Sensors and related methods for continuous analyte monitoring

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] Incorporation by Interaction of Related Applications Any claim of priority or any amendment thereto identified in the application data sheet is hereby incorporated by reference into this specification under 37 CFR 1.57. This application claims the benefit of U.S. Application No. 14 / 250,320, filed Apr. 10, 2014, and U.S. Application No. 14 / 250,341, filed Apr. 10, 2014. The foregoing applications are hereby incorporated by reference in their entireties into this specification and are hereby expressly made a part hereof.

[0002] This embodiment relates to systems and methods for measuring the concentration of an analyte in a host.

Background Art

[0003] Diabetes mellitus is a disorder in which the pancreas is unable to produce sufficient insulin (type I or insulin-dependent), and / or insulin is ineffective (type 2 or non-insulin-dependent). In a diabetic state, an affected person suffers from hyperglycemia, which can cause a series of physiological disorders (associated with microvascular deterioration, e.g., renal failure, skin ulcers, or bleeding into the vitreous of the eye). Hypoglycemic reactions (hypoglycemia) can be caused by inadvertent overdosage of insulin, or extreme exercise or inadequate food intake after normal dosing of insulin or glucose-lowering agents.

[0004] Conventionally, a person suffering from diabetes carries a self - monitoring blood glucose (SMBG) monitor, which typically requires an uncomfortable finger prick to obtain a blood sample for measurement. Due to the lack of comfort and convenience associated with finger pricks, a person with diabetes usually measures glucose levels only 2 - 4 times a day. Unfortunately, the measurement intervals can be so far apart that a person with diabetes may be too late to notice a hyperglycemic or hypoglycemic state and may then suffer dangerous side effects. Not only do diabetic patients tend not to obtain SMBG values in a timely manner, but patients also tend not to know whether their blood glucose levels are rising (getting higher) or falling (getting lower) based on conventional methods. Diabetic patients may thus be hindered from making knowledge - based decisions about insulin therapy.

[0005] Another device that diabetic patients use to monitor blood glucose is a continuous analyte sensor. A continuous analyte sensor typically includes a sensor that is placed subcutaneously, transdermally (e.g., transcutaneously), or intravascularly. The sensor measures the concentration of a given analyte in the body, generates a raw signal, which is transmitted to an electronic device associated with the sensor. The raw signal is converted into an output value, which is displayed on a display. The output value obtained from the conversion of the raw signal is typically presented in a form that provides the user with meaningful information, such as blood glucose expressed in mg / dL units. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0006] The various embodiments have a plurality of features, none of which are the only ones involved in their desirable attributes. Without limiting the scope of the embodiments as defined in the following claims, their more prominent features will be considered more briefly herein. After considering this discussion and, in particular, after reading the section entitled "DETAILED DESCRIPTION OF THE INVENTION", one will understand how the features of the embodiments provide the advantages described herein.

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

[0008] Recognizing the aforementioned problem, in a first aspect, some of the present embodiments include a sensor device for measuring the concentration of an analyte in a host, the sensor device comprising a sensor unit including a sensor body, at least one electrode, and a film covering at least a portion of the at least one electrode, the sensor body having a smooth tip; a piercing element including a material that rapidly dissolves after being inserted into the host, the piercing element being in contact with the sensor tip and capable of piercing the tissue; and a placement unit that is separated from the sensor tip and is configured to support the sensor device on the outer surface of the host's skin.

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

[0010] In an embodiment of the first aspect, the piercing element is adhered to the sensor tip.

[0011] In an embodiment of the first aspect, the piercing element is not fixed to the sensor tip but is maintained in a contact state in contact with the sensor tip.

[0012] In an embodiment of the first aspect, a sleeve surrounding the sensor tip and the piercing element maintain a contact state in contact with each other.

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

[0014] In certain embodiments of the first aspect, the coating includes a sharp coating tip.

[0015] In certain embodiments of the first aspect, the material of the piercing element includes a material that inhibits wound.

[0016] In certain embodiments of the first aspect, the material of the piercing element includes a material that promotes rapid wound healing.

[0017] In certain embodiments of the first aspect, the material of the piercing element includes a material that induces osmotic pressure or colloidal osmotic pressure.

[0018] In certain embodiments of the first aspect, the material of the piercing element includes one or more drugs.

[0019] In certain embodiments of the first aspect, the material of the piercing element includes vascular endothelial growth factor (VEGF).

[0020] In certain embodiments of the first aspect, the material of the piercing element includes at least one of salts, metal salts, sugars, synthetic polymers, polylactic acid, polyglycolic acid, or polyphosphazene.

[0021] In certain embodiments of the first aspect, the material of the piercing element biodegrades / dissolves within 1 day after insertion into the host.

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

[0023] In certain embodiments of the first aspect, the piercing element does not extend beyond the sensor tip or extends only slightly in the direction of the placement unit.

[0024] In certain embodiments of the first aspect, the piercing element extends beyond the sensor tip in the direction of the placement unit but stops before the electrode.

[0025] In certain embodiments of the first aspect, the placement unit includes a guiding portion configured to guide the insertion of the sensor unit through the host's skin so that the sensor unit can be inserted through the host's skin without substantial buckling and to support the column strength of the sensor body.

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

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

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

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

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

[0031] In certain embodiments of the first aspect, the placement unit includes a sensor electronics unit operably and removably connected to the sensor body.

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

[0033] Furthermore, recognizing the foregoing problems, in the second aspect, some of these embodiments include a method of fabricating a sensor device, the method including immersing a tip of the sensor in a liquid to form a liquid coating on the sensor tip and withdrawing the sensor tip from the liquid while controlling withdrawal parameters such that the coating forms a sharp tip extending from the sensor tip, the sharp tip being capable of piercing tissue.

[0034] In certain embodiments of the second aspect, the parameters include at least one of the length (L) of the sensor wetted by the liquid, the viscosity of the liquid, and the withdrawal rate.

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

[0036] In certain embodiments 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 certain embodiments of the second aspect, the withdrawal rate is 20 to 30 inches per second.

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

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

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

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

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

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

[0045] Recognizing the foregoing problem, in a third aspect, some of the embodiments of this disclosure include a sensor device for measuring the concentration of an analyte in a host, the sensor device including 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, and a piercing element including a material that rapidly dissolves when inserted into the host and including a sharp tip capable of piercing tissue and a lumen for receiving the sensor unit.

[0046] In certain embodiments of the third aspect, the sensor body has a smooth tip.

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

[0048] In certain embodiments of the third aspect, the sensor unit is fixed to the piercing element.

[0049] In certain embodiments of the third aspect, the material of the piercing element includes a material that inhibits wound formation.

[0050] In certain embodiments of the third aspect, the material of the piercing element includes a material that promotes rapid wound healing.

[0051] In certain embodiments of the third aspect, the material of the piercing element includes a material that induces osmotic or oncotic pressure.

[0052] In certain embodiments of the third aspect, the material of the piercing element includes one or more drugs.

[0053] In certain embodiments of the third aspect, the material of the piercing element comprises vascular endothelial growth factor (VEGF).

[0054] In certain embodiments of the third aspect, the material of the piercing element comprises at least one of salts, metal salts, sugars, synthetic polymers, polylactic acid, polyglycolic acid, or polyphosphazenes.

[0055] In certain embodiments of the third aspect, the material of the piercing element biodegrades / dissolves within 1 day after insertion into the host.

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

[0057] Another aspect of this embodiment includes the recognition that the material of the membrane of the analyte sensor is soft and tends to peel off when the sensor advances within the tissue. This problem is particularly severe 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 and leaves a coating of a thin membrane surrounding the sides at the tip of the sensor body. Some of the embodiments of this embodiment provide a solution to this problem.

[0058] Recognizing the aforementioned problem, in a fourth aspect, some of the embodiments of this embodiment include a sensor device for measuring the concentration of an analyte in a host, the sensor device comprising 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, and a placement unit that is remote from the sensor tip and configured to support the sensor device on the outer surface of the host's skin, wherein the membrane comprises a hardening agent that provides increased column strength to the sensor unit such that the sensor unit can be inserted through the host's skin without substantial buckling.

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

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

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

[0062] In an embodiment of the fourth aspect, the exposed tip of the sensor body contains a material that does not react with hydrogen peroxide.

[0063] In an embodiment of the fourth aspect, the curing agent includes cyanoacrylate.

[0064] Furthermore, recognizing the above problems, in a fifth aspect, some of the present embodiments include a sensor device for measuring the concentration of an analyte in a host, the sensor device including 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, and a placement unit that is separated from the sensor tip and is configured to support the sensor device on the outer surface of the host's skin, wherein the membrane contains a curing agent that improves the column strength of the sensor unit, enhances the adhesion of the membrane to the at least one electrode, and the membrane containing the curing agent allows permeability of the analyte.

[0065] In an embodiment of the fifth aspect, the curing agent is suspended in a 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 contains a material that does not react with hydrogen peroxide.

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

[0070] Furthermore, recognizing the aforementioned problem, in a sixth aspect, some of the present embodiments include a method of fabricating a sensor device, the method including coating a wire with a film, cutting the coated wire to a desired length, thereby forming a sensor tip, and exposing the coated wire to a curing agent such that the film absorbs the curing agent.

[0071] In an embodiment of the sixth aspect, exposing the coated wire includes at least immersing the sensor tip in the curing agent.

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

[0073] In an embodiment of the sixth aspect, some of the present embodiments further include sharpening the sensor tip to form a sharp tip capable of piercing tissue.

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

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

[0076] In an embodiment of the sixth aspect, the quenching agent includes cyanoacrylate or silane.

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

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

[0079] Furthermore, recognizing the foregoing problems, in a seventh aspect, some of the present embodiments include a method of fabricating a sensor device, the method comprising cutting a wire to a desired length, thereby forming a sensor tip, sharpening the sensor tip to form a sharp tip capable of penetrating tissue, coating the wire including the sharpened sensor tip with a membrane, and exposing the coated wire to a curing agent such that the membrane absorbs the curing agent.

[0080] In an embodiment of the seventh aspect, exposing the coated wire includes immersing at least the sensor tip in the curing agent.

[0081] In an embodiment of the seventh aspect, some of the present embodiments further include curing the membrane to cure the curing agent.

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

[0083] Recognizing 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 in the host without using 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 an insertion element at the distal end of the sensor unit and configured to penetrate the skin and / or tissue of the host. The sensor device further includes a placement unit spaced from the sensor tip and configured to support the sensor device on the outer surface of the skin of the host. The sensor body includes a stimulus-responsive material that changes at least one material property in response to a stimulus.

[0084] In an embodiment of the eighth aspect, at least one material property is at least one of hardness, shape, permeability, relative hydrophilicity, elastic modulus, or the higher-order structure of polymer orientation.

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

[0086] In an embodiment of the eighth aspect, the stimulus that induces a change in at least one material property is at least one of temperature, hydration, radiation, electrical stimulation, or 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 an embodiment 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 before insertion into the host's skin.

[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 host's skin.

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

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

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

[0096] Another aspect of this embodiment involves the recognition that the materials used to form the membrane of the analyte sensor are often soft and thus tend to delaminate (i.e., peel off and sometimes separate) when the sensor advances through the 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 and leaves a coating of a thin membrane surrounding the sides at the tip of the sensor body. Some of the embodiments of this embodiment provide a solution to this problem, including methods of forming the tip without damaging the tip and simultaneously maintaining the integrity of the tip after applying the membrane.

[0097] Recognizing the foregoing problem, in a ninth aspect, some of the embodiments of this embodiment include a method of fabricating a sensor device configured to be implanted in a host without using an inserter. The method includes forming a piercing tip on a sensor unit that includes a sensor body, at least one electrode, and a membrane that coats at least a portion of the at least one electrode. The membrane is applied to the sensor unit before forming the piercing tip on the sensor unit.

[0098] In an embodiment of the ninth aspect, the method further includes applying a membrane to the sensor unit.

[0099] In an embodiment of the ninth aspect, forming the piercing tip includes forming an annular channel on the outer periphery of a wire coated with a membrane.

[0100] In certain embodiments of the ninth aspect, the annular channel extends partially into the wire through the membrane.

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

[0102] In certain embodiments 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 certain embodiments of the ninth aspect, the necking forms a piercing tip at the sensor body.

[0104] In certain embodiments of the ninth aspect, the method further includes coating the piercing tip with a protective outer layer.

[0105] In certain embodiments of the ninth aspect, forming the piercing tip includes selectively removing portions of the membrane coating from the wire stock.

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

[0107] In certain embodiments of the ninth aspect, the method further includes separating the wire stock at spaced positions to form a plurality of membrane-coated sensor wires.

[0108] In certain embodiments of the ninth aspect, forming the piercing tip includes exposing the distal end surface of the sensor body.

[0109] In certain embodiments of the ninth aspect, the method further includes applying a coating to the distal end of the sensor body.

[0110] In certain embodiments of the ninth aspect, the coating renders the exposed distal end surface of the sensor body non-electrically active.

[0111] In certain embodiments of the ninth aspect, forming the piercing tip includes applying a terminal cap to the distal end of the membrane-coated sensor wire.

[0112] In certain embodiments of the ninth aspect, the terminal cap includes the piercing tip.

[0113] In certain embodiments of the ninth aspect, forming the piercing tip includes applying a plurality of membrane layers to the sensor body.

[0114] In certain embodiments of the ninth aspect, forming the piercing tip further includes 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 includes shaping the rigid coating to result in the piercing tip.

[0116] In certain embodiments of the ninth aspect, the method further includes applying a membrane to the sensor body.

[0117] In certain embodiments of the ninth aspect, the method further includes applying the piercing tip to the distal end of the sensor body.

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

[0119] In certain embodiments of the ninth aspect, the method further includes applying a retractable introduction sheath around the sensor body.

[0120] In certain embodiments of the ninth aspect, forming the piercing tip includes applying the piercing tip to the distal end of the sensor body over the membrane.

[0121] In certain embodiments of the ninth aspect, the piercing tip includes a biodegradable and / or bioabsorbable material.

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

[0123] In certain embodiments of the ninth aspect, applying the piercing tip to the distal end of the sensor body on the membrane includes casting the piercing tip on the distal end of the sensor body and on the membrane using a mold.

[0124] In certain embodiments of the ninth aspect, applying the piercing tip to the distal end of the sensor body on the membrane includes injection molding or insert molding.

[0125] In certain embodiments of the ninth aspect, applying the piercing tip to the distal end of the sensor body on the membrane includes inserting the distal end of the sensor body into the proximal end of the open piercing tip.

[0126] In certain embodiments of the ninth aspect, the method further includes pressing the proximal end of the piercing tip.

[0127] In certain embodiments of the ninth aspect, applying the piercing tip to the distal end of the sensor body on the membrane includes overmolding the piercing tip on the distal end of the sensor body and on the membrane.

[0128] Another aspect of this embodiment includes the recognition that applying the membrane to the sharp sensor tip presents problems. For example, a sharp tip can break and / or cause delamination of the membrane, especially when the sensor is subject to frictional forces during the sensor insertion process. Also, applying the membrane to the sharp sensor tip can blunt the tip, making the tip less effective for direct press insertion of the sensor. Some of these embodiments provide solutions to these problems, including methods of applying the membrane to the sharp tip without damaging the tip while maintaining the integrity of the tip.

[0129] Recognizing the foregoing problems, in a tenth aspect, some of the present embodiments include a method of fabricating a sensor device configured to be embedded in a host without using an inserter. The method includes forming a piercing tip on a sensor unit including a sensor body, at least one electrode, and a film covering at least a portion of the at least one electrode. The piercing tip is formed on the sensor unit before applying the film to the sensor unit.

[0130] In an embodiment of the tenth aspect, forming the piercing tip includes immersing the sensor body in a film solution to form a film on the sensor body.

[0131] In an embodiment of the tenth aspect, forming the piercing tip further includes removing a portion of the film at the distal end of the sensor body after the film solution has dried to expose the distal end of the sensor body.

[0132] In an embodiment of the tenth aspect, removing a portion of the film at the distal end of the sensor body includes laser ablation, electrolytic polishing, bead blasting, dry ice blasting, or firing.

[0133] In an embodiment of the tenth aspect, the method further includes 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 film solution at the distal end of the sensor body before the film solution dries.

[0135] In an embodiment of the tenth aspect, removing a portion of the film solution includes wiping or blotting the distal end of the sensor body.

[0136] In an embodiment of the tenth aspect, the method further includes applying a film to the sensor body and the piercing tip.

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

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

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

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

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

[0142] In an embodiment of the tenth aspect, the core and the outer layer include different materials.

[0143] In an embodiment of the tenth aspect, the core includes a material that repels the membrane.

[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-wetting.

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

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

[0148] In an embodiment 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, the thickness of at least one of the layers is less than the thickness of at least another of the layers.

[0150] In an embodiment of the tenth aspect, the method further includes applying a film to the sensor body and the piercing tip.

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

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

[0153] In an embodiment of the tenth aspect, the method further includes applying a film to the sensor body and the piercing tip by immersing them in a film solution.

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

[0155] In an embodiment of the tenth aspect, the method further includes immersing the piercing tip in a release agent that prevents the film from adhering to the piercing tip.

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

[0157] In an embodiment of the tenth aspect, the method further includes applying a film to the sensor body and the piercing tip.

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

[0159] In an embodiment of the tenth aspect, the sacrificial material is photosensitive, thermosensitive, or soluble, and treating the piercing tip includes applying light, applying heat, or applying a solvent.

[0160] In an embodiment of the tenth aspect, the method further includes applying a membrane to the piercing tip by immersing the piercing tip downward into a membrane solution and then inverting the sensor unit so that the piercing tip faces upward before the solution dries.

[0161] In an embodiment of the tenth aspect, the method further includes applying a membrane to the sensor body by immersing the piercing tip upward into a membrane solution such that only a portion of the sensor body is immersed 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 piercing tip to form an annular channel, where an edge is defined by the distal end of the channel.

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

[0164] In an embodiment of the tenth aspect, the edge results in the dissipation of the liquid meniscus of the membrane solution, whereby the piercing tip remains uncoated with the membrane.

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

[0166] In an embodiment of the tenth aspect, the method further includes removing a first portion of the outer layer and a 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 includes removing a portion of the core to form the piercing tip.

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

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

[0171] In an embodiment of the tenth aspect, the attached cap includes 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 includes removing a section of the outer core proximal to the piercing tip to form a window.

[0174] In an embodiment of the tenth aspect, removing a section of the outer core includes laser ablation.

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

[0176] In an embodiment of the tenth aspect, the method further includes immersing the sensor body in a membrane solution to form a membrane inside the window.

[0177] In an embodiment of the tenth aspect, the sensor body includes a thin, flat microelectromechanical systems (MEMS) substrate.

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

[0179] In an embodiment of the tenth aspect, the method further includes forming a film on the substrate.

