aspect, the sensor device further comprises a highly permeable outer layer.

[0254] In an embodiment of the twenty-fourth aspect, the outer layer comprises a hydrogel.

[0255] In recognition of any of the problems described herein, in a twenty-fifth aspect, some of the present embodiments include a sensor device for measuring a concentration of an analyte in a host, the sensor device being configured to be implanted into the host without the use of an inserter. The sensor device includes a sensor unit including a sensor body, at least one electrode, and a membrane covering at least a portion of the at least one electrode. The sensor device further includes a piercing element at a distal end of the sensor unit and configured to pierce the skin and / or tissue of the host. The sensor device further includes a mounting unit spaced from the sensor tip and configured to support the sensor device on an outer surface of the host's skin. The membrane is applied to the sensor body by printing.

[0256] In an embodiment of the twenty-fifth aspect, the sensor body comprises polytetrafluoroethylene (PTFE).

[0257] Various present embodiments will now be described in detail, with an emphasis on noting advantageous features. These embodiments illustrate novel and inventive sensors and related methods for continuous analyte monitoring, as shown in the accompanying drawings, which are for illustrative purposes only. The drawings are not necessarily drawn to scale, and they are provided solely to illustrate the present embodiments. These drawings include the following figures, in which like numbers indicate like parts: [Brief explanation of the drawings]

[0258] [Figure 1] 1 is a schematic cross-sectional view of a continuous analyte sensor according to an embodiment. [Figure 2A] 1A-1C are schematic side views of exemplary shapes of tissue-piercing tips of continuous analyte sensors according to the present embodiments. [Figure 2B] 1A-1C are schematic side views of exemplary shapes of tissue-piercing tips of continuous analyte sensors according to the present embodiments. [Figure 2C] 1A-1C are schematic side views of exemplary shapes of tissue-piercing tips of continuous analyte sensors according to the present embodiments. [Figure 2D] 1A-1C are schematic side views of exemplary shapes of tissue-piercing tips of continuous analyte sensors according to the present embodiments. [Figure 2E] 1A-1C are schematic side views of exemplary shapes of tissue-piercing tips of continuous analyte sensors according to the present embodiments. [Figure 2F] 1A-1C are schematic side views of exemplary shapes of tissue-piercing tips of continuous analyte sensors according to the present embodiments. [Figure 2G] 1A-1C are schematic side views of exemplary shapes of tissue-piercing tips of continuous analyte sensors according to the present embodiments. [Figure 2H] 1A-1C are schematic side views of exemplary shapes of tissue-piercing tips of continuous analyte sensors according to the present embodiments. [Figure 3A] FIG. 10 is a top perspective view of a further continuous analyte sensor according to the present embodiments. [Figure 3B] FIG. 10 is a top perspective view of a further continuous analyte sensor according to the present embodiments. [Figure 3C] FIG. 10 is a top perspective view of a further continuous analyte sensor according to the present embodiments. [Figure 3D] FIG. 10 is a top perspective view of a further continuous analyte sensor according to the present embodiments. [Figure 4] 1 is a continuous analyte sensor according to an embodiment. [Figure 5] FIG. 1 is a front perspective view of a system for inserting a continuous analyte sensor into a host, according to an embodiment. [Figure 6] FIG. 10 is a front perspective view of another system for inserting a continuous analyte sensor into a host, according to the present embodiments. [Figure 7] 1 is a continuous analyte sensor according to an embodiment. [Figure 8] 1 is a continuous analyte sensor according to an embodiment. [Figure 9] 1 is a continuous analyte sensor according to an embodiment. [Figure 10] 1 is a continuous analyte sensor according to an embodiment. [Figure 11] FIG. 1 is a front elevation view of a sensor configured for direct pressure insertion, according to an embodiment. [Figure 12] FIG. 12 is a rear elevation view of the sensor of FIG. 11. [Figure 13] FIG. 10 is a schematic front elevation view of another sensor configured for direct pressure insertion, according to the present embodiments. [Figure 14] FIG. 14 is a schematic rear elevation view of the sensor of FIG. 13. [Figure 15] FIG. 10 is a schematic side perspective view of another sensor configured for direct pressure insertion, according to the present embodiments. [Figure 16] FIG. 10 is a schematic end perspective view of another sensor configured for direct pressure insertion, according to the present embodiments. [Figure 17] FIG. 17 is a schematic end perspective view of the sensor of FIG. 16 after the sensor has been rolled into a cylindrical shape. [Figure 18] FIG. 1 is a schematic side elevation view of a sensor configured for direct pressure insertion, according to an embodiment. [Figure 19] FIG. 19 is a schematic side elevational view of the sensor of FIG. 18 after the retractable introducer sheath has been retracted. [Figure 20] FIG. 1 is a schematic distal end perspective view of a sensor configured for direct push insertion, according to an embodiment. [Figure 21] FIG. 21 is a schematic distal end elevation view of the sensor of FIG. 20. [Figure 22] 1 is a schematic distal end elevation view of a sensor configured for direct push insertion, according to an embodiment; FIG. [Figure 23] FIG. 1 is a schematic side elevation view of a sensor configured for direct pressure insertion, according to an embodiment. [Figure 24] 1 is a schematic side perspective view of a sensor configured for direct pressure insertion, according to an embodiment; FIG. [Figure 25] FIG. 1 is a schematic side elevation view of a sensor configured for direct pressure insertion, according to an embodiment. [Figure 26] 1 is a schematic cross-sectional side view of a sensor configured for direct pressure insertion, according to an embodiment; [Figure 27] FIG. 1 is a schematic side elevation view of a sensor configured for direct pressure insertion, according to an embodiment. [Figure 28]FIG. 1 is a schematic side elevation view of a sensor configured for direct pressure insertion, according to an embodiment. [Figure 29] FIG. 1 is a schematic side elevation view of a sensor configured for direct pressure insertion, according to an embodiment. [Figure 30] FIG. 1 is a schematic side elevation view of a sensor configured for direct pressure insertion, according to an embodiment. [Figure 30A] 1A-1C are schematic side elevation views of a process for making a sensor configured for direct push insertion, according to the present embodiments. [Figure 30B] 1A-1C are schematic side elevation views of a process for making a sensor configured for direct push insertion, according to the present embodiments. [Figure 31] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 32] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 33] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 34] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 35] 10A-10C are schematic cross-sectional side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 36] 10A-10C are schematic cross-sectional side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 37] 10A-10C are schematic cross-sectional side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 38] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 39]10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 40] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 41] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 42] 10A-10C are schematic cross-sectional side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 43] 10A-10C are schematic cross-sectional side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 44] 10A-10C are schematic cross-sectional side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 45] 10A-10C are schematic cross-sectional side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 46] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 47] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 48] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 49] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 50] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 51]10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 52] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 52A] 10A-10C are schematic cross-sectional side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 53] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 54] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 54A] 54A is a detailed view of the portion of FIG. 54 indicated by circle 54A-54A in FIG. 54. FIG. [Figure 55] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 56] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 57] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 58] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 59] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 60] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 61] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 62] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 63] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 64] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 65] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 66] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 67] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 68] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 69] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 70] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 71] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 72] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 73] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 74]10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 75] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 76] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 76A] 10A-10C are schematic end elevation views of another process for making a sensor configured for direct push insertion, according to the present embodiments. [Figure 76B] 76B is a cross-sectional schematic end view of a process for making a sensor configured for direct push insertion, according to FIG. 76A. [Figure 76C] 76B is a cross-sectional schematic end view of a process for making a sensor configured for direct push insertion, according to FIG. 76A. FIG. [Figure 76D] 76B is a cross-sectional schematic end view of a process for making a sensor configured for direct push insertion, according to FIG. 76A. FIG. [Figure 77] 10A-10C are schematic top plan views of another process for fabricating a sensor configured for direct pressure insertion, according to the present embodiments. [Figure 78] FIG. 78 is a schematic side elevation view of the process of FIG. 77. [Figure 79] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 80] 10A-10C are schematic top plan views of another process for fabricating a sensor configured for direct pressure insertion, according to the present embodiments. [Figure 81] 10A-10C are schematic top plan views of another process for fabricating a sensor configured for direct pressure insertion, according to the present embodiments. [Figure 82] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 83]10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 84] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 85] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. [Figure 86] 10A-10C are schematic side elevation views of another process for fabricating a sensor configured for direct push insertion, according to the present embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0259] The following detailed description describes the present embodiments with reference to the drawings, in which reference numbers label elements of the present embodiments, and these reference numbers are reproduced below in connection with a discussion of the corresponding drawing features.

[0260] The drawings and their descriptions may depict sizes, shapes, and configurations of various components. Such depictions and descriptions are not intended to be limiting. Alternative sizes, shapes, and configurations are also contemplated within the scope of the present embodiments. Furthermore, the drawings and their descriptions may depict certain components of the device as integrally formed and certain other components as separate parts. Components shown and described herein as integrally formed may, in alternative embodiments, be formed as separate parts. Furthermore, components shown and described herein as formed as separate parts may, in alternative embodiments, be integrally formed. As used herein, the term integral describes a single, unified part.

[0261] overview The embodiments described herein provide various mechanisms for inserting a transcutaneous sensor directly into a host without the use of a separate applicator, i.e., without using anything other than the sensor device itself. Direct pressure insertion of a wire, particularly a transcutaneous sensor (e.g., an electrode) having a thin, wire-like geometry, can be technically challenging due to the risk of buckling associated with the sensor. Direct pressure insertion of the sensor also presents challenges associated with damaging a membrane disposed over the sensor during the insertion process. If not protected, the membrane may peel off from the sensor or be mechanically damaged during the insertion process. It is also desirable to avoid having exposed metal (or other conductive material) at the tip of the sensor, as exposed metal may be electroactive and add background signal (noise) and / or alter the sensitivity of the sensor. The embodiments described herein are designed to overcome the aforementioned challenges by providing a miniature sensor device that can provide structural support (e.g., in the form of mechanical / structural properties such as column strength) for direct insertion of a transcutaneous sensor and protect the membrane from damage during the insertion process.

[0262] 1 illustrates a schematic side view of one embodiment of a transcutaneous sensor device 100 configured to continuously measure an analyte concentration (e.g., glucose concentration) in a host and provide a data stream indicative of the analyte concentration in the host, according to the present embodiments. Sensors such as the one illustrated in FIG. 1 are sometimes referred to as "thumbtack" sensors because they resemble a thumbtack.

[0263] 1 , sensor device 100 includes an internal body portion 102 (also referred to as a sensor unit) configured for insertion under a host's skin 104 and an external body portion 106 configured to remain on the host's skin surface after sensor insertion. Internal body portion 102 includes a tissue-piercing element 108 configured to pierce the host's skin 104 and a sensor body 110. Sensor body 110 includes a support member 112 including one or more electrodes and a membrane 114 disposed over at least a portion of support member 112. Support member 112 may be referred to as sensor body 112, and these two terms are used interchangeably herein.

[0264] The external body portion 106 includes a mounting unit 116 that may include a sensor electronics unit (not shown) embedded therein or detachably secured thereto, or alternatively may be configured to be operably connected to a separate electronics unit. Further details regarding the sensor device 100 and its components can be found in U.S. Patent Application Publication No. 2011 / 0077490, the disclosure of which is incorporated herein in its entirety.

[0265] tissue piercing element The tissue-piercing element 108 of the sensor device 100 is configured to pierce the host's skin 104 and open and define a passageway for inserting the sensor body 110 into the host's tissue. In some embodiments, the tissue-piercing element 108 may be integral with the support member 112. In other embodiments, the tissue-piercing element 108 may be a separate component. In such embodiments, the tissue-piercing element 108 may be secured to the support member 112 using an adhesive or the like. Alternatively, the tissue-piercing element 108 may simply abut the smooth distal surface of the support member 112 and / or membrane 114. In such embodiments, an outer sleeve or band (not shown) may surround the junction of the tissue-piercing element 108 and the support member 112 / membrane 114.

[0266] Skin generally comprises multiple layers, including the epidermis, dermis, and subcutaneous layer. The epidermis contains several layers within its structure, including the stratum corneum, the outermost layer, typically about 10 to 20 microns thick, and the basal layer, the deepest layer of the epidermis. The epidermis typically does not contain blood vessels, but exchanges metabolic products via diffusion into and out of the dermis. Without wishing to be bound by theory, it is believed that the basal layer's survival is supported by angiogenesis, and therefore interstitial fluid in the basal layer adequately represents host analyte (e.g., glucose) levels. Beneath the epidermis is the dermis, which is about 1 mm to about 3 mm thick and contains blood vessels, lymphatic vessels, and nerves. The subcutaneous layer lies below the dermis and is composed mostly of lipids. The subcutaneous layer functions to insulate the body from thermal extremes. It also contains connective tissue and a few blood vessels.

[0267] In some embodiments, the internal body portion 102 of the sensor device 100 may have a length long enough to allow at least a portion of the sensor body 110 to reside within the stratum basale. This may be desirable in some cases because the epidermis contains few blood vessels or nerve endings. Thus, sensor insertion may be relatively painless, and the host may experience little bleeding or discomfort due to insertion. In some of these embodiments, the internal body portion 102 of the sensor device 100 may have a length of about 0.1 mm to about 1.5 mm, or about 0.2 mm to about 0.5 mm. In other embodiments, the internal body portion 102 of the sensor device 100 may have a length that allows at least a portion of the sensor body 110 to reside in the dermis layer. This may be desirable in some cases because the dermis is better vascularized than the subcutaneous layer and therefore may provide sufficient analyte (e.g., glucose) for measurement and may reduce measurement delays associated with changes in the host's analyte concentration, such as those that occur after a meal. The metabolically active tissue near the outer dermis (and stratum basale as well) allows for rapid equilibration of interstitial fluid with blood. In some of these embodiments, the sensor device's internal body portion 102 may have a length of about 1 mm to about 7 mm, or about 2 mm to about 6 mm. In still other embodiments, the sensor device's internal body portion 102 may have a length that allows at least a portion of the sensor body 110 to reside in the subcutaneous layer. Without wishing to be bound by theory, it is believed that the subcutaneous layer may reduce variations in analyte concentration readings associated with temperature fluctuations because the subcutaneous layer functions to insulate the body from temperature extremes. In some of these embodiments, the sensor device's internal body portion 102 may have a length of about 3 mm to about 10 mm, or about 5 mm to about 7 mm.

[0268] The tissue-piercing element can have any of a variety of geometries and dimensions, including those that minimize tissue trauma and reduce the force required to penetrate the skin. For example, in some embodiments, the tissue-piercing element may include a substantially conical distal tip, as illustrated in FIG. 1, such that the cross-sectional dimension (e.g., diameter) of the tissue-piercing element tapers toward a point 118 at the distal end of the tip, thereby providing a sharpened tip configured to facilitate skin penetration. As illustrated in FIG. 2B, in other embodiments, the distal tip of the tissue-piercing element may be beveled, such as at a bevel angle α, e.g., between about 5° and about 66°, or between about 10° and about 55°, or between about 40° and about 50°. In further embodiments, one or more surfaces of the tip may be curved to facilitate skin penetration when the sensor device is pressed downward, as illustrated in FIGS. 2C-2H and 3D. In some embodiments, curved surfaces may be advantageous because they provide a larger cutting surface area for the tissue-piercing element than straight surfaces, thus providing smoother and more controlled insertion of the sensor unit into the skin. Additionally, tissue-piercing elements with curved surfaces may cause less trauma to the tissue being pierced than those with straight surfaces.

[0269] The tissue-piercing element of the sensor device is designed to have appropriate flexibility and rigidity, as well as sufficient column strength, to allow it to remain intact and prevent substantial buckling upon insertion of the sensor device through the host's skin into the internal body portion. Any of a variety of biocompatible materials possessing these properties can be used to form the tissue-piercing element, including, but not limited to, metals, ceramics, semiconductors, organics, polymers, composites, and combinations or mixtures thereof. Metals that can be used include, for example, stainless steel (e.g., 18-8 surgical stainless steel), nitinol, gold, silver, nickel, titanium, tantalum, palladium, gold, and combinations or alloys thereof. Polymers that can be used include, for example, polycarbonate, polymethacrylic acid, ethylene vinyl acetate, polytetrafluoroethylene (TEFLON®), and polyester. In some embodiments, the tissue-piercing element functions as a reference electrode and may include a conductive material, such as a silver-containing material. In certain embodiments, the tissue-piercing element has sufficient column strength to allow a user to press the sensor unit against the skin using thumb or finger force without substantial buckling of the tissue-piercing element. Therefore, the structure of the tissue-piercing unit will not fracture when subjected to the resistance (e.g., axial force) associated with tissue and skin penetration. In some embodiments, the tissue-piercing element may have a column strength capable of withstanding an axial load of greater than about 0.5 Newtons (N), greater than about 1 N, greater than about 2 N, greater than about 5 N, or greater than about 10 N without substantial buckling. Often, increasing the thickness of the column of material also increases column strength. In some embodiments, the base 120 of the distal tip may have an outer diameter of about 0.05 mm to about 1 mm, or about 0.1 mm to about 0.5 mm, or about 0.15 mm to about 0.3 mm to provide the desired column strength for the tissue-piercing element.

[0270] Some of the tissue-piercing elements described herein are configured to protect the membrane of the sensor body. As described elsewhere herein, the membrane can be relatively delicate and therefore potentially damaged during insertion of the sensor unit into a host. As a result, any damage to the membrane can affect the performance of the sensor device and its ability to function properly. For example, in some embodiments, one or more portions of the tissue-piercing element 108 may be formed with a larger cross-sectional area (along a plane transverse to the longitudinal axis of the tissue-piercing element 108) than that of the sensor body 110. By having a larger cross-sectional area than the sensor body 110, the tissue-piercing element 108 of the sensor device 100 is configured to pierce the host's skin 104 and open and define a passage for inserting the sensor body 110 into tissue. Thus, the risk of penetration-resistant forces damaging the membrane 140 and / or peeling it away from the remainder of the sensor body 110 during the insertion process is reduced. In some embodiments, the largest cross-sectional dimension transverse to the longitudinal axis of tissue-piercing element 108 is less than about 0.1 mm, or less than about 0.05 mm, or less than about 0.03 mm.

[0271] In some embodiments, one or more layers of one or more polymers and / or bioactive agents may be coated onto the tissue-piercing element. Coating the surface of the tissue-piercing element with a bioactive agent can result in release of the bioactive agent into the subcutaneous tissue during and / or after insertion of the sensor device into the body. In further embodiments, one or more polymer layers may be used to control the release rate of one or more bioactive agents. Such polymers may include, but are not limited to, parylene, parylene C, parylene N, parylene F, poly(hydroxymethyl-p-xylylene-co-p-xylylene) (PHPX), poly(lactic-co-glycolic acid) (PLGA), polyethylene-co-vinyl acetate (PEVA), poly-L-lactic acid (PLA), poly-N-butyl methacrylate (PBMA), phosphoryl chloride, poly(isobutylene-co-styrene), polyoxyethylene (POE), polyglycolide (PGA), (poly(L-lactic acid), poly(amic acid) (PAA), polyethylene glycol (PEG), derivatives of one or more of these polymers, and combinations or mixtures thereof.

[0272] In some embodiments, one or more regions of the surface of the tissue-piercing element may include one or more recessed portions (e.g., cavities, depressions, openings, grooves, channels, etc.) configured to function as reservoirs or depots for holding bioactive agents. The recessed portions may be formed in any preselected location and have preselected depths, sizes, geometries, and dimensions according to the intended application. The use of reservoirs or depots can increase the amount of bioactive agent that the tissue-piercing element can hold and deliver. In further embodiments, the tissue-piercing element may be hollow with cavities and connected to one or more openings on its surface via various passageways, such that the bioactive agent can be released from the cavities through the openings. In some embodiments, for example, as shown in FIGS. 3A and 3B , tissue-piercing element 310 includes pocket 312 shaped and dimensioned to support sensor 314 with a membrane disposed thereon.