[0180] Another aspect of this embodiment includes the recognition that forming a sharp distal tip on the sensor presents problems such that the film cannot function properly, such as contamination of the film surface and / or damage to the film. Contamination of the film can change the properties of the film, such as by diffusion. For example, due to contamination, the permeability properties of the film (e.g., selective permeability) can be reduced. Damage to the film can also affect the functionality of the sensor. For example, if the removal of the film extends to the portion intended to cover the electroactive surface that forms the electrode beyond the distal tip, the diffusion properties of the sensor are substantially modified and become uncontrollable, so the sensor can become defective. On the other hand, if excessive film material is present at the distal tip of the sensor, the distal tip of the sensor can become blunt and be less effective in piercing the skin and / or tissue. Some of the embodiments of this embodiment 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 can be formed on the sensor during the step of separating the sensor wire into individual sensors. For example, the separation process can include, without limitation, mechanical pressing, hot pressing, laser ablation, extrusion, cutting, etc. By forming the piercing tip during separation, a sharp distal tip can be formed before applying the film to the sensor, thereby avoiding secondary contamination and damage of the delicate film by subsequent tip-forming steps.

[0181] Recognizing the foregoing problems, in an eleventh aspect, some of the present embodiments include a method of fabricating a sensor device configured to be embedded in a host without using an inserter. The method includes forming a piercing tip on a sensor unit that includes a sensor body, at least one electrode, and a film covering at least a portion of the at least one electrode. Forming the piercing tip includes removing material from the sensor body.

[0182] In certain embodiments of the eleventh aspect, forming the piercing tip includes severing a wire stock while exposing the wire stock to cyanoacrylate vapor.

[0183] In certain embodiments of the eleventh aspect, the method includes a continuous reel-to-reel process.

[0184] In certain embodiments of the eleventh aspect, forming the piercing tip includes immersing a distal end of the sensor body.

[0185] In certain embodiments of the eleventh aspect, immersing the distal end of the sensor body includes immersing it in an etching solution or a polishing solution.

[0186] In certain embodiments of the eleventh aspect, forming the piercing tip includes electrolytic polishing.

[0187] In certain embodiments of the eleventh aspect, forming the piercing tip includes moving the sensor body relative to a polishing surface while the sensor body forms an angle Θ with 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 one embodiment of the eleventh aspect, the sensor body is held within a support fixture that is moved relative to the polished surface.

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

[0192] In one embodiment of the eleventh aspect, removing a portion of the outer layer includes mechanical cutting, laser ablation, bead blasting, polishing, or chemical etching.

[0193] In one embodiment of the eleventh aspect, forming the piercing tip portion includes applying tension to the sensor along the longitudinal axis of the sensor wire.

[0194] In one embodiment of the eleventh aspect, the applied tension causes the sensor wire to neck down in the intermediate region.

[0195] In one embodiment of the eleventh aspect, the applied tension further causes the sensor wire to break in the intermediate region.

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

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

[0198] In one embodiment of the eleventh aspect, forming the piercing tip portion includes placing the sensor wire between opposing cutting blades and separating the sensor wire into at least two pieces.

[0199] In one embodiment of the eleventh aspect, an angle of 30 degrees to 145 degrees is defined by a cutting edge defined by a converging surface of one of the cutting blades.

[0200] In an embodiment of the eleventh aspect, this angle is not a right angle.

[0201] Furthermore, recognizing the foregoing problems, in a twelfth aspect, some of the present embodiments include a method of fabricating a sensor device configured to be embedded in a host without using an inserter. The method includes forming a piercing tip on a sensor unit including a sensor body, at least one electrode, and a film covering at least a portion of the at least one electrode. Forming the piercing tip includes adding a material to the sensor body.

[0202] In an embodiment of the twelfth aspect, forming the piercing tip includes immersing the sensor body in a bath of polymer material.

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

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

[0205] In an embodiment of the twelfth aspect, forming the piercing tip includes immersing the sensor body in the bath, withdrawing the sensor body from the bath, and when the sensor body is withdrawn, the immersion coating on the sensor body hardens to form the piercing tip.

[0206] Recognizing any of the problems described herein, in a 13th aspect, some of the present embodiments include a sensor device for measuring the concentration of an analyte in a host, the sensor device being configured to be embedded in the host without using 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 connection with the core wire. The at least one electrode is formed by printing.

[0207] In an embodiment of the 13th aspect, the at least one electrode includes a first electrode, a second electrode, and a third electrode, and these electrodes are axially spaced along the sensor device.

[0208] In an embodiment of the 13th aspect, the second electrode does not extend over the entire outer circumference of the jacket.

[0209] In an embodiment of the 13th aspect, the sensor device further includes a conductive trace extending along the jacket between the first electrode and the third electrode.

[0210] In an embodiment of the 13th aspect, the sensor device further includes an insulating material overlapping at least a portion of the conductive trace.

[0211] In an embodiment of the 13th aspect, the distal end of the sensor device includes a piercing tip.

[0212] In an embodiment of the 13th aspect, the distal end of the sensor device is non-electrically active.

[0213] Recognizing any of the problems described herein, in a 14th aspect, some of the present embodiments include a sensor device for measuring the concentration of an analyte in a host, the sensor device being configured to be embedded in the host without using 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 at least one electrode along the core wire. At least one electrode is formed by printing.

[0214] In an embodiment of the 14th aspect, at least one electrode includes a first electrode, a second electrode, and a third electrode, and these electrodes are axially spaced along the sensor device.

[0215] In an embodiment of the 14th aspect, the first and second electrodes do not extend over the entire outer circumference of the core wire.

[0216] In an embodiment of the 14th aspect, the distal end of the sensor device includes a piercing tip.

[0217] In an embodiment of the 14th aspect, at least one electrode is printed on the core wire using a platinum paste.

[0218] Recognizing any of the problems described herein, in a 15th aspect, some of the present embodiments include a sensor device for measuring the concentration of an analyte in a host, the sensor device being configured to be embedded in the host without using an inserter. The sensor device includes a sensor body formed as a flat plate that is rolled into a cylinder.

[0219] In an embodiment of the 15th aspect, the cylinder includes an overlapping region where the opposing edges of the flat plate converge.

[0220] In an embodiment of the 15th aspect, the overlapping portions of the opposing edges are fixed to each other.

[0221] In an embodiment of the 15th aspect, the overlapping portions are fixed to each other with an adhesive.

[0222] In an embodiment of the 15th aspect, the adhesive dissolves after the sensor device is embedded in the host.

[0223] In an embodiment of the 15th aspect, when the adhesive dissolves, the rounded sensor body spreads and returns to its planar shape.

[0224] Recognizing any of the problems described herein, in the 16th aspect, some of the embodiments include a sensor device for measuring the concentration of an analyte in a host, the sensor device being configured to be embedded in the host without using 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 that is at the distal end of the sensor unit and is configured to pierce the skin and / or tissue of the host. The sensor device further includes a placement unit that is remote from the sensor tip and is configured to support the sensor device on the outer surface of the host's skin. The sensor device further includes a retractable introduction sheath configured to cover at least a portion of the membrane during insertion of the sensor device.

[0225] In an embodiment of the 16th aspect, the proximal end of the tissue piercing element has a diameter larger than the diameter of the sensor body.

[0226] In an embodiment of the 16th aspect, the diameter of the introduction sheath is substantially the same as or smaller than the diameter of the proximal end of the tissue piercing element.

[0227] Recognizing any of the problems described herein, in a 17th aspect, some of the present embodiments include a sensor device for measuring the concentration of an analyte in a host, the sensor device being configured to be embedded in the host without using 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 placement unit that is remote from the sensor tip and configured to support the sensor device on the 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 17th aspect, the cross-section of the sensor body defines a positive sign shape having four equally spaced troughs.

[0229] In an embodiment of the 17th aspect, the cross-section of the sensor body defines a circle having a single trough.

[0230] In an embodiment of the 17th aspect, at least one electrode is located in at least one trough.

[0231] In an embodiment of the 17th aspect, at least one electrode and at least one membrane fit snugly around or recess under the outer perimeter of the sensor body.

[0232] Recognizing any of the problems described herein, in an eighteenth aspect, some of the present embodiments include a sensor device for measuring the concentration of an analyte in a host, the sensor device being configured to be embedded in the host without using 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 that is at a distal end of the sensor unit and is configured to pierce the host's skin and / or tissue. The sensor device further includes a placement unit that is remote from the sensor tip and is configured to support the sensor device on the outer surface of the host's skin. The sensor device further includes a retractable introduction sheath configured to cover at least a portion of the membrane during insertion of the sensor device.

[0233] Recognizing any of the problems described herein, in a nineteenth aspect, some of the present embodiments include a sensor device for measuring the concentration of an analyte in a host, the sensor device being configured to be embedded in the host without using 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 that is at a distal end of the sensor unit and is configured to pierce the host's skin and / or tissue. The sensor device further includes a placement unit that is remote from the sensor tip and is configured to support the sensor device on the 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] Recognizing any of the problems described herein, in a 20th aspect, some of the present embodiments include a sensor device for measuring the concentration of an analyte in a host, the sensor device being configured to be embedded in the host without using an inserter. The sensor device includes a sensor unit including a sensor body, at least one electrode, and a film covering at least a portion of the at least one electrode. The sensor device further includes a piercing element that is at a distal end of the sensor unit and is configured to pierce the host's skin and / or tissue. The sensor device further includes a placement unit that is remote from the sensor tip and is configured to support the sensor device on the outer surface of the host's skin. The sensor body includes a plurality of depressions.

[0236] In an embodiment of the 20th aspect, the film is disposed in at least one of the depressions.

[0237] In an embodiment of the 20th aspect, the film fits snugly over or is recessed under the outer surface of the sensor body.

[0238] In an embodiment of the 20th aspect, the depressions are randomly arranged.

[0239] Recognizing any of the problems described herein, in a 21st aspect, some of the present embodiments include a sensor device for measuring the concentration of an analyte in a host, the sensor device being configured to be embedded in the host without using an inserter. The sensor device includes a sensor unit including a sensor body, at least one electrode, and a film covering at least a portion of the at least one electrode. The sensor device further includes a piercing element that is at a distal end of the sensor unit and is configured to pierce the host's skin and / or tissue. The sensor device further includes a placement unit that is remote from the sensor tip and is configured to support the sensor device on the outer surface of the host's skin. The sensor device further includes a plurality of axially spaced depressions in the sensor body.

[0240] In an embodiment of the 21st aspect, the membrane is disposed within the recess.

[0241] In an embodiment of the 21st aspect, the sensor device further includes an outer layer of a material that is permeable to one or more selected analytes.

[0242] Recognizing any of the problems described herein, in the 22nd aspect, some of these embodiments include a sensor device for measuring the concentration of an analyte in a host, the sensor device being configured to be implanted in the host without using 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 that is at the distal end of the sensor unit and is configured to pierce the skin and / or tissue of the host. The sensor device further includes a placement unit that is remote from the sensor tip and is configured to support the sensor device on the 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 22nd aspect, the protective outer layer includes a material that dissolves when inserted into the skin and / or tissue of the host.

[0244] In an embodiment of the 22nd aspect, the material of the protective outer layer includes polyvinyl-pyrrolidone (PVP).

[0245] Recognizing any of the problems described herein, in a 23rd aspect, some of the present embodiments include a sensor device for measuring the concentration of an analyte in a host, the sensor device being configured to be embedded in the host without using 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 placement 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 some embodiments of the 23rd aspect, the outer layer covers substantially all of the sensor body but includes at least one window.

[0247] In some embodiments of the 23rd aspect, the window is positioned over at least one electrode such that the at least one electrode is exposed to contact with the host's tissue and / or body fluid.

[0248] In some embodiments of the 23rd aspect, the outer layer includes cyanoacrylate.

[0249] Recognizing any of the problems described herein, in a 24th aspect, some of the present embodiments include a sensor device for measuring the concentration of an analyte in a host, the sensor device being configured to be implanted in the host without using an inserter. The sensor device includes a sensor unit including a sensor body, at least one electrode, and a film covering at least a portion of the at least one electrode. The sensor device further includes a piercing element that is at a distal end of the sensor unit and is configured to pierce the host's skin and / or tissue. The sensor device further includes a placement unit that is remote from the sensor tip and is 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 greater thickness than the wire.

[0250] In certain embodiments of the 24th aspect, the outer coating includes at least one window corresponding to the location of the at least one electrode.

[0251] In certain embodiments of the 24th aspect, the film is disposed within the window.

[0252] In certain embodiments of the 24th aspect, the film is recessed below the outer surface of the outer coating.

[0253] In certain embodiments of the 24th aspect, the sensor device further includes a highly permeable outer layer.

[0254] In certain embodiments of the 24th aspect, the outer layer includes a hydrogel.

[0255] Recognizing any of the problems described herein, in a 25th aspect, some of the present embodiments include a sensor device for measuring the concentration of an analyte in a host, the sensor device being configured to be embedded in the host without using an inserter. The sensor device includes a sensor unit including a sensor body, at least one electrode, and a film covering at least a portion of the at least one electrode. The sensor device further includes a piercing element that is at a distal end of the sensor unit and is configured to pierce the skin and / or tissue of the host. The sensor device further includes a placement unit that is remote from the sensor tip and is configured to support the sensor device on an outer surface of the skin of the host. The film is applied to the sensor body by printing.

[0256] In an embodiment of the 25th aspect, the sensor body includes polytetrafluoroethylene (PTFE).

[0257] Hereinafter, various embodiments of the present invention will be described in detail with an emphasis on highlighting advantageous features. These embodiments show novel and inventive sensors and related methods for continuous analyte monitoring shown in the accompanying drawings for illustrative purposes only. The drawings are not necessarily drawn to scale and are provided only to illustrate the embodiments. These drawings include the following figures, and like numbers indicate like parts.

Brief Description of the Drawings

[0258]

Figure 1

Figure 2A

Figure 2B

Figure 2C

Figure 2D

Figure 2E

Figure 2F

Figure 2G

Figure 2H

Figure 3A

Figure 3B

Figure 3C

Figure 3D

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

Figure 18

Figure 19

Figure 20

Figure 21

Figure 22

Figure 23

Figure 24

Figure 25

Figure 26

Figure 27

Figure 28

Figure 29

Figure 30

Figure 30A

Figure 30B

Figure 31

Figure 32

Figure 33

Figure 34

Figure 35

Figure 36

Figure 37

Figure 38

Figure 39

Figure 40

Figure 41

Figure 42

Figure 43

Figure 44

Figure 45

Figure 46

Figure 47

Figure 48

Figure 49

Figure 50

Figure 51

Figure 52

Figure 52A

Figure 53

Figure 54

Figure 54A

Figure 55

Figure 56

Figure 57

Figure 58

Figure 59

Figure 60

Figure 61

Figure 62

Figure 63

Figure 64

Figure 65

Figure 66

Figure 67

Figure 68

Figure 69

Figure 70

Figure 71

Figure 72

Figure 73

Figure 74

Figure 75

Figure 76

Figure 76A

Figure 76B

Figure 76C

Figure 76D

Figure 77

Figure 78

Figure 79

Figure 80

Figure 81

Figure 82

Figure 83

Figure 84

Figure 85

Figure 86

[0259] The following detailed description explains this embodiment with reference to the drawings. In the drawings, elements of this embodiment are labeled with reference numerals. These reference numerals are reproduced below in connection with the consideration of the corresponding features of the drawings.

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

[0261] Overview The embodiments described herein provide various mechanisms for directly inserting a transdermal sensor into a host without using a separate applicator, i.e., without using anything other than the sensor device itself. Direct pressure insertion of a transdermal sensor having a wire, particularly a thin wire-like geometry (e.g., an electrode), can be technically difficult due to the risk of buckling associated with the sensor. Direct pressure insertion of the sensor also presents issues related to damaging the membrane disposed over the sensor during the insertion process. Without protecting the membrane, the membrane can 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 the exposed metal can be electroactive and add to the background signal (noise) and / or vary the sensitivity of the sensor. The embodiments described herein are designed to overcome the foregoing problems by providing a small sensor device that can provide structural support (e.g., in the form of mechanical / structural properties such as column strength) for the direct insertion of the transdermal sensor and can protect the membrane from damage during the insertion process.

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

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

[0264] The external portion 106 includes a placement unit 116 that may include a sensor electronics unit (not shown) embedded therein or separably fixed thereto, or alternatively may be configured to be operably connected to a separate electronic device 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 by reference 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 passage for inserting the sensor body 110 into the host's tissue. In some embodiments, the tissue piercing element 108 may be integrated 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 fixed to the support member 112 using an adhesive or the like. Alternatively, the tissue piercing element 108 may simply abut against the smooth distal surface of the support member 112 and / or the 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] The skin generally comprises multiple layers, including the epidermis, dermis, and subcutaneous layers. The epidermis includes several layers within its structure, including the stratum corneum, which is the outermost layer and typically about 10 to 20 microns thick, and the basal layer, which is the deepest layer of the epidermis. The epidermis usually does not contain blood vessels but exchanges metabolites with the dermis by diffusion to and from it. Without wishing to be bound by theory, the interstitial fluid of the basal layer is thought to adequately represent the host analyte (e.g., glucose) levels because the basal layer is supported for survival by angiogenesis. 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 is beneath the dermis and is mostly composed of lipids. The subcutaneous layer functions to protect the body from temperature extremes. It also contains connective tissue and a small number of blood vessels.

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

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

[0269] The tissue piercing element of the sensor device is designed to have appropriate flexibility, rigidity, and sufficient column strength so as to remain intact and prevent substantial buckling when inserting the in-vivo portion of the sensor device through the host's skin. Any of a variety of biocompatible materials having 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 the user to press the sensor unit against the skin using the force of the thumb or finger without substantial buckling of the tissue piercing element. Thus, the structure of the tissue piercing unit does not break when subjected to the resistance (e.g., axial force) associated with piercing the tissue and skin. In some embodiments, the tissue piercing element may have a column strength that can withstand an axial load exceeding about 0.5 newtons (N), or exceeding about 1 N, or exceeding about 2 N, or exceeding about 5 N, or exceeding about 10 N without substantial buckling. Often, increasing the thickness of the column of an object also increases the 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 to 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 thus may be damaged during insertion of the sensor unit into the 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 can be formed to have 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 passageway for inserting the sensor body 110 into the tissue. Thus, the risk of the penetration - resistance force damaging the membrane 140 and / or peeling it off the remainder of the sensor body 110 during the insertion process is reduced. In some embodiments, the largest dimension of the cross-section transverse to the longitudinal axis of the 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 on the tissue piercing element. By coating the surface of the tissue piercing element with a bioactive agent, release of the bioactive agent into the subcutaneous tissue can be effected during and / or after insertion of the in vivo portion of the sensor device. In further embodiments, one or more polymer layers may be used to control the release rate of one or more bioactive agents. Such polymers can include 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), phosphorylcholine, 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, but are not limited thereto.