[0273] In certain embodiments, the intracorporeal portion of the sensor device is configured to remain substantially stationary within the host's tissue, thereby preventing movement or motion of the sensor body relative to the surrounding tissue. Movement or motion can cause inflammation at the sensor implantation site due to irritation and can generate noise in the sensor signal due to motion-related artifacts. Therefore, to avoid the aforementioned problems, it may be advantageous to provide an anchoring mechanism that provides support to the intracorporeal portion of the sensor device. In some embodiments, the tissue-piercing element may include a textured surface in one or more regions. The texture can roughen the surface of the tissue-piercing element, thereby providing surface irregularities with a greater surface area than an untextured (e.g., smooth) surface. Thus, the amount of bioactive agent, polymer, and / or coating that the tissue-piercing element can carry and release in situ is increased compared to an untextured surface. Furthermore, it is believed that a textured surface may also be advantageous in some cases, as the increased surface area can enhance immobilization of the intracorporeal portion of the sensor device within the host's tissue. In certain embodiments, the tissue-piercing element may include a surface topography, such as a porous surface (e.g., porous parylene), a ribbed surface, etc. In certain embodiments, anchoring may be provided by prongs, prongs, barbs, wings, hooks, bulbous portions (e.g., at the distal end), S-shaped bends along the tissue-piercing element, graduated diameters, combinations thereof, and the like, which may be used alone or in combination to stabilize the sensor within the subcutaneous tissue. For example, in certain embodiments, the tissue-piercing element may include one or more anchoring members configured to expand outward (e.g., toward a plane perpendicular to the longitudinal axis of the sensor unit) during or after insertion of the sensor unit. Outward deployment of the anchoring members results in the tissue-piercing element being compressed against the surrounding tissue, thus reducing (or preventing) movement and / or rotation of the sensor unit and thereby facilitating anchoring of the sensor unit.In some embodiments, the fixation members are formed from a shape memory material, such as nitinol, that can be configured to transform from a martensitic state to an austenitic state at a particular temperature (e.g., room or body temperature). In the martensitic state, the fixation members are in a ductile, contracted configuration. In the austenitic state, the fixation members expand to become more rigid and form a larger, predetermined shape. While nitinol is described herein as an example of a shape memory material that can be selected to form the fixation members, it should be understood that other similar materials (e.g., shape memory materials) can also be used.

[0274] The tissue-piercing element of the sensor device can be introduced subcutaneously at any of a variety of angles relative to the mounting surface (the lower surface of the mounting unit), and thus relative to the skin surface. For example, in some embodiments, the distal tip of the tissue-piercing element can extend substantially perpendicular to the mounting surface, while in other embodiments, the distal tip can extend at an angle of, for example, about 15°, 20°, 30°, 40°, 45°, 60°, 75°, 80°, 90°, 105°, 100°, 120°, 135°, 140°, 150°, 160°, or 165° relative to the mounting surface.

[0275] In an alternative embodiment, the sensor body may be embedded or encapsulated in a needle formed from a biodegradable material to provide protection for the membrane during insertion of the sensor device. After insertion, the needle gradually biodegrades, leaving behind the sensor body, which can then be activated. Any of a variety of biodegradable materials (e.g., non-interfering carbohydrates) may be used. In some embodiments, the biodegradable material contains a specific concentration of the analyte to be measured, resulting in an initial calibration point for the sensor device.

[0276] As illustrated in FIG. 1 , the sensor device 100 may include a skin-contacting mounting unit 116 configured to be secured to a host. In some embodiments, the mounting unit 116 includes a base 122 adapted to be secured to the host's skin. The base 122 may be formed from a variety of rigid or flexible materials and may have a low profile to reduce protrusion of the sensor device from the host during use. In some embodiments, the base 122 is at least partially formed from a flexible material configured to conform to the contours of the skin, thereby reducing or eliminating motion-related imperfections associated with the host's movements. In certain embodiments, the base 122 of the mounting unit 116 includes an adhesive material or layer 124, also referred to as an adhesive pad, preferably disposed on the bottom surface of the mounting unit, and may also include a peelable backing layer (not shown). Thus, the backing layer is removed and the base 122 of the mounting unit 116 is pressed against the host's skin 104, thereby adhering the mounting unit 116 to the host's skin 104. The adhesive pad may be selected and designed appropriately to stretch, expand, conform, and / or vent the area (e.g., the host's skin). In some embodiments, the mounting unit comprises a guide portion (not shown) configured to guide the insertion of sensor device 100 through the host's skin 104 and to support the column strength of support member 112 so that sensor device 100 may be inserted through the host's skin 104 without substantial buckling.

[0277] While FIG. 1 illustrates one configuration for providing membrane protection, other sensor body configurations are also possible. For example, some of the sensor bodies described herein may include a support member 330 configured to partially surround the sensor, as illustrated in FIGS. 3A and 3B, or to substantially surround the sensor, as illustrated in FIG. 3C. Unlike other embodiments described elsewhere herein, in the embodiment illustrated in FIGS. 3A-3D, the support member 330 does not include a working electrode. Instead, one or more working electrodes are disposed as components separate from the support member 330. In some embodiments, the support member 330 may also function as a reference electrode.

[0278] 3A, the support member 330 includes a longitudinal recess 332 configured to at least partially accommodate a sensor (e.g., a working electrode with a membrane disposed thereon). In some embodiments, the longitudinal recess may have a length corresponding to less than about 90%, or less than about 75%, or less than about 50%, or less than about 33%, or less than about 25% of the length of the support member 330. In other embodiments, the longitudinal recess may extend substantially the entire length of the support member 330, as illustrated in FIG. 3B. In certain embodiments, the support member 330 may encompass more than about 10%, or more than about 25%, or more than about 33%, or more than about 50%, or more than about 75% of the outer perimeter (e.g., circumference) of the sensor.

[0279] As shown in FIG. 3C , in some embodiments, the sensor (e.g., working electrode) is substantially surrounded by a support member 330. The support member 330 may be provided with one or more window portions 334 (openings or slots extending through the thickness of the wall of the support member 330) that expose certain portions of the electrode to biological fluid (e.g., interstitial fluid), thereby allowing the biological fluid to diffuse toward and contact the electroactive surface of the working electrode and the membrane disposed thereon. In this embodiment, the working electrode and the membrane disposed thereon are essentially contained within the support member 330 and are therefore protected during packaging, handling, and / or insertion of the device. The window portion 334 may have any of a variety of shapes and dimensions. For example, in some embodiments, the window portion may be formed to have a circular or substantially circular shape, while in other embodiments, the electrode may be formed in a shape resembling an oval, a polygon (e.g., a triangle, square, rectangle, parallelogram, trapezoid, pentagon, hexagon, octagon), etc. In certain embodiments, the window portion may comprise a section extending around the circumference of the longitudinal cross section of the support member. For example, the support member may be fabricated by using a hypotube with a window portion cut into it in a helical configuration by ablation, etching, or other techniques.

[0280] transparency Conventional glucose sensors measure current in the nanoAmp range. In contrast to conventional glucose sensors, preferred embodiments are configured to measure current in the picoAmp range, and in some embodiments, femtoAmps. That is, for every unit (mg / dL) of glucose measured, at least 1 picoAmp of current is measured. In some embodiments, from about 1, 2, 3, 4, or 5 picoAmps to about 25, 50, 100, 250, or 500 picoAmps of current are measured for every unit (mg / dL) of glucose measured.

[0281] Bioactive Agents Various bioactive agents are known to promote fluid influx or efflux. Thus, incorporating a bioactive agent into the membrane can increase fluid bulk, bulk fluid flow, and / or diffusion rates (further promoting glucose and oxygen influx), thereby reducing non-uniform noise. In some embodiments, fluid bulk and / or bulk fluid flow is increased at the sensor (e.g., near the outer surface of the sensor) by incorporating one or more bioactive agents. In some embodiments, the sensor is configured to include a bioactive agent that stimulates the release of soluble mediators known to irritate the wound and cause localized fluid influx at the wound site. In some embodiments, the sensor is configured to include a vasodilatory bioactive agent that can cause localized fluid influx from the vasculature.

[0282] A variety of bioactive agents may be found useful in preferred embodiments. Exemplary bioactive agents include, but are not limited to, blood-brain barrier disrupting agents and vasodilators, vasodilators, angiogenic factors, and the like. Useful bioactive agents include mannitol, sodium thiosulfate, VEGF / VPF, NO, NO donors, leptin, bradykinin, histamine, blood components, platelet-rich plasma (PRP), matrix metalloproteinases (MMPs), basic fibroblast growth factor (bFGF) (also known as heparin-binding growth factor-II and fibroblast growth factor II), acidic fibroblast growth factor (aFGF) (also known as heparin-binding growth factor-I and fibroblast growth factor-I), vascular endothelial growth factor (VEGF), platelet-derived endothelial growth factor BB (PDEGF-BB), angiopoietin-1, transforming growth factor beta (TGF-β), transforming growth factor These include, but are not limited to, transforming growth factor (TGF-α), hepatocyte growth factor, tumor necrosis factor-α (TNF-α), placental growth factor (PLGF), angiogenin, interleukin-8 (IL-8), hypoxia inducible factor-I (HIF-I), the angiotensin-converting enzyme (ACE) inhibitor quinaprilat, angiotropin, thrombospondin, the peptide KGHK, low oxygen tension, lactate, insulin, leptin, copper sulfate, estradiol, prostaglandins, cox inhibitors, endothelial cell binding agents (e.g., decorin or vimentin), glenipin, hydrogen peroxide, nicotine, and growth hormone. Still other useful bioactive agents include enzymes, cytotoxic or necrotic agents (e.g., pactataxyl, actinomycin, doxorubicin, daunorubicin, epirubicin, bleomycin, plicamycin, mitomycin), cyclophosphamide, chlorambucil, uramustine, melphalan, bryostatin, inflammatory bacterial cell wall components, histamine, pro-inflammatory factors, and the like.

[0283] Bioactive agents can be added during sensor fabrication by incorporating the desired bioactive agent into the fabrication materials of one or more sensor layers or into an external biomaterial, such as a porous silicone membrane. For example, the bioactive agent can be mixed with a solution during membrane formation, which is then applied to the sensor during fabrication. Alternatively, the completed sensor can be immersed in or sprayed with a solution of the bioactive agent, for example. The amount of bioactive agent can be controlled by varying its concentration, varying the dwell time during immersion, applying multiple layers until a desired thickness is reached, etc., as disclosed elsewhere herein. In an alternative embodiment, the bioactive agent is microencapsulated before application to the sensor. For example, a microencapsulated bioactive agent can be sprayed onto the completed sensor or incorporated into a structure such as an outer mesh or exfoliation layer. Microencapsulation can provide increased flexibility in controlling the release rate of the bioactive agent, the time at which release occurs, and / or the duration of release.

[0284] Chemical stimulation systems / methods may be incorporated into external sensor structures, such as biointerface membranes (described elsewhere herein) or exfoliating layers, that release stimulants into the local environment. For example, in some embodiments, a "exfoliating layer" may release (e.g., exfoliate or leach) molecules into the local vicinity of the sensor, accelerating osmotic fluid movement. In some embodiments, the exfoliating layer may provide a mild stimulus to promote a mild inflammatory / foreign body response, thereby stabilizing cells and preventing the accumulation of aligned fibrous capsules and promoting fluid sac formation.

[0285] The exfoliation layer may be composed of any convenient biocompatible material, including, but not limited to, hydrophilic degradable materials such as polyvinyl alcohol (PVA), PGC, polyethylene oxide (PEO), polyethylene glycol-polyvinylpyrrolidone (PEG-PVP) blends, PEG-sucrose blends, hydrogels such as polyhydroxyethyl methacrylate (pHEMA), polymethyl methacrylate (PMMA), or other polymers with rapidly degrading ester bonds. In certain embodiments, absorbable suture materials may be used that degrade into compounds with acid residues. Acid residues are chemical irritants that stimulate inflammation and wound healing. In certain embodiments, these components include glycolic acid and lactic acid-based polymers, polyglactin, polydioxone, polydyconate, poly(dioxanone), poly(trimethylene carbonate) copolymers, and poly(caprolactone) homopolymers and copolymers.

[0286] In other exemplary embodiments, the release layer may be a layer of materials listed elsewhere herein for the first domain, including hydrophilic polymers such as polyvinylpyrrolidone (PVP), polyhydroxyethyl methacrylate, polyvinyl alcohol, polyacrylic acid, and the like, copolymers or blends with polyethers such as polyethylene glycol, and block copolymers thereof, including, for example, diblock, triblock, alternating, random, and graft copolymers (block copolymers are described in U.S. Pat. No. 4,803,243 and U.S. patents). In one preferred embodiment, the release layer is composed of polyurethane and a hydrophilic polymer. For example, the hydrophilic polymer can be polyvinylpyrrolidone. In one preferred embodiment, the release layer is a polyurethane containing 5 weight percent or more polyvinylpyrrolidone and 45 weight percent or less polyvinylpyrrolidone. Preferably, the release layer is a polyurethane containing 20 weight percent or more polyvinylpyrrolidone and 35 weight percent or less polyvinylpyrrolidone, and most preferably about 27 weight percent polyvinylpyrrolidone.

[0287] In other embodiments, the release layer may comprise a silicone elastomer, such as a silicone elastomer and a copolymer blend of poly(ethylene oxide) and poly(propylene oxide), as disclosed in co-pending U.S. patent application Ser. No. 11 / 404,417, filed Apr. 14, 2006. In one embodiment, the silicone elastomer is a dimethyl and methylhydrogen-siloxane copolymer. In one embodiment, the silicone elastomer includes vinyl substituents. In one embodiment, the silicone elastomer is an elastomer produced by curing a MED-4840 blend. In one embodiment, the copolymer includes hydroxy substituents. In one embodiment, the copolymer is a triblock poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) polymer. In one embodiment, the copolymer is a triblock poly(propylene oxide)-poly(ethylene oxide)-poly(propylene oxide) polymer. In one embodiment, the copolymer is a PLURONIC® polymer. In one embodiment, the copolymer is PLURONIC® F-127. In one embodiment, at least a portion of the copolymer is crosslinked. In one embodiment, about 5% w / w to about 30% w / w of the membrane is the copolymer.

[0288] The release layer can take any shape or geometry, symmetrical or asymmetrical, that promotes fluid influx at a desired location on the sensor, such as, for example, the sensor head or the electrochemically reactive surface. The release layer can be positioned on one or both sides of the sensor. In another example, the release layer can be applied to a small portion of the sensor or to the entire sensor.

[0289] In one exemplary embodiment, an exfoliant layer containing polyethylene oxide (PEO) is applied to the outside of the sensor, allowing direct access to the skin surrounding the sensor. The PEO leaches out of the exfoliant layer and is taken up by local cells, which release pro-inflammatory factors. The pro-inflammatory factors diffuse through the surrounding tissue and stimulate an inflammatory response, including fluid influx. Thus, initial noise can be reduced or eliminated, and sensor function can be improved.

[0290] In another exemplary embodiment, the exfoliation layer is applied to the sensor in combination with an outer porous layer, such as a mesh or porous biointerface as disclosed elsewhere herein. In one embodiment, local cells access the exfoliation layer through through-pores in the porous silicone biointerface. In one example, the exfoliation layer material is applied to the sensor before applying the porous silicone. In another example, the exfoliation layer material may be absorbed into a lower portion of the porous silicone (e.g., a portion of the porous silicone that will be adjacent to the sensor after the porous silicone is applied to the sensor) before applying the porous silicone to the sensor.

[0291] wound control Non-uniform noise can be reduced in some embodiments by wound suppression (e.g., during sensor insertion). Wound suppression includes any system or method that reduces and / or eliminates the amount of wound that occurs during sensor insertion. Without wishing to be bound by theory, it is believed that if wound suppression, or at least significantly reduced, the sensor will be surrounded by substantially normal tissue (e.g., tissue substantially similar to the tissue prior to sensor insertion). Substantially normal tissue is believed to have a lower metabolism than wounded tissue, producing fewer interferents and reducing initial noise.

[0292] Wounding can be inhibited by adapting the sensor's structure to either inhibit wounding or promote rapid healing, e.g., a structure that does not cause substantial wounding (e.g., a structure configured to prevent wounding), a structure that promotes wound healing, an anti-inflammatory structure, etc. In one exemplary embodiment, the sensor is configured to have a low profile, zero footprint, or a smooth surface. For example, the sensor can be formed from a substantially thin wire, e.g., a wire having a diameter of about 50 μm to about 116 μm. Preferably, the sensor is small enough to fit into a very small gauge needle, e.g., a 30-, 31-, 32-, 33-, 34-, or 35-gauge needle (or smaller), e.g., based on the stub. Generally, the smaller the needle, the less trauma there is during insertion. For example, a very small needle can reduce the amount of tissue disruption, thereby reducing the subsequent wound healing response. In an alternative embodiment, the surface of the sensor is lubricated with a lubricious coating to reduce trauma during sensor insertion.

[0293] Wounding can also be reduced by including a wound-inhibiting agent (bioactive agent) that either reduces the amount of initial wounding or inhibits the wound healing process. Without wishing to be bound by theory, applying a wound-inhibiting agent, such as an anti-inflammatory, immunosuppressant, anti-infective, or removal agent, to the sensor can create a local dormant environment and inhibit wound healing. In a dormant environment, bodily processes, such as increased cellular metabolism associated with wound healing, can have minimal impact on the sensor. If the tissue surrounding the sensor is unaffected, it can continue its normal metabolism, facilitating sensor function.

[0294] In some embodiments, compounds and / or factors useful for wound control include first generation H1-receptor antagonists: ethylenediamines (e.g., mepyramine (pyrilamine), antazoline), ethanolamines (e.g., diphenhydramine, carbinoxamine, doxylamine, clemastine, and dimenhydrinate), alkylamines (pheniramine, chlorphenamine (chlorpheniramine), dexchlorphenamine, brompheniramine, and triprolidine), piperazines (cyclizine, hydroxyzine, and meclizine), and tricyclic compounds (promethazine, alimemazine (trimeprazine), cycloheptadine, and azatadine); Second generation H1-receptor antagonists such as acrivastine, astemizole, cetirizine, loratadine, mizolastine, azelastine, levocabastine, and olopatadine; mast cell stabilizers such as cromoglycate (cromolyn) and nedocromil; anti-inflammatory agents such as acetometaphen, aminosalicylic acid, aspirin, celecoxib, choline magnesium trisalicylate, diclofenac potassium, diclofenac sodium, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, interleukin (IL)-10, IL-6 muteins, anti-IL-6 iNOS inhibitors (e.g., L-NMDA), interferon, ketoprofen, ketorolac, leflunomide, melenamic acid, mycophenolic acid, mizoribine, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, rofecoxib, salsalate, sulindac, and tolmetin;Corticosteroids such as cortisone, hydrocortisone, methylprednisolone, prednisone, prednisolone, betamethesone, beclomethasone dipropionate, budesonide, dexamethasone sodium phosphate, flunisolide, fluticasone propionate, paclitaxel, tacrolimus, tranilast, triamcinolone acetonide, betamethasone, fluocinolone, fluocinonide, betamethasone dipropionate, betamethasone valerate, desonide, desoximetasone, fluocinolone, triamcinolone, triamcinolone acetonide, clobetazoline propionate and dexamethasone; immunosuppressants and / or immunomodulators, such as antiproliferative agents, cell cycle inhibitors (e.g., paclitaxel, cytochalasin D, infiximab), taxol, actinomycin, mitomycin, VEGF promoters, estradiol, NO donors, QP-2, tacrolimus, tranilast, actinomycin, everolimus, methotrexate, mycophenolic acid, angiopeptin, vincristine, mitomycin, statins, C MYC antisense, sirolimus (and analogs), RestenASE, 2-chloro-deoxyadenosine, PCNA ribozyme, batimstat, prolyl hydroxylase inhibitors, PPARγ ligands (e.g., troglitazone, rosiglitazone, pioglitazone), halofuginone, C-proteinase inhibitors, probucol, BCP671, EPC antibodies, catchin, glycation agents, endothelin inhibitors (e.g., ambrisentan, tesosentan, bosentan), statins (e.g., cerivastatin), Escherichia coli heat-labile enterotoxin, and advanced coatings; anti-infectives, such as anthelmintics (mebendazole);Antibiotics, such as aminoclycosides (gentamicin, neomycin, tobramycin), antifungal antibiotics (amphotericin b, fluconazole, griseofulvin, itraconazole, ketoconazole, nystatin, micatin, tolnaftate), cephalosporins (cefaclor, cefazolin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, cephalexin), beta-lactam antibiotics (cefotetan, meropenem), chloramphenicol, macrolides (azithromycin, clarithromycin, erythromycin), penicillins (penicillin G sodium salt, amoxicillin, ampicillin, dicloxacillin, nafcillin, piperacillin) , ticarcillin), tetracyclines (doxycycline, minocycline, tetracycline), bacitracin; clindamycin; colistin metasodium; polymyxin B sulfate; vancomycin; antiviral medications including acyclovir, amantadine, didanosine, efavirenz, foscarnet, ganciclovir, indinavir, lamivudine, nelfinavir, ritonavir, saquinavir, silver, stavudine, valacyclovir, valganciclovir, and zidovudine; quinolones (ciprofloxacin, levofloxacin); sulfonamides (sulfadiazine, sulfisoxazole); sulfones (dapsone); furazolidone; metronidazole; pentamidine; sulfanilamidum crystallinum crystallinum); gatifloxacin; and sulfamethoxazole / trimethoprim; interferent removers such as superoxide dismutase (SOD), thioredoxin, glutathione peroxidase and catalase, antioxidants such as uric acid and vitamin C, iron compounds, heme compounds, and some heavy metals; artificial protective coating components such as albumin, fibrin, collagen, endothelial cells, wound closure chemicals, blood products, platelet-rich plasma, growth factors, etc., but are not limited to these;

[0295] Without wishing to be bound by theory, in addition to the analyte sensor configurations described elsewhere herein, applying a lubricious coating to the sensor can substantially reduce and / or inhibit noise generation by substantially preventing trauma to the host. Thus, in some embodiments, a lubricious coating may be applied to the internal body portion of the sensor to reduce foreign body responses to the implanted sensor. As used herein, the term "lubricious coating" is used in its ordinary sense and includes, without limitation, surface treatments that provide reduced surface friction. Various polymers are suitable for use as lubricious sensor coatings, including, but not limited to, polyethylene, polycarbonate, polyurethane, poly(ethylene oxide), poly(ethylene oxide)-poly(propylene oxide) copolymers, and the like. In one exemplary embodiment, one or more layers of HydroMed™, a polyether-polyurethane manufactured by CardioTech International, Inc. (Wilmington, MA), are applied to the sensor (e.g., over the resistive domain).

[0296] Soluble tip Sensors such as those described above are sometimes referred to as "thumbtack" sensors because they resemble a thumbtack. One aspect of the present embodiments includes the recognition that thumbtack sensors include a sharpened tip that remains embedded in tissue for the entire life of the sensor. Leaving a sharpened tip in the body for an extended period of time can cause trauma to surrounding tissue, resulting in scarring and inhibited wound healing. Some of the present embodiments provide a solution to this problem. In some embodiments, the tip is configured to dissolve between implanted sensor sessions, for example, within about 3, 5, 7, or 10 days.

[0297] 1 , tissue-piercing element 108 may be a separate and distinct component from sensor body 112, for example. In such an embodiment, sensor body 112 may include a smooth tip or distal face 126. Tissue-piercing element 108 similarly includes a smooth proximal face 128 that abuts sensor body tip 126. As noted above, tissue-piercing element 108 may or may not be fixed to sensor body 112.

[0298] In some embodiments, the tissue-piercing element 108 may comprise a biodegradable material or a material that dissolves rapidly after insertion into a host. Upon insertion, degradation of the tissue-piercing element 108 may occur spontaneously due to acid residues. In such embodiments, it is desirable for any sensor membrane(s) to be pH-sensitive. The rate of degradation of the tissue-piercing element 108 depends on the amount of tip material present. For example, the material may biodegrade / dissolve within 3 days, or 2 days, or 1 day, or 12 hours, or 6 hours, or 3 hours, or 2 hours, or 1 hour after insertion into a host. In certain embodiments, the material may dissolve within a time frame before the sensor begins to operate. In such embodiments, the dissolved material of the tissue-piercing element 108 may not interfere with sensor calibration.

[0299] Exemplary materials for tissue-piercing element 108 include at least one of salts, metal salts, sugars, synthetic polymers, glues or adhesives (such as cyanoacrylates), polylactic acid (PLA), polyglycolic acid, poly(lactic-co-glycolic acid) (PLGA), polyanhydrides, polyphosphazenes, or any material with glass-like properties. In particular, PLA, PLGA, and polyanhydrides all have sufficient hardness for this type of application. For example, the hardness of tissue-piercing element 108 may range from 35D to 55D, such as 45D.

[0300] In some embodiments, the material of the tissue-piercing element 108 can be tailored or modified to achieve desired properties, such as dissolution time and hardness. For example, the tissue-piercing element 108 can be treated with an annealing or curing cycle and / or crosslinking. Crosslinking can be light-based, such as irradiation with UV light. In some embodiments, tailoring can include material tailoring. For example, the hardness of the tissue-piercing element 108 can be improved by incorporating hydroxyapatite, as in some bone implants, into the formulation. Such formulations dramatically increase hardness, and their inclusion tends to result in faster dissolution times.

[0301] If a polymeric material is selected for tissue-piercing element 108, it may have a degree of crystallinity, which may also be defined by its Rockwell hardness. For example, the material may have a Rockwell hardness of 25D to 65D, e.g., about 45D. An appropriate Rockwell hardness allows the polymer to undergo various processing steps without tearing or damage to the polymer.

[0302] In some embodiments, the tissue-piercing element 108 may include a coating that covers at least a portion of the sensor body 112, including the sensor tip 126. For example, with reference to FIG. 4 , a length L of the distal end of the sensor body 412 and membrane 414 may be immersed in a liquid bath (not shown). The length L may be selected to coat the sensor tip sufficiently to achieve good adhesion without coating any electrodes on the sensor. For example, L may be in the range of 0.1 to 4 mm, e.g., 2 to 3 mm. When the sensor is withdrawn from the bath, the coating remains on the length L, extending distally from the sensor body tip 426 to form the dissolvable tissue-piercing tip 408. After the coating hardens, the portion extending from the sensor tip may be sharpened to provide a tissue-fiber-coated tip 418.

[0303] In certain exemplary embodiments, the viscosity of the liquid bath is less than 100 cP, the draw speed is 20-30 in / sec, and immediately exposed to UV (or thermal) crosslinking to harden and form the thickness. A tip mold or draw-through fixture that clamps and cures in one step to form a sharp conical shape is advantageous.

[0304] Another embodiment for creating a sharp sensor tip using a polymer is to apply a voltage to the material while it is curing. The voltage changes the shape of the polymer into a sharp point. Once curing is complete and the voltage is removed, a sharp tip remains. Curing can include irradiation, drying, heating, etc. Another embodiment includes heating the material and stretching it like glass.

[0305] As described above, the sensor 400 may include one or more features that either inhibit wound healing or promote rapid healing, or both. In certain embodiments, these features may be present in the dissolving tip 408. For example, one or more bioactive agents may be integrated into the dissolving tip 408 by combining with the liquid bath material during the immersion process. Alternatively, the dissolving tip 408 may be immersed in a subsequent liquid bath before or after curing, thereby coating the dissolving tip 408 with one or more bioactive agents. Exemplary bioactive agents have been discussed in detail above and will not be repeated here. However, certain bioactive agents may, for example, induce osmotic or oncotic pressure.

[0306] In certain embodiments, the material of dissolving tip 408 can have an effect on sensor 400. For example, if dissolving tip 408 is a salt, it can create an osmotic gradient that draws bodily fluids into the tissue surrounding sensor 400, causing it to activate faster or avoid initial signal decay. dissolvable needle

[0307] Some of the present embodiments relate to sensors that require a needle for insertion into a host. For example, referring to FIG. 5 , a sensor 500 may be housed within a lumen 504 of a needle 502. Another aspect of the present embodiments involves the recognition that the need to remove the needle after sensor insertion complicates the insertion process, including the need to electrically connect the sensor with the sensor electronics after insertion. Some of the present embodiments provide a solution to this problem.

[0308] 5, needle 502 includes lumen 504 and sharp distal tip 506 and may be similar to a standard hypodermic needle 502. However, the material of needle 502 may be biodegradable or capable of dissolving after insertion into the host. The material and material properties of needle 502 may be similar to those described above with respect to dissolvable tissue-piercing tip 506. These materials and material properties have been discussed in detail above and will not be repeated here. However, polyanhydrides are one particularly advantageous material for needle 502 because they can be readily formed into tubes and shaped by cutting.

[0309] In some embodiments, the sensor 500 may be received within the lumen 504 but not attached to the needle 502 (FIG. 5), and may be held within the needle by frictional forces, for example, and / or coupled to a base, such as the base 122 shown in FIG. 1. In other embodiments, the sensor 500 may be attached to the needle 502 (FIG. 6) using mechanical or chemical coupling techniques, as would be understood by one skilled in the art.

[0310] In this embodiment, the needle 502 is biodegradable / dissolvable, so it does not need to be removed from the host after the sensor 500 is inserted. Instead, the needle 502 harmlessly biodegrades, thereby eliminating the traumatic tip 506 and leaving only the sensor 500. The dissolvable needle 502, therefore, simplifies the process of inserting the sensor 500 into a host. Additionally, because the needle 502 does not need to be withdrawn, the sensor 500 can be electrically connected to sensor electronics (not shown) prior to insertion. Advantageously, this aspect eliminates the need to connect the sensor 500 to the sensor electronics after insertion, which can be challenging.

[0311] As with the dissolvable tissue-piercing tip 506 embodiment described above, the present dissolvable needle 502 may include one or more bioactive agents for wound control and / or promoting rapid wound healing. These bioactive agents may be similar to those described above and may be applied / integrated into the needle 502 using the same techniques as described above.

[0312] In certain embodiments, the needle 502 may be at least partially dissolvable. In such embodiments, the needle may have strong and weak sections (or more and less soluble sections) such that the weak sections dissolve more rapidly in the body and the strong sections subsequently separate from each other. The strong sections may eventually dissolve, albeit more slowly than the weak sections. Such embodiments may be described as "segmented," referring to how the weak sections dissolve more rapidly, allowing a rigid segment, e.g., PLA or PGA, that provides sufficient strength during insertion to be fragmented without damaging the body during or after insertion of the sensor.

[0313] Film hardener One aspect of the present embodiments involves the recognition that the membrane material of the analyte sensor is soft and tends to peel off as the sensor is advanced through tissue. This problem is particularly acute in sensors formed by a process in which the sensor is first coated with a membrane and then the tip is sharpened. This process exposes the sensor body, leaving a thin membrane coating surrounding the sides of the tip of the sensor body. Some of the present embodiments provide a solution to this problem.

[0314] FIG. 7 illustrates a sensor unit 700 similar to the sensor device 100 described above and shown in FIG. 1 . The sensor unit 700 includes a sensor body 702 at least partially covered by a membrane 704. Rather than having a separate tissue-piercing element as in the previous embodiment, the distal ends 706 of the sensor body 702 and membrane 704 are instead sharpened to form a tissue-piercing tip 708. The sensor is sharpened after being coated with the membrane 704, leaving a portion of the sensor body 702 exposed at the sharpened tip 708. In an alternative embodiment, illustrated in FIG. 8 , the sensor body 802 may be sharpened before being coated with the membrane 804, resulting in the sharpened tip 808 being covered by the membrane 804.

[0315] In the embodiments of Figures 7 and 8, the distal end of the sensor body 702 / 802 may be sharpened by any of a variety of methods, such as laser ablation, mechanical grinding, diamond wire, high-speed cutting, abrasive water jet cutting, wire or plunge electrical discharge machining, electrochemical machining, electrochemical etching, electrochemical polishing, stamping, or any other method.

[0316] In either of the embodiments illustrated in FIGS. 7 and 8 , the soft membrane 704, 804 tends to delaminate as the sensor advances through tissue during the process of insertion into a host. Furthermore, due to its very small diameter, the sensor of FIGS. 7 and 8 may lack the column strength necessary to insert through a host's skin without substantial buckling. To address these issues, some of the present embodiments provide a stiffening agent 900 that either coats the membrane 902 ( FIG. 9 ) or is integrated into the membrane 902 ( FIG. 10 ). The stiffening agent 900 increases the column strength of the sensor body 904 so that the sensor unit 906 can be inserted through a host's skin 908 without substantial buckling. The stiffening agent 900 can also improve adhesion of the membrane 902 to the sensor body 904 and / or stiffen the membrane 902 so that it is more resistant to delamination as the sensor advances through tissue during the process of insertion into a host. Preferably, however, the curing agent 900 allows permeability of the analyte into the membrane 902 so as not to interfere with the ability of the sensor to function.

[0317] 9 and 10 illustrate an embodiment in which the tip 910 of the sensor body 904 is exposed through the membrane 902 / curing agent 900, this embodiment also contemplates that the tip 910 of the sensor body 904 may be covered by the membrane 902 / curing agent 900, similar to the embodiment of FIG. 8. When the tip 910 of the sensor body 904 is exposed through the membrane 902 / curing agent 900, in certain embodiments, the material of the sensor body 904 is selected so as not to react with the selected analyte and / or products of the analyte reaction. Such reactions may generate background current, which may adversely affect sensor performance.

[0318] In one embodiment, the material of the sensor body 904 may be formed with a core that does not react with hydrogen peroxide. One such sensor body is platinum-coated tantalum, where the tantalum core, due to its electrochemical properties, does not react with hydrogen peroxide or introduce additional background signal. The small amount of exposed platinum is unlikely to contribute significantly to the background signal.

[0319] In certain embodiments, the curing agent 900 comprises a cyanoacrylate. Cyanoacrylate is an advantageous material for use in this application because it can penetrate membranes, cures quickly, is very rigid, and can be machined after curing if desired. Cyanoacrylate can also quench any enzymes present on the tip and can be coated onto any electrochemically active surface. Other exemplary materials include epoxies and UV adhesives.

[0320] In one embodiment, a method for fabricating a sensor device includes coating a wire with a film. The coated wire is then cut to a desired length to form a sensor wire with a tip. An exemplary method for performing these steps is described in U.S. Patent Publication No. 2011-0027453-A1, the entire contents of which are incorporated herein by reference. The coated sensor wire is then exposed to a curing agent so that the film absorbs the curing agent. The curing agent is then cured, if necessary.

[0321] Exposing the coated wire to the sclerosing agent may include immersing at least the sensor tip in a liquid bath of the sclerosing agent. After withdrawing the sensor wire from the liquid bath, the film is cured to harden the sclerosing agent. The sensor tip may then be sharpened to form a sharp point capable of penetrating tissue. In alternative embodiments, the sensor wire may be sharpened before applying the film to the sensor wire or after applying the film to the sensor wire but before applying the sclerosing agent.

[0322] In embodiments where the sensor tip is sharpened after applying the film and curing agent, a quenching agent may be applied to the sharpened sensor tip to quench all active surfaces exposed during the sharpening step. For example, platinum (Pt) or enzyme layers are considered "active surfaces." In some embodiments, the quenching agent may include cyanoacrylate or silane. Silanes may be particularly advantageous because they are lubricious and may aid in the sensor's penetration into the skin.

[0323] In embodiments that include a quenching agent, the quenching agent can be applied using chemical vapor deposition (CVD) or physical vapor deposition (PVD). For example, a two-step application process may be used that includes a masking agent, followed by a spray agent, followed by a rinse cycle.

[0324] In another embodiment, a method of making a sensor device includes coating a wire with a film. The coated wire is then cut to a desired length to form a sensor wire with a tip. The coated wire is then exposed to a hardening agent so that the hardening agent coats the film. Further processing steps, such as hardening and sharpening, may then be performed, similar to those of the previous embodiment.

[0325] In another embodiment, a method of making a sensor device includes cutting a wire to a desired length to form a sensor wire having a tip. The sensor tip is then sharpened to form a sharp point capable of penetrating tissue. The sensor wire, including the sharpened sensor tip, is then coated with a film. The coated sensor wire is then exposed to a stiffening agent such that the film absorbs the stiffening agent. Further processing steps, such as hardening, may be performed similar to those in the previous embodiment.

[0326] In another embodiment, a method for making a sensor device includes cutting a wire to a desired length to form a sensor wire having a tip. The sensor tip is then sharpened to form a sharp point capable of penetrating tissue. The sensor wire, including the sharpened sensor tip, is then coated with a membrane. By coating the membrane, the host's body fluids are separated from the enzyme by a protective membrane system, preventing the enzyme from leaching into the host and ensuring a controlled diffusion path of the host's body fluids through the membrane system containing the enzyme. The coated sensor wire is then exposed to a hardening agent so that the hardening agent coats the membrane. Further processing steps, such as hardening, may be performed similar to those of the previous embodiment.

[0327] Stimuli-responsive materials In any of the embodiments described herein, the sensor body (e.g., wire) may be one or more "stimulus-responsive materials" that change at least one property in response to a stimulus. For example, the sensor body may be a shape memory metal (or a more rigid metal such as Ti) and / or a shape memory polymer. In such embodiments, the sensor body may be held in a first configuration, which may be curved or straight, while in the first state. During or after the insertion process, the wire transitions to a second state, which may be curved or straight.

[0328] In some embodiments, the sensor is in a straight, rigid state at a first temperature and in a curved, flexible state at a second temperature. During use, the original temperature of the sensor body is changed (e.g., by heating or cooling) to the first temperature, causing the sensor to become straight and rigid, properties that facilitate penetration into skin and tissue. After at least a portion of the sensor has penetrated the skin and tissue, the sensor body returns to the second temperature, at which point it becomes curved and flexible, thereby providing comfort to the patient wearing the sensor.

[0329] In yet another embodiment, the sensor body includes one or more "stimulus-responsive materials" that provide tissue-compatible mechanical properties upon insertion and application of a stimulus. It is advantageous to match the inserted sensor body to the natural tissue architecture and modulus to reduce trauma and foreign body responses caused by the presence of the sensor and body movement, which can adversely alter the sensor's output. For example, the elastic modulus of the sensor body can be approximately 0.5-10 kPa.

[0330] Examples of material properties that can change in response to a stimulus include, but are not limited to, hardness (e.g., from a hardness comparable to that of a typical needle outside the body to a softness substantially closer to that of subcutaneous tissue than a typical needle inside the body), shape, permeability, relative hydrophilicity, conformation of polymer orientation, etc. Examples of stimuli used to change properties include, but are not limited to, temperature (e.g., 37°C for changes inside the body), pressure, hydration of the subcutaneous environment upon insertion, radiation (e.g., UV) provided by a skin patch, electromagnetic stimuli such as voltage, magnetic fields such as inductive magnetic fields, etc. Examples of stimulus-responsive materials include, but are not limited to, polymers such as shape memory polymers, polyurethanes, polyesters, polyamides, polyacrylates, polyethers, and copolymers thereof, alloys such as shape memory alloys (e.g., copper-aluminum-nickel (Cu-Al-Ni), nickel-titanium (NiTi), iron-manganese-silicon (Fe-Mn-Si), or copper-zinc-aluminum (Cu-Zn-Al)), etc.

[0331] One example includes a sensor body formed from polyurethane that changes its elastic modulus by a factor of 10 at 37° C. Other examples include a sensor body formed from a polyurethane copolymer or the like that softens when an electrical or radiant (e.g., UV) stimulus is applied immediately after sensor insertion.

[0332] Sensor Certain embodiments described herein provide various mechanisms for inserting a transcutaneous sensor directly into a host without the use of a separate applicator, i.e., without using anything other than the sensor device itself. Direct pressure insertion of a wire, particularly a transcutaneous sensor (e.g., an electrode) having a thin, wire-like geometry, can be technically challenging due to the risk of buckling associated with the sensor. Direct pressure insertion of the sensor also presents challenges associated with damaging a membrane disposed over the sensor during the insertion process. If not protected, the membrane may peel off from the sensor or be mechanically damaged during the insertion process. It is also desirable to avoid having exposed metal (or other conductive material) at the tip of the sensor, as exposed metal may be electroactive and add background signal (noise) and / or alter the sensitivity of the sensor. The embodiments described herein are designed to overcome the aforementioned challenges by providing a miniature sensor device that can provide structural support (e.g., in the form of mechanical / structural properties such as column strength) for direct insertion of a subcutaneous sensor and protect the membrane from damage during the insertion process.

[0333] In some embodiments, sensors are designed in a configuration that allows electrodes (e.g., working and / or reference electrodes) to be printed onto the sensor body (e.g., core). Unlike printing materials onto a planar substrate, printing materials (e.g., electrode materials) onto wires, such as the majority of sensor embodiments described herein, presents unique challenges, particularly for wires intended for implantation having diameters less than 400 microns (μm). Figures 11-14 illustrate various sensor designs that allow electrodes to be printed onto the sensor body formed in wire form.

[0334] FIG. 11 is a front view of the sensor 1000, and FIG. 12 is a rear view of the sensor 1000. Referring to FIG. 11, the sensor 1000 comprises a conductive core wire 1002 having a non-conductive outer layer or jacket 1004. The core wire 1002 may be a conductive metal, such as, but not limited to, platinum, tantalum, platinum-iridium, etc., in some embodiments, or may be formed from a non-conductive material (e.g., a polymer or a non-conductive metal) in other embodiments. In some embodiments, the core wire 1002 may form an electrode (e.g., a working, reference, or counter electrode). The non-conductive jacket 1004 may be a polymer, such as, but not limited to, polyurethane, parylene, silicone, polyurethane, polyimide, or polyamide-imide. Axially spaced electrodes 1008, 1010 are provided on the non-conductive jacket 1004. In one embodiment, the sensor comprises a first electrode, a second electrode 1008, and a third electrode 1010 formed from the core wire 1002. The electrodes 1008, 1010 can be, for example, but not limited to, platinum, platinum-iridium, carbon, silver, silver / silver chloride, and / or any other material known to be used to form electrodes (e.g., working, reference, or counter electrodes).

[0335] 12 , the electrode 1008 does not extend around the entire circumference of the jacket 1004. A gap at the circumference allows a conductive trace 1012, configured to contact and bond between the electrode 1010 and the conductive component 1006, to extend along the jacket 1004. A layer 1014 of electrically insulating material overlies the conductive trace 1012 to prevent contact between the conductive trace 1012 and the electrode 1008. In one example, the system includes three electrodes: electrode 1008, which comprises a reference or counter electrode, and first and third electrodes 1002, 1010, which comprise working electrodes. In another embodiment of a system having three electrodes, electrode 1010 functions as the reference or counter electrode, while electrode 1008 functions as the working electrode. In another example, the system includes two electrodes. In one such embodiment, the core wire 1002 does not function as a working electrode and therefore may be formed from a non-conductive material. In this embodiment, one of the electrodes 1008 or 1010 functions as a working electrode, and the other electrode 1008 or 1010 functions as a reference or counter electrode.