[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 a reservoir or storage location for retaining a bioactive agent. The recessed portions may be formed at any preselected location, and may have any preselected depth, size, geometry, and dimensions, according to the intended use. By using a reservoir or storage location, the amount of bioactive agent that can be retained and delivered by the tissue piercing element can be increased. In further embodiments, the tissue piercing element may be hollow with a cavity and may be connected to one or more openings on its surface via various passageways, such that bioactive agent can be released from the cavity through the openings. In some embodiments, for example, as shown in FIGS. 3A and 3B, the tissue piercing element 310 comprises a pocket 312 that is shaped and sized to support a sensor 314 with a membrane disposed thereon.

[0273] In certain embodiments, the in-vivo portion of the sensor device is configured to remain substantially stationary within the host's tissue, such that movement or motion of the sensor body relative to the surrounding tissue is prevented. Movement or motion can cause inflammation at the sensor implantation site due to irritation and can generate noise in the sensor signal due to artificial effects associated with the movement. Thus, it may be advantageous to provide a fixation mechanism that provides support to the in-vivo portion of the sensor device to avoid the aforementioned problems. In some embodiments, the tissue piercing element may include a surface patterned in one or more regions. The patterning can roughen the surface of the tissue piercing element, thereby providing surface irregularities with a larger surface area than that of a non-patterned (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 that having a non-patterned surface. Additionally, the patterned surface can also be advantageous in some cases as it can enhance the immobilization of the in-vivo portion of the sensor device within the host's tissue due to the increased surface area. In certain embodiments, the tissue piercing element may include surface topographies such as a porous surface (e.g., porous parylene), a ridged surface. In certain embodiments, fixation can be provided by claws, protrusions, hooks, barbs, hooks, spherical portions (e.g., at the distal end), S-shaped bends along the tissue piercing element, a stepwise varying diameter, combinations thereof, etc., that can be used alone or in combination to stabilize the sensor within the subcutaneous tissue. For example, in certain embodiments, the tissue piercing element may comprise one or more fixation members configured to expand outwardly (e.g., in a direction towards a plane perpendicular to the longitudinal axis of the sensor unit) during or after insertion of the sensor unit. The outward expansion of the fixation members results in the tissue piercing element being pressed against the surrounding tissue, thus facilitating the fixation of the sensor unit to reduce (or prevent) movement and / or rotation of the sensor unit.In some embodiments, the fixed member may be formed from a shape memory material such as nitinol configured to transform from a martensitic state to an austenitic state at a specific temperature (e.g., room temperature or body temperature). In the martensitic state, the fixed member is ductile and in a contracted configuration. In the austenitic state, the fixed member becomes more rigid and at the same time expands to form a larger predetermined shape. Although nitinol is described herein as an example of a shape memory material that may be selected to form the fixed member, it should be understood that other similar materials (e.g., shape memory materials) may also be used.

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

[0275] In an alternative embodiment, to provide protection of the membrane during insertion of the sensor device, the sensor body may be embedded in or encapsulated by a needle formed from a biodegradable material. After insertion, the needle gradually biodegrades, leaving the sensor body behind, 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 certain concentration of the analyte being measured, such that an initial calibration point of the sensor device can be obtained as a result.

[0276] As shown in FIG. 1, the sensor device 100 may include a skin contact mounting unit 116 configured to be fixed to a host. In some embodiments, the mounting unit 116 includes a base 122 adapted to be fixed to the skin of the host. The base 122 may be formed from various rigid or flexible materials and may have a low profile to reduce the sensor device protruding 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 irregularities of the skin, thereby reducing or eliminating movement-related drawbacks associated with the operation of the host. In certain embodiments, the base 122 of the mounting unit 116 includes an adhesive material or adhesive layer 124, also referred to as an adhesive pad, preferably disposed on the bottom surface of the mounting unit, and may also include a removable backing layer (not shown). Thus, the mounting unit 116 is adhered to the skin 104 of the host by removing the backing layer and pressing the base 122 of the mounting unit 116 against the skin 104 of the host. An adhesive pad suitable for stretching, elongating, conforming, and / or ventilating the area (e.g., the skin of the host) can be selected and designed. In some embodiments, the mounting unit includes a guiding portion (not shown) configured to guide the insertion of the sensor device 100 through the skin 104 of the host and support the column strength of the support member 112 such that the sensor device 100 can be inserted through the skin 104 of the host without substantial buckling.

[0277] FIG. 1 illustrates one configuration for providing protection of the membrane, although 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 configured to substantially surround the sensor as illustrated in FIG. 3C. Unlike other embodiments described elsewhere herein, in the embodiments illustrated in FIGS. 3A-3D, the support member 330 does not include a working electrode. Instead, one or more working electrodes are disposed as a component different from the support member 330. In some embodiments, the support member 330 may also function as a reference electrode.

[0278] In the embodiment illustrated in FIG. 3A, the support member 330 includes a longitudinal recess 332 configured to at least partially receive the 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 over the entire length of the support member 330 as illustrated in FIG. 3B. In certain embodiments, the support member 330 may surround 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 periphery (e.g., the outer circumference) of the sensor.

[0279] As shown in FIG. 3C, in some embodiments, a sensor (e.g., a 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 a biological fluid (e.g., interstitial fluid), thereby allowing the biological fluid to diffuse towards 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 housed within the support member 330 and are thus protected during device packaging, handling, and / or insertion. The window portions 334 can 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 similar to an ellipse, polygon (e.g., triangle, square, rectangle, parallelogram, trapezoid, pentagon, hexagon, octagon), etc. In certain embodiments, the window portion may include a section that extends around the outer periphery of the longitudinal cross-section of the support member. For example, the support member can be fabricated using a hypodermic tube with the window portion cut out in a spiral configuration by ablation, etching, or other techniques.

[0280] Permeability 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, in femtoamps. That is, for all units (mg / dL) of glucose measured, a current of at least 1 picoamp is measured. In some embodiments, a current of about 1, 2, 3, 4, or 5 picoamps to about 25, 50, 100, 250, or 500 picoamps is measured for all units (mg / dl) of glucose measured.

[0281] Bioactive agent Various bioactive agents are known to promote the inflow or outflow of fluids. Thus, by incorporating a bioactive agent into a membrane, the fluid bulk, bulk fluid flow, and / or diffusion rate can be increased (further promoting the inflow of glucose and oxygen), thereby reducing non-constant noise. In some embodiments, the fluid bulk and / or bulk fluid flow is increased at a 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 irritates a wound and stimulates the release of a soluble mediator known to cause a local inflow of fluid to the wound site. In some embodiments, the sensor is configured to include a vasodilatory bioactive agent that can cause a local inflow of fluid from a vascular structure.

[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, angiogenesis factors, etc. Useful bioactive agents include mannitol, sodium thiosulfate, VEGF / VPF, NO, NO donors, leptin, bradykinin, histamine, blood components, platelet-rich plasma (PRP), matrix metalloproteinase (MMP), 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 cell growth factor BB (PDEGF-BB), angiopoietin-1, transforming growth factor β (TGF-β), transforming growth factor α (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-1), angiotensin-converting enzyme (ACE) inhibitor captoprilat, angiotropin, thrombospondin, peptide KGHK, hypoxia pressure, lactic acid, insulin, leptin, copper sulfate, estradiol, prostaglandin, cox inhibitor, endothelial cell binder (e.g., decorin or vimentin), glenipin, hydrogen peroxide, nicotine, and growth hormone, but are not limited to these. Further other useful bioactive agents include enzymes, cytotoxic agents or necrotizing agents (e.g., pactataxyl, actinomycin, doxorubicin, daunorubicin, epirubicin, bleomycin, plicamycin, mitomycin), cyclophosphamide, chlorambucil, uracil mustard, melphalan, bryostatin, inflammatory bacterial cell wall components, histamine, inflammation promoting factors, etc.

[0283] The bioactive agent can be added during the manufacture of the sensor by incorporating the desired bioactive agent into the manufacturing material of one or more sensor layers or into an external biological material such as a porous silicone membrane. For example, the bioactive agent may be mixed with a solution during film formation, which is subsequently applied to the sensor during manufacture. Alternatively, the completed sensor may be immersed in, for example, a solution of the bioactive agent or sprayed with it. The amount of the bioactive agent can be controlled by varying its concentration, varying the dwell time during immersion, applying multiple layers until the desired thickness is reached, etc., as disclosed elsewhere in this specification. In an alternative embodiment, the bioactive agent is encapsulated in microcapsules before being applied to the sensor. For example, the bioactive agent encapsulated in microcapsules may be sprayed onto the completed sensor or incorporated into a structure such as an outer mesh layer or a peeling layer. Encapsulation in microcapsules can result in an improvement in flexibility in controlling the release rate, the time at which release occurs, and / or the duration of release of the bioactive agent.

[0284] A chemical system / method of stimulation may be incorporated into an external sensor structure that releases a stimulant into the local environment, such as a biological interface membrane (described elsewhere in this specification) or a peeling layer. For example, in some embodiments, the "peeling layer" can release (e.g., peel off or leach out) molecules into the local vicinity of the sensor and accelerate fluid movement by osmotic pressure. In some embodiments, the peeling layer provides a mild stimulus, promotes the body's response to mild inflammation / foreign bodies, thereby preventing cells from stabilizing, accumulating an aligned fibrous capsule, and promoting the formation of fluid cavities.

[0285] The peeling layer can 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) mixtures, PEG - sucrose mixtures, hydrogels such as polyhydroxyethyl methacrylate (pHEMA), polymethyl methacrylate (PMMA), or other polymers having rapidly degradable ester bonds. In certain embodiments, absorbable suture materials that degrade into compounds having acid residues can be used. Acid residues are chemical stimulants that stimulate inflammation and wound healing. In certain embodiments, these components include glycolic acid and lactic acid - based polymers, polyglyactin, polydioxone, polydyconate, poly(dioxanone), poly(trimethylene carbonate) copolymers, and poly(caprolactone) homopolymers and copolymers, among others.

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

[0287] In other embodiments, the release layer may include a silicone elastomer, such as a copolymer mixture of silicone elastomer and poly(ethylene oxide) and poly(propylene oxide) as disclosed in co-pending U.S. Patent Application No. 11 / 404,417, filed April 14, 2006. In one embodiment, the silicone elastomer is a dimethyl and methyl hydrogen-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 mixture. 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% weight / weight to about 30% weight / weight of the membrane is the copolymer.

[0288] The release layer can take on any shape or geometry, symmetric or asymmetric, that promotes fluid inflow at a desired location of the sensor, e.g., at the sensor head or an electrochemically reactive surface, by way of example. 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 or the entire sensor.

[0289] In one exemplary embodiment, a peeling layer containing polyethylene oxide (PEO) is applied outside the sensor, where the skin around the sensor can directly access the peeling layer. PEO leaches out from the peeling layer and is taken up by local cells, which release inflammation-promoting factors. The inflammation-promoting factors diffuse through the surrounding tissue and stimulate an inflammatory response including the influx of body fluids. Thus, the initial noise can be reduced or eliminated, and the sensor function can be improved.

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

[0291] Wound suppression In some embodiments, non-constant noise can be reduced by wound suppression (e.g., during sensor insertion). Wound suppression includes any system or method in which the amount of wound generated during sensor insertion is reduced and / or eliminated. Without wishing to be bound by theory, if the wound is suppressed or at least significantly reduced, it is believed that the sensor will be surrounded by substantially normal tissue (e.g., tissue substantially similar to the tissue before sensor insertion). Substantially normal tissue is thought to have a lower metabolism than wounded tissue, produce fewer interfering substances, and reduce initial noise.

[0292] The structure of the sensor can be adapted to be either one that suppresses wounds or promotes rapid healing, for example, by adapting it to a structure that does not cause substantial wounds (for example, a structure configured to prevent wounds), a structure that promotes wound healing, an anti-inflammatory structure, etc., so that wounds can be suppressed. 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 such as 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, such as, for example, a 30, 31, 32, 33, 34, or 35 gauge needle (or smaller) on a stub basis. Generally, the smaller the needle, the lower the amount of trauma during insertion. For example, a very small needle can reduce the amount of tissue damage, thereby reducing the subsequent wound healing response. In an alternative embodiment, the surface of the sensor is smoothed with a lubricating coating to reduce trauma during sensor insertion.

[0293] Wounds can also be reduced by including a wound suppressant (bioactive agent) that either reduces the amount of the initial wound or suppresses the wound healing process. Without wishing to be bound by theory, applying a wound suppressant such as an anti-inflammatory agent, an immunosuppressant, an anti-infective agent, or a scavenger to the sensor can locally create a quiescent environment and suppress wound healing. In a quiescent environment, the impact of body processes such as an increase in cell metabolism associated with wound healing on the sensor can be minimized. If the tissue around the sensor is not affected, that tissue can continue normal metabolism and promote sensor function.

[0294] In some embodiments, compounds and / or factors useful for wound inhibition include first-generation H1-receptor antagonists: ethylenediamines (e.g., mepyramine (pyrilamine), antazoline), ethanolamines (e.g., diphenhydramine, carbinoxamine, doxylamine, clemastine, and dimenhydrinate), alkylamines (pheniramine, chlorpheniramine, dexchlorpheniramine, brompheniramine, and triprolidine), piperazines (cyclizine, hydroxyzine, and meclizine), and tricyclic compounds (promethazine, alimemazine (trimethoprazine), cycloheptazine, and azatadine); second-generation H1-receptor antagonists, e.g., acrivastine, astemizole, cetirizine, loratadine, mizolastine, azelastine, levocabastine, and olopatadine; mast cell stabilizers, e.g., cromoglycic acid (cromolyn) and nedocromil; anti-inflammatory agents, e.g., acetometaphen, aminosalicylic acid, aspirin, celecoxib, choline magnesium trisalicylate, diclofenac potassium, diclofenac sodium, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, interleukin (IL)-10, IL-6 mutein, anti-IL-6 iNOS inhibitor (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, betamethasone, beclomethasone dipropionate, budesonide, dexamethasone sodium phosphate, flunisolide, fluticasone propionate, paclitaxel, tacrolimus, tranilast, triamcinolone acetonide, betamethasone, fluocinolone, fluocinonide, betamethasone dipropionate, betamethasone valerate, desonide, desoxymethasone, fluocinolone, triamcinolone, triamcinolone acetonide, clobetasol propionate, and dexamethasone; immunosuppressive agents and / or immunomodulatory agents, such as antiproliferative agents, cell cycle inhibitors (e.g., paclitaxel, cytochalasin D, infiximab), taxol, actinomycin, mitomycin, agents that promote VEGF, estradiol, NO donors, QP-2, tacrolimus, tranilast, actinomycin, everolimus, methothrexate, 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, catechin, glycating agents, endothelin inhibitors (e.g., ambrisentan, tesosentan, bosentan), statins (e.g., cerivastatin), Escherichia coli heat-labile enterotoxin, and evolved coatings; anti-infective agents, such as anthelmintics (mebendazole);Antibiotics, such as aminoclycoside (gentamicin, neomycin, tobramycin), antifungal antibiotics (amphotericin b, fluconazole, griseofulvin, itraconazole, ketoconazole, nystatin, micatin, tolnaftate), cephalosporin (cefaclor, cefazolin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, cephalexin), β-lactam antibiotics (cefotetan, meropenem), chloramphenicol, macrolide (azithromycin, clarithromycin, erythromycin), penicillin (penicillin G sodium salt, amoxicillin, ampicillin, dicloxacillin, nafcillin, piperacillin, ticarcillin), tetracycline (doxycycline, minocycline, tetracycline), bacitracin; clindamycin; colistin methanesulfonate; polymyxin b sulfate; vancomycin; acyclovir, amantadine, didanosine, efavirenz, foscarnet, ganciclovir, indinavir, lamivudine, nelfinavir, ritonavir, saquinavir, silver, stavudine, valacyclovir, valganciclovir, zidovudine; quinolone (ciprofloxacin, levofloxacin); sulfonamide (sulfadiazine, sulfisoxazole); sulfone (dapsone); furazolidone; metronidazole; pentamidine; sulfanilamidum crystallinum; gatifloxacin; and sulfamethoxazole / trimethoprim; interference substance 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 not limited thereto.;

[0295] While not desiring to be bound by theory, in addition to the configurations of the analyte sensors described elsewhere herein, applying a lubricious coating to the sensor can substantially reduce and / or suppress the generation of noise by substantially preventing trauma to the host. Thus, in some embodiments, a lubricious coating may be applied to the in vivo portion of the sensor to reduce the body's response to foreign objects to the implanted sensor. As used herein, the term "lubricious coating" is used in its ordinary sense and includes surface treatments that provide, without limitation, a reduction in surface friction. Various polymers, such as, but not limited to, polyethylene, polycarbonate, polyurethane, poly(ethylene oxide), poly(ethylene oxide)-poly(propylene oxide) copolymers, etc., are suitable for use as lubricious sensor coatings. 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] Dissolvable tip Sensors such as those described above are sometimes referred to as "trocar" sensors because they are similar to trocars. One aspect of this embodiment includes the recognition that a trocar sensor includes a sharpened tip that remains embedded in tissue throughout the life of the sensor. Leaving a sharpened tip in the body for an extended period of time can cause trauma to the surrounding tissue, resulting in scarring and inhibition of wound healing. Some of the embodiments herein provide a solution to this problem. In some embodiments, the tip is configured to dissolve, for example, within about 3, 5, 7, or 10 days during an implantable sensor session.

[0297] As described above and referring also to FIG. 1, the tissue piercing element 108 can be, for example, a distinct and different component from the sensor body 112. In such an embodiment, the sensor body 112 can include a smooth tip or distal surface 126. The tissue piercing element 108 similarly includes a smooth proximal surface 128 that abuts the sensor body tip 126. As described above, the tissue piercing element 108 may or may not be fixed to the sensor body 112.

[0298] In some embodiments, the tissue piercing element 108 can include a biodegradable material or a material that rapidly dissolves after insertion into the host. Upon insertion, degradation of the tissue piercing element 108 can occur spontaneously by 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 can biodegrade / dissolve within 3 days, or within 2 days, or within 1 day, or within 12 hours, or within 6 hours, or within 3 hours, or within 2 hours, or within 1 hour after insertion into the host. In certain embodiments, the material can dissolve within the time frame before the sensor begins to operate. In such embodiments, the dissolved material of the tissue piercing element 108 should not interfere with sensor calibration.

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

[0300] In some embodiments, the material of the tissue piercing element 108 can be adjusted or modified to achieve desired properties such as dissolution time, hardness, etc. For example, the tissue piercing element 108 can be processed by annealing or curing cycles and / or crosslinking. Crosslinking can be light-based, such as irradiation with UV light, for example. In some embodiments, the adjustment can include matching the materials. For example, the hardness of the tissue piercing element 108 can be improved by incorporating hydroxyapatite into the formulation, such as in some bone implants. Such formulations dramatically improve the hardness. Also, including these tends to result in a faster dissolution time.

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

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

[0303] In certain exemplary embodiments, the viscosity of the liquid bath is less than 100 cP, the draw rate is 20 - 30 inches per second, and it is immediately exposed to UV (or heat) crosslinking to cure and form a thickness. A tip mold or draw-through fixture that performs clamping and curing in one step to form a sharp conical shape is advantageous.