[0336] 11 and 12 may be advantageously formed by printing, such as 3-D printing. For example, the second and third electrodes 1008, 1010 may be printed on the outside of the non-conductive jacket 1004. The distal end 1016 of the sensor 1000 may be sharpened to form a tissue-piercing tip (not shown).

[0337] In embodiments in which the core 1002 does not function as an electrode (e.g., in a two-electrode sensor system), the distal end 1016 of the core 1002 of the sensor 1000 may be non-conductive so that it does not generate a background signal. For example, the conductive core wire 1002 may be passivated at the distal end 1016 by electrochemical polymerization. In other embodiments, the distal end 1016 of the sensor may be capped with a non-conductive material such as, for example, polyurethane, parylene, silicone, polyurethane, polyimide, polyamide-imide, or other insulating material(s).

[0338] 13 and 14 illustrate another sensor 1020 configured for direct push insertion according to the present embodiment. FIG. 13 is a front view of the sensor 1020, and FIG. 14 is a rear view of the sensor 1020. The sensor 1020 is somewhat similar to the sensor 1000 of FIGS. 11 and 12, except that the core wire 1002 may be omitted. Instead, as shown in FIG. 14, the electrodes 1022, 1024, 1026 are provided on a non-conductive layer 1028 and are electrically connected to the sensor electronics (not shown) by conductive traces 1030, 1032, 1034 provided on the outer surface of the non-conductive layer 1028. In the embodiment shown, the electrode 1024 does not extend the entire periphery of the non-conductive layer 1028, thereby providing a conductive path for the electrode 1026 around the electrode 1024 without using a short circuit. Similarly, electrode 1022 also does not extend around the entire periphery of non-conductive layer 1028, thereby providing a conductive path for electrodes 1026 and 1028 around electrode 1022. Electrodes 1022, 1024, 1026 may be working, reference, and / or counter electrodes. For example, in one embodiment, electrode 1026 functions as the working electrode, while electrode 1024 functions as the reference electrode and electrode 1022 functions as the counter electrode. Elements illustrated in Figures 11-14, as well as all other figures provided herein, may not be drawn to scale and are provided solely to illustrate and facilitate a better understanding of the present embodiments.

[0339] While the embodiments shown in Figures 11-14 are designed to have a configuration that allows for printing of electrodes, such sensor designs may alternatively or additionally be fabricated by any of a variety of techniques described herein or elsewhere.

[0340] Often, the sensor geometry and membrane properties can be difficult to control with a sharpened tip. Potential damage also exists in this region. Therefore, it may be desirable for the tip not to be part of the working electrode. Furthermore, electrode materials (e.g., platinum) are often expensive, and reducing the use of such material(s) (e.g., by not making the tip part of the electrode) can be advantageous. FIG. 15 illustrates another sensor 1040 configured for direct push insertion according to this embodiment. In this embodiment, the sensor 1040 includes a core wire 1042 and two electrodes 1044, 1048 provided along the wire 1042. In alternative embodiments, the sensor may include one, three, four, five, or more electrodes, at least one of which is a working electrode and at least one of which is a counter or reference electrode. The core wire 1042 may be formed from a conductive material (e.g., tantalum or stainless steel) or a non-conductive material, such as a polymer or a non-conductive metal.

[0341] Referring again to FIG. 15 , the electrodes 1044, 1048 may comprise a conductive material such as, but not limited to, platinum, platinum-iridium, carbon, silver, silver / silver chloride, and / or any other material known to form electrodes (e.g., working, reference, or counter electrodes). In one embodiment, the electrodes 1044, 1048 are both working electrodes, and thus collectively form an array of working electrodes. In this specific embodiment, the electrodes 1044, 1048 may share conductive traces or paths. In another embodiment, one electrode is the working electrode and the other is the reference or counter electrode. In some embodiments, the core wire 1042 may be surrounded by multiple layers of conductive material, with at least one insulating layer disposed between every two layers of conductive material. In these embodiments, the working electrodes each have a dedicated electrical connection to an electrical contact through a respective conductive layer.

[0342] In one process for fabricating the sensor 1040, the core wire 1042 is positioned on a substrate 1046, and the electrodes 1044, 1048 can be printed onto the core wire 1042 using platinum paste (e.g., by pad printing). Any of a variety of printing techniques can be used, such as, but not limited to, pad printing or 3-D printing. Selectively placing layers of platinum paste along the length of the non-conductive core wire 1042 can advantageously reduce material usage and maintain a non-electroactive sensor tip. In some embodiments in which the wire core 1042 is coated with multiple layers of conductive material (with insulating layers disposed between them), these conductive materials may be formed from a non-electroactive conductive material, such as tantalum. Layers of platinum or silver / silver chloride, both of which are conductive and electroactive, can then be pad printed onto these conductive layers to form electroactive surfaces, thereby forming electrodes. This method allows for low-cost sensor production, as the raw material costs of tantalum and other conductive, non-electroactive materials can be lower than materials that are both conductive and electroactive (e.g., platinum).

[0343] There is often a trade-off between ease of sensor insertion and patient comfort. Sensors formed from rigid, inflexible materials are, all else being equal, less likely to buckle during sensor insertion than soft, flexible sensors. However, after implantation, due to their rigidity and inflexibility, such sensors may be uncomfortable for the patient wearing them, especially when there is normal movement at the sensor site. In contrast, sensors formed from soft, flexible materials are more likely to buckle during sensor insertion and therefore may not be a viable sensor design for implantation by direct insertion.

[0344] 16 and 17 illustrate one concept that overcomes the two design criteria described above. Referring to FIG. 16, a sensor 1060 is formed on a flat substrate, such as a planar substrate-based sensor. The sensor 1060 can incorporate any of the sensor features described herein (e.g., electroactive surfaces and membranes) as well as any features found in any conventional implantable sensor. Prior to sensor insertion, the flat plate is rolled into a cylindrical shape, as shown in FIG. 17. The rolled cylindrical shape provides sufficient column strength for press-insertion into the host's skin and tissue during the implantation procedure. Rolling the planar sensor creates an overlap region 1062 where two opposing edges 1064, 1066 come together. The overlap region can be secured to one another with, for example, an adhesive, a tie layer, a temporary adhesive, or the like, as will be understood by those skilled in the art. For example, an adhesive may be applied to the overlap region 1062, where the adhesive dissolves after the sensor 1060 is implanted. As the adhesive dissolves, the curled substrate unfolds and resumes its flat shape ( FIG. 16 ). A flat sensor 1060 may be more flexible than a curled sensor 1060, making the sensor 1060 more comfortable for the host. Alternatively, the adhesive may not completely dissolve and instead simply weaken, thereby increasing the flexibility or pliability of the sensor 1060 without completely unfolding. In the illustrated embodiment, the sensor 1060 includes a flat or straight tip 1068 in both its flat ( FIG. 16 ) and curled ( FIG. 17 ) configurations. However, the sensor 1060 may also include a beveled tip in either its flat or curled configuration, or both, such that the sensor mimics the (sharp) shape of the tip of an insertion needle. Due to its unique design, the sensor 1060 illustrated in FIGS. 16 and 17 provides both strong resistance to buckling during sensor insertion and patient comfort after insertion.

[0345] In other embodiments, the column strength of the sensor may not be sufficient to completely prevent the possibility of buckling during sensor insertion. There are a number of possible reasons for this. For example, the sensor may be designed with a focus on softness and flexibility to provide better comfort to the patient. To reduce the risk of the sensor buckling during insertion, in some embodiments a sheath may be used to provide the sensor with additional column strength during sensor insertion.

[0346] Furthermore, the sheath can be designed to be formed, at least in part (e.g., the intraluminal surface), from a material with properties that reduce the risk of damaging the membrane. Materials that can be used include, but are not limited to, silicone rubber, polyurethane, nylon, or any other material that does not (or only causes minimal) damage to the membrane. In addition to providing additional column strength, the sheath can also protect the membrane from contact with (and the resulting shear forces from) the skin and / or tissue as the sensor passes through the skin and / or tissue upon deployment. In some embodiments, the intraluminal surface of the sheath is lubricious, i.e., has a low coefficient of friction, thereby reducing friction that may exist when the sheath is retracted. This protects the membrane from potential abrasion-induced damage. Lubricious surfaces can be created by topically coating and / or incorporating into the sheath's base material surface-modifying additive(s), such as silicone, fatty acids, fluorinated polymers (e.g., PTFE), or other similar materials.

[0347] 18, the sensor 1070 includes a retractable introducer sheath 1072 that covers the membrane 1074 during the insertion procedure. The introducer sheath 1072 not only protects the membrane 1074 during the insertion procedure, but also supports the sensor 1070 and can provide the sensor 1070 with additional column strength to improve resistance to buckling. After insertion, the introducer sheath 1072 is retracted (FIG. 19), leaving the sensor 1070, without the membrane 1074 covering it, implanted within the host's skin and underlying tissue.

[0348] 19 , in the illustrated embodiment, the sensor 1070 includes a tissue-piercing element 1076 having a diameter larger than that of the sensor body 1078. However, the relative dimensions of the illustrated components are by way of example only and not limitation. The introducer sheath 1072 may have an outer diameter substantially the same as or smaller than the diameter of the tissue-piercing element 1076. In alternative embodiments, a tissue-piercing element may not be provided. The length of the introducer sheath 1072 may be substantially equal to, shorter than, or longer than the length of the sensor body 1078. As described above, after insertion of the sensor 1070, the introducer sheath 1072 is withdrawn from the skin. The introducer sheath 1072 may be withdrawn into a mounting unit (not shown). For example, the mounting unit may include a pull tab that can be activated to remove the sheath manually (by a user) or automatically (by a mechanical design triggered by connection between the electronics unit and the mounting unit).

[0349] Often, unprotected membranes can be damaged and / or delaminated during sensor insertion, potentially rendering the implantable sensor unusable. In some embodiments, the sensor is designed with a portion at the distal end that has a larger cross-sectional profile than the rest of the sensor. This configuration provides a protective effect, whereby the distal end portion protects (partially or fully) the rest of the sensor from contacting tissue as the sensor slides through tissue during sensor insertion. In some embodiments, one or more regions of the surface of the sensor body and / or tissue-piercing element can include one or more recessed portions (e.g., cavities, depressions, openings, grooves, channels, etc.) configured to function as reservoirs or storage locations for retaining a bioactive agent. The recessed portions can be formed at any preselected location and have a preselected depth, size, geometry, and / or dimensions according to the intended application. The use of reservoirs or storage locations can increase the amount of bioactive agent that the sensor can hold and deliver. In further embodiments, the sensor body and / or tissue-piercing element may be hollow having a cavity and connected to one or more openings on its surface via various passageways such that the bioactive agent can be released from the cavity through the openings. In some embodiments, the sensor body and / or tissue-piercing element may include a pocket shaped and dimensioned to support the sensor with the membrane disposed thereon.

[0350] 20-22 illustrate an embodiment incorporating the aforementioned concepts into its design. As shown, each sensor 1080, 1082 includes a cross-section that defines at least one recessed region or trough extending along the length of the sensor. With reference to FIGS. 20 and 21, sensor 1080 defines a "plus sign" or x-shaped cross-section that defines four equally spaced troughs 1084 throughout the length of the sensor's longitudinal axis, except at distal end 1085 (FIG. 21). At distal end 1085, sensor 1080 includes multiple circumferential sections 1088 that provide the distal end of sensor 1080 with a larger cross-sectional profile than the remainder of sensor 1080. With reference to FIG. 22, along its longitudinal axis, sensor 1082 defines a circular cross-section with a single trough or cutout 1086, except at distal end 1087, where there are no troughs or cutouts and the cross-section is completely circular. The troughs 1084, 1086 can define a space for placing the electrodes and membranes covering the electrodes, so that the electrodes and membranes are at least flush with, or preferably recessed beneath, the outer periphery 1088, 1090 of the sensor 1080, 1082. Recessing the electrodes and membranes (or positioning them flush with the outer periphery of the sensor) protects the membrane from damage caused by shear forces induced by the host's skin / tissue during the sensor insertion procedure by creating space between the membrane and the host's skin and tissue. The troughs do not need to extend all the way to the tip of the sensor body to further protect the membrane during sensor insertion. After the sensor 1080, 1082 is inserted, settlement / relaxation of the host's tissue increases the desired contact between the electrodes and the host's bodily fluids, which is necessary for proper sensor function. The cross-sectional shapes illustrated in Figures 20-22 are merely examples. This embodiment includes sensors of any of a variety of cross-sectional shapes, including, without limitation, any general polygon, star (with any number of points), square, pentagon, heptagon, octagon, ellipse, etc. This embodiment may have any number of troughs for positioning electrodes, for example, 1, 2, 3, 5, 9, 12, or more.

[0351] FIG. 23 illustrates another sensor 1102 configured for direct push insertion according to this embodiment. The sensor 1102 of FIG. 23 includes a protective sheath 1104 that covers the sensor 1102 during the insertion process. After inserting the sensor 1102, the sheath 1104 is partially or fully retracted to expose the sensor 1102 and / or the sensor tip 1106. Similar to the embodiment illustrated in FIG. 18, the protective sheath 1104 not only protects the membrane during the insertion procedure but can also provide additional column strength to improve resistance to buckling. Additionally, the sheath increases the volume and cross-sectional area of ​​the sheath / sensor assembly. Thus, when the sheath is removed (partially or completely), a small space may be created between the sheath and the surrounding tissue. This space is then filled by the surrounding tissue as the tissue moves toward the sensor. Without wishing to be bound by theory, a better tissue-sensor interface may be formed when the tissue moves toward and contacts the sensor than vice versa (e.g., less trauma, less inflammation, less risk of bleeding, etc.).

[0352] FIG. 24 illustrates another sensor 1108 configured for direct pressure insertion, according to this embodiment. The sensor 1108 includes one or more through-holes 1110, with membrane(s) 1112 disposed within the through-holes 1110. In the illustrated embodiment, the sensor 1108 includes a tissue-piercing distal tip 1114, although in alternative embodiments, the tissue-piercing distal tip 1114 may be omitted. In some embodiments, the through-holes are shaped and sized to enhance certain sensor characteristics. While the through-holes 1110 shown in FIG. 24 are substantially circular, in some embodiments, the through-holes may be shaped or sized differently. These differences may result in different electroactive surface behavior and / or measurements at each of these through-holes. For example, deeper through-holes may contain a larger volume of interstitial fluid compared to shallower through-holes. Thus, in some situations, electrodes corresponding to deeper through-holes may provide a better signal-to-noise ratio or some other characteristic. On the other hand, the volume of water entering a shallow through-hole may turn over more quickly, and the electrode corresponding to the shallow through-hole may have less lag time issues, which may be important if the patient's analyte concentration changes rapidly. In other embodiments, the shapes and dimensions of the various through-holes may be differently designed to measure different species. For example, one of the through-holes may have a different shape and / or dimensions than another such that the corresponding electrode is better able to measure oxygen but not another analyte (e.g., glucose).

[0353] Instead of, or in addition to, through-holes, the sensor may include one or more depressions 1118 into which the membrane(s) are placed. For example, FIG. 25 illustrates another sensor 1116 configured for direct pressure insertion according to this embodiment. The sensor 1116 shown in FIG. 25 includes a plurality of depressions 1118, or indentations, or pores, or cavities, etc. (for simplicity, hereinafter referred to as depressions 1118) on its outer surface. The depressions 1118 may be arranged in a pattern or may be arranged randomly.

[0354] In some embodiments, the sensor 1116 may be coated with a particle-containing membrane system including a conductive component dispersed in a non-conductive component (e.g., a polymeric membrane material). The conductive component may include a plurality of conductive particles dispersed throughout the membrane system, some of which are coated, at least in part, with an enzymatic material (e.g., glucose oxidase) configured to produce a species measured by the conductive particles that generates a signal. The conductive particles may include any of a variety of conductive electroactive materials, such as, for example, platinum, platinum-iridium, graphite, silver, silver chloride, carbon, and / or conductive polymers.

[0355] In other embodiments, at least one of the recesses 1118, such as some of the recesses 1118 or all of the recesses 1118, may contain an enzyme and / or membrane material. For example, the membrane may be flush with or recessed below the outer surface of the sensor 1116. Recessing the membrane(s) (or positioning them flush with the outer surface of the sensor 1116) protects the membrane from damage due to shear forces caused by the host's skin / tissue during the sensor insertion procedure by creating space between the membrane and the host's skin and tissue. After the sensor 1116 is inserted, settlement / relaxation of the host's tissue increases the desired contact between the electrodes and / or membrane and the host's bodily fluids, which is necessary for proper sensor function. Alternatively, the membrane may protrude from the outer surface of the sensor 1116. The sensor 1116 shown in FIG. 25 further includes an outer bio-protective layer (not shown) or bio-interface layer formed from a hydrophilic material to allow for easy sensor insertion with low pressure and reduced friction with surrounding tissue.

[0356] In some embodiments, the sensor may include a rigid outer layer that provides additional column strength to provide additional resistance to buckling during sensor insertion.

[0357] FIG. 26 illustrates another sensor 1120 configured for direct pressure insertion according to this embodiment. The sensor 1120 includes a plurality of axially spaced depressions 1122 configured to receive an enzyme and / or membrane material 1124. The sensor 1120 further includes an outer layer 1126 made of a material that is permeable to one or more selected analytes, including, without limitation, glucose. The outer layer 1126 not only insulates and protects the underlying sensor 1120 / membrane 1124 system during the sensor insertion procedure, but can also provide rigidity and / or increased column strength for resistance to buckling during insertion. Because the outer layer 1126 is highly permeable to one or more selected analytes, it does not have a substantial adverse effect on the functionality of the sensor 1120.

[0358] Any of the embodiments described herein can incorporate an outer layer. Examples of materials for the outer layer 1126 include, but are not limited to, non-glucose-limiting hydrogels, polymer and / or carbohydrate films (e.g., cellulose acetate films), or metal films with micropore structures or microchannels that allow the analyte (e.g., glucose) to pass therethrough, or lattice structures formed from metals or rigid polymers and with openings sized to allow the analyte to pass therethrough. Polymers and / or sugars that can be used include, but are not limited to, cyanoacrylate polymers, polyurethanes, polyurethane ureas, polyacrylates, polystyrenes, polysulfones, polyether ketones, polycarbonates (e.g., polytrimethyl carbonate), polyimides, polyesters, polyethers, epoxides, maltose, PVP, polyethylene, L-lactide, or polycaprolactone.

[0359] As discussed above, the hardness of the outer layer 1126 can provide additional column strength to the sensor and enhance its ability to protect the membrane. For any sensors described herein that include an outer layer, the outer layer can be formed using a material having a hardness of about 30 to about 95, sometimes about 70 to about 90, and sometimes about 50 to about 70 Shore A.

[0360] FIG. 27 illustrates another sensor 1128 configured for direct pressure insertion, according to this embodiment. The sensor 1128 includes a sensor body 1130 having an overlying membrane 1132 and a protective outer layer 1134 disposed over the sensor 1128 / membrane 1132 system. The protective outer layer 1134 not only insulates and protects the underlying sensor 1128 / membrane 1132 system during the sensor insertion procedure, but may also provide stiffness and / or rigidity for increased column strength and resistance to buckling during insertion. The protective outer layer 1134 may include, for example, without limitation, a dissolvable material such as a polymer. In some embodiments, the protective layer is formed from a material that is in a rigid state when dry and / or at room temperature (or below). In this rigid state, the protective layer protects the membrane from damage during insertion and further improves the column strength of the sensor, thereby enabling insertion. Upon exposure to body temperature and / or hydration, the protective layer becomes soft and flexible. In this state, the protective layer provides greater comfort to the patient-wearer. Examples of dissolvable and / or degradable polymers include, but are not limited to, polyvinylpyrrolidone (PVP), polymeric sugars such as caramel, polyvinyl acetate, polyethylene glycol, polyesters, polyamino acids, polycarbonates, polyanhydrides, polylactic acid, polyglycolic acid, polydioxanone, polyhydroxybutyric acid, polyhydroxyvaleric acid, polycaprolactone, polyanhydrides (e.g., aliphatic polyanhydrides in the backbone or side chains, or aromatic polyanhydrides with benzene in the side chains), polyorthoesters, polyamino acids (e.g., poly-L-lysine, polyglutamic acid), pseudopolyamino acids (e.g., polyamino acid backbones modified), polycyanoacrylates, polyphosphazenes, and combinations or copolymers of these and other similar polymers. Examples of non-polymeric dissolvable materials include, but are not limited to, sugars (e.g., maltose), liquid oleic acid, vitamin E, peanut oil, and cottonseed oil, and other similar compounds. After the sensor 1128 is inserted and the protective outer layer 1134 dissolves, the sensor 1128 becomes more flexible (compared to a coated sensor 1128) for enhanced host comfort.Alternatively, the protective outer layer 1134 may comprise a material that does not completely dissolve but softens after insertion into the host to enhance the comfort and wearability of the sensor 1128. Examples of softenable materials include, without limitation, hydrophilic polymers, shape-memory polymers, such as, but not limited to, polyurethane, polyester, polyamide, polycarbonate, polyether, polylactic acid, polyglycolic acid, polydioxanone, polyhydroxybutyric acid, polyhydroxyvaleric acid, polycaprolactone, polyanhydrides, polyorthoesters, polyamino acids, pseudopolyamino acids, polycyanoacrylates, or polyphosphazenes, as well as copolymers, blends, or combinations thereof, and similar polymers. The protective outer layer 1134 may be formed by dipping the sensor body 1130 and membrane 1132 into a solution of the outer layer 1134 material, which subsequently solidifies and hardens. The dipping process can be adjusted to result in a thinner coating at the tip 1136 to aid insertion. The solutions can be reactive and non-reactive, and the reactive solutions can be further reacted to increase the strength of protection and mechanical support for insertion.