[0304] Another embodiment for fabricating 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 to a pointed tip. When 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 can include one or more aspects that either inhibit a wound or promote rapid healing, or both. In certain embodiments, these aspects can be present at the soluble tip 408. For example, one or more bioactive agents can be incorporated into the soluble tip 408 by combining them with the material of the liquid bath during an immersion process. Alternatively, before or after curing, the soluble tip 408 can be immersed in a subsequent liquid bath, thereby coating the soluble tip 408 with one or more bioactive agents. Exemplary bioactive agents have been discussed in detail above and are not repeated here. However, certain bioactive agents can, for example, induce an osmotic pressure or colloidal osmotic pressure.

[0306] In certain embodiments, the material of the soluble tip 408 can have an effect on the sensor 400. For example, if the soluble tip 408 is a salt, this can create an osmotic pressure gradient that draws body fluid towards the tissue surrounding the sensor 400, which can result in it activating earlier or avoiding initial signal attenuation. Soluble needle

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

[0308] Referring to FIG. 5, the needle 502 can include a lumen 504 and a sharp distal tip 506 and can be similar to a standard hypodermic needle 502. However, the material of the needle 502 can be biodegradable or can dissolve after insertion into the host. The material and material properties of the needle 502 can be similar to those described above with respect to the soluble 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 the needle 502 because they can easily form tubes and can be shaped by cutting.

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

[0310] In this embodiment, since the needle 502 is biodegradable / dissolvable, there is no need to remove it from the host after the sensor 500 is inserted. Instead, the needle 502 biodegrades without causing harm, thereby eliminating the traumatic tip 506 and leaving only the sensor 500. The dissolvable needle 502 thus simplifies the process of inserting the sensor 500 into the host. Additionally, since 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 could have been a problem.

[0311] As in the above-described embodiments of the dissolvable tissue piercing tip 506, the dissolvable needle 502 may include one or more bioactive agents for suppressing trauma and / or promoting rapid wound healing. These bioactive agents may be the same as those described above and may be applied / integrated into the needle 502 using the same techniques as those 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 portions (or more and less dissolvable portions), such that in the body, the weak portions dissolve more rapidly and the strong portions then separate from each other. The strong portions may dissolve eventually, albeit more slowly than the weak portions. Such embodiments may be described as "fractionated" with respect to how the weak portions dissolve more rapidly and enable a rigid segment, such as PLA or PGA, that provides sufficient strength during insertion to fragment without damaging the body during or after sensor insertion.

[0313] membrane hardener One aspect of this embodiment includes the recognition that the material of the membrane of the analyte sensor is soft and tends to peel off when the sensor advances within the tissue. This problem is particularly severe 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 and leaves a coating of a thin membrane surrounding the sides at the tip of the sensor body. Some of the embodiments herein 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. Instead of having a separate tissue piercing element as in the previous embodiments, the distal ends 706 of the sensor body 702 and the membrane 704 are sharpened to form a tissue piercing tip 708. Since the sensor is sharpened after being coated with the membrane 704, a portion of the sensor body 702 is 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, and as a result, the sharpened tip 808 will be covered by the membrane 804.

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

[0316] In any of the embodiments illustrated in FIGS. 7 and 8, the soft membranes 704, 804 tend to peel off when advancing through the tissue during the process of inserting the sensor into the host. Further, due to their very small diameter, the sensors of FIGS. 7 and 8 may lack the column strength necessary to be inserted through the host's skin without substantial buckling. To address these issues, some of these embodiments provide a hardening agent 900 that either coats the membrane 902 (FIG. 9) or is integrated into the membrane 902 (FIG. 10). The hardening agent 900 provides an increase in the column strength of the sensor body 904 such that the sensor unit 906 can be inserted through the host's skin 908 without substantial buckling. The hardening agent 900 also improves the adhesion of the membrane 902 to the sensor body 904 and / or stiffens the membrane 902 such that it is more resistant to peeling when the sensor advances through the tissue during the process of being inserted into the host. However, preferably, the hardening agent 900 allows for the permeability of the analyte into the membrane 902 such that it does not interfere with the sensor's ability to function.

[0317] FIGS. 9 and 10 illustrate embodiments where the tip 910 of the sensor body 904 is exposed through the membrane 902 / hardening agent 900, but this embodiment also contemplates that the tip 910 of the sensor body 904 can be coated with the membrane 902 / hardening agent 900, similar to the embodiment of FIG. 8. When the tip 910 of the sensor body 904 is exposed through the membrane 902 / hardening agent 900, in certain embodiments, the material of the sensor body 904 is selected such that it does not react with the selected analyte and / or the product of the analyte reaction. Such a reaction can generate a background current, which can negatively affect the performance of the sensor.

[0318] In one embodiment, the material of the sensor body 904 may be formed using a core that does not react with hydrogen peroxide. One such sensor body is tantalum coated with platinum, where the tantalum core, due to its electrochemical properties, neither reacts with hydrogen peroxide nor contributes to further background signal. The exposure of a small amount of platinum is not likely to significantly contribute to the background signal.

[0319] In certain embodiments, the curing agent 900 includes cyanoacrylate. Cyanoacrylate is a material that is advantageous for use in this application because it can permeate the membrane, cure rapidly, is very hard, and can be machined after curing if necessary. Cyanoacrylate can also destroy any enzymes present at the tip and can coat any electrochemically active surface. Other exemplary materials include epoxies and UV adhesives.

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

[0321] Exposing the coated wire to the curing agent can include immersing at least the sensor tip in a liquid bath of the curing agent. After withdrawing the sensor wire from the liquid bath, the membrane is cured to cure the curing agent. Thereafter, the sensor tip can be sharpened to form a sharp tip capable of piercing tissue. In an alternative embodiment, the sensor wire may be sharpened before applying the membrane to the sensor wire or after applying the membrane to the sensor wire but before applying the curing agent.

[0322] In embodiments where the sensor tip is sharpened after applying the membrane and hardener, a quenching agent may be applied to the sharpened sensor tip to eliminate any active surfaces that are exposed during the sharpening step. For example, platinum (Pt) or an enzyme layer may be considered an "active surface". In some embodiments, the quenching agent may include cyanoacrylate or silane. Silane may be particularly advantageous as it is lubricious and may assist the sensor in penetrating 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 spraying agent, followed by a rinsing cycle.

[0324] In another embodiment, a method of fabricating a sensor device includes coating a wire with a membrane. The coated wire is then cut to a desired length to form a sensor wire having a tip. The coated wire is then exposed to a hardener such that the hardener coats the membrane. Further processing steps may then be performed as in the previous embodiments, such as curing and sharpening.

[0325] In another embodiment, a method of fabricating 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 tip that can penetrate tissue. The sensor wire, including the sharpened sensor tip, is then coated with a membrane. The coated sensor wire is then exposed to a hardener such that the membrane absorbs the hardener. Further processing steps may then be performed as in the previous embodiments, such as curing.

[0326] In another embodiment, a method of fabricating a sensor device includes cutting a wire to a desired length to form a sensor wire having a tip portion. The sensor tip portion is then sharpened to form a sharp tip capable of penetrating tissue. The sensor wire, including the sharpened sensor tip portion, is then coated with a membrane. By coating the membrane, the host body fluid is separated from the enzyme by the protective membrane system, avoiding the enzyme from leaching into the host, and ensuring control of the diffusion path of the host body fluid through the membrane system containing the enzyme. The coated sensor wire is then exposed to a curing agent such that the curing agent coats the membrane. Further processing steps may be performed as in the previous embodiments, such as curing.

[0327] Stimulus-responsive material In any of the embodiments described herein, the sensor body (e.g., a wire) can be one or more "stimulus-responsive materials" that change at least one property in response to a stimulus. For example, the sensor body can 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 can be held in a first configuration that can be curved or straight while in a first state. During or after the insertion process, the wire transitions to a second state that can 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 changes to the first temperature (e.g., by heating or cooling), thereby causing the sensor to be straight and rigid, i.e., having properties that facilitate penetration into the 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 mechanical properties adapted to the tissue upon insertion and application of the stimulus. To reduce the body response to trauma and foreign bodies caused by the presence of the sensor and body movement, it is advantageous to match the inserted sensor body to the natural tissue constructs and coefficients, since such body responses to such trauma or foreign bodies can unfavorably change the output of the sensor. For example, the elastic modulus of the sensor body can be about 0.5 to 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 equivalent to that of a typical needle outside the body to a softness closer to that of a typical needle in the body, in fact, closer to subcutaneous tissue), shape, permeability, relative hydrophilicity, higher-order structures of polymer orientation, etc. Examples of stimuli used to change the properties include, but are not limited to, temperature (e.g., 37 °C for changes in the body), pressure, hydration into the subcutaneous environment upon insertion, radiation provided by a skin patch (e.g., UV), electromagnetic stimulation, e.g., by voltage, magnetic field, e.g., by an inductive magnetic field, 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 a polyurethane that changes its elastic modulus by a factor of 10 at 37 °C. Other examples include sensor bodies formed from polyurethane copolymers that soften when an electrical or radiation (e.g., UV) stimulus is applied immediately after sensor insertion.

[0332] Sensor Certain embodiments described herein provide various mechanisms for directly inserting a transcutaneous sensor into a host without using 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 difficult due to the risk of buckling associated with the sensor. Direct pressure insertion of the sensor also presents issues related to damaging the membrane disposed on the sensor during the insertion process. If the membrane is not protected, the membrane can peel off from the sensor or be mechanically damaged during the insertion process. It is also desirable to have no exposed metal (or other conductive material) at the tip of the sensor, as the exposed metal can be electroactive and add background signal (noise) and / or vary the sensitivity of the sensor. The embodiments described herein are designed to overcome the aforementioned problems by providing a small 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 can protect the membrane from damage during the insertion process.

[0333] In some embodiments, the sensor is designed in a configuration where electrodes (e.g., working and / or reference electrodes) can be printed onto a sensor body (e.g., a core). Unlike printing materials onto a planar substrate, printing materials (e.g., electrode materials) onto a wire presents unique challenges, particularly for wires having a diameter of less than 400 microns (μm) and intended for embedding, as is the case for the majority of the sensor embodiments described herein. FIGS. 11 - 14 illustrate various sensor designs in which electrodes can be printed onto a sensor body formed in a wire shape.

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

[0335] Referring to FIG. 12, the electrode 1008 does not extend over the entire outer circumference of the jacket 1004. The gap in the outer circumference allows a conductive trace 1012, which is configured to contact and join between the electrode 1010 and the conductive component 1006, to extend along the jacket 1004. A layer 1014 of electrically insulating material covers over the conductive trace 1012 to prevent contact between the conductive trace 1012 and the electrode 1008. In one embodiment, the system comprises three electrodes: the electrode 1008 including a reference electrode or a counter electrode, and the first and third electrodes 1002, 1010 including working electrodes. In another embodiment of the system having three electrodes, the electrode 1010 functions as a reference or counter electrode while the electrode 1008 functions as a working electrode. In another example, the system comprises two electrodes. In one such embodiment, the core wire 1002 does not function as a working electrode and thus 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] As described above, the sensors 1000 of FIGS. 11 and 12 are 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 where the core 1002 does not function as an electrode (e.g., in two-sensor systems), the distal end 1016 of the core 1002 of the sensor 1000 may be non-conductive, and as a result, it does not generate a background signal. For example, the conductive core wire 1002 can be inactivated 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] Figures 13 and 14 illustrate another sensor 1020 configured to perform direct pressure 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 the non-conductive layer 1028 and are electrically connected to sensor electronics (not shown) by conductive traces 1030, 1032, 1034 provided on the outer surface of the non-conductive layer 1028. In the illustrated embodiment, the electrode 1024 does not extend entirely around the outer 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, the electrode 1022 also does not extend entirely around the outer periphery of the non-conductive layer 1028, thereby providing a conductive path for the electrodes 1026 and 1028 around the electrode 1022. The electrodes 1022, 1024, 1026 can be working electrodes, reference electrodes, and / or counter electrodes. For example, in one embodiment, the electrode 1026 functions as a working electrode, while the electrode 1024 functions as a reference electrode, and the electrode 1022 functions as a counter electrode. The elements illustrated in FIGS. 11-14, as well as all other figures provided herein, may not be drawn to scale and are provided merely to illustrate the present embodiment and to aid in its better understanding.

[0339] The embodiments shown in FIGS. 11-14 are designed to have a configuration that enables printing of the electrodes, but such sensor designs can alternatively or additionally be manufactured by any of the various techniques described herein or elsewhere.

[0340] Often, the geometry of the sensor and the properties of the membrane can be difficult to control at the sharpened tip. There is also a potential for damage in this area. Therefore, it may be desirable for the tip not to be part of the working electrode. Additionally, 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 to perform direct pressure 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 comprise one, three, four, five, or more electrodes, at least one of these electrodes being a working electrode and at least one of these electrodes being a counter or reference electrode. The core wire 1042 can be formed from a conductive material (e.g., tantalum or stainless steel) or a non-conductive material such as a polymer or non-conductive metal.

[0341] Referring again to FIG. 15, the electrodes 1044, 1048 can include a conductive material such as platinum, platinum-iridium, carbon, silver, silver / silver chloride, and / or any other material known to form electrodes (e.g., working, reference, or counter electrodes), but are not limited thereto. In one embodiment, both electrodes 1044, 1048 are working electrodes, and thus, collectively form an array of working electrodes. In this particular embodiment, the electrodes 1044, 1048 can share a conductive trace or path. In another embodiment, one electrode is a working electrode and the other electrode is a 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 therebetween for every two layers of conductive material. In these embodiments, the working electrodes each have a dedicated electrical connection to an electrical contact through an individual conductive layer.

[0342] In one process for fabricating sensor 1040, core wire 1042 is positioned on substrate 1046 and electrodes 1044, 1048 can be printed onto core wire 1042 using a platinum paste (e.g., by pad printing). Any of a variety of printing techniques can be used, such as pad printing or 3-D printing, but are not limited thereto. Advantageously, by selectively disposing a layer of platinum paste along the length of non-conductive core wire 1042, the use of materials can be reduced and a non-electrically active sensor tip can be maintained. In some embodiments where wire core 1042 is coated by a plurality of conductive material layers with insulating layers disposed therebetween, these conductive materials may be formed from a non-electrically active conductive material such as tantalum, for example. A layer of platinum or silver / silver chloride, both conductive and electroactive, can then be pad printed onto these conductive layers to form an electroactive surface and thereby form electrodes. Since the raw material costs of tantalum and other conductive non-electrically active materials can be lower than those of materials that are conductive and electroactive (e.g., platinum), sensors can be manufactured at low cost by using this method.

[0343] There is often a trade-off between ease of sensor insertion and patient comfort. A sensor formed of a rigid, non-flexible material is less likely to buckle during sensor insertion than a soft, flexible sensor, all other things being equal. However, after implantation, due to its rigidity and non-flexibility, such a sensor may not be comfortable for the patient wearing the sensor, especially if there is normal movement at the sensor site. In contrast, a sensor formed of a soft, flexible material is likely to buckle during sensor insertion and may therefore not be a viable sensor design for implantation by direct insertion.

[0344] Figures 16 and 17 illustrate one concept that overcomes the two design criteria described above. Referring to FIG. 16, sensor 1060 is formed on a flat substrate, such as a sensor based on a planar substrate. Sensor 1060 can incorporate any sensor features described herein (e.g., electroactive surfaces and membranes) and 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 to press-fit into the host's skin and tissue during the implantation procedure. By rolling the planar sensor, an overlapping region 1062 is created where two opposing edges 1064, 1066 meet. The overlapping portions can be fixed to each other, for example, with an adhesive, a bonding layer, a temporary adhesive, etc., as would be understood by those skilled in the art. For example, an adhesive may be applied to the overlapping region 1062, where the adhesive dissolves after the sensor 1060 is implanted. When the adhesive dissolves, the rolled substrate unfolds and returns to its planar shape (FIG. 16). Since the planar sensor 1060 can be more flexible than the rolled sensor 1060, the sensor 1060 can be more comfortable for the host. Alternatively, the adhesive may not dissolve completely, but instead may simply weaken, thereby improving the flexibility or softness of the sensor 1060 without fully unfolding. In the illustrated embodiment, sensor 1060 includes a planar or linear tip 1068 in both its planar form (FIG. 16) and its rolled form (FIG. 17). However, sensor 1060 may include a beveled tip such that in either, or both, its planar and rolled forms, the sensor mimics the (sharp) shape of the tip of the 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 in order to provide better comfort to the patient. In some embodiments, a sheath may be used to provide additional column strength to the sensor during sensor insertion to reduce the risk of buckling of the sensor during insertion.

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

[0347] Referring to FIG. 18, sensor 1070 includes a retractable introduction sheath 1072 that covers membrane 1074 during the insertion procedure. Introduction sheath 1072 not only protects membrane 1074 during the insertion procedure, but can also support sensor 1070 and provide additional column strength to sensor 1070 to improve its resistance to buckling. After insertion, introduction sheath 1072 is retracted (FIG. 19), leaving sensor 1070 with membrane 1074 uncovered embedded in the host's skin and the underlying tissue.

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

[0349] Often, the unprotected membrane can be damaged and / or delaminated during sensor insertion. This can potentially render the implantable sensor unusable. In some embodiments, the sensor is designed to have a portion at the distal end with a larger cross-sectional profile than the rest of the sensor. This configuration provides a protective effect, such that when the sensor slides through tissue during sensor insertion, the portion at the distal end described above (partially or fully) protects the rest of the sensor from contacting the tissue. In some embodiments, one or more regions of the surface of the sensor body and / or the tissue piercing element may include one or more recessed portions (e.g., cavities, depressions, openings, grooves, channels, etc.) configured to function as a reservoir or storage site for holding a bioactive agent. The recessed portions may be formed at any preselected location, with any preselected depth, size, geometry, and / or dimensions, according to the intended use. By using a reservoir or storage site, the amount of bioactive agent that the sensor can hold and deliver can be increased. In further embodiments, the sensor body and / or the tissue piercing element may be hollow with a cavity and may be 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 the tissue piercing element may comprise a pocket that is shaped and sized to support a sensor with a membrane disposed thereon.

[0350] Figures 20-22 illustrate embodiments incorporating the foregoing concepts into a 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. Referring to FIGS. 20 and 21, sensor 1080 defines a "positive sign" shape or an x-shaped cross-section that defines four equally spaced troughs 1084 over the entire length of the longitudinal axis of the sensor, except for the distal end 1085 (FIG. 21). At the distal end 1085, sensor 1080 includes a plurality of outer peripheral sections 1088 that provide a larger cross-sectional profile at the distal end of sensor 1080 than the remainder of sensor 1080. Referring to FIG. 22, along its longitudinal axis, sensor 1082 defines a circular cross-section having a single trough or notch 1086, except for the distal end 1087 where there is no trough or notch and the cross-section is completely circular. Troughs 1084, 1086 can define a space for disposing electrodes and a membrane that coats the electrodes, such that as a result, the electrodes and the membrane will at least closely overlap or preferably recess under the outer perimeters 1088, 1090 of sensors 1080, 1082. By recessing the electrodes and the membrane (or positioning them to closely overlap the outer perimeter of the sensor), a space is created between the membrane and the host's skin and tissue to protect the membrane from damage by shear forces caused by the host's skin / tissue during the sensor insertion procedure. The troughs need not extend completely to the tip of the sensor body to further protect the membrane during sensor insertion. After sensors 1080, 1082 are inserted, the fixation / relaxation of the host's tissue increases the desired contact between the electrodes and the host's body fluid required for proper sensor function. The cross-sectional shapes illustrated in FIGS. 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 shape (having any number of points), quadrilateral, pentagon, heptagon, octagon, ellipse, etc. This embodiment can have any number of troughs for positioning, for example, one, two, three, five, nine, twelve, or more electrodes.

[0351] FIG. 23 illustrates another sensor 1102 configured to perform direct pressure insertion according to the present embodiment. The sensor 1102 of FIG. 23 includes a protective sheath 1104 that covers the sensor 1102 during the insertion process. After the sensor 1102 is inserted, the sheath 1104 is retracted partially or completely to expose the sensor 1102 and / or the sensor tip 1106. Similar to the embodiment illustrated in FIG. 18, the protective sheath 1104 can not only protect the membrane during the insertion procedure, but also provide additional column strength to improve resistance to buckling. Further, 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 can occur between the sheath and the surrounding tissue. This space then becomes filled by the surrounding tissue as the tissue moves towards the sensor. Without wishing to be bound by theory, when the tissue moves towards and contacts the sensor, a better tissue-sensor interface can be formed than in the reverse case (e.g., less trauma, less inflammation, less risk of bleeding, etc.).

[0352] FIG. 24 illustrates another sensor 1108 configured to perform direct pressure insertion according to this embodiment. The sensor 1108 includes one or more through-holes 1110, and the membrane(s) 1112 are disposed within these 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. The through-holes 1110 shown in FIG. 24 are substantially circular, although in some embodiments, the through-holes may be shaped or sized differently. These differences can result in different behaviors of the electroactive surfaces and / or different measurements in each of these through-holes. For example, a deep through-hole can contain a larger volume of interstitial fluid compared to a shallow through-hole. Thus, in some situations, the electrodes corresponding to deep 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 has a faster replacement rate, and the electrodes corresponding to shallow through-holes may have fewer delay time problems, which can be important when the analyte concentration in the patient changes rapidly. In other embodiments, the various shapes and dimensions of the through-holes can be designed differently for measuring various species. For example, one of the through-holes may have a shape and / or dimensions such that the corresponding electrode can better measure oxygen rather than another analyte (e.g., glucose) compared to the others.

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

[0354] In some embodiments, sensor 1116 can be coated by a particle-containing film system that includes a conductive component dispersed in a non-conductive component (e.g., a polymer film material). The conductive component can include a plurality of conductive particles dispersed throughout the film system, some of which are at least partially coated with an enzyme material (e.g., glucose oxidase) configured to generate a species that is measured by the conductive particles that generate a signal. The conductive particles can 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 recesses 1118, such as some or all of recesses 1118, can contain an enzyme and / or a membrane material. For example, the membrane can fit snugly over the outer surface of sensor 1116 or can be recessed beneath the outer surface of sensor 1116. By recessing the membrane(s) (or positioning them to fit snugly over the outer surface of sensor 1116), a space is created between the membrane and the host's skin and tissue to protect the membrane from damage by shear forces caused by the host's skin / tissue during the sensor insertion procedure. After sensor 1116 is inserted, the settling / relaxation of the host's tissue increases the desired contact between the electrodes and / or membrane and the host's body fluid that is required for proper sensor function. Alternatively, the membrane can protrude from the outer surface of sensor 1116. Sensor 1116 shown in FIG. 25 further includes an outer bioprotective layer (not shown) or a biointerface layer formed from a hydrophilic material to enable easy sensor insertion and reduced friction with the surrounding tissue even with a weak pressing force.

[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 to perform direct pressure insertion according to the present embodiment. Sensor 1120 includes a plurality of axially spaced recesses 1122 configured to receive an enzyme and / or membrane material 1124. Sensor 1120 further includes an outer layer 1126 made of a material that is permeable to one or more selected analytes, including but not limited to glucose. Outer layer 1126 not only protects and safeguards the sensor 1120 / membrane 1124 system below during the sensor insertion procedure, but can also provide stiffness and / or increased column strength for resistance to buckling during insertion. Since outer layer 1126 is highly permeable to one or more selected analytes, it has no substantial adverse effect on the functionality of sensor 1120.

[0358] Any of the embodiments described herein can incorporate an outer layer. Examples of materials for outer layer 1126 include, but are not limited to, non-glucose limiting hydrogels, polymer and / or carbohydrate films (e.g., cellulose acetate film), or metal films having microporous structures or microchannels that allow an analyte (e.g., glucose) to pass therethrough, or lattice structures formed from a metal or rigid polymer and having apertures sized to allow an analyte to pass therethrough. Polymers and / or saccharides 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 described above, the hardness of the outer layer 1126 can provide additional column strength to the sensor and enhance its ability to protect the film. For any sensor described in this application with an outer layer, the outer layer can be formed using materials that have a hardness of about 30 to about 95, sometimes about 70 to about 90, and sometimes about 50 to about 70 on the Shore A scale.

[0360] Figure 27 illustrates another sensor 1128 configured to perform direct pressure insertion according to this embodiment. The sensor 1128 includes a sensor body 1130 having an overlapping membrane 1132 and a protective outer layer 1134 disposed over the sensor 1128 / membrane 1132 system. The protective outer layer 1134 not only protects and safeguards the sensor 1128 / membrane 1132 system below during the sensor insertion procedure, but may also provide hardness 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 soluble material such as a polymer. In some embodiments, the protective layer is formed from a material that is in a rigid state when dried and / or at room temperature (or lower than room temperature). 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. When exposed to body temperature and / or hydration, the protective layer becomes soft and flexible. In this state, the protective layer provides better comfort to the patient wearer. Examples of soluble and / or degradable polymers include, without limitation, polyvinyl-pyrrolidone (PVP), polymeric saccharides such as carmellose, polyvinyl acetate, polyethylene glycol, polyester, 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 having benzene in the side chains), polyorthoesters, polyamino acids (e.g., poly-L-lysine, polyglutamic acid), pseudo-polyamino acids (e.g., where the backbone of the polyamino acid is modified), polycyanoacrylate, polyphosphazene, and combinations or copolymers of these and other similar polymers. Examples of non-polymeric soluble materials include, without limitation, saccharides (e.g., maltose), liquid oleic acid, vitamin E, peanut oil, and cottonseed oil, and other similar compounds. After inserting the sensor 1128 and the protective outer layer 1134 has dissolved, the sensor 1128 becomes more flexible (compared to the coated sensor 1128) for enhanced comfort of the host.Alternatively, the protective outer layer 1134 may include a material that does not completely dissolve but softens after insertion into the host to enhance the comfort and feel of the sensor 1128. Examples of softening 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, pseudo-polyamino acids, polycyanoacrylate, or polyphosphazene, and copolymers, blends, or combinations thereof, and similar polymers. The protective outer layer 1134 can be formed by immersing the sensor body 1130 and the membrane 1132 in a solution of the outer layer 1134 material, which subsequently solidifies and cures. The immersion process can be adjusted to provide a thinner coating at the tip 1136 to assist insertion. The solution can be reactive or non-reactive, and the reactive solution can be further reacted to increase the protective strength and mechanical support for insertion.

[0361] FIG. 28 illustrates another sensor 1138 configured to perform direct pressure insertion according to the present 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 is / are positioned over the electrodes such that the electrodes (and any optional film(s) overlapping the electrodes) are exposed for contact with the host tissue and / or body fluid. The outer layer 1140 not only protects and safeguards the sensor 1138 / film system beneath it during the sensor insertion procedure, but can also provide rigidity and / or increased column strength for resistance to buckling during insertion. Exemplary materials for the outer layer 1140 include, without limitation, 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.

[0362] FIG. 29 illustrates another sensor 1144 configured to perform direct pressure insertion according to the present embodiment. The sensor 1144 includes a conductive wire 1146 that may include metal or any other conductive material. An outer coating 1148 is disposed on the wire 1146. The outer coating 1148 may have a greater thickness than the wire 1146. For example, the outer coating 1148 may be 1.5 times thicker than the wire 1146, may be 2 times thicker than the wire 1146, may be 2.5 times thicker than the wire 1146, may be 3 times thicker than the wire 1146, may be 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 a polymer, without limitation, such as cyanoacrylate polymer, polyurethane, polyurethane urea, polyacrylate, polystyrene, polysulfone, polyether ketone, polycarbonate, polyimide, polyester, polyether, epoxide, polytetrafluoroethylene, 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] The sensor 1144 further includes a highly permeable outer layer 1154, without limitation, such as a hydrogel, that overlaps the membrane 1152 in the region(s) of the window(s) 1150. The highly permeable outer layer 1154 provides mechanical buffering against damage to the membrane 1152 and / or the electrode(s) positioned below the highly permeable outer layer 1154.

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

[0366] FIG. 30 illustrates another sensor 1156 configured to perform direct pressure insertion according to this embodiment. The sensor 1156 includes a membrane 1158 that is applied only to one or more regions of the sensor 1156. The membrane 1158 may closely overlap the outer surface 1160 of the sensor 1156, may be recessed below the outer surface 1160 of the sensor 1156, or may protrude from the outer surface 1160 of the sensor 1156. In embodiments where the membrane 1158 closely overlaps or is recessed below the outer surface 1160 of the sensor 1156, the membrane 1158 may be positioned within one or more openings or windows within 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 lithography if the film formation can be site-specific. In some embodiments, printing is preferred because it allows for highly localized and controlled film formation.

[0367] The outer surface 1160 of the sensor 1156 of FIG. 30 may include a polymer, without limitation to regions other than the membrane 1158, such as polytetrafluoroethylene (PTFE), cyanoacrylate polymer, polyurethane, polyurethane urea, polyacrylate, polystyrene, polysulfone, polyether ketone, polycarbonate, polyimide, polyester, polyether, epoxide, and combinations, blends, or copolymers thereof. At the distal end of the polymer, a piercing tip 1162 may be included that is configured to penetrate the skin and / or tissue and has desirable properties for insertion. This sensor 1156 of FIG. 30 advantageously simplifies the process of creating the sensor 1156 by not "blunting" the distal tip 1162 by applying the membrane 1158 to the tip 1162. This sensor 1156 of FIG. 30 can advantageously be used in combination with membrane protection in other forms, such as any of the embodiments described elsewhere herein. Manufacturing techniques

[0368] One aspect of this embodiment includes the recognition that the materials used to form the membrane of an analyte sensor are often soft and thus tend to delaminate (i.e., peel and sometimes separate) as the sensor advances through the 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 and leaves a coating of a thin membrane surrounding the sides at the tip of the sensor body. Some of these embodiments provide a solution to this problem that includes a method of forming the tip without damaging the tip and at the same time maintaining the integrity of the tip after applying the membrane.

[0369] Regarding sensor manufacturing, there are two approaches regarding whether the membrane coating step should precede the tip forming step sharpened, or whether the tip forming step sharpened should precede the membrane coating step. In the first approach, the membrane is coated on the sensor processing member prior to the immersion that forms the sharpened distal end. In this first approach, the technical challenge involves finding a technique that enables the creation of a sharpened tip without causing damage to the membrane and / or without creating excess membrane at the tip.

[0370] Referring to FIGS. 30A and 30B, in one way of adopting the first approach, the membrane 1161 is coated on the sensor processing member 1163. In some cases involving immersion, beads 1165 (FIG. 30A) can be formed at one end of the processing member 1163. Then, for example, using laser ablation, or mechanical cutting or grinding, the distal end of the processing member 1163 is sharpened to form the tip 1167 (FIG. 30B). By doing this, the beads 1165 at the distal end of the processing member 1163 are removed. In the illustrated embodiment, sharpening the distal end of the processing member 1163 involves removing material only from one side of the processing member 1163, and thus forming a tip 1167 having a shape similar to the tip of a hypodermic needle. In an alternative embodiment, the material can be removed from both sides of the processing member 1163 to form a wedge-shaped tip. In yet a further alternative embodiment, the material can be removed from the processing member 1163 at 360 degrees to form a conical tip.

[0371] FIGS. 31 - 33 illustrate another process for creating a sensor that adopts the first approach. Referring to FIG. 31, the conductive wire 1164 includes a membrane 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] The processes of FIGS. 31 - 33 may include the step of applying the membrane 1166 to the wire 1164, or the process may start with the wire 1164 already coated with the membrane 1166. An annular channel 1168 is then formed around the entire outer circumference of the coated wire 1164. The channel 1168 extends through the membrane 1166 and partially into the wire 1164. The channel 1168 can 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 membrane from covering the distal tip, which is advantageous because in other processes, the membrane subsequently has to be removed from the tip, thereby adding another process step.

[0373] Referring to FIG. 32, either after or simultaneously with the formation of the channel 1168, tension is applied to the coated wire 1164. The tension induces strain in the wire 1164 within the region of the channel 1168, causing necking and ultimately fracture of the wire 1164. The necking process results in sharp tips 1170 at each end of the two cut wire pieces 1164, each of these sharp tips 1170 including the conductive wire material 1164 which can be metal. In some embodiments, in addition to subjecting the channel 1168 of the wire 1164 to tension, the channel 1168 may be further 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 tip may be subjected to further mechanical processing (e.g., by using a sharpener, grinder, mold, etc.) to shape the distal tip to be sharp. This sharp tip 1170 can advantageously be used to penetrate the skin and / or tissue during the sensor insertion process.

[0374] Referring to FIG. 33, a sharp tip portion 1170 formed by tearing the coated wire 1164 may subsequently be coated with a protective outer layer 1172 to protect the exposed conductive wire 1164 and / or film 1166. The protective outer layer 1172 may include, for example, without limitation, cured polymers such as cyanoacrylate polymers, polyurethanes, polyurethane ureas, polyacrylates, polystyrenes, polysulfones, polyether ketones, polycarbonates, polyimides, polyesters, polyethers, epoxides, polytetrafluoroethylene, and copolymers, combinations, or blends thereof. Additionally, 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 with respect to the outer protective layer. Any process may be applied to the protective outer layer 1172, such as a solution-based coating in which reactive monomers and / or oligomers or non-reactive polymers are pre-dissolved, mixed, or dispersed, extrusion, or printing, or any other process described herein or elsewhere with respect to coating.

[0375] The sensors formed by the processes of FIGS. 31-33 advantageously include a sharp tip portion 1170 that can be used to penetrate the skin and / or tissue during the sensor insertion process. In certain embodiments, the film 1166 preferably does not overlap the sharp tip portion 1170 in order to avoid blunting of the tip portion 1170, which would render the tip portion 1170 less effective for penetrating the skin and / or tissue.

[0376] Figure 34 corresponds to another process for fabricating a sensor that employs the first approach described above, where the membrane is coated onto the sensor machining member prior to the formation of the sharpened distal tip. This process includes a wire stock 1174 having a membrane coating 1176. The wire stock 1174 can be a non-conductive and non-electrically active material such as, without limitation, polyurethane, polyurethane urea, polyacrylate, polystyrene, polysulfone, polyether ketone, polycarbonate, polyimide, polyester, polyether, polyamide, and blends, combinations, or copolymers thereof. The process of Figure 34 can include the step of applying the membrane 1176 to the wire stock 1174, or the process can begin with a wire stock 1174 that already has the membrane 1176 coated thereon.

[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 merely an example and is not limiting.

[0378] In the process of Figure 34, the entire length of the wire stock 1174 is coated with the membrane 1176. Then, when the winding of the wire stock 1174 is unwound from the reel 1178, portions of the membrane 1176 are selectively removed at spaced positions along the wire stock 1174. The membrane 1176 can be removed at various positions related to the final sensor, such as the tip and / or any other position along the length of the final sensor. In one non-limiting example, the membrane 1176 can be removed by a laser ablation process using a laser 1180. After a particular portion of the membrane 1176 has been removed, the wire stock 1174 is cut at the spaced positions to form a plurality of membrane-coated sensor wires. Advantageously, for the membrane-coated sensor wire, the sensor tip does not have the membrane 1176 that can smooth the tip and make the tip unsuitable for penetration into the skin and / or tissue.

[0379] In an alternative process, the membrane 1176 may be removed from the sensor tip by the detachment step itself. Thus, for example, a separate step (other than the detachment step) may not be required 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 metal. After detachment, then, another material, such as a polymer cap or a second coating, may be applied to cover the sensor tip to prevent the tip from generating a background signal when the sensor is inserted into the 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 not only to protect the underlying membrane or to improve the column strength of the sensor, but also to inhibit movement of the sensor membrane during sensor insertion. A typical sensor membrane is fragile and can shift in position during the sensor insertion process, resulting in a degradation of sensor performance. It is preferred that the sensor remain in the correct position on the sensor wire with little or no mechanical movement relative to the sensor wire. Movement of the membrane can cause the membrane to no longer cover the electrode(s). Similarly, in extreme cases, the membrane can become completely delaminated from the sensor. In addition, the sensor tip may be exposed before or during the insertion process, generating a background signal and / or causing variations in sensor sensitivity. Further, after applying the membrane, it may be desirable to grind or otherwise process the tip of the sensor. Grinding or other processing can expose the sensor wire, which can also generate a background signal and / or cause variations in sensor sensitivity. Referring to FIGS. 35 - 37, the process of fabricating the sensor employs the above-described first approach of coating a film on the sensor machining member prior to forming the sharpened distal dipping 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 of the conductive materials disclosed elsewhere in this specification. In an alternative embodiment, a process similar to that shown in FIGS. 35 - 37 can involve a bare wire 1182 (i.e., without a film thereon) and a step of 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 sharp tip 1190. Alternatively, the sharp tip 1190 may be obtained by a process other than grinding, including any of the other sharpening, cutting, or severing techniques disclosed herein or elsewhere. Through grinding or other processing, the distal end 1186 of the sensor wire 1182 is exposed.

[0381] Referring to FIG. 37, a coating 1192 is applied to the distal end 1186 of the membrane coating wire 1188. The coating 1192 can be, for example, without limitation, a hard polymer such as, for example, cyanoacrylate, or a cyanoacrylate polymer, polyurethane, polyurethane urea, polyacrylate, polystyrene, polysulfone, polyether ketone, polycarbonate, polyimide, polyester, polyether, epoxide, or any other material(s) that can prevent detectable movement of the 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. Advantageously, the coating 1192 creates an impermeable barrier on the exposed end face 1192 of the conductive sensor wire 1182, rendering the end face 1192 non-electrically active and thus unable to generate a background signal and / or cause variations in sensor sensitivity. The coating 1192 can also penetrate the membrane 1184 to cure or harden the membrane 1184, adhere it more firmly to the wire 1182, and further mechanically stabilize the membrane 1184.