[0361] 28 illustrates another sensor 1138 configured for direct pressure insertion, according to this embodiment. The sensor 1138 includes an outer layer 1140 made of a rigid or stiff material. The outer layer 1140 covers substantially all of the sensor 1138 but includes at least one opening or window 1142. The window(s) 1142 are positioned over the electrodes such that the electrodes (and any membrane(s) overlying the electrodes) are exposed for contact with the host's tissue and / or bodily fluids. The outer layer 1140 not only insulates and protects the underlying sensor 1138 / membrane system during the sensor insertion procedure, but can also provide stiffness and / or increased column strength for resistance to buckling during insertion. Exemplary materials for the outer layer 1140 include, without limitation, cyanoacrylate polymers, polyurethanes, polyurethaneureas, polyacrylates, polystyrenes, polysulfones, polyetherketones, polycarbonates (e.g., polytrimethylcarbonate), polyimides, polyesters, polyethers, epoxides, maltose, PVP, polyethylene, L-lactide, or polycaprolactone.

[0362] 29 illustrates another sensor 1144 configured for direct push insertion according to this embodiment. The sensor 1144 includes a conductive wire 1146, which may include a metal or any other conductive material. An outer coating 1148 is disposed on the wire 1146. The outer coating 1148 may have a thickness greater than that of the wire 1146. For example, the outer coating 1148 may be 1.5 times thicker than the wire 1146, 2 times thicker than the wire 1146, 2.5 times thicker than the wire 1146, 3 times thicker than the wire 1146, 3.5 times thicker than the wire 1146, or the outer coating 1148 may have any thickness relative to the wire 1146. The outer coating 1148 may include polymers such as, without limitation, cyanoacrylate polymers, polyurethanes, polyurethane ureas, polyacrylates, polystyrenes, polysulfones, polyether ketones, polycarbonates, polyimides, polyesters, polyethers, epoxides, polytetrafluoroethylenes, and copolymers, combinations, or blends thereof.

[0363] The outer coating 1148 may include at least one opening or window 1150 corresponding to the location(s) of the electrode(s). For example, the window(s) 1150 may be formed by ablation, such as laser ablation. A membrane 1152 may be disposed within the window(s) 1150 and may be recessed below the outer surface of the outer coating 1148. The recessed membrane 1152 is spaced from the host's skin and / or tissue during the sensor insertion process, thereby protecting the membrane 1152 from damage that may occur due to friction between the membrane 1152 and the host's skin and / or tissue.

[0364] Sensor 1144 further includes a highly permeable outer layer 1154, such as, without limitation, a hydrogel, overlying membrane 1152 in the region(s) of window(s) 1150. Highly permeable outer layer 1154 provides mechanical buffering against damage to membrane 1152 and / or electrode(s) positioned below highly permeable outer layer 1154.

[0365] Advantageously, although not required, the sensor 1144 of Figure 29 allows for continuous reel-to-reel processing. Additionally, if desired, the entire sensor 1144 assembly, including all or some of the components shown in Figure 29, may be further processed by laser ablation and / or mechanical die cutting to remove any excess material and / or create new edges that face the host tissue.

[0366] FIG. 30 illustrates another sensor 1156 configured for direct pressure insertion according to the present embodiment. The sensor 1156 includes a membrane 1158 applied only to one or more regions of the sensor 1156. The membrane 1158 may be flush with the outer surface 1160 of the sensor 1156, recessed below the outer surface 1160 of the sensor 1156, or protruding from the outer surface 1160 of the sensor 1156. In embodiments in which the membrane 1158 is flush with or recessed below the outer surface 1160 of the sensor 1156, the membrane 1158 may be positioned within one or more openings or windows in the outer surface 1160 of the sensor 1156. The membrane 1158 can be applied to the sensor 1156 according to any desired process, such as printing, or, if the deposition can be site-specific, lithographic processing. In some embodiments, printing is preferred because it allows for highly localized and controlled deposition.

[0367] The outer surface 1160 of the sensor 1156 of FIG. 30 , in areas other than the membrane 1158, may include a polymer such as, without limitation, polytetrafluoroethylene (PTFE), cyanoacrylate polymer, polyurethane, polyurethaneurea, polyacrylate, polystyrene, polysulfone, polyetherketone, polycarbonate, polyimide, polyester, polyether, epoxide, and combinations, blends, or copolymers thereof. The distal end of the polymer may include a piercing tip 1162 configured to penetrate skin and / or tissue and having desirable insertion characteristics. This sensor 1156 of FIG. 30 advantageously simplifies the process of fabricating the sensor 1156 by not “blunting” the distal tip 1162 by applying a membrane 1158 to the tip 1162. This sensor 1156 of FIG. 30 may advantageously be used in combination with other forms of membrane protection, such as any of the embodiments described elsewhere herein. Manufacturing technique

[0368] One aspect of the present embodiments involves the recognition that materials used to form the membrane of analyte sensors are often soft and therefore prone to delamination (i.e., peeling and sometimes flaking) as the sensor is advanced through skin and / or tissue. This problem is particularly acute in sensors formed by a process in which the sensor is first coated with a membrane and then the tip is sharpened. This process exposes the sensor body, leaving a thin membrane coating surrounding the sides of the tip of the sensor body. Some of the present embodiments provide solutions to this problem, including methods for forming the tip after applying the membrane without damaging the tip, while simultaneously maintaining the integrity of the tip.

[0369] With regard to sensor fabrication, there are two approaches regarding whether a film coating step should precede a sharpened tip formation step, or whether a sharpened tip formation step should precede a film coating step. In the first approach, a film is coated onto the sensor processing element prior to the dipping that forms the sharpened distal tip. In this first approach, the technical challenge involves finding a technique that allows for the creation of a sharpened tip without causing damage to the film and / or creating excess film at the tip.

[0370] 30A and 30B, in one method employing the first approach, a film 1161 is coated onto a sensor processing element 1163. In some cases involving dipping, a bead 1165 (FIG. 30A) may be formed on one end of the processing element 1163. The distal end of the processing element 1163 is then sharpened to a tip 1167 (FIG. 30B), for example, using laser ablation or mechanical cutting or grinding. Doing this removes the bead 1165 from the distal end of the processing element 1163. In the illustrated embodiment, sharpening the distal end of the processing element 1163 involves removing material from only one side of the processing element 1163, thus forming a tip 1167 having a shape similar to the tip of a hypodermic needle. In an alternative embodiment, material may be removed from both sides of the processing element 1163 to form a wedge-shaped tip. In yet a further alternative embodiment, material may be removed from the workpiece 1163 in a full 360° to form a conical tip.

[0371] 31-33 illustrate another process for making a sensor employing the first approach. Referring to FIG. 31, a conductive wire 1164 includes a film coating 1166. The wire 1164 can be a metal, such as, without limitation, tantalum, platinum, stainless steel, platinum-iridium, silver, silver chloride, palladium, or any other metal.

[0372] 31-33 may include applying a film 1166 to the wire 1164, or the process may begin with the wire 1164 already coated with the film 1166. An annular channel 1168 is then formed around the entire circumference of the coated wire 1164. The channel 1168 extends partially through the film 1166 and into the wire 1164. The channel 1168 may be formed by any process, such as mechanical cutting, grinding, laser ablation, heating, etc. In the illustrated embodiment, the channel 1168 has a v-shaped cross-section, but the channel 1168 may have any of a variety of cross-sectional shapes. This process has been found to prevent the film from covering the distal tip, which is advantageous because in other processes, the film must subsequently be removed from the tip, which adds another process step.

[0373] Referring to FIG. 32 , tension is applied to the coated wire 1164 either after or simultaneously with the formation of the channels 1168. The tension induces strain in the wire 1164 in the region of the channels 1168, causing necking and ultimately breakage of the wire 1164. The necking process results in a sharp tip 1170 at each end of the two severed wire pieces 1164, each of which comprises a conductive wire material 1164, which may be metal. In some embodiments, in addition to subjecting the channels 1168 of the wire 1164 to tension, the channels 1168 may also be subjected to heating. During or after the necking process, in some cases, the tips 1170 may be in a soft and / or malleable state. In some embodiments, the surface of the tips may be subjected to further mechanical processing (e.g., by use of a sharpener, grinder, mold, etc.) to shape the distal tips to be sharp. This sharpened tip 1170 can be advantageously used to pierce the skin and / or tissue during the sensor insertion process.

[0374] 33 , the sharp tip 1170 formed by tearing the coated wire 1164 may then be covered with a protective outer layer 1172 to protect the exposed conductive wire 1164 and / or membrane 1166. The protective outer layer 1172 may include, for example, without limitation, a cured polymer, such as a cyanoacrylate polymer, polyurethane, polyurethaneurea, polyacrylate, polystyrene, polysulfone, polyetherketone, polycarbonate, polyimide, polyester, polyether, epoxide, polytetrafluoroethylene, and copolymers, combinations, or blends thereof. In addition, the protective outer layer 1172 may include any other protective layer material described herein or elsewhere and may further have the mechanical properties described herein for outer protective layers. The protective outer layer 1172 may be subjected to any process, such as solution-based coating, extrusion, or printing in which reactive monomers and / or oligomers or non-reactive polymers are pre-dissolved, mixed, or dispersed, or any other process described herein or elsewhere for coating.

[0375] 31-33 advantageously includes a sharpened tip 1170 that can be used to penetrate skin and / or tissue during the sensor insertion process. In certain embodiments, membrane 1166 preferably does not overlap sharpened tip 1170 to avoid blunting tip 1170, which would make tip 1170 less effective at penetrating skin and / or tissue.

[0376] Figure 34 corresponds to another process for fabricating a sensor employing the first approach described above, in which a film is coated onto the sensor processing element prior to the formation of the sharpened distal tip. This process includes a wire stock 1174 having a film coating 1176. The wire stock 1174 can be a non-conductive, non-electroactive material such as, without limitation, polyurethane, polyurethaneurea, polyacrylate, polystyrene, polysulfone, polyetherketone, polycarbonate, polyimide, polyester, polyether, polyamide, and blends, combinations, or copolymers thereof. The process of Figure 34 can include applying the film 1176 to the wire stock 1174, or the process can begin with the wire stock 1174 already coated with the film 1176.

[0377] The wire stock 1174 shown in Figure 34 is wound on a reel 1178, and the process of Figure 34 is suitable for use in a continuous reel-to-reel process. However, the reel 1178 shown in Figure 34 is by way of example only and is not intended to be limiting.

[0378] In the process of FIG. 34 , the entire length of the wire stock 1174 is coated with the film 1176. Then, as the wire stock 1174 unwinds from the reel 1178, portions of the film 1176 are selectively removed at spaced locations along the wire stock 1174. The film 1176 may be removed at various locations relative to the final sensor, such as the tip and / or any other location along the length of the final sensor. In one non-limiting example, the film 1176 may be removed in a laser ablation process using a laser 1180. After certain portions of the film 1176 are removed, the wire stock 1174 is cut at spaced locations to form a plurality of film-coated sensor wires. The film-coated sensor wire advantageously has a sensor tip that is free of the film 1176, which may smooth the tip and make the tip unsuitable for penetration into skin and / or tissue.

[0379] In an alternative process, the detachment step itself may remove the membrane 1176 from the sensor tip. Thus, for example, a separate step (other than the detachment step) may not be performed to remove the membrane 1176 from the sensor tip. In yet another alternative process, the membrane removal and detachment steps may be performed as described above, but the wire stock 1174 may comprise a conductive material, such as a metal. After detachment, another material, for example, a polymer cap or second coating, may then be applied to cover the sensor tip to prevent the tip from generating a background signal when the sensor is inserted into a host.

[0380] As described elsewhere herein, there is a need for an implantable sensor that incorporates a layer of rigid material at the distal end of the sensor to not only protect the underlying membrane or improve the column strength of the sensor, but also to inhibit sensor membrane movement during sensor insertion. Typical sensor membranes are fragile and can shift position during the sensor insertion process, resulting in reduced sensor performance. It is preferable that the sensor remain in place on the sensor wire with little or no mechanical movement relative to the sensor wire. Membrane movement can cause the membrane to no longer cover the electrode(s). Similarly, in extreme cases, the membrane can completely delaminate from the sensor. Additionally, the sensor tip can become exposed before or during the insertion process, generating background signal and / or varying sensor sensitivity. Furthermore, it may be desirable to grind or otherwise treat the sensor tip after applying the membrane. Grinding or other treatment can expose the sensor wire, which can also generate background signal and / or varying sensor sensitivity. Referring to FIGS. 35-37, a process for fabricating a sensor employs the first approach described above, in which a film is coated on the sensor processing element prior to the formation of the sharpened distal immersion portion. This process involves a conductive wire 1182 having a film coating 1184. The wire 1182 can be a conductive material, including, but not limited to, any conductive material disclosed elsewhere herein. In an alternative embodiment, a process similar to that shown in FIGS. 35-37 can involve a bare wire 1182 (i.e., no film thereon) and applying a film 1184 to the wire 1182. Referring to FIG. 36, the distal end 1186 of the film-coated wire 1188 is ground to obtain a sharpened tip 1190. Alternatively, the sharpened tip 1190 may be obtained by a process other than grinding, including any other sharpening, cutting, or severing technique disclosed herein or elsewhere. Through grinding or other processing, the distal end 1186 of the sensor wire 1182 is exposed.

[0381] 37 , a coating 1192 is applied to the distal end 1186 of the membrane-coated wire 1188. The coating 1192 can be, for example, without limitation, a hard polymer such as cyanoacrylate or a cyanoacrylate polymer, polyurethane, polyurethaneurea, polyacrylate, polystyrene, polysulfone, polyetherketone, polycarbonate, polyimide, polyester, polyether, epoxide, or any other material(s) capable of preventing movement of the detectable membrane during sensor insertion. The coating 1192 can be applied by any desired process, such as, but not limited to, dip coating, spraying, vapor deposition, extrusion, molding, or printing. The coating 1192 advantageously creates an impermeable barrier at the exposed end surface 1192 of the conductive sensor wire 1182, rendering the end surface 1192 non-electroactive and therefore unable to generate background signal and / or cause variations in sensor sensitivity. Coating 1192 may also penetrate membrane 1184, hardening or stiffening membrane 1184 and causing it to adhere more firmly to wire 1182, making membrane 1184 more mechanically stable.

[0382] As mentioned above, there are two approaches to sensor fabrication regarding whether a membrane coating step should precede a sharpened tip formation step, or whether a sharpened tip formation step should precede a membrane coating step. In one approach described above, a membrane is coated on the sensor processing member prior to dipping to form the sharpened distal tip. In the second approach, a sharpened distal tip is formed on the processing member prior to the membrane coating process. In the second approach, one common technical challenge involves preventing or preventing the membrane material from coating the sharpened distal tip, thereby blunting the tip and making sensor insertion more difficult (or painful).

[0383] In some embodiments, a material (e.g., a membrane or outer layer material) is coated onto a sensor processing element (e.g., a sensor wire) using a dipping technique, in which the sensor processing element is immersed in a solution containing a material to form a thin film or layer on the processing element. Often, the distal end of the processing element is the first portion of the processing element to be immersed because it is positioned vertically lower than the other portions of the processing element during the immersion process. Due to gravity, the applied coating typically sags toward the lowest end (i.e., the distal end) of the sensor processing element, resulting in a blunted distal tip that, in some embodiments, is used to penetrate skin and / or tissue. Without wishing to be bound by theory, all else being equal, gravity-induced sagging problems may be more severe for coatings formed from low-viscosity solutions compared to high-viscosity solutions.

[0384] 38 and 39 illustrate a process designed to overcome these technical challenges. Referring to FIG. 38 , this process involves a sensor wire 1194 having a sharpened distal tip 1196. The sensor wire 1194 is immersed tip-side down in a membrane solution, forming a membrane 1198 on the sensor wire 1194. After the membrane solution dries, a portion of the solidified membrane 1198 is removed at the distal end 1200 of the sensor wire 1194, as shown in FIG. 39 . The membrane 1198 can be removed using any of a variety of processes, such as, without limitation, laser ablation, electropolishing, bead blasting, dry ice blasting, baking, or any other process. After the membrane 1198 is removed from the distal end 1200 of the sensor wire 1194, the exposed portion 1202 of the sensor wire 1194 may be coated with a protective layer (not shown), such as a hard polymer. Exemplary materials for the protective layer include, without limitation, cyanoacrylate polymers, polyurethanes, polyurethaneureas, polyacrylates, polystyrenes, polysulfones, polyetherketones, polycarbonates, polyimides, polyesters, polyethers, epoxides, and any other materials used to form protective layers disclosed herein or elsewhere.

[0385] 40 and 41 illustrate another process for removing membrane material from the distal end of a sensor wire. Referring to FIG. 40, a sensor 1204 is immersed in membrane solution, and the still-wet solution 1206 forms a bead 1208 at the distal end 1210 of the sensor. Referring to FIG. 41, the distal end 1210 can be wiped or wiped with a fibrous body 1212 while the membrane solution 1206 is still wet. At the distal end 1210 of the sensor 1204, some of the membrane solution 1206 is absorbed by the fibrous body 1212, as shown in FIG. 41. The fibrous body 1212 can include, for example, without limitation, a cloth, a cotton swab, a wick pad, a sponge, etc. In another embodiment, instead of absorbing the excess membrane coating at the distal end, the tip can be used to contact the bead 1208 to break its surface tension, thereby causing some (if not all) of the excess membrane coating to fall off the distal tip. In certain embodiments, this procedure may be performed in conjunction with the process described above for absorbing excess membrane coating.

[0386] 42 and 43 illustrate another process for fabricating a sensor configured for direct push insertion according to the present embodiments. Referring to FIG. 42 , the process includes a wire 1214 having a film coating 1216. The wire 1214 can be a conductive material, such as a metal, such as, without limitation, tantalum, platinum, or any other material described herein or elsewhere for use as a conductive and / or electroactive material. The process of FIGS. 42 and 43 may include applying a film 1216 to the wire 1214, or the process may begin with a wire 1214 already coated with a film 1216. The film 1216 may include a single layer, or may include multiple layers 1218 as shown.

[0387] Referring to FIG. 43 , an end cap 1220 is applied to the tip of the membrane-coated wire 1214. The end cap 1220 comprises a material that is rigid, preferably resistant to biofouling (e.g., resistant to protein adhesion to the membrane, which can reduce the membrane's permeability to analytes), and can be formed or machined. Exemplary materials include, without limitation, polytetrafluoroethylene (PTFE), cyanoacrylate polymers, polyurethanes, polyurethaneureas, polyacrylates, polystyrenes, polysulfones, polyetherketones, polycarbonates, polyimides, polyesters, polyethers, and epoxides. The end cap 1220 can be applied to the sensor by any desired process, such as coating, injection molding, or mechanical interlocking from a preformed tip made of polymer or metal. The end cap 1220 may include or be treated to provide a sharp tip 1222. The sharpened tip 1222 is configured to penetrate skin and / or tissue such that the sensor is configured for direct pressure insertion. The end cap 1220 advantageously facilitates direct pressure insertion while simultaneously covering the distal end of the sensor wire 1214 so that it is not conductive. The end cap 1220 also provides a barrier to protect the distal end of the membrane 1216, preventing the membrane 1216 from slipping off the end of the sensor wire 1214.

[0388] 44 and 45 illustrate another process for fabricating a sensor configured for direct push insertion according to the present embodiments. Referring to FIG. 44 , this process includes a wire 1224 having a film coating 1226. The wire 1224 can be a conductive material, such as a metal, including, but not limited to, tantalum, platinum, silver, silver chloride, and any other conductive metal described herein or elsewhere. The film 1226 can include more than one layer 1228, such as two layers, three layers, four layers, five layers, or any number of layers. The process of FIGS. 44 and 45 may include applying the film 1226 to the wire 1224, or the process may begin with a wire 1224 already coated with the film 1226. Applying the film 1226 to the wire 1224 may include printing, coating, vapor deposition, extrusion, or any other process described herein or elsewhere for coating a material onto a sensor fabrication member. Furthermore, in the case of a multi-layer film 1226, the process for forming each layer 1228 may be repeated any number of times until the desired number of layers is achieved. Also, at least one layer 1228 of a multi-layer film 1226 may be formed by a different process than the process(es) used to form at least one other layer 1228.