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

[0383] In some embodiments, a material (e.g., a membrane or outer layer material) is coated onto a sensor processing member (e.g., a sensor wire) using a dipping technique, where the sensor processing member is immersed in a solution containing a material for forming a thin film or layer on the processing member. Often, the distal end of the processing member is the portion of the processing member that is first immersed, as it is placed at a lower vertical position than other portions of the processing member during the dipping process. Due to gravity, the applied coating typically drips towards the lowest end (i.e., the distal end) of the sensor processing member, resulting in, in some embodiments, blunting of the distal tip used for piercing the skin and / or tissue. Without wishing to be bound by theory, all else being equal, the gravity-induced dripping problem can be more severe for coatings formed from low-viscosity solutions compared to high-viscosity solutions.

[0384] Figures 38 and 39 illustrate a process designed to overcome these technical challenges. Referring to Figure 38, this process includes a sensor wire 1194 having a sharp distal tip 1196. The sensor wire 1194 is immersed in a membrane solution with the tip side down, and a membrane 1198 is formed 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 Figure 39. The membrane 1198 can be removed using any of a variety of processes, such as, without limitation, laser ablation, electrolytic polishing, bead blasting, dry ice blasting, firing, or any other process. After removing the membrane 1198 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, polyurethane ureas, polyacrylates, polystyrenes, polysulfones, polyether ketones, polycarbonates, polyimides, polyesters, polyethers, epoxides, and any other materials used to form a protective layer disclosed herein or elsewhere.

[0385] Figures 40 and 41 illustrate another process for removing the membrane material from the distal end of the sensor wire. Referring to FIG. 40, the sensor 1204 is immersed in the membrane solution, and the still-wet solution 1206 forms beads 1208 at the distal end 1210 of the sensor. Referring to FIG. 41, the distal end 1210 can be wiped with the 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, cloth, cotton swabs, wick pads, sponges, and the like. In another embodiment, instead of absorbing the excess membrane coating at the distal end, the tip can be used to contact the beads 1208 to break the surface tension, thereby dropping (if not all) a portion of the excess membrane coating from the distal tip. In certain embodiments, this procedure may be performed in conjunction with the above-described process for absorbing the excess membrane coating.

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

[0387] Referring to FIG. 43, a terminal cap 1220 is applied to the tip of the membrane-coated wire 1214. The terminal cap 1220 is rigid and preferably resistant to biofouling (e.g., resistant to protein attachment to the membrane, which can reduce the permeability of the membrane to the analyte), and includes a material that can be formed or machined. Exemplary materials include, without limitation, polytetrafluoroethylene (PTFE), cyanoacrylate polymer, polyurethane, polyurethane urea, polyacrylate, polystyrene, polysulfone, polyether ketone, polycarbonate, polyimide, polyester, polyether, and epoxide. The terminal cap 1220 can be applied to the sensor by any desired process such as coating, injection molding, or mechanical interlocking from a pre-formed tip made of polymer or metal. The terminal cap 1220 may include a pointed tip 1222 or may be processed to provide a pointed tip 1222. The pointed tip 1222 is configured to penetrate the skin and / or tissue such that the sensor is configured for direct pressure insertion. The terminal cap 1220 advantageously facilitates direct pressure insertion and simultaneously coats the distal end of the sensor wire 1214 so that it does not become conductive. The terminal cap 1220 can also provide a barrier to protect the distal end of the membrane 1216 and prevent the membrane 316 from slipping off the end of the sensor wire 1214.

[0388] Figures 44 and 45 illustrate another process for fabricating a sensor configured to perform direct pressure insertion according to this embodiment. Referring to Figure 44, this process includes a wire 1224 having a film coating 1226. The wire 1224 can be a conductive material, such as a metal, for example, without limitation, 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 Figures 44 and 45 may include the step of applying the film 1226 to the wire 1224, or this process may start with a wire 1224 that already has the film 1226 coated thereon. Applying the film 1226 to the wire 1224 can include printing, coating, vapor deposition, extrusion, or any other process described herein or elsewhere for coating a material onto a sensor processing member. Further, 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 the multi-layer film 1226 may be formed by a process different from the process(es) used to form at least one other layer 1228.

[0389] Referring to Figure 44, a rigid coating 1230 is formed over the film 1226 at the tip of the sensor. The rigid coating 1230 can include a cyanoacrylate polymer, polyurethane, polyurethane urea, polyacrylate, polystyrene, polysulfone, polyether ketone, 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 can 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] Referring to FIG. 45, the rigid coating 1230 is shaped to provide a sharp tip 1232. The sharp 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 having the sharp tip 1232 advantageously facilitates direct pressure insertion and at the same time coats the distal end of the sensor wire 1224 so that it does not become conductive. The rigid coating 1230 also provides a barrier to protect the distal end of the membrane 1226 and can prevent the membrane 1226 from slipping off the end of the sensor wire 1224.

[0391] FIGS. 46-48 illustrate another process for fabricating a sensor configured for direct pressure insertion according to this embodiment. The sensors produced according to FIGS. 46-48 advantageously do not expose the end portion of the sensor wire, and as a result, the sensor wire is not electroactive at the tip, does not generate a background signal, and does not adversely affect the sensitivity of the sensor. Referring to FIG. 46, the sensor 1234 includes a sensor body 1236 and a piercing tip 1238. The tip 1238 includes a substantially triangular cross-section having a sharp distal end 1240. The proximal end 1242 of the tip 1238 defines a diameter that is larger than the diameter of the sensor body 1236. However, the shape of the sensor 1234 shown is merely an example and is not limiting.

[0392] Referring further to FIG. 46, a membrane 1244 is applied to a sensor 1234 that includes a sensor body 1236 and a piercing tip 1238. The membrane 1244 can be applied by any desired method such as a dipping coating, a spray coating, a brush coating, printing, extrusion, or any other method described herein or elsewhere for coating a membrane onto a sensor processing member (e.g., the sensor body). Referring 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 a particular analyte (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. The coating 1246 can be applied by any desired method such as any method described herein or elsewhere for coating a material onto a processing member. In still other embodiments, instead of applying the coating 1246, the membrane 1244 may be inactivated by a light source or a heat source that can be used to denature the enzyme in the membrane 1244.

[0393] Referring to FIG. 48, a retractable introduction sheath 1248 is applied around the sensor body 1236. The outer diameter of the introduction sheath 1248 is substantially the same as or smaller than its diameter at the proximal end 1242 of the piercing tip 1238. The introduction sheath 1248 covers and protects the membrane 1244 during the sensor insertion procedure and reduces the likelihood that the membrane 1244 will shift or be damaged.

[0394] Figures 49 to 51 illustrate another process for fabricating a sensor configured to perform direct pressure insertion according to the present embodiment. The sensor generated according to Figures 49 to 51 advantageously does not expose the end portion of the sensor wire, and as a result, at the tip, the sensor wire is not electroactive, does not generate a background signal, and does not adversely affect the sensitivity of the sensor. Referring to Figure 49, sensor 1250 includes sensor body 1252, and membrane 1254 is applied to sensor body 1252. Sensor body 1252 can be a conductive material, such as, without limitation, a metal such as tantalum, platinum, or any other conductive metal disclosed herein or elsewhere. Membrane 1254 can be applied by any desired method, such as dip coating, spray coating, brush coating, printing, extrusion, and / or combinations thereof.

[0395] Referring to Figure 50, piercing tip 1256 is applied to the distal end of sensor body 1252. Tip 1256 may be formed in a separate process or as part of the same process that forms sensor body 1252. Tip 1256 may be added to the distal end of sensor body 1252 by any desired process, such as mechanical crimping, press fitting, welding (such as ultrasonic welding), shrink tubing, application of heat, etc. Tip 1256 may include the same material as sensor body 1252 or a different material. For example, tip 1256 may be conductive, such as made of metal, or non-conductive, such as made of non-metal. Exemplary materials for tip 1256 include, without limitation, cyanoacrylate polymer, polyurethane, polyurethane urea, polyacrylate, polystyrene, polysulfone, polyether ketone, polycarbonate, polyimide, polyester, polyether, polyamide, and epoxide.

[0396] The distal end 1256 includes a substantially triangular cross-section having a pointed distal tip 1258. The proximal end 1260 of the distal end 1256 defines a diameter, which is larger than the diameter of the sensor body 1252. However, the shape of the sensor 1250 shown is merely an example and is not limiting.

[0397] Referring to FIG. 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 its diameter at the proximal end 1260 of the piercing distal end 1256. The introducer sheath 1262 covers and protects the membrane 1254 during the sensor insertion procedure, reducing the possibility that the membrane 1254 will shift or be damaged. The introducer sheath 1262 can be made of, for example, metal or non-metal. A non-metal sheath can be made of, for example, without limitation, polyolefin, polyurethane, polyurethane urea, polyacrylate, polystyrene, polysulfone, polyether ketone, polycarbonate, polyimide, polyester, polyether, polyamide, epoxide, or any other material.

[0398] The process of FIGS. 49-51 advantageously maintains the sharpness of the piercing distal end 1256 by not applying the membrane 1254 to the distal end 1256. Also, since there is no membrane 1254 on the piercing distal end 1256, the possibility that the membrane 1254 will tear and / or delaminate during the sensor insertion process is reduced.

[0399] FIG. 52 illustrates another process for fabricating a sensor configured to perform direct pressure insertion according to the present embodiment. 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 can be formed by any process, including, without limitation, dipping, adhesion, 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 for manufacturing an implantable device. In some embodiments, the material of the tip 1270 may include, for example, without limitation, biodegradable / biocompatible materials. Exemplary materials include, without limitation, polymers such as polyvinylpyrrolidone (PVP) and / or polyvinyl alcohol (PVA), sugars such as maltose, and the like.

[0400] The process of FIG. 52 advantageously creates the sharp tip 1270 after the membrane 1268 has been applied to the sensor body 1266. Accordingly, no membrane 1268 that could blunt the sharp tip 1270 is applied to the sharp tip 1270. Another advantage regarding embodiments having a tip 1270 that includes a biodegradable / biocompatible material is host comfort, since the tip 1270 dissolves after insertion. By using a biodegradable / biocompatible tip, the possibility that the tip remains in the body if the tip becomes separated from the sensor can be avoided.

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

[0402] FIG. 52A corresponds to another process for fabricating a sensor configured to perform direct pressure insertion according to the present embodiment. Sensor 1269 includes core wire 1271 and an electrical insulating layer 1273 over core wire 1271. Insulating layer 1273 includes a gap 1275 that exposes a portion of core wire 1271 immediately 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 can include, for example and without limitation, silver chloride. Membrane coating 1281 covers conductive layer 1279, the exposed portion of core wire 1271, and the portion of insulating layer 1273 on the distal side of gap 1275. Distal tip 1277 of core wire 1271 is sharpened prior to the application of membrane coating 1281.

[0403] FIG. 53 corresponds to another process for fabricating a sensor configured to perform direct pressure insertion according to the present 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 rigid enough to form piercing tip 1282 and may include a material that does not necessarily adhere well (or even repels) to membrane 1280. For example, the material of core 1276 may have a low surface energy and may be non-wetting. 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 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 thin films, such as polytetrafluoroethylene. The pre-treatment includes, for example, without limitation, manipulating the surface of the core 1276 to promote the destruction of the thin film. Alternatively, the pre-treatment includes coating with a hydrophobic substance (e.g., a superhydrophobic material) if the portion of the coated membrane to be coated first is hydrophilic, or coating with a hydrophilic substance (e.g., a superhydrophilic material) if the portion of the coated membrane to be coated first is hydrophobic. The hydrophobicity of the surface can be measured by the contact angle with water. The larger the water contact angle, the higher the hydrophobicity of the surface. Generally, if the water contact angle is less than 90°, the surface is considered hydrophilic, and if the water contact angle is greater than 90°, the surface is considered hydrophobic. In some embodiments, the surface of the pre-treated core 1276 is hydrophobic and has a contact angle greater than about 120°, sometimes greater than about 135°, and sometimes greater than about 160°. In some embodiments, the surface of the pre-treated core 1276 is hydrophilic and has a contact angle less than about 60°, sometimes less than about 45°, and sometimes less than about 30°.

[0405] Exemplary materials for the membrane material include, without limitation, any material that can be used to form a membrane on the 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 hereby incorporated 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 the process corresponding to FIG. 53, the outer layer 1278 and / or the film 1280 can be applied to the core 1276 or the sensor body 1274 by any of a variety of coating techniques, such as dipping, spraying, electrodeposition, immersion, casting, or combinations of these techniques. In some embodiments, the core 1276 can proceed 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, after moving the core 1276 in the shape of an elongated object using a reel-to-reel system, it is separated into individual processing members, and after the separation process, the individual processing members are moved using a robotic system. Processes that can be used to apply the outer layer and / or the film include, but are not limited to, those described in U.S. Patent Publication No. 2011-0027458-A1, which is hereby incorporated by reference in its entirety.

[0407] The sharp distal tip 1282 can be formed by any of a variety of techniques, such as, without limitation, cutting by mechanical grinding, diamond wire, high-speed cutting, abrasive waterjet cutting, electrical discharge machining by wire or plunger, electrochemical etching, electrochemical polishing, electrolytic machining, stamping, laser cutting, or any other method for cutting and / or shaping the processing member. In certain embodiments, the sharp distal tip 1282 is formed by electrochemical grinding, which is a process of removing conductive material by grinding using a negatively charged grinding wheel, an electrolytic solution, and a positively charged processing member (in this case, the sensor 1272). The material removed from the processing member remains in the electrolytic solution, whereby the residual coating formed on the surface of the sharpened distal tip can be removed. The above-described techniques (e.g., electrochemical etching, electrochemical grinding) can also be used to form a sharp distal tip on any of the sensors described herein.

[0408] Figures 54 and 54A correspond to another process for fabricating a sensor configured to perform 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 comprises a plurality of layers 1290, where the thickness of each layer 1290 is less than the thickness of a typical single-layer membrane, but the combined thickness of layers 1290 is substantially equal to the thickness of a typical single-layer membrane. For example, membrane 1288 may comprise two layers 1290, or three layers 1290, or four layers 1290, or any other number of layers 1290. The thickness of each layer 1290 can 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 application in an implantable analyte sensor. The thickness of layers 1290 can vary, where one or more of layers 1290 may be thicker or thinner than other layers 1290. In the process corresponding to FIGS. 54 and 54A, applying the membrane layer 1290 to sensor body 1286 can include any of a variety of coating techniques such as, for example, printing, dipping, extrusion, spraying, electrodeposition, casting, or combinations thereof.

[0409] Figures 55 and 56 illustrate another process for fabricating a sensor configured to perform direct pressure insertion according to this embodiment. Referring to FIG. 55, sensor 1292 includes a sensor body 1294 having a sharp distal tip 1296. A membrane 1298 is applied over sensor body 1294 and tip 1296. Then, referring to FIG. 56, membrane 1298 is removed from tip 1296 but not from sensor body 1294. Membrane 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 (polishing, etc.), UV light, or any other process for removing a polymeric material from a substrate.

[0410] Figures 57 and 58 illustrate another process for fabricating sensor 1300 configured to perform direct pressure insertion according to this embodiment. Referring to FIG. 57, sensor 1300 includes a sensor body 1302 having a sharp distal tip 1304. Membrane 1306 is applied over sensor body 1302 and tip 1304 by dipping into membrane solution 1308. Due to gravity, the deposited membrane 1306 forms "beads" in the region of the distal tip 1304. This geometry is typical when the membrane is applied in the dipping process, especially when the membrane solution has a particular viscosity. In certain cases, the beads of membrane 1306 material on distal tip 1304 undesirably blunt tip 1304. Thus, referring to FIG. 58, this process includes dipping the membrane-coated distal tip 1304 into solvent 1310 to dissolve membrane 1306 and substantially remove the membrane 1306 material from the sharp tip 1304 of sensor 1300. Solvent 1310 can include, for example, without limitation, tetrahydrofuran (THF), dimethylacetamide (DMAC), hexafluoroisopropanol, methylene chloride, methanol, methyl ethyl ketone, toluene, and dimethylformamide. In some embodiments, the distal end beads can also be avoided by removing excess material at the tip before solidifying by whipping, spraying, etc.

[0411] FIG. 59 corresponds to another process for fabricating a sensor configured to perform direct pressure insertion according to the present embodiment. Sensor 1312 includes a sensor body 1314 having a sharp distal tip 1316. Membrane 1318 is applied over sensor body 1314 and tip 1316 by dipping into a membrane solution (not shown). Then, before the membrane solution dries, tip 1316 is dipped into a release agent 1320 that prevents membrane 418 from adhering to tip 1316. Release agent 1320 can include, for example, without limitation, silicone, petroleum-based oil, fluorinated compounds (e.g., tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer or perfluoroalkoxy), polytetrafluoroethylene, polyimide, polyetherimide, polyethersulfide, glycerin, and the like.

[0412] FIG. 60 corresponds to another process for fabricating a sensor configured to perform direct pressure insertion according to the present embodiment. Sensor 1322 includes a sensor body 1324 having a sharp distal tip 1326. Sharp tip 1326 is coated with a sacrificial material 1328 that protects tip 1326 during subsequent steps of applying membrane 1330 to sensor 1322 and is then removed, as described below. Sacrificial material 1328 can be any of a variety of materials that allow for simple removal. In certain embodiments, the sacrificial layer can be photosensitive, thermosensitive, soluble, and / or pH sensitive, among others.

[0413] In any of the processes described herein for making a sharp tip at the distal end of a fine sensor wire, including but not limited to the processes described in the preceding paragraphs, 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 enhancing 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, sugar, salt, degradable polymers, and wax.

[0414] After applying the sacrificial layer 1328 to the sharp distal tip 1326 of the sensor 1322, a membrane 1330 is applied to the sensor 1322. By using the sacrificial layer, a simplified application of the membrane becomes possible, and as a result, during the application process, the membrane 1330 may cover not only the sensor 1324 but also the distal tip 1326. The distal tip 1326 may then be processed to facilitate removal of the membrane 1330 from the sharp distal tip 1326 without damaging the tip 1326 by breaking and / or removing the sacrificial layer. The type of processing after applying the membrane depends on the type of sacrificial material(s) used, but may include, for example, without limitation, applying light, heat, solvent, and / or combinations thereof.

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

[0416] Figures 61 and 62 illustrate another process for fabricating a sensor configured to perform direct pressure insertion according to this embodiment. The sensor 1332 includes a sensor body 1334 having a sharp distal tip 1336. In a typical dipping process for applying the membrane 1338, the sensor 1332 is vertically dipped with the distal tip 1336 facing downward as shown in Figure 61. When the membrane solution 1338 is dried with the distal tip 1336 facing downward, the membrane 1338 solution is drawn downward by gravity, resulting in the formation of beads. The beads blunt the distal tip 1336, making the tip less effective for piercing the skin and / or tissue.