[0389] 44, a rigid coating 1230 is formed on the membrane 1226 at the tip of the sensor. The rigid coating 1230 may include a cyanoacrylate polymer, polyurethane, polyurethaneurea, polyacrylate, polystyrene, polysulfone, polyetherketone, polycarbonate, polyimide, polyester, polyether, polyamide, epoxide, or any other rigid polymer described herein or elsewhere for forming an outer layer (e.g., a protective outer layer). The process for forming the rigid coating 1230 may include solution-based coating, extrusion, or molding, or any other process described herein or elsewhere for coating a material onto a sensor processing member.

[0390] 45 , the rigid coating 1230 is shaped to provide a pointed tip 1232. The pointed tip 1232 is configured to penetrate the skin and / or tissue such that the sensor is configured for direct pressure insertion. The rigid coating 1230 with the pointed tip 1232 advantageously facilitates direct pressure insertion while simultaneously coating the distal end of the sensor wire 1224 so that it is not conductive. The rigid coating 1230 also provides a barrier to protect the distal end of the membrane 1226, preventing the membrane 1226 from slipping off the end of the sensor wire 1224.

[0391] 46-48 illustrate another process for fabricating a sensor configured for direct pressure insertion according to this embodiment. Sensors produced according to FIGS. 46-48 advantageously do not expose the distal end of the sensor wire, and as a result, the sensor wire is not electroactive at the tip, generating a background signal and adversely affecting the sensitivity of the sensor. Referring to FIG. 46, sensor 1234 includes a sensor body 1236 and a piercing tip 1238. Tip 1238 includes a substantially triangular cross-section with a pointed distal end 1240. A proximal end 1242 of tip 1238 defines a diameter that is larger than the diameter of sensor body 1236. However, the illustrated shape of sensor 1234 is by way of example only and is not intended to be limiting.

[0392] With further reference to FIG. 46 , a membrane 1244 is applied to the sensor 1234, including the sensor body 1236 and the piercing tip 1238. The membrane 1244 may be applied by any desired method, such as dip coating, spray coating, brush coating, printing, extrusion, or any other method described herein or elsewhere for coating a membrane onto a sensor fabrication member (e.g., a sensor body). With reference to FIG. 47 , a coating 1246 is applied to the piercing tip 1238 of the sensor 1234. The coating 1246 prevents the piercing tip 1238 from functioning as an electroactive surface. In some embodiments, the coating 1246 may include a material (e.g., silicone) that prevents certain analytes (e.g., glucose) from passing therethrough. In other embodiments, the coating 1246 may include a material that inactivates the membrane 1244, for example, by denaturing an enzyme in the membrane 1244 that is required for signal generation. Coating 1246 can be applied by any desired method, such as any of the methods described herein or elsewhere for coating a material onto a workpiece. In yet other embodiments, instead of applying coating 1246, membrane 1244 can be inactivated by a light or heat source that can be used to denature the enzymes in membrane 1244.

[0393] 48, a retractable introducer sheath 1248 is applied around the sensor body 1236. The outer diameter of the introducer sheath 1248 is substantially the same as or smaller than the diameter of the piercing tip 1238 at its proximal end 1242. The introducer sheath 1248 covers and protects the membrane 1244 during the sensor insertion procedure, reducing the likelihood of the membrane 1244 becoming dislodged or damaged.

[0394] 49-51 illustrate another process for fabricating a sensor configured for direct pressure insertion according to this embodiment. Sensors produced according to FIGS. 49-51 advantageously do not expose the distal end of the sensor wire, and as a result, the sensor wire at the distal end is not electroactive, does not generate background signals, and does not adversely affect the sensitivity of the sensor. Referring to FIG. 49, sensor 1250 includes a sensor body 1252, and a film 1254 is applied to sensor body 1252. Sensor body 1252 can be a conductive material, such as, for example, a metal such as, but not limited to, tantalum, platinum, or any other conductive metal disclosed herein or elsewhere. Film 1254 can be applied by any desired method, such as dip coating, spray coating, brush coating, printing, extrusion, and / or combinations thereof.

[0395] 50 , a piercing tip 1256 is applied to the distal end of the sensor body 1252. The tip 1256 may be formed in a separate process or as part of the same process that forms the sensor body 1252. The tip 1256 may be affixed to the distal end of the sensor body 1252 by any desired process, such as mechanical crimping, press-fitting, welding (such as ultrasonic welding), shrink tubing, application of heat, etc. The tip 1256 may comprise the same material as the sensor body 1252 or a different material. For example, the tip 1256 may be conductive, such as metallic, or non-conductive, such as non-metallic. Exemplary materials for the tip 1256 include, without limitation, cyanoacrylate polymers, polyurethanes, polyurethane ureas, polyacrylates, polystyrenes, polysulfones, polyether ketones, polycarbonates, polyimides, polyesters, polyethers, polyamides, and epoxides.

[0396] The tip 1256 includes a substantially triangular cross-section with a pointed distal end 1258. A proximal end 1260 of the tip 1256 defines a diameter that is larger than the diameter of the sensor body 1252. However, the shape of the sensor 1250 shown is by way of example only and is not limiting.

[0397] 51 , a retractable introducer sheath 1262 is applied around the sensor body 1252. The outer diameter of the introducer sheath 1262 is substantially the same as or smaller than the diameter at the proximal end 1260 of the penetration tip 1256. The introducer sheath 1262 covers and protects the membrane 1254 during the sensor insertion procedure, reducing the likelihood of the membrane 1254 becoming dislodged or damaged. The introducer sheath 1262 can be made of, for example, metallic or non-metallic. Non-metallic sheaths can be made from, for example, without limitation, polyolefin, polyurethane, polyurethane urea, polyacrylate, polystyrene, polysulfone, polyether ketone, polycarbonate, polyimide, polyester, polyether, polyamide, epoxide, or any other material.

[0398] 49-51 advantageously maintains the sharpness of the piercing tip 1256 by not applying a membrane 1254 to the tip 1256. Additionally, the absence of membrane 1254 on piercing tip 1256 reduces the likelihood of membrane 1254 tearing and / or delaminating during the sensor insertion process.

[0399] FIG. 52 illustrates another process for fabricating a sensor configured for direct pressure insertion according to the present embodiment. The sensor 1264 includes a sensor body 1266, a membrane 1268 over the sensor body 1266, and a sharp distal tip 1270 applied over the membrane 1268. The tip 1270 may be formed by any process, such as, but not limited to, dipping, gluing, melting / cooling, solvent casting / drying, molding (e.g., extrusion or injection molding, press molding, or in-situ polymerization in a mold), machining of a substrate, 3-D printing, casting, sintering, forging, machining, or other known methods of manufacturing implantable devices. In some embodiments, the material of the tip 1270 may include, for example, but not limited to, a biodegradable / bioabsorbable material. Exemplary materials include, but are not limited to, polymers such as polyvinylpyrrolidone (PVP) and / or polyvinyl alcohol (PVA), sugars such as maltose, and the like.

[0400] 52 advantageously creates the sharp tip 1270 after the membrane 1268 is applied to the sensor body 1266. Thus, the sharp tip 1270 does not have the membrane 1268 applied to it, which could blunt the tip 1270. Another advantage of embodiments having a tip 1270 comprising a material that is biodegradable / bioabsorbable is host comfort, as the tip 1270 dissolves after insertion. Using a biodegradable / bioabsorbable tip avoids the possibility of the tip remaining in the body if the tip becomes detached from the sensor.

[0401] One aspect of the present embodiments includes the recognition that applying a film to a sharp sensor tip presents challenges. For example, a sharp tip can tear the film and / or cause delamination of the film, especially when the sensor is subjected to frictional forces during the sensor insertion process. Also, applying a film to a sharp sensor tip can dull the tip, making it less effective for direct pressure insertion of the sensor. Some of the present embodiments provide solutions to these problems, including methods for applying a film to a sharp tip without damaging the tip, while maintaining the integrity of the tip.

[0402] 52A corresponds to another process for making a sensor configured for direct push insertion according to this embodiment. Sensor 1269 includes a core wire 1271 and an electrically insulating layer 1273 over core wire 1271. Insulating layer 1273 includes a gap 1275 that exposes a portion of core wire 1271 just proximal to distal tip 1277. Conductive layer 1279 is disposed over insulating layer 1273 proximal to, but not distal to, gap 1275. Conductive layer 1279 may include, for example, without limitation, silver chloride. A film coating 1281 covers conductive layer 1279, the exposed portion of core wire 1271, and the portion of insulating layer 1273 distal to gap 1275. Distal tip 1277 of core wire 1271 is sharpened prior to application of film coating 1281.

[0403] 53 corresponds to another process for fabricating a sensor configured for direct pressure insertion according to this embodiment. Sensor 1272 includes a sensor body 1274 having a core 1276 and an outer layer 1278, and a membrane 1280 applied over outer layer 1278 but not over core 1276. Core 1276 and outer layer 1278 include different materials. Core 1276 includes a material that is sufficiently rigid to form a piercing tip 1282 and may also include a material that does not necessarily adhere well to (or even repel) membrane 1280. For example, the material of core 1276 may have a low surface energy and may be non-wettable. In contrast, outer layer 1278 includes a material to which membrane 1280 readily adheres.

[0404] Exemplary materials for the core 1276 include, without limitation, stainless steel, titanium, tantalum, and / or polymers, and the first layer may include platinum, platinum-iridium, gold, palladium, iridium, graphite, carbon, conductive polymers, and / or alloys. Alternatively, the core 1276 may include a material that has been pre-treated or coated with another material that repels the coating of the membrane 1280. Exemplary materials for the pre-treated core 1276 include, without limitation, materials that prevent the formation of a thin film, such as polytetrafluoroethylene. Pre-treatment may include, for example, without limitation, manipulating the surface of the core 1276 to promote the rupture of a thin film. Alternatively, pre-treatment may include coating with a hydrophobic material (e.g., a superhydrophobic material) if the portion of the coated membrane that is initially coated is hydrophilic, or, conversely, coating with a hydrophilic material (e.g., a superhydrophilic material) if the portion of the coated membrane that is initially coated is hydrophobic. The hydrophobicity of a surface can be measured by its contact angle with water. The larger the water contact angle, the more hydrophobic the surface. Generally, a surface is considered hydrophilic if the water contact angle is less than 90°, and hydrophobic if the water contact angle is greater than 90°. In some embodiments, the surface of pre-treated core 1276 is hydrophobic, having a contact angle greater than about 120°, sometimes greater than about 135°, and sometimes greater than about 160°. In some embodiments, the surface of pre-treated core 1276 is hydrophilic, having a contact angle less than about 60°, sometimes less than about 45°, and sometimes less than about 30°.

[0405] Exemplary membrane materials include, but are not limited to, any material that can be used to form a membrane on an analyte sensor. Membrane materials that can be used include, but are not limited to, those described in U.S. Patent Publication No. 2009-0247856-A1, which is incorporated herein by reference in its entirety. The membranes described in U.S. Patent Publication No. 2009-0247856-A1 can also be used to form a membrane on any of the sensors described herein.

[0406] In a process corresponding to FIG. 53 , the outer layer 1278 and / or film 1280 may be applied to the core 1276 or sensor body 1274 by any of a variety of coating techniques, such as dipping, spraying, electrodeposition, immersion, casting, or a combination of these techniques. In some embodiments, the core 1276 may progress through a series of stations by any of a variety of other transport mechanisms, such as, for example, a robotic system, a conveyor system, and other similar systems. These other transport mechanisms may be used in combination with (or as an alternative to) a reel-to-reel system. For example, in one embodiment, a reel-to-reel system is used to move the core 1276 in the shape of an elongated object, followed by separation into individual workpieces, and a robotic system is used to move the individual workpieces after the separation process. Processes that can be used to apply the outer layer and / or film include, but are not limited to, those described in, for example, U.S. Patent Publication No. 2011-0027458-A1, which is incorporated herein by reference in its entirety.

[0407] The sharpened distal tip 1282 can be formed by any of a variety of techniques, such as, without limitation, mechanical grinding cutting, diamond wire, high-speed milling, abrasive waterjet cutting, wire or plunge electrical discharge machining, electrochemical etching, electrochemical polishing, electrochemical machining, stamping, laser cutting, or any other method for cutting and / or shaping a workpiece. In one particular embodiment, the sharpened distal tip 1282 is formed by electrochemical grinding, a process that removes conductive material by grinding with a negatively charged grinding wheel, an electrolyte, and a positively charged workpiece (in this case, sensor 1272). The material removed from the workpiece remains in the electrolyte, which can remove any residual coating that may have formed on the surface of the sharpened distal tip. The techniques described above (e.g., electrochemical etching, electrochemical grinding) can also be used to form a sharpened distal tip on any of the sensors described herein.

[0408] 54 and 54A correspond to another process for fabricating a sensor configured for direct pressure insertion according to this embodiment. Sensor 1284 includes a sensor body 1286 and a membrane 1288 applied over sensor body 1286. Referring to FIG. 54A , membrane 1288 includes multiple layers 1290, where the thickness of each layer 1290 is less than the thickness of a typical single-layer membrane, but the thickness of the assembled layers 1290 is substantially equal to the thickness of a typical single-layer membrane. For example, membrane 1288 may include two layers 1290, or three layers 1290, or four layers 1290, or any other number of layers 1290. The thickness of each layer 1290 may be from about 0.5 microns to about 10 microns, sometimes from about 1 micron to about 5 microns, or any other thickness suitable for implantable analyte sensor applications. The thickness of the layers 1290 may vary, where one or more of the layers 1290 may be thicker or thinner than the other layers 1290. In a process corresponding to Figures 54 and 54A, applying the membrane layers 1290 to the sensor body 1286 may include any of a variety of coating techniques, such as, for example, printing, dipping, extrusion, spraying, electrodeposition, casting, or a combination thereof.

[0409] 55 and 56 illustrate another process for fabricating a sensor configured for direct pressure insertion according to the present embodiments. Referring to FIG. 55 , a sensor 1292 includes a sensor body 1294 having a sharpened distal tip 1296. A film 1298 is applied over the sensor body 1294 and tip 1296. Then, referring to FIG. 56 , the film 1298 is removed from the tip 1296 but not from the sensor body 1294. The film 1298 can be removed using any process, such as, without limitation, etching (e.g., dry, wet, reactive ion, and / or chemical etching), laser ablation, mechanical peeling (such as grinding), UV light, or any other process for removing polymeric material from a substrate.

[0410] 57 and 58 illustrate another process for fabricating a sensor 1300 configured for direct pressure insertion according to this embodiment. Referring to FIG. 57 , the sensor 1300 includes a sensor body 1302 having a sharp distal tip 1304. A membrane 1306 is applied over the sensor body 1302 and tip 1304 by immersion in a membrane solution 1308. Due to gravity, the deposited membrane 1306 forms a “bead” in the region of the distal tip 1304. This geometry is typical when membranes are applied by a immersion process, especially when the membrane solution has a certain viscosity. In certain cases, the bead of membrane 1306 material on the distal tip 1304 can disadvantageously dull the tip 1304. 58, the process includes immersing the membrane-coated distal tip 1304 in a solvent 1310 to dissolve the membrane 1306 and substantially remove the membrane 1306 material from the sharp tip 1304 of the sensor 1300. The solvent 1310 may include, for example, without limitation, tetrahydrofuran (THF), dimethylacetamide (DMAC), hexafluoroisopropanol, methylene chloride, methanol, methyl ethyl ketone, toluene, and dimethylformamide. In some embodiments, distal tip beading can also be avoided by removing excess material from the tip before solidifying by whipping, spraying, etc.

[0411] 59 corresponds to another process for fabricating a sensor configured for direct pressure insertion according to this embodiment. Sensor 1312 includes a sensor body 1314 with a sharpened distal tip 1316. A membrane 1318 is applied over the sensor body 1314 and tip 1316 by immersion in a membrane solution (not shown). Then, before the membrane solution dries, tip 1316 is immersed in a release agent 1320 that prevents the membrane 1318 from adhering to tip 1316. The release agent 1320 may include, for example, without limitation, silicone, petroleum-based oil, fluorinated compounds (e.g., tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer or perfluoroalkoxy), polytetrafluoroethylene, polyimide, polyetherimide, polyether sulfide, glycerin, etc.

[0412] 60 corresponds to another process for fabricating a sensor configured for direct pressure insertion according to the present embodiment. The sensor 1322 includes a sensor body 1324 having a sharpened distal tip 1326. The sharpened tip 1326 is coated with a sacrificial material 1328 that protects the tip 1326 during the subsequent step of applying a membrane 1330 to the sensor 1322, as described below, and is then removed. The sacrificial material 1328 can be any of a variety of materials that allow for simple removal. In certain embodiments, the sacrificial layer can be light-sensitive, heat-sensitive, soluble, and / or pH-sensitive, etc.

[0413] In any of the processes described herein for creating a sharp tip at the distal end of a fine sensor wire, including but not limited to the process described in the preceding paragraph, the sensor wire can be embedded in a sacrificial layer prior to any step of removing material from the wire (e.g., grinding, laser cutting, etc.). The sacrificial layer can increase the strength of the wire material, thereby increasing the effectiveness of the material removal process by reducing the likelihood of the wire breaking during the material removal process. Examples of sacrificial layer materials suitable for use in the process of FIG. 60 include, but are not limited to, sugars, salts, degradable polymers, and waxes.

[0414] After the sacrificial layer 1328 is applied to the sharp distal tip 1326 of the sensor 1322, the film 1330 is applied to the sensor 1322. The use of a sacrificial layer allows for simplified application of the film, such that the film 1330 may cover not only the sensor 1324 but also the distal tip 1326 during the application process. The distal tip 1326 may then be treated to destroy and / or remove the sacrificial layer, thereby facilitating removal of the film 1330 from the sharp distal tip 1326 without damaging the tip 1326. The type of treatment after applying the film depends on the type of sacrificial material(s) used, but may include, for example, without limitation, application of light, heat, solvents, and / or combinations thereof.

[0415] In another process, the membrane may be applied to the sensor, including over the sharpened distal tip, without any sacrificial material. The portion of the membrane applied to the distal tip may then be heated until it softens sufficiently so that it can be mechanically removed, for example, by scraping. For example, the softening step may include melting the membrane.

[0416] 61 and 62 illustrate another process for making a sensor configured for direct pressure insertion according to this embodiment. The sensor 1332 includes a sensor body 1334 with a sharpened distal tip 1336. In a typical dipping process for applying the membrane 1338, the sensor 1332 is dipped vertically with the distal tip 1336 facing downward, as shown in FIG. 61. As the membrane solution 1338 dries with the distal tip 1336 facing downward, gravity pulls the membrane 1338 solution downward, resulting in the formation of beads. The beads blunt the distal tip 1336, making the tip less effective at penetrating skin and / or tissue.

[0417] The process corresponding to FIG. 62 solves this problem by using gravity to mitigate the possibility of beading. Referring to FIG. 62 , after immersion in membrane solution 1338 and before the solution dries, sensor 1332 is inverted so that sharp tip 1336 faces upward. In this orientation, gravity pulls membrane solution 1338 away from tip 1336, thereby reducing the possibility of beading. Instead, membrane 1338 is more evenly distributed across the distal end of sensor 1332, as shown in FIG. 62 , maintaining a sharp distal tip 1336. In an alternative process, sensor 1332 may be rotated about an axis perpendicular to the longitudinal axis of sensor 1332 while membrane solution 1338 dries, allowing centripetal force to pull membrane 1338 away from tip 1336. In the process of rotating sensor 1332, sensor 1332 may be oriented horizontally, for example.

[0418] 63 illustrates another process for making a sensor configured for direct pressure insertion according to this embodiment. Sensor 1340 includes a sensor body 1342 having a sharp distal tip 1344. When sensor 1340 is immersed in membrane solution 1346, it is inverted so that the sharp tip 1344 faces upward. Sensor 1340 is only partially immersed, so that the membrane solution 1346 never comes into contact with the sharp tip 1344. Sensor 1340 is then removed from membrane solution 1346 and allowed to dry. Because the membrane solution 1346 never comes into contact with the sharp tip 1344, the sharpness of the tip 1344 is maintained.

[0419] FIG. 64 illustrates another process for fabricating a sensor configured for direct pressure insertion, according to the present embodiment. The sensor 1348 includes a sensor body 1350 having a sharp distal tip 1352. Just proximal to the tip 1352, an annular channel 1354 or depression is formed in the sensor body 1350. In some embodiments, a band of material is removed from the sensor 1348 to form the annular channel 1354 or depression. However, in other embodiments, the annular channel 1354 or depression may be formed by any of a variety of processes used to change the shape of a wire, such as, but not limited to, etching, skiving, grinding, or stamping. The distal end of the channel 1354 defines an edge 1356. When the sensor 1348 is subsequently immersed in a membrane solution, the edge 1356 causes the liquid meniscus of the membrane solution to break, thereby leaving the tip 1352 of the sensor 1348 uncovered by the membrane 1360. Advantageously, membrane 1360 does not dull sharp tip 1352 .