[0417] The process corresponding to FIG. 62 solves this problem by reducing the possibility of bead formation using gravity. Referring to FIG. 62, after immersion in the membrane solution 1338 and before the solution dries, the sensor 1332 is inverted, such that the sharp tip 1336 is facing upward. In this orientation, gravity pulls the membrane solution 1338 away from the tip 1336, thereby reducing the possibility of bead formation. Instead, the membrane 1338 is evenly dispersed by the entire distal end of the sensor 1332, as shown in FIG. 62, and the sharp distal tip 1336 is maintained. In an alternative process, the sensor 1332 may be rotated about an axis perpendicular to the longitudinal axis of the sensor 1332 while the membrane solution 1338 dries, and the centrifugal force can pull the membrane 1338 away from the tip 1336. In the process of rotating the sensor 1332, the sensor 1332 can be oriented, for example, horizontally.

[0418] FIG. 63 illustrates another process for fabricating a sensor configured to perform direct pressure insertion according to the present embodiment. The sensor 1340 includes a sensor body 1342 having a sharp distal tip 1344. When immersing the sensor 1340 in the membrane solution 1346, the sensor 1340 is inverted such that the sharp tip 1344 faces upward. The sensor 1340 is only partially immersed, such that the membrane solution 1346 never contacts the sharp tip 1344. Subsequently, the sensor 1340 is removed from the membrane solution 1346 and dried. Since the membrane solution 1346 never contacts the sharp tip 1344, the sharpness of the tip 1344 is maintained.

[0419] FIG. 64 illustrates another process for fabricating a sensor configured to perform direct pressure insertion according to the present embodiment. The sensor 1348 includes a sensor body 1350 having a sharp distal tip 1352. An annular channel 1354 or indentation is formed in the sensor body 1350 immediately proximal to the tip 1352. In some embodiments, material is removed from the sensor 1348 in a strip to form the annular channel 1354 or indentation. However, in other embodiments, the annular channel 1354 or indentation may be formed by any of a variety of processes used to change the shape of the wire, such as, but not limited to, etching, skiving, grinding, or stamping. The distal end of the channel 1354 defines an edge 1356. Subsequently, when the sensor 1348 is immersed in the membrane solution, the edge 1356 causes the liquid meniscus of the membrane solution to disappear, whereby the tip 1352 of the sensor 1348 remains uncoated by the membrane 1360. Advantageously, the membrane 1360 does not blunt the sharp tip 1352.

[0420] One aspect of the present embodiment includes the recognition that forming a sharp distal tip on the sensor presents problems such that the membrane may not function properly, such as contamination of the membrane surface and / or damage to the membrane. Membrane contamination can change the properties of the membrane, such as by diffusion. For example, contamination can reduce the permeability properties (e.g., selective permeability) of the membrane. Damage to the membrane can also affect the functionality of the sensor. For example, if the removal of the membrane extends to a portion intended to cover the electroactive surface that forms the electrode beyond the distal tip, the diffusion properties of the sensor are substantially modified and become uncontrollable, so the sensor can become defective. On the other hand, if excessive membrane material is present at the distal tip of the sensor, the distal tip of the sensor can become blunt and less effective for piercing the 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] Figures 65 - 67 illustrate another process for fabricating a sensor configured to perform direct pressure insertion according to the present embodiment. Referring to Figure 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] Remove the first portion or band 1370 and the second portion or band 1372 of the outer layer 1368 to expose the core 1366. The first band 1370 of the material to be removed is located at the 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] Referring to FIG. 66, a cap 1376 is attached over the distal tip portion 1374 of the sensor 1362. The attached cap 1376 includes a sharp distal end and extends over the exposed portion 1378 of the proximal core 1366 of the exposed cap 1376, leaving the exposed portion of the core 1366. The cap 1376 may include an absorbent material such that the cap 1376 dissolves or is absorbed by the host body after the sensor 1362 has been inserted into the host's skin and / or tissue. The material of the cap 1376 may include a soluble polymer, such as, without limitation, a degradable polymer including polyvinyl-pyrrolidone (PVP), a polymerized saccharide such as caramel, polyvinyl acetate, polyethylene glycol, polyester, polyamino acid, polycarbonate, polyanhydride, polylactic acid, polyglycolic acid, polydioxanone, polyhydroxybutyric acid, polyhydroxyvaleric acid, polycaprolactone, polyanhydride (e.g., aliphatic polyanhydride in the backbone or side chain, or aromatic polyanhydride having benzene in the side chain), polyorthoester, polyamino acid (e.g., poly-L-lysine, polyglutamic acid), pseudo-polyamino acid (e.g., the backbone of the polyamino acid is modified), polycyanoacrylate, polyphosphazene, as well as combinations or copolymers of these and other similar polymers.

[0424] FIG. 67 illustrates an alternative configuration of the cap 1376' that extends further proximally along the sensor 1362. For example, the cap 1376' may extend proximally far enough to cover at least a portion of the outer layer 1368 proximal to the region where the second band 1372 of the outer layer 1368 is removed.

[0425] In some embodiments, an elongated object (e.g., a wire) in the form of an individual processing member corresponding to an individual sensor member is exposed to an agent that inactivates a catalytic site (e.g., an enzyme domain). The inactivating agent can be in any of a variety of forms such as a liquid or a vapor. For example, in the process corresponding to FIG. 68, wire stock 1380 is exposed to vapor 1382 (e.g., cyanoacrylate) during severance (i.e., the process of cutting the wire stock into individual processing members corresponding to sensor members). The vapor 1382 inactivates the catalytic site at the sensor tip, thereby solving the problem of high baseline signals from the exposed metal at the tip. The process of FIG. 68 is advantageously suitable for reel-to-reel continuous processing, although this is not essential.

[0426] A variety of 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 can be ground, or laser cut / laser ablated, or cut, or thermally formed (particularly with respect to plastic materials), or processed according to any other technique(s) that can be used to sharpen the distal tip. The various processes for creating a sharp tip can result in a variety of tip shapes, including, without limitation, an angled shape (similar to a hypodermic needle profile), a conical shape (similar to the tip of a pencil), or a stepped shape (similar to a needle for acupuncture).

[0427] Figure 69 corresponds to another process for fabricating a sensor configured to perform direct pressure insertion according to this embodiment. In the process corresponding to Figure 69, the distal end 1384 of the sensor wire 1386 is immersed in a chemical substance 1388 to remove material from the end of the wire 1386 and form a sharp tip 1390. The chemical substance 1388 in which the wire 1386 is immersed can be, for example, an etching solution, such as an acid, or a polishing solution. In an alternative embodiment, the material may be removed from the end of the wire 1386 by electropolishing. In a further embodiment, the material may be removed mechanically, for example, by scraping it off or by mechanical polishing. Referring back to Figure 69, the process illustrated there can be advantageous for forming a tip on a very fine flexible wire that may not function well with more conventional processes, such as grinding, for forming a sharp tip.

[0428] Figure 70 corresponds to another process for fabricating a sensor configured to perform direct pressure insertion according to this embodiment. In the process of Figure 70, while keeping the distal end 1392 of the sensor wire 1394 at an angle Θ of 0° to 90° with respect to the polishing surface 1396, the distal end 1392 of the sensor wire 1394 is drawn across the entire polishing surface 1396. For example, Θ may be from about 15° to about 55°, sometimes from about 15° to about 30°, and other times from about 30° to about 45°, or any other suitable angle. The wire 1394 may be held within a support fixture (not shown) as it is moved with respect to the polishing surface 1396. Alternatively, the wire 1394 may remain stationary and the polishing surface 1396 may be moved with respect to the wire 1394. By the process of Figure 70, for example, a wedge-shaped tip 1398 having a flat bevel 1400 on the distal end 1392 of the wire 1394 is obtained. The wedge-shaped tip 1398 can be simpler and / or less expensive to fabricate than a multi-faceted (e.g., pyramid-shaped) or conical tip.

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

[0430] FIG. 71 corresponds to another process for fabricating a sensor configured to perform direct pressure insertion according to this embodiment. In FIG. 71, the 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 is removed from the inner core 1404 at the distal end of the sensor wire 1402, 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 to be able to penetrate the 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 such 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 processes of the present process for forming the sensor wire form a sharp distal tip by adding material to the sensor wire. For example, FIGS. 72 and 73 illustrate another process for fabricating a sensor configured to perform direct pressure insertion according to the present embodiment. Referring to FIG. 72, the sensor wire 1410 is immersed in a bath of polymer material 1412. The polymer material 1412 can include, for example, without limitation, a conductive polymer, a polyelectrolyte, an amphoteric ion polymer, etc. After removing the sensor from the bath, as shown in FIG. 73, a voltage is applied across the entire polymer material 1412. The voltage causes the polymer material 1412 to elongate, forming a sharp tip 1414.

[0432] For example, the processes of FIGS. 72 and 73 can include electrospinning. In electrospinning, when a sufficiently high voltage is applied to a droplet, the liquid becomes charged and the electrostatic repulsive force acts against the surface tension, causing the droplet to spread. At the critical point, a liquid stream jets out from the surface. This jetting point is known as the Taylor cone. If the molecular binding force of the liquid is sufficiently high, no dispersion of the stream occurs (if it does, electrospraying is performed on the droplet), and a charged liquid jet is formed. When the jet dries in air, the form of the current flow changes from ohmic to convective because the charge moves to the surface of the fiber. The jet is then elongated by a whipping process caused by an electrostatic repulsive force initiated by small bends in the fiber until it accumulates on a grounded collector. The elongation and refinement of the fiber resulting from this bending instability result in the formation of homogeneous fibers with diameters on the nanometer scale.

[0433] Figures 74 and 75 illustrate another process for fabricating a sensor configured to perform direct pressing and insertion according to this embodiment. Referring to FIG. 74, the sensor wire 1416 is immersed in a bath 1418 of molten polymer, or a mixture of reactive monomers / oligomers, or dissolved polymer, or polymer mixture. Referring to FIG. 75, by immersing the sensor wire 1416, an immersion coating 1420 is created on the portion of the sensor wire 1416 immersed in the bath 1418. Referring to FIG. 75, the wire 1416 is withdrawn from the bath 1418, and when the wire 1416 is withdrawn, the immersion coating 1420 cures to create a sharp tip 1422 on the sensor wire 1416. The withdrawal speed and angle can be controlled so that the tip has the desired shape and sharpness. The tip may then be cooled and cured, dried and solidified, or cured by exposure to external irradiation, humidity, and / or light. In some embodiments, after the wire 1416 is withdrawn from the bath 1418 of molten polymer, the tip 1422 is placed in a mold to generate a sharp tip 1422.

[0434] Figure 76 illustrates another process for fabricating a sensor configured to perform direct pressing and insertion according to this embodiment. In the process of FIG. 76, the sensor wire 1424 includes a sensor body 1426 and a film 1428 that covers at least a portion of the sensor body 1426. A hard and sharp tip 1430 is fixed to the sensor wire 1424 covered with the film. For example, the tip 1430 may be cast onto the wire 1424 using a mold 1432. When the tip 1430 is a formable material such as thermoplastic, the tip 1430 may be injection molded or insert molded and fixed to the sensor body 1426. To avoid exposing the film to high temperatures, other curable materials such as two-component polyurethane may be used in a low-temperature liquid injection molding process (LIM).

[0435] In any of the embodiments described in this specification, the distal tip of the sensor processing member can be formed by press molding. For example, in the embodiment illustrated in FIG. 76A, the sensor processing member 1431 is first introduced into a station for press molding. Next, the shaping element 1433 is moved from the expanded position (FIG. 76A) to the contracted position (FIG. 76B), whereby the distal end of the processing member 1431 is formed into the desired shape. FIG. 76B shows a cross section of the portion of the sensor processing member 1431 that is shaped by the shaping element 1433 and is proximal to the portion illustrated in FIG. 76C. The one in FIG. 76C is proximal to the distal tip illustrated in FIG. 76D, and the one in FIG. 76D has a cross section with a substantially zero area and forms a sharp tip. In the embodiments shown in FIGS. 76A-76D, there are two shaping elements 1433, and these shape the distal end of the processing member 1431 into a conical shape having a circular cross section. However, in other embodiments, any number of shaping elements, for example, 3, 4, 5, 9, 10, or more, may be present. In addition, the shaping element 1433 may be configured to shape the distal end into any of a variety of shapes, such as triangular, rectangular, square, pentagonal, or hexagonal.

[0436] FIGS. 77 and 78 illustrate another process for fabricating a sensor configured to perform direct pressure insertion according to this embodiment. FIG. 77 is a top plan view, and FIG. 78 is a side view. Referring to FIGS. 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 the skin and / or tissue. However, the illustrated shape is merely an example and is not limiting. The outer core 1436 can include any material such as a polymer.

[0437] In the processes of FIGS. 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 processing member. In one embodiment, the outer surface of the PCB 534 includes a platinum layer resistant to laser ablation. Thus, when the section of the outer core 1436 is removed by laser ablation, a portion of the PCB 1434 under the window 1440 remains intact. The sensor 1442 is subsequently immersed in a membrane solution. The membrane 1444 coats the exposed platinum surface of the PCB 1434 within the window 1440, and this surface defines the working electrode of the final sensor 1442.

[0438] FIG. 79 illustrates another process for fabricating a sensor configured to perform direct pressure insertion according to this embodiment. The sensor 1446 includes a sensor body 1448 having a smooth distal end 1450. The piercing tip 1452 is located over 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 press-fit to secure the tip 1452 to the sensor body 1448. In some embodiments, the membrane is applied before the sensor body 1448 is press-fit to the tip 1452. In other embodiments, the membrane is applied after the sensor body 1448 is press-fit to the tip 1452. In a further embodiment, the sensor 1446 is immersed upside down (i.e., with the tip 1452 up) so that the solution never contacts the tip. This process avoids the possibility of the membrane adhering to the tip (and blunting the tip).

[0439] In another embodiment, the piercing tip may be overmolded onto the distal end of the sensor body. The tip to be overmolded may include, for example, without limitation, a rigid polymer such as 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 this embodiment includes the recognition that it is difficult to form three electrodes on an analyte sensor. For example, by applying a third layer to the sensor wire, the wire manufacturing process becomes very complex and it becomes very difficult to achieve the concentricity of all the layers. If all the layers are not concentric, it may be difficult to perform further processing steps such as skiving with the desired accuracy. Further, 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 embodiments provide solutions to these problems.

[0441] For example, FIGS. 80 and 81 illustrate another process for fabricating a sensor configured to perform direct pressure insertion according to this embodiment. Referring to FIG. 80, sensor 1456 includes a thin, flat microelectromechanical 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 MEMS substrate 1458. Conductive trace 1459 provides an electrical connection between electrode 1457 of sensor 1456 and an electrical contact (not shown). Referring to FIG. 81, substrate 1458 is coated with a membrane 1462. For example, membrane coating 1462 is applied in a dip coating process to obtain a conformal coating. In the illustrated embodiment, membrane coating 1462 is substantially cylindrical and covers the piercing tip 1460 of substrate 1458.

[0443] The processes illustrated in FIGS. 80 and 81 advantageously utilize the benefits of both MEMS processing and dip coating to obtain a cylindrical direct pressure insertion sensor having three electrodes. By using MEMS technology, all three electrodes can be readily fabricated on a flat flexible substrate 1458. For example, the working electrode (and possibly the other electrodes) may be on the top and bottom surfaces of the substrate 1458 for averaging. The substrate 1458 having the electrodes is subsequently immersed in a hard film solution to obtain a cylindrical film coating 1462. The film 1462 may be, for example, a shape memory material and / or a thermo / hydration softening material. The film coating 1462 need not be cylindrical, but a cylindrical film coating advantageously allows for the radial diffusion of the analyte, which promotes faster mass transfer by radial diffusion and results in a shorter response time to reach a steady state, which is beneficial. Further, the MEMS substrate 1458 may be inert, thereby eliminating tip robustness issues.

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

[0445] For example, FIG. 82 illustrates another process for fabricating a sensor configured to perform direct pressure insertion according to this embodiment. Forming a sensor tip configured to pierce skin and / or tissue can be difficult with certain materials. Typical processes such as grinding are not suitable for materials such as aluminum, tantalum, etc. FIG. 82 illustrates an alternative process of pulling on the sensor to form a sharp tip.

[0446] Generally, when an elongated piece of material is placed under tension along its longitudinal axis and pulled beyond its elastic limit, plastic deformation begins. Depending on the properties of the material, the material can "neck". Necking is a local 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 the point at which necking occurs, subsequent deformation is concentrated in the necking region. In practice, in a sample having a circular cross-section, necking results in a local decrease in diameter. Eventually, the sample breaks at or near the center of the necking section. This break results in two "half necks", each of which contains a sharp tip that can be used to form the piercing tip of the sensor.

[0447] According to the above process and referring also to FIG. 82, the sensor wire 1470 is in a state of being tensioned along its longitudinal axis A L Necking occurs in the intermediate region 1472 of the sensor wire 1470. After breakage, two sensors with sharp piercing tips are formed. Further processing such as removal, polishing, and further sharpening may be performed on the piercing tips.

[0448] In one alternative, as shown in FIG. 83, a portion of the sensor wire 1470 may be heated before and / or during the process of applying tension. 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 and makes necking and breakage more likely to occur in the heated region 1476.

[0449] In yet another alternative, after tension has been applied to the sensor wire and necking has begun but before breakage, the tension is released and the two portions of the sensor wire on either side of the necking region are separated by any process such as shearing, cutting, laser ablation, etc.

[0450] Figures 84 to 86 illustrate another process for fabricating a sensor configured to perform direct pressure insertion according to this embodiment. Referring to FIG. 84, the sensor wire 1478 is positioned between opposing cutting blades 1480. The cutting blades 1480 separate the sensor wire 1478 into small pieces, and subsequently, each of these is processed to obtain the sensor. FIG. 84 shows the first embodiment 1480 of the cutting blade in solid lines and the second embodiment 1480' of the cutting blade in dashed lines. In the solid-line embodiment 1480, each blade 1480 includes a cutting edge defined by converging surfaces 1482 at a first angle Φ1. In the dashed-line embodiment, each blade 1480' includes a cutting edge defined by converging surfaces 1484 at a second angle Φ2, where Φ2 > Φ1. FIG. 85 illustrates the shape of the cut portion 1486 made in the sensor wire 1478 by the blade 1480 of the solid-line embodiment, and FIG. 86 illustrates the shape of the cut portion 1486' made in the sensor wire 1478' by the blade 1480' of the dashed-line embodiment. Since Φ2 > Φ1, the cut portion 1486' made in the sensor wire 1478' by the blade 1480' of the dashed-line embodiment has an angle φ2 defined between the converging surfaces of the piercing tip portion 1488' of the sensor 1490' in FIG. 86 that is smaller compared to the angle φ1 defined between the converging surfaces of the piercing tip portion 1488 of the sensor wire 1490 in FIG. 85. The smaller angle φ2 advantageously results in a sharper tip in the sensor wire 1490' in FIG. 86 compared to the sensor wire 1490 in FIG. 85. Therefore, by using the blade 1480' of the dashed-line embodiment in FIG. 84, a sharper piercing tip portion can be obtained.