[0420] One aspect of the present embodiments includes the recognition that forming a sharp distal tip on a sensor presents challenges, such as membrane surface contamination and / or membrane damage, which can prevent the membrane from functioning properly. Membrane contamination can alter membrane properties, such as diffusion. For example, contamination can reduce the membrane's permeability properties (e.g., permselectivity). Damage to the membrane can also affect sensor functionality. For example, if membrane removal extends beyond the distal tip into portions intended to cover the electroactive surfaces forming the electrodes, the sensor's diffusion properties can be substantially altered and uncontrollable, rendering the sensor defective. On the other hand, if excess membrane material is present at the sensor's distal tip, the sensor's distal tip can become blunt and less effective at penetrating skin and / or tissue. Some of the present embodiments include solutions to these problems, including methods of forming a sharp distal tip by removing material from the tip and methods of forming a sharp distal tip by adding material to the tip.

[0421] 65-67 illustrate another process for fabricating a sensor configured for direct pressure insertion according to the present embodiments. Referring to FIG. 65, sensor 1362 includes a sensor body 1364 having a core 1366 and an outer layer 1368. Core 1366 may include, for example, without limitation, tantalum or any other material. Outer layer 1368 may include, for example, without limitation, platinum or any other material.

[0422] A first portion or band 1370 and a second portion or band 1372 of the outer layer 1368 are removed to expose the core 1366. The first band 1370 of removed material is located at a distal tip 1374 of the sensor body 1364, and the second band 1372 is located proximal to the distal tip 1374. The first and second bands 1370, 1372 can be removed using any process, such as skiving, etching, grinding, stamping, or any other process. A portion of the core 1366 is also removed at the tip 1374 to form a sharp distal tip 1374. The core 1366 material can be removed using any process.

[0423] 66, a cap 1376 is attached over the distal tip 1374 of the sensor 1362. The attached cap 1376 includes a sharpened distal end and extends over the exposed portion of the core 1366, leaving a portion 1378 of the core 1366 proximal to the cap 1376 exposed. The cap 1376 may include an absorbable material such that the cap 1376 dissolves or is absorbed by the host's body after the sensor 1362 is inserted into the host's skin and / or tissue. Materials for the cap 1376 may include soluble polymers, such as, but not limited to, degradable polymers including polyvinyl-pyrrolidone (PVP), polymeric sugars such as caramel, polyvinyl acetate, polyethylene glycol, polyesters, polyamino acids, polycarbonates, polyanhydrides, polylactic acid, polyglycolic acid, polydioxanone, polyhydroxybutyric acid, polyhydroxyvaleric acid, polycaprolactone, polyanhydrides (e.g., aliphatic polyanhydrides in the backbone or side chains, or aromatic polyanhydrides with benzene in the side chains), polyorthoesters, polyamino acids (e.g., poly-L-lysine, polyglutamic acid), pseudopolyamino acids (e.g., polyamino acids with modified backbones), polycyanoacrylates, polyphosphazenes, and combinations or copolymers of these and other similar polymers.

[0424] 67 illustrates an alternative configuration of cap 1376′ in which cap 1376′ extends further proximally along sensor 1362. For example, cap 1376′ can extend proximally enough to cover at least a portion of outer layer 1368 proximal to the area where second band 1372 of outer layer 1368 is removed.

[0425] In some embodiments, an elongated object (e.g., a wire) in its former form as individual workpieces corresponding to individual sensor elements is exposed to an agent that deactivates catalytic sites (e.g., enzyme domains). The deactivating agent can be in any of a variety of forms, such as a liquid or vapor. For example, in the process corresponding to FIG. 68, wire stock 1380 is exposed to vapor 1382 (e.g., cyanoacrylate) during severing (i.e., the process of cutting the wire stock into individual workpieces corresponding to sensor elements). The vapor 1382 deactivates the catalytic sites at the sensor tip, thereby solving the problem of a high baseline signal from the exposed metal at the tip. The process of FIG. 68 is advantageously suitable for continuous reel-to-reel processing, although this is not required.

[0426] Various processes are contemplated for creating a sharp tip at the distal end of a fine sensor wire. For example, the distal end of the sensor wire may be ground, or laser cut / laser ablated, or milled, or thermoformed (especially for plastic materials), or treated according to any other technique(s) that can be used to sharpen the distal tip. Various processes for creating a sharp tip may result in various tip shapes, such as, without limitation, a bevel (similar to a hypodermic needle profile), a conical shape (similar to a pencil point), or a stepped shape (similar to an acupuncture needle).

[0427] FIG. 69 corresponds to another process for making a sensor configured for direct push insertion according to the present embodiment. In the process corresponding to FIG. 69 , the distal end 1384 of a sensor wire 1386 is dipped into a chemical 1388 to remove material from the end of the wire 1386 and form a sharp tip 1390. The chemical 1388 in which the wire 1386 is dipped can be, for example, an etchant, such as an acid, or an abrasive. In an alternative embodiment, material may be removed from the end of the wire 1386 by electropolishing. In a further embodiment, material may be mechanically removed, for example, by mechanical scraping or mechanical polishing. Referring back to FIG. 69 , the process illustrated therein can be advantageous for forming tips on very fine, flexible wires that may not work well with more traditional processes, such as grinding, to form sharp tips.

[0428] FIG. 70 corresponds to another process for fabricating a sensor configured for direct push insertion according to this embodiment. In the process of FIG. 70 , the distal end 1392 of the sensor wire 1394 is drawn across the polishing surface 1396 while the sensor wire 1394 is held at an angle Θ between 0° and 90° relative to the polishing surface 1396. For example, Θ may be between about 15° and about 55°, sometimes between about 15° and about 30°, and other times between about 30° and about 45°, or any other suitable angle. The wire 1394 may be held in a support fixture (not shown) as it is moved relative to the polishing surface 1396. Alternatively, the wire 1394 may remain stationary and the polishing surface 1396 may be moved relative to the wire 1394. The process of FIG. 70 results in, for example, a wedge-shaped tip 1398 having a flat bevel 1400 on the distal end 1392 of the wire 1394. A wedge-shaped tip 1398 may be simpler and / or less expensive to fabricate than a multi-faceted (eg, pyramidal) or conical point.

[0429] 70, the support fixture for holding the wire 1394 may comprise a block having a small hole for receiving the wire 1394, with the longitudinal axis of the hole oriented at an angle Θ relative to the polishing surface 1396. In another alternative, the wire 1394 may be held between two flat blocks cut at an angle Θ relative to the polishing surface 1396.

[0430] FIG. 71 corresponds to another process for fabricating a sensor configured for direct push insertion according to this embodiment. In FIG. 71 , a sensor wire 1402 includes an inner core 1404 and an outer layer 1406. The inner core 1404 has a very small diameter, for example, less than about 400 μm, less than about 200 μm, or less than about 100 μm. In the process of FIG. 71 , a portion of the outer layer 1406 at the distal end of the sensor wire 1402 is removed from the inner core 1404, exposing a short length 1408 of the inner core 1404 only at the distal end. The exposed length 1408 of the inner core 1404 has a sufficiently small diameter that it can penetrate skin and / or tissue. The exposed portion 1408 of the inner core 1404 is preferably long enough to penetrate the host to the desired depth, but preferably as short as possible to achieve the desired depth, so that the outer layer 1406 provides support to the exposed portion 1408 of the inner core 1404 to increase the column strength of the exposed portion 1408. The outer layer 1406 can be removed from the inner core 1404 using any process, such as peeling, laser ablation, bead blasting, polishing, chemical etching, or any other process.

[0431] Some of the present processes for forming the sensor wire add material to the sensor wire to form a sharpened distal tip. For example, FIGS. 72 and 73 illustrate another process for making a sensor configured for direct push insertion according to the present embodiments. Referring to FIG. 72 , a sensor wire 1410 is immersed in a bath of polymer material 1412. The polymer material 1412 may include, for example, without limitation, conductive polymers, polyelectrolytes, zwitterionic polymers, etc. After removing the sensor from the bath, a voltage is applied across the polymer material 1412, as shown in FIG. 73 . The voltage causes the polymer material 1412 to elongate, forming a sharpened tip 1414.

[0432] For example, the processes in Figures 72 and 73 may involve electrospinning. In electrospinning, when a sufficiently high voltage is applied to a droplet, the liquid becomes charged, and electrostatic repulsion counters surface tension, causing the droplet to spread. At a critical point, a liquid stream ejects from the surface. This ejection point is known as a Taylor cone. If the liquid's molecular cohesion is sufficiently high, the stream does not break up (in which case the droplets are electrosprayed), and a charged liquid jet is formed. As the jet dries in air, the current flow regime changes from ohmic to convective as charge transfers to the surface of the fiber. The jet is then elongated by a whipping process driven by electrostatic repulsion initiated by a small bend in the fiber until it accumulates on a grounded collector. The resulting elongation and refinement of the fiber due to this bending instability leads to the formation of homogeneous fibers with nanometer-scale diameters.

[0433] 74 and 75 illustrate another process for fabricating a sensor configured for direct push insertion according to the present embodiments. Referring to FIG. 74, a sensor wire 1416 is dipped into a bath 1418 of molten polymer, or a reactive monomer / oligomer mixture, or a dissolved polymer, or a polymer mixture. Referring to FIG. 75, dipping the sensor wire 1416 creates a dip coating 1420 on the portion of the sensor wire 1416 that is immersed in the bath 1418. Referring to FIG. 75, the wire 1416 is withdrawn from the bath 1418, and the dip coating 1420 hardens as the wire 1416 is withdrawn, creating a sharp tip 1422 on the sensor wire 1416. The rate and angle of withdrawal can be controlled to achieve the desired tip shape and sharpness. The tip may then be cooled and hardened, dried and solidified, or hardened by exposure to external radiation, humidity, and / or light. In some embodiments, after the wire 1416 is drawn from a bath 1418 of molten polymer, the tip 1422 is placed in a mold to create a sharp tip 1422 .

[0434] FIG. 76 illustrates another process for fabricating a sensor configured for direct push insertion according to this embodiment. In the process of FIG. 76, a sensor wire 1424 includes a sensor body 1426 and a membrane 1428 covering at least a portion of the sensor body 1426. A hard, sharp tip 1430 is affixed to the membrane-covered sensor wire 1424. For example, the tip 1430 may be cast into the wire 1424 using a mold 1432. If the tip 1430 is a moldable material, such as a thermoplastic, the tip 1430 may be injection molded or insert molded to secure it to the sensor body 1426. To avoid exposing the membrane to high temperatures, other curable materials, such as two-part polyurethane, may be used in a low-temperature liquid injection molding (LIM) process.

[0435] In any of the embodiments described herein, the distal tip of the sensor processing element can be shaped by press forming. For example, in the embodiment illustrated in FIG. 76A, the sensor processing element 1431 is first introduced into a station for press forming. The shaping element 1433 is then moved from an extended position ( FIG. 76A ) to a retracted position ( FIG. 76B ), thereby shaping the distal end of the processing element 1431 into the desired shape. FIG. 76B illustrates a cross-section of a portion of the sensor processing element 1431 that has been shaped by the shaping element 1433 and is proximal to the portion illustrated in FIG. 76C , which is proximal to the distal tip illustrated in FIG. 76D , which has a cross-section that has nearly zero area and forms a sharp tip. 76A-76D, there are two shaping elements 1433 that shape the distal end of the working member 1431 into a conical shape with a circular cross-section. However, in other embodiments, there may be any number of shaping elements, such as three, four, five, nine, ten, or more. Additionally, the shaping elements 1433 may be configured to shape the distal end into any of a variety of shapes, such as a triangle, rectangle, square, pentagon, or hexagon.

[0436] Figures 77 and 78 illustrate another process for fabricating a sensor configured for direct pressure insertion according to the present embodiment. Figure 77 is a top plan view, and Figure 78 is a side view. Referring to Figures 77 and 78, this process includes a planar flexible printed circuit board (PCB) 1434 embedded in an outer core 1436. In the illustrated embodiment, the outer core 1436 is substantially cylindrical and includes a conical distal tip 1438 configured to penetrate skin and / or tissue. However, the illustrated shape is by way of example only and is not limiting. The outer core 1436 may comprise any material, such as a polymer.

[0437] 77 and 78 , a section of the outer core 1436 proximal to the conical tip 1438 is removed to form a window 1440. For example, the section of the outer core 1436 may be removed by laser ablation or any other process described herein or elsewhere for removing material from a workpiece. In one embodiment, the outer surface of the PCB 534 includes a platinum layer that is resistant to laser ablation. Thus, when the section of the outer core 1436 is removed by laser ablation, the portion of the PCB 1434 underlying the window 1440 remains intact. The sensor 1442 is then immersed in a membrane solution. The membrane 1444 covers the exposed platinum surface of the PCB 1434 within the window 1440, which defines the working electrode of the final sensor 1442.

[0438] FIG. 79 illustrates another process for making a sensor configured for direct pressure insertion according to this embodiment. The sensor 1446 includes a sensor body 1448 with a blunt distal end 1450. A piercing tip 1452 is located on the distal end 1450. The tip 1452 includes an open proximal end 1454 that receives the distal end 1450 of the sensor body 1448. The proximal end 1454 of the piercing tip 1452 is then crimped to secure the tip 1452 to the sensor body 1448. In some embodiments, a membrane is applied before crimping the sensor body 1448 onto the tip 1452. In other embodiments, the membrane is applied after crimping the sensor body 1448 onto the tip 1452. In a further embodiment, the sensor 1446 is immersed upside down (i.e., tip 1452 facing up) so that the solution never contacts the tip. This process avoids the possibility of the membrane adhering to the tip (and dulling the tip).

[0439] In another embodiment, the piercing tip may be overmolded onto the distal end of the sensor body. The overmolded tip may comprise a rigid polymer such as, for example, but not limited to, a two-part polyurethane. The rigid tip may be overmolded onto the distal end of the sensor body after the membrane has been applied to the sensor body.

[0440] Another aspect of the present embodiments includes the recognition that forming three electrodes on an analyte sensor is difficult. For example, applying a third layer to the sensor wire significantly complicates the wire manufacturing process, making it very difficult to achieve concentricity for all layers. If all layers are not concentric, further processing steps, such as skiving, can be difficult to perform with the desired precision. Furthermore, the tip of the sensor can reduce the accuracy of the sensor if the conductive material and / or enzyme(s) at the tip are exposed to the environment. Some of the present embodiments provide solutions to these problems.

[0441] For example, Figures 80 and 81 illustrate another process for fabricating a sensor configured for direct pressure insertion according to the present embodiment. Referring to Figure 80, sensor 1456 includes a thin, flat micro-electromechanical systems (MEMS) substrate 1458. For example, MEMS substrate 1458 can be fabricated using photolithography, etching, and / or other MEMS processes.

[0442] The distal end of the substrate includes a tapered piercing tip 1460. An electroactive surface or electrode 1457 is printed on the MEMS substrate 1458. Conductive traces 1459 provide electrical connection between the electrode 1457 and electrical contacts (not shown) of the sensor 1456. Referring to FIG. 81 , the substrate 1458 is coated with a membrane 1462. For example, the membrane coating 1462 is applied in a dip coating process to provide a conformal coating. In the illustrated embodiment, the membrane coating 1462 is substantially cylindrical and covers the piercing tip 1460 of the substrate 1458.

[0443] The process illustrated in Figures 80 and 81 advantageously utilizes the benefits of both MEMS processing and dip coating to obtain a cylindrical, direct-pressure insertion sensor with three electrodes. Using MEMS technology, all three electrodes can be easily fabricated on a flat, flexible substrate 1458. For example, the working electrode (and possibly other electrodes) can be on the top and bottom surfaces of the substrate 1458 for averaging purposes. The substrate 1458 with the electrodes is then immersed in a hardening film solution to obtain a cylindrical membrane coating 1462. The membrane 1462 can be, for example, a shape-memory material and / or a heat / hydration softening material. While the membrane coating 1462 need not be cylindrical, a cylindrical membrane coating advantageously allows for radial diffusion of the analyte, which is beneficial because radial diffusion promotes more rapid mass transfer and shorter response times to achieve steady state. Additionally, the MEMS substrate 1458 can be inert, thereby eliminating tip robustness issues.

[0444] One aspect of this embodiment includes the recognition that the piercing tip may be formed on the sensor during the step of separating the sensor wire into individual sensors. For example, the separation process may include, without limitation, mechanical pressing, hot pressing, laser ablation, extrusion, cutting, etc. By forming the piercing tip during separation, a sharp distal tip may be formed before applying the membrane to the sensor, thereby avoiding cross-contamination and damage to the delicate membrane from subsequent tip formation steps.

[0445] For example, Figure 82 illustrates another process for fabricating a sensor configured for direct pressure insertion, according to this embodiment. Forming a sensor tip configured to penetrate skin and / or tissue can be difficult with certain materials. Typical processes, such as grinding, are not suitable for materials such as aluminum and tantalum. Figure 82 illustrates an alternative process in which the sensor is pulled to form a sharp tip.

[0446] Generally, when a strip of material is placed under tension along its longitudinal axis and stretched beyond its elastic limit, plastic deformation begins. Depending on the material's properties, the material may "neck." Necking is a localized concentration of strain that occurs when the cross-sectional area of ​​the material increases and the stress in the reduced cross section simultaneously increases. Necking rapidly increases the rate of deformation in the region of the reduced cross section. From that point on, all further deformation is concentrated in the necked region. In practice, in a sample with a circular cross section, necking results in a localized diameter reduction. Eventually, the sample breaks at or near the center of the necked section. This break results in two "half necks," each containing a sharp point that can be used to form the penetration tip of a sensor.

[0447] According to the process described above and with reference to FIG. 82, the sensor wire 1470 is aligned along its longitudinal axis A L The sensor wire 1470 is under tension along the length of the sensor wire 1470. The sensor wire 1470 necks at the mid-region 1472. After breaking, two sensors are formed with sharpened piercing tips. The piercing tips may be further processed, such as removed, ground, or further sharpened.

[0448] In one alternative, a portion of the sensor wire 1470 may be heated before and / or during the tensioning process, as shown in Fig. 83. For example, heat may be applied using a resistive heating element 1474, a flame, or any other heat source. The applied heat softens the wire material, making the heated region 1476 more susceptible to necking and breakage.

[0449] In one alternative, after tension is applied to the sensor wire so that necking begins to occur, but before breakage, the tension may be released and the two portions of the sensor wire on either side of the necking region may be separated by any process, such as shearing, cutting, laser ablation, etc.

[0450] 84-86 illustrate another process for fabricating a sensor configured for direct pressure insertion according to this embodiment. Referring to FIG. 84, a sensor wire 1478 is positioned between opposing cutting blades 1480. The cutting blades 1480 separate the sensor wire 1478 into small pieces, each of which is subsequently processed to yield a sensor. FIG. 84 illustrates a first embodiment of a cutting blade 1480 in solid lines and a second embodiment of a cutting blade 1480′ in dashed lines. In the solid embodiment 1480, each blade 1480 includes a cutting edge defined by converging surfaces 1482 at a first angle Φ1. In the dashed embodiment, each blade 1480′ includes a cutting edge defined by converging surfaces 1484 at a second angle Φ2, where Φ2 > Φ1. Figure 85 illustrates the shape of the cut 1486 made in the sensor wire 1478 by the blade 1480 of the solid embodiment, and Figure 86 illustrates the shape of the cut 1486' made in the sensor wire 1478' by the blade 1480' of the dashed embodiment. Because Φ > Φ, the cut 1486' made in the sensor wire 1478' by the blade 1480' of the dashed embodiment has a smaller angle Φ defined between the converging surfaces of the piercing tip 1488' of the sensor wire 1490' of Figure 86 compared to the angle Φ defined between the converging surfaces of the piercing tip 1488 of the sensor wire 1490 of Figure 85. The smaller angle Φ advantageously results in a sharper tip for the sensor wire 1490' of Figure 86 compared to the sensor wire 1490 of Figure 85. Thus, a sharper piercing tip can be achieved by using the blade 1480' of the dashed embodiment of Figure 84.