[0451] Methods and devices suitable for use in conjunction with aspects of the preferred embodiments are described in U.S. Patent No. 4,757,022, U.S. Patent No. 4,994,167, U.S. Patent No. 6,001,067, U.S. Patent No. 6,558,321, U.S. Patent No. 6,702,857, U.S. Patent No. 6,741,877, U.S. Patent No. 6,862,465, U.S. Patent No. 6,931,327, U.S. Patent No. 7,074,307, U.S. Patent No. 7,081,195, U.S. Patent No. 7,108,778, U.S. Patent No. 7,110,803, U.S. Patent No. 7,134,999, U.S. Patent No. 7,136,689, 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 No. 7,591,801, U.S. Patent No. 7,599,726, U.S. Patent No. 7,613,491, U.S. Patent No. 7,615,007, U.S. Patent No. 7,632,228, U.S. Patent No. 7,637,868, U.S. Patent No. 7,640,048, U.S. Patent No. 7,651,596, U.S. Patent No. 7,654,956, U.S. Patent No. 7,657,297, U.S. Patent No. 7,711,402, U.S. Patent No. 7,713,574, U.S. Patent No. 7,715,893, U.S. Patent No. 7,761,130, U.S. Patent No. 7,771,352, U.S. Patent No. 7,774,145, 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. 7,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. 8,060,174, U.S. Patent No. 8,064,977, U.S. Patent No. 8,073,519, 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 No. 8,229,536, U.S. Patent No. 8,231,531, U.S. Patent No. 8,233,958, U.S. Patent No. 8,233,959, U.S. Patent No. 8,249,684, U.S. Patent No. 8,251,906, U.S. Patent No. 8,255,030, U.S. Patent No. 8,255,032, U.S. Patent No. 8,255,033, U.S. Patent No. 8,257,259, U.S. Patent No. 8,260,393, U.S. Patent No. 8,265,725, U.S. Patent No. 8,275,437, U.S. Patent No. 8,275,438, U.S. Patent No. 8,277,713, U.S. Patent No. 8,280,It is disclosed in 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. Patent No. 8,311,749, U.S. Patent No. 8,313,434, U.S. Patent No. 8,321,149, U.S. Patent No. 8,332,008, U.S. Patent No. 8,346,338, U.S. Patent No. 8,364,229, U.S. Patent No. 8,369,919, U.S. Patent No. 8,374,667, U.S. Patent No. 8,386,004, and U.S. Patent No. 8,394,021.,

[0452] Methods and devices suitable for use in conjunction with aspects of the preferred embodiments are described 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, 2006-0020188-A1, 2006-0020190-A1, 2006-0020191-A1, 2006-0020192-A1, 2006-0036140-A1, 2006-0036143-A1, 2006-0040402-A1, 2006-0068208-A1, 2006-0142651-A1, 2006-0155180-A1, 2006-0198864-A1, 2006-0200020-A1, 2006-0200022-A1, 2006-0200970-A1, 2006-0204536-A1, 2006-0224108-A1, 2006-0235285-A1, 2006-0249381-A1, 2006-0252027-A1, 2006-0253012-A1, 2006-0257995-A1, 2006-0258761-A1, 2006-0263763-A1, 2006-0270922-A1, 2006-0270923-A1, 2007-0027370-A1, 2007-0032706-A1, 2007-0032718-A1, 2007-0045902-A1, 2007-0059196-A1, 2007-0066873-A1, 2007-0173709-A1,U.S. Patent Publication No. 2007-0173710-A1, U.S. Patent Publication No. 2007-0208245-A1, U.S. Patent Publication No. 2007-0208246-A1, U.S. Patent Publication No. 2007-0232879-A1, U.S. Patent Publication No. 2008-0045824-A1, U.S. Patent Publication No. 2008-0083617-A1, U.S. Patent Publication No. 2008-0086044-A1, U.S. Patent Publication No. 2008-0108942-A1, U.S. Patent Publication No. 2008-0119703-A1, U.S. Patent Publication No. 2008-0119704-A1, U.S. Patent Publication No. 2008-0119706-A1, U.S. Patent Publication No. 2008-0183061-A1, U.S. Patent Publication No. 2008-0183399-A1, U.S. Patent Publication No. 2008-0188731-A1, U.S. Patent Publication No. 2008-0189051-A1, U.S. Patent Publication No. 2008-0194938-A1, U.S. Patent Publication No. 2008-0197024-A1, U.S. Patent Publication No. 2008-0200788-A1, U.S. Patent Publication No. 2008-0200789-A1, U.S. Patent Publication No. 2008-0200791-A1, U.S. Patent Publication No. 2008-0214915-A1, U.S. Patent Publication No. 2008-0228054-A1, U.S. Patent Publication No. 2008-0242961-A1, U.S. Patent Publication No. 2008-0262469-A1, U.S. Patent Publication No. 2008-0275313-A1, U.S. Patent Publication No. 2008-0287765-A1, U.S. Patent Publication No. 2008-0306368-A1, U.S. Patent Publication No. 2008-0306434-A1, U.S. Patent Publication No. 2008-0306435-A1, U.S. Patent Publication No. 2008-0306444-A1, U.S. Patent Publication No. 2009-0018424-A1, U.S. Patent Publication No. 2009-0030294-A1, U.S. Patent Publication No. 2009-0036758-A1, U.S. Patent Publication No. 2009-0036763-A1, U.S. Patent Publication No. 2009-0043181-A1, U.S. Patent Publication No. 2009-0043182-A1, U.S. Patent Publication No. 2009-0043525-A1, U.S. Patent Publication No. 2009-0045055-A1, U.S. Patent Publication No. 2009-0062633-A1, U.S. Patent Publication No. 2009-0062635-A1, U.S. Patent Publication No. 2009-0076360-A1US Patent Publication No. 2009-0099436-A1, US Patent Publication No. 2009-0124877-A1, US Patent Publication No. 2009-0124879-A1, US Patent Publication No. 2009-0124964-A1, US Patent Publication No. 2009-0131769-A1, US Patent Publication No. 2009-0131777-A1, US Patent Publication No. 2009-0137886-A1, US Patent Publication No. 2009-0137887-A1, US Patent Publication No. 2009-0143659-A1, US Patent Publication No. 2009-0143660-A1, US Patent Publication No. 2009-0156919-A1, US Patent Publication No. 2009-0163790-A1, US Patent Publication No. 2009-0178459-A1, US Patent Publication No. 2009-0192366-A1, US Patent Publication No. 2009-0192380-A1, US Patent Publication No. 2009-0192722-A1, US Patent Publication No. 2009-0192724-A1, US Patent Publication No. 2009-0192751-A1, US Patent Publication No. 2009-0203981-A1, US Patent Publication No. 2009-0216103-A1, US Patent Publication No. 2009-0240120-A1, US Patent Publication No. 2009-0240193-A1, US Patent Publication No. 2009-0242399-A1, US Patent Publication No. 2009-0242425-A1, US Patent Publication No. 2009-0247855-A1, US Patent Publication No. 2009-0247856-A1, US Patent Publication No. 2009-0287074-A1, US Patent Publication No. 2009-0299155-A1, US Patent Publication No. 2009-0299156-A1, US Patent Publication No. 2009-0299162-A1, US Patent Publication No. 2010-0010331-A1, US Patent Publication No. 2010-0010332-A1, US Patent Publication No. 2010-0016687-A1, US Patent Publication No. 2010-0016698-A1, US Patent Publication No. 2010-0030484-A1, US Patent Publication No. 2010-0036215-A1, US Patent Publication No. 2010-0036225-A1, US Patent Publication No. 2010-0041971-A1, US Patent Publication No. 2010-0045465-A1, US Patent Publication No. 2010-0049024-A1, US Patent Publication No. 2010-0076283-A1,U.S. Patent Publication No. 2010-0081908-A1, U.S. Patent Publication No. 2010-0081910-A1, U.S. Patent Publication No. 2010-0087724-A1, U.S. Patent Publication No. 2010-0096259-A1, U.S. Patent Publication No. 2010-0121169-A1, U.S. Patent Publication No. 2010-0161269-A1, U.S. Patent Publication No. 2010-0168540-A1, U.S. Patent Publication No. 2010-0168541-A1, U.S. Patent Publication No. 2010-0168542-A1, U.S. Patent Publication No. 2010-0168543-A1, U.S. Patent Publication No. 2010-0168544-A1, U.S. Patent Publication No. 2010-0168545-A1, U.S. Patent Publication No. 2010-0168546-A1, U.S. Patent Publication No. 2010-0168657-A1, U.S. Patent Publication No. 2010-0174157-A1, U.S. Patent Publication No. 2010-0174158-A1, U.S. Patent Publication No. 2010-0174163-A1, U.S. Patent Publication No. 2010-0174164-A1, U.S. Patent Publication No. 2010-0174165-A1, U.S. Patent Publication No. 2010-0174166-A1, U.S. Patent Publication No. 2010-0174167-A1, U.S. Patent Publication No. 2010-0179401-A1, U.S. Patent Publication No. 2010-0179402-A1, U.S. Patent Publication No. 2010-0179404-A1, U.S. Patent Publication No. 2010-0179408-A1, U.S. Patent Publication No. 2010-0179409-A1, U.S. Patent Publication No. 2010-0185065-A1, U.S. Patent Publication No. 2010-0185069-A1, U.S. Patent Publication No. 2010-0185070-A1, U.S. Patent Publication No. 2010-0185071-A1, U.S. Patent Publication No. 2010-0185075-A1, U.S. Patent Publication No. 2010-0191082-A1, U.S. Patent Publication No. 2010-0198035-A1, U.S. Patent Publication No. 2010-0198036-A1, U.S. Patent Publication No. 2010-0212583-A1, U.S. Patent Publication No. 2010-0217557-A1, U.S. Patent Publication No. 2010-0223013-A1, U.S. Patent Publication No. 2010-0223022-A1, U.S. Patent Publication No. 2010-0223023-A1, U.S. Patent Publication No. 2010-0228109-A1, U.S. Patent Publication No. 2010-0228497-A1US Patent Publication No. 2010-0240975-A1, US Patent Publication No. 2010-0240976 C1, US Patent Publication No. 2010-0261987-A1, US Patent Publication No. 2010-0274107-A1, US Patent Publication No. 2010-0280341-A1, US Patent Publication No. 2010-0286496-A1, US Patent Publication No. 2010-0298684-A1, US Patent Publication No. 2010-0324403-A1, US Patent Publication No. 2010-0331656-A1, US Patent Publication No. 2010-0331657-A1, US Patent Publication No. 2011-0004085-A1, US Patent Publication No. 2011-0009727-A1, US Patent Publication No. 2011-0024043-A1, US Patent Publication No. 2011-0024307-A1, US Patent Publication No. 2011-0027127-A1, US Patent Publication No. 2011-0027453-A1, US Patent Publication No. 2011-0027458-A1, US Patent Publication No. 2011-0028815-A1, US Patent Publication No. 2011-0028816-A1, US Patent Publication No. 2011-0046467-A1, US Patent Publication No. 2011-0077490-A1, US Patent Publication No. 2011-0118579-A1, US Patent Publication No. 2011-0124992-A1, US Patent Publication No. 2011-0125410-A1, US Patent Publication No. 2011-0130970-A1, US Patent Publication No. 2011-0130971-A1, US Patent Publication No. 2011-0130998-A1, US Patent Publication No. 2011-0144465-A1, US Patent Publication No. 2011-0178378-A1, US Patent Publication No. 2011-0190614-A1, US Patent Publication No. 2011-0201910-A1, US Patent Publication No. 2011-0201911-A1, US Patent Publication No. 2011-0218414-A1, US Patent Publication No. 2011-0231140-A1, US Patent Publication No. 2011-0231141-A1, US Patent Publication No. 2011-0231142-A1, US Patent Publication No. 2011-0253533-A1, US Patent Publication No. 2011-0263958-A1, US Patent Publication No. 2011-0270062-A1, US Patent Publication No. 2011-0270158-A1, US Patent Publication No. 2011-0275919-A1,U.S. Patent Publication No. 2011-0290645-A1, U.S. Patent Publication No. 2011-0313543-A1, U.S. Patent Publication No. 2011-0320130-A1, U.S. Patent Publication No. 2012-0035445-A1, U.S. Patent Publication No. 2012-0040101-A1, U.S. Patent Publication No. 2012-0046534-A1, U.S. Patent Publication No. 2012-0078071-A1, U.S. Patent Publication No. 2012-0108934-A1, No., US Patent Publication No. 2012-0130214-A1, US Patent Publication No. 2012-0172691-A1, US Patent Publication No. 2012-0179014-A1, US Patent Publication No. 2012-0186581-A1, US Patent Publication No. 2012-0190953-A1, US Patent Publication No. 2012-0191063-A1, US Patent Publication No. 2012-0203467-A1, US Patent Publication No. 2012-0209098-A1, US Patent Publication No. 2012-0215086-A1, US Patent Publication No. 2012-0215087-A1, US Patent Publication No. 2012-0215201-A1, US Patent Publication No. 2012-0215461-A1, US Patent Publication No. 2012-0215462-A1, US Patent Publication No. 2012-0215496-A1, US Patent Publication No. 2012-0220979-A1, US Patent Publication No. 2012-0226121-A1, US Patent Publication No. 2012-0228134-A1, US Patent Publication No. 2012-0238852-A1, US Patent Publication No. 2012-0245448-A1, US Patent Publication No. 2012-0245855-A1, US Patent Publication No. 2012-0255875-A1, US Patent Publication No. 2012-0258748-A1, US Patent Publication No. 2012-0259191-A1, US Patent Publication No. 2012-0260323-A1, US Patent Publication No. 2012-0262298-A1, US Patent Publication No. 2012-0265035-A1, US Patent Publication No. 2012-0265036-A1, US Patent Publication No. 2012-0265037-A1, US Patent Publication No. 2012-0277562-A1, US Patent Publication No. 2012-0277566-A1, US Patent Publication No. 2012-0283541-A1, US Patent Publication No. 2012-0283543-A1, US Patent Publication No. 2012-0296311-A1, US Patent Publication No. 2012-0302854-A1, US Patent Publication No. 2012-0302855-A1, US Patent Publication No. 2012-0323100-A1, US Patent Publication No. 2013-0012798-A1, US Patent Publication No. 2013-0030273-A1, US Patent Publication No. 2013-0035575-A1, US Patent Publication No. 2013-0035865-A1, US Patent Publication No. 2013-0035871-A1,Disclosed in U.S. Patent Publication No. 2005-0056552-A1 and U.S. Patent Publication No. 2005-0182451-A1.

[0453] Methods and devices suitable for use in conjunction with aspects of the preferred embodiments are described in U.S. Application No. 09 / 447,227, filed November 22, 1999, entitled "DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS"; U.S. Application No. 12 / 828,967, filed July 1, 2010, entitled "HOUSING FOR AN INTRAVASCULAR SENSOR"; U.S. Application No. 13 / 461,625, filed May 1, 2012, entitled "DUAL ELECTRODE SYSTEM FOR A CONTINUOUS ANALYTE SENSOR"; U.S. Application No. 13 / 594,602, filed August 24, 2012, entitled "POLYMER MEMBRANES FOR CONTINUOUS ANALYTE SENSORS"; U.S. Application No. 13 / 594,734, filed August 24, 2012, entitled "POLYMER MEMBRANES FOR CONTINUOUS ANALYTE SENSORS"; U.S. Application No. 13 / 607,162, filed September 7, 2012, entitled "SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR DATA FOR SENSOR CALIBRATION"; U.S. Application No. 13 / 624,727, filed September 21, 2012, entitled "SYSTEMS AND METHODS FOR PROCESSING AND TRANSMITTING SENSOR DATA"; U.S. Application No. 13 / 624,808, filed September 21, 2012, entitled "SYSTEMS AND METHODS FOR PROCESSING AND TRANSMITTING SENSOR DATA"; U.S. Application No. 13 / 624,U.S. Application No. 13 / 732,848, filed on January 2, 2013, entitled "ANALYTE SENSORS HAVING A SIGNAL-TO-NOISE RATIO SUBSTANTIALLY UNAFFECTED BY NON-CONSTANT NOISE"; U.S. Application No. 13 / 733,742, filed on January 3, 2013, entitled "END OF LIFE DETECTION FOR ANALYTE SENSORS"; U.S. Application No. 13 / 733,810, filed on January 3, 2013, entitled "OUTLIER DETECTION FOR ANALYTE SENSORS"; U.S. Application No. 13 / 742,178, filed on January 15, 2013, entitled "SYSTEMS AND METHODS FOR PROCESSING SENSOR DATA"; U.S. Application No. 13 / 742,694, filed on January 16, 2013, entitled "SYSTEMS AND METHODS FOR PROVIDING SENSITIVE AND SPECIFIC ALARMS"; U.S. Application No. 13 / 742,841, filed on January 16, 2013, entitled "SYSTEMS AND METHODS FOR DYNAMICALLY AND INTELLIGENTLY MONITORING A HOST’S GLYCEMIC CONDITION AFTER AN ALERT IS TRIGGERED"; and U.S. Application No. 13 / 747,746, filed on January 23, 2013, entitled "DEVICES, SYSTEMS, AND METHODS TO COMPENSATE FOR EFFECTS OF TEMPERATURE ON IMPLANTABLE SENSORS.",

[0454] The foregoing description sets forth the best mode contemplated of carrying out the invention, as well as the best mode of making and using the means and processes thereof, in terms that are complete, clear, concise, and exact, so as to enable a person of ordinary skill in the art to which the invention pertains to make and use the invention. The invention, however, is subject to variations and alternative configurations from those described above, which are fully equivalent. As a result, the invention is not limited to the specific embodiments disclosed. On the contrary, the invention is directed to and is defined by the following claims, which specifically point out the subject matter of the invention and claim it in broad terms, and is intended to cover all variations and alternative configurations within the spirit and scope of the invention that are included in the following claims. Although the present disclosure has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are illustrative or exemplary and are not to be construed as limiting.

[0455] All references cited herein are hereby incorporated by reference in their entirety. To the extent that the 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 have the meaning that is ordinary and customary to those of ordinary skill in the art and shall not be limited to a special or customized meaning unless explicitly defined herein. It should be noted that the use of a particular term in describing a particular feature or aspect of the present disclosure is not to be construed as implying that the term is redefined herein to include any specific characteristics of the feature or aspect of the present disclosure to which the term relates. The terms and phrases used in this application, as well as their variants, should be construed as having no restrictive connotations, unless otherwise expressly stated, especially in the appended claims.By way of example of the foregoing, the term "including" means "including without limitation", "including but not limited to", etc., and the term "comprising", as used herein, is synonymous with "including", "containing", or "characterized by", is inclusive or unrestricted, and does not exclude additional unrecited elements or method steps. The term "having" should be construed as "having at least", and the term "include" should be construed as "including but not limited to". The term "example" is used to provide an illustrative example of the item under discussion and is neither complete nor limiting of the list. Adjectives such as "known", "ordinary", "standard", etc. and