[0451] Suitable methods and devices for use in conjunction with aspects of the preferred embodiments are disclosed in U.S. Patent Nos. 4,757,022, 4,994,167, 6,001,067, 6,558,321, 6,702,857, 6,741,877, 6,862,465, 6,931,327, 7,074,307, 7,081,195, 7,108,778, 7,110,803, 7,134,999, 7,115,109, and 7,121,114. 36,689, U.S. Patent No. 7,192,450, U.S. Patent No. 7,226,978, U.S. Patent No. 7,276,029, U.S. Patent No. 7,310,544, U.S. Patent No. 7,364,592, U.S. Patent No. 7,366,556, U.S. Patent No. 7,379,765, U.S. Patent No. 7,424,318, U.S. Patent No. 7,460,898, U.S. Patent No. 7,467,003, U.S. Patent No. 7,471,972, U.S. Patent No. 7,494,465, U.S. Patent No. 7,497,827, U.S. Patent No. 7,519,408, U.S. Patent No. 7,583,990, U.S. Patent Nos. 7,591,801, 7,599,726, 7,613,491, 7,615,007, 7,632,228, 7,637,868, 7,640,048, 7,651,596, 7,654,956, 7,657,297, 7,711,402, 7,713,574, 7,715,893, 7,761,130, 7,771,352, 7,774,1 45, U.S. Patent No. 7,775,975, U.S. Patent No. 7,778,680, U.S. Patent No. 7,783,333, U.S. Patent No. 7,792,562, U.S. Patent No. 7,797,028, U.S. Patent No. 7,826,981, U.S. Patent No. 7,828,728, U.S. Patent No. 7,831,287, U.S. Patent No. 7,835,777, U.S. Patent No. 7,857,760, U.S. Patent No. 7,860,545, U.S. Patent No. 7,875,293, U.S. Patent No. 7,881,763, U.S. Patent No. 7,885,697, U.S. Patent No. 7,896,809, U.S. Patent No.899,511, U.S. Patent No. 7,901,354, U.S. Patent No. 7,905,833, U.S. Patent No. 7,914,450, U.S. Patent No. 7,917,186, U.S. Patent No. 7,920,906, U.S. Patent No. 7,925,321, U.S. Patent No. 7,927,274, U.S. Patent No. 7,933,639, U.S. Patent No. 7,935,057, U.S. Patent No. 7,946,984, U.S. Patent No. 7,949,381, U.S. Patent No. 7,955,261, U.S. Patent No. 7,959,569, U.S. Patent No. 7,970,448, U.S. Patent No. 7,974,672, U.S. Patent No. 7,976,492, U.S. Patent No. 7,979,104, U.S. Patent No. 7,986,986, U.S. Patent No. 7,998,071, U.S. Patent No. 8,000,901, U.S. Patent No. 8,005,524, U.S. Patent No. 8,005,525, U.S. Patent No. 8,010,174, U.S. Patent No. 8,027,708, U.S. Patent No. 8,050,731, U.S. Patent No. 8,052,601, U.S. Patent No. 8,053,018, U.S. Patent No. 8,060,173, U.S. Patent No. 8,064,977, U.S. Patent No. 8,070,079 3,519, U.S. Patent No. 8,073,520, U.S. Patent No. 8,118,877, U.S. Patent No. 8,128,562, U.S. Patent No. 8,133,178, U.S. Patent No. 8,150,488, U.S. Patent No. 8,155,723, U.S. Patent No. 8,160,669, U.S. Patent No. 8,160,671, U.S. Patent No. 8,167,801, U.S. Patent No. 8,170,803, U.S. Patent No. 8,195,265, U.S. Patent No. 8,206,297, U.S. Patent No. 8,216,139, U.S. Patent No. 8,229,534, U.S. Patent No. 8,229,535, U.S. Patent Nos. 8,229,536, 8,231,531, 8,233,958, 8,233,959, 8,249,684, 8,251,906, 8,255,030, 8,255,032, 8,255,033, 8,257,259, 8,260,393, 8,265,725, 8,275,437, 8,275,438, 8,277,713, 8,280,475, U.S. Patent No. 8,282,549, U.S. Patent No. 8,282,550, U.S. Patent No. 8,285,354, U.S. Patent No. 8,287,453, U.S. Patent No. 8,290,559, U.S. Patent No. 8,290,560, U.S. Patent No. 8,290,561, U.S. Patent No. 8,290,562, U.S. Patent No. 8,292,810, U.S. Patent No. 8,298,142, U.S. and U.S. Patent Nos. 8,311,749, 8,313,434, 8,321,149, 8,332,008, 8,346,338, 8,364,229, 8,369,919, 8,374,667, 8,386,004, and 8,394,021.

[0452] Suitable methods and devices for use in conjunction with aspects of the preferred embodiments include those disclosed in U.S. Patent Publication Nos. 2003-0032874-A1, 2005-0033132-A1, 2005-0051427-A1, 2005-0090607-A1, 2005-0176136-A1, 2005-0245799-A1, 2006-0015020-A1, 2006-0016700-A1, and 2006-0020188-A1. 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[0453] Suitable methods and devices for use in conjunction with aspects of the preferred embodiments include those described in U.S. application Ser. No. 09 / 447,227, entitled "DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS," filed Nov. 22, 1999; U.S. application Ser. No. 12 / 828,967, entitled "HOUSING FOR AN INTRAVASCULAR SENSOR," filed July 1, 2010; U.S. application Ser. No. 13 / 461,625, entitled "DUAL ELECTRODE SYSTEM FOR A CONTINUOUS ANALYTE SENSOR," filed May 1, 2012; U.S. application Ser. No. 13 / 594,602, entitled "POLYMER MEMBRANES FOR CONTINUOUS ANALYTE SENSORS," filed Aug. 24, 2012; U.S. application Ser. No. 13 / 594,602, entitled "POLYMER MEMBRANES FOR CONTINUOUS ANALYTE SENSORS," filed Aug. 24, 2012; U.S. application Ser. No. 13 / 594,734 entitled "ANALYTE SENSORS," filed on September 7, 2012; U.S. application Ser. No. 13 / 607,162 entitled "SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR DATA FOR SENSOR CALIBRATION," filed on September 7, 2012; U.S. application Ser. No. 13 / 624,727 entitled "SYSTEMS AND METHODS FOR PROCESSING AND TRANSMITTING SENSOR DATA," filed on September 21, 2012; U.S. application Ser. No. 13 / 624,808 entitled "SYSTEMS AND METHODS FOR PROCESSING AND TRANSMITTING SENSOR DATA," filed on September 21, 2012; U.S. application Ser. No. 13 / 624,808 entitled "SYSTEMS AND METHODS FOR PROCESSING AND TRANSMITTING SENSOR DATA," filed on September 21, 2012;No. 812, entitled "Analyte Sensors Having a Signal-to-Noise Ratio Substantially Unaffected by Non-Constant Noise," filed January 2, 2013; U.S. Application No. 13 / 732,848, entitled "End of Life Detection for Analyte Sensors," filed January 3, 2013; U.S. Application No. 13 / 733,742, entitled "Outlier Detection for Analyte Sensors," filed January 3, 2013; U.S. Application No. 13 / 742,178, entitled "Systems and Methods for Processing Sensor Data," filed January 15, 2013; U.S. Application No. 13 / 742,178, entitled "Systems and Methods for Processing Sensor Data," filed January 16, 2013; No. 13 / 742,694, entitled "SYSTEMS AND METHODS FOR DYNAMICALLY AND INTELLIGENTLY MONITORING A HOST'S GLYCEMIC CONDITION AFTER AN ALERT IS TRIGGERED," filed January 16, 2013; and U.S. Application No. 13 / 747,746, entitled "DEVICES, SYSTEMS, AND METHODS TO COMPENSATE FOR EFFECTS OF TEMPERATURE ON IMPLANTABLE SENSORS," filed January 23, 2013.

[0454] The foregoing description sets forth the best mode contemplated for carrying out this invention, and the best mode of the means and process for making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains to make and use it. The invention is, however, susceptible to variations and alternative constructions from those described above, which are fully equivalents. Consequently, the invention is not limited to the particular embodiments disclosed. On the contrary, the invention covers all variations and alternative constructions included within the spirit and scope of the invention, which is broadly set forth in the following claims, which particularly point out and distinctly claim the subject matter of the invention. While the present disclosure has been illustrated and described in detail in the drawings and foregoing description, such illustration and description is illustrative or exemplary and is not to be considered restrictive.

[0455] All references cited herein are incorporated by reference in their entirety. To the extent that publications and patents or patent applications incorporated by reference conflict with the present disclosure contained herein, the present specification is intended to supersede and / or precede any such conflicting material.

[0456] Unless otherwise defined, all terms (including technical and scientific terms) shall be given their ordinary and customary meaning to those of ordinary skill in the art and shall not be limited to any special or customized meaning unless expressly defined herein. It should be noted that the use of a particular term in describing a particular feature or aspect of the present disclosure shall not be deemed to imply that the term has been redefined herein to be limited to include any specific characteristics of the feature or aspect of the present disclosure with which the term is associated. Terms and phrases used in this application, and variations thereof, should be considered open-ended as opposed to limiting, unless expressly stated otherwise, particularly in the appended claims.As examples of the foregoing, the term "including" means "including without limitation," "including but not limited to," etc., and the term "comprising," as used herein, is incompatible with "including," "containing," or "characterized by." the term "examples" is used to provide illustrative examples of the items being discussed and is not intended to be exhaustive or limiting of the listing; adjectives such as "known," "conventional," "standard," and similar terms should not be considered to limit the items described to those available at a given time or at a given time, but should be interpreted to encompass known, conventional, or standard technology that may be available or known at any time now or in the future; and terms such as "preferably," "preferred," "desired," or "desirable," and words of similar meaning, should not be understood to imply that a particular feature is critical, essential, or even essential to the structure or function of the invention, but are merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention. Similarly, a group of items connected by the conjunction "and" should not be construed as requiring each and every one of the items to be present in the group, but should be construed as "and / or" unless expressly stated otherwise. Similarly, a group of items connected by the conjunction "or" should not be construed as requiring mutual exclusion between items in the group, but should be construed as "and / or" unless expressly stated otherwise.

[0457] When a range of values ​​is provided, the upper and lower limits, and each intermediate value between the upper and lower limits of the range, are encompassed within that embodiment.

[0458] With respect to the use of substantially all plural and / or singular terms herein, those skilled in the art can convert from plural to singular and / or from singular to plural as appropriate to the situation and / or application. Various singular / plural permutations may be expressly set forth herein for clarity. The indefinite articles "a" or "an" do not exclude plurals. A single processor or other unit may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims shall not be construed as limiting their scope.

[0459] It will be further understood by those skilled in the art that where a specific number of introduced claim recitations are intended, such intent will be expressly recited in the claims and that, absent such recitation, no such intent exists. For example, as an aid to understanding, the claims appended below may include the use of the preambles "at least one" and "one or more" to introduce claim recitations. However, the use of such phrases should not be construed as implying that introducing a claim recitation with the indefinite article "a" or "an" limits any particular claim that includes such an introduced claim recitation to embodiments that include only one such recitation, even when the same claim includes the preface "one or more" or "at least one" and an indefinite article such as "a" or "an" (e.g., "a" and / or "an" should typically be interpreted to mean "at least one" or "one or more"), as is the case with the use of definite articles used to introduce claim recitations. Additionally, even when a specific number of introduced claim recitations is explicitly recited, it will be understood that such a recitation should typically be interpreted to mean at least the recited number (e.g., the bare recitation of "two recitations," without any modifiers, typically means at least two recitations or more than two recitations). Furthermore, in instances where conventional analogies to "at least one of A, B, and C, etc." are used, such limitations are generally intended in the sense that one of ordinary skill in the art would understand the practice (e.g., "a system having at least one of A, B, and C" would include, but is not limited to, systems having A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.).In instances where conventional analogies to "at least one of A, B, or C, etc." are used, such limitation is generally intended in the sense that one of ordinary skill in the art would understand the practice (e.g., "a system having at least one of A, B, or C" would include, but is not limited to, systems having A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those skilled in the art that virtually all disjunctive words and / or phrases expressing two or more alternative terms, whether in the description, claims, or drawings, are understood to contemplate the possibility of including one of those terms, either of those terms, or both terms. For example, the phrase "A or B" will be understood to include the possibilities of "A" or "B" or "A and B."

[0460] All numbers expressing quantities of ingredients, reaction conditions, and so forth should be understood as being modified in all instances by the term "about." Accordingly, unless otherwise indicated, the numerical parameters set forth herein are approximations and may vary depending upon the desired properties sought to be obtained. Finally, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claim in any specification claiming priority to this specification, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

[0461] Moreover, while the foregoing has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be apparent to those skilled in the art that certain changes and modifications may be practiced. Therefore, the descriptions and examples should not be construed as limiting the invention to the specific embodiments and examples described herein, but rather are intended to cover all modifications and alternatives falling within the true scope and spirit of the invention. [Explanation of symbols]

[0462] 100 Sensor Devices 102 Internal body parts 104 Skin 106 External parts 108 Tissue Penetration Element 110 Sensor body 112 Support member 114 Membrane 116 Skin contact type mounting unit 122 Base 124 Adhesive layer 126 Tip 128 Proximal surface 140 membrane 310 Tissue Penetration Element 312 Pocket 314 Sensors 330 Support member 332 depression 334 Window part 400 sensors 408 Soluble tip 412 Sensor body 414 Membrane 418 Tissue fiber coated tip 426 Sensor body tip 500 sensors 502 needles 504 Lumen 506 Dissolved tissue insertion tip 700 Sensor Unit 702 Sensor body 704 Membrane 708 Tip 802 Sensor body 804 Membrane 808 Tip 900 Hardener 902 Membrane 904 Sensor body 906 Sensor Unit 908 Skin 910 Tip 1000 sensors 1002 Conductive core wire 1004 Non-conductive jacket 1006 Conductive components 1008, 1010 electrode 1012 Conductive Trace 1016 Distal end 1020 Sensor 1022, 1024, 1026 electrode 1028 Non-conductive layer 1040 Sensor 1042 Core Wire 1044, 1048 electrode 1046 Base material 1060 Sensor 1062 overlapping area 1064, 1066 Edge 1070 Sensor 1072 Introducer sheath 1074 Membrane 1076 Tissue Penetration Element 1078 Sensor body 1080, 1082 sensors 1084, 1086 Trough 1085 distal end 1088, 1090 outer circumference 1102 Sensor 1104 Protective sheath 1106 Sensor tip 1108 Sensor 1110 through hole 1112 Membrane 1114 Tissue-piercing distal tip 1116 Sensor 1118 hollow 1120 Sensor 1122 depression 1124 Membrane 1126 Outer layer 1128 Sensor 1130 Sensor body 1132 Membrane 1134 Protective outer layer 1136 Tip 1138 Sensor 1140 Outer layer 1142 window 1144 Sensor 1146 Wire 1148 Outer Coating 1150 Window 1152 Membrane 1154 Highly permeable outer layer 1156 Sensor 1158 Membrane 1160 External surface 1161 Membrane 1162 Distal tip 1163 Sensor processing parts 1164 Wire 1165 beads 1166 Membrane 1167 Tip 1168 channels 1170 Tip 1172 Protective outer layer 1174 Wire Stock 1176 Film Coating 1178 reels 1180 Laser 1182 Conductive Wire 1184 Membrane 1186 Distal end 1188 Film-coated wire 1190 Tip 1192 Coating 1194 Sensor Wire 1196 Distal tip 1198 Membrane 1200 distal end 1202 Exposed part 1204 Sensor 1206 Solution 1208 Beads 1210 Distal end 1212 Fibrous body 1214 Wire 1216 Film Coating 1218 Yes 1220 End cap 1224 Wire 1226 Film Coating 1228 Membrane 1230 Rigid Coating 1232 Tip 1234 Sensor 1236 Sensor body 1238 Penetration tip 1240 distal end 1242 proximal end 1244 Membrane 1246 Coating 1248 Retractable introducer sheath 1250 Sensor 1252 Sensor body 1254 Membrane 1256 Tip 1258 Distal end 1260 proximal end 1262 Retractable introducer sheath 1264 Sensor 1266 Sensor body 1268 Membrane 1269 Sensor 1270 Tip 1271 Core Wire 1273 Electrical insulating layer 1277 Distal tip 1275 Gap 1279 Conductive Layer 1280 Membrane 1284 Sensor 1286 Sensor body 1288 Membrane 1290 Multiple Layers 1292 Sensors 1294 Sensor body 1296 Distal tip 1298 Membrane 1300 Sensors 1302 Sensor body 1304 Distal tip 1306 Membrane 1310 Solvent 1312 Sensor 1314 Sensor body 1316 Tip 1320 Stripping agent 1322 Sensor 1324 Sensor body 1326 Tip 1328 Sacrificial Materials 1330 Membrane 1332 Sensor 1334 Sensor body 1336 Distal tip 1338 Membrane 1340 Sensor 1342 Sensor body 1344 Distal tip 1346 Membrane Solution 1348 Sensor 1350 Sensor body 1352 Distal tip 1354 Annular Channel 1356 Edge 1360 Membrane 1362 Sensor 1364 Sensor body 1366 cores 1368 Outer layer 1370, 1372 Obi 1374 Distal tip 1376, 1376' Cap 1380 Wire Stock 1382 above 1384 distal end 1386 Wire 1388 Chemicals 1390 Tip 1394 Sensor Wire 1396 Polished surface 1398 Tip 1400 bevel 1402 Sensor Wire 1404 Inner Core 1406 Outer layer 1408 Exposed part 1410 Sensor Wire 1412 Polymer Materials 1414 Tip 1416 Sensor Wire 1418 tank 1420 Dip Coating 1422 Tip 1424 Sensor Wire 1426 Sensor body 1428 Membrane 1430 Tip 1431 Sensor processing parts 1432 type 1433 Sculptural Elements 1434 PCB 1436 outer core 1438 Tip 1440 Window 1442 Sensor 1444 Membrane 1446 Sensor 1448 Sensor body 1450 distal end 1452 Penetration tip 1454 proximal end 1456 Sensor 1457 Electrode 1458 MEMS substrate 1459 Conductive Trace 1460 Penetration tip 1462 Membrane 1470 Sensor Wire 1472 Intermediate area 1474 Resistance Heating Element 1476 heating area 1478, 1478' sensor wire 1480, 1480' cutting blade 1482, 1484 surface 1486, 1486' cutting section 1488, 1488' Insertion tip 1490, 1490' sensor wire

Claims

1. A sensor device for measuring a concentration of an analyte in a host, the sensor device configured for implantation into the host without the use of an inserter; a sensor unit comprising a sensor body, at least one electrode, and a membrane covering at least a portion of the at least one electrode; a piercing element at a distal end of the sensor unit, the piercing element configured to pierce the skin and / or tissue of the host; a mounting unit spaced from the sensor tip and configured to support the sensor device on an external surface of the host's skin; The sensor device, wherein the sensor body includes a stimulus-responsive material that changes at least one material property in response to a stimulus.

2. The sensor device of claim 1 , wherein the at least one material property is at least one of hardness, shape, permeability, relative hydrophilicity, elastic modulus, or conformation of polymer orientation.

3. The sensor device of claim 2 , wherein the sensor body is rigid outside the body and flexible inside the body.

4. The sensor device of claim 1 , wherein the stimulus that induces the change in the at least one material property is at least one of temperature, hydration, radiation, an electrical stimulus, or a magnetic field.

5. The sensor device of claim 1 , wherein the sensor body is a polymer.

6. The sensor device of claim 5 , wherein the sensor body is polyurethane, polyester, polyamide, polyacrylate, or polyether, or a copolymer thereof.

7. The sensor device of claim 1 , wherein the stimulus-responsive material is a shape memory metal.

8. 8. The sensor device of claim 7, wherein the shape memory metal is copper-aluminum-nickel (Cu-Al-Ni), nickel-titanium (NiTi), iron-manganese-silicon (Fe-Mn-Si), or copper-zinc-aluminum (Cu-Zn-Al).

9. The sensor device of claim 1 , wherein the sensor body defines a first shape prior to insertion into the skin of the host.

10. 10. The sensor device of claim 9, wherein the sensor body defines a memorized shape, and wherein the sensor body returns to the memorized shape after insertion into the skin of the host.

11. The sensor device of claim 10 , wherein the first shape is curved or linear, and the stored shape is curved or linear.

12. The sensor device of claim 10 , wherein stored spring energy is released from the sensor body when the sensor body returns to the memorized shape.

13. 13. The sensor device of claim 12, wherein the released spring energy creates a whipping action that facilitates penetration into the host's skin.

14. 1. A method of making a sensor device configured to be implanted into a host without the use of an inserter, comprising: forming a piercing tip on a sensor unit including a sensor body, at least one electrode, and a membrane covering at least a portion of the at least one electrode; The method, wherein the membrane is applied to the sensor unit prior to forming the piercing tip on the sensor unit.

15. The method of claim 14 further comprising applying the membrane to the sensor unit.

16. 15. The method of claim 14, wherein forming the piercing tip comprises forming an annular channel around the circumference of the film-coated wire.

17. 17. The method of claim 16, wherein the annular channel extends through the membrane and partially into the wire.

18. 17. The method of claim 16, further comprising applying tension to the coated wire.

19. 20. The method of claim 18, wherein the tension induces strain in the wire adjacent the annular channel, causing necking and breakage of the wire.

20. 20. The method of claim 19, wherein the necking forms the piercing tip in the sensor body.

21. 21. The method of claim 20, further comprising coating the piercing tip with a protective outer layer.

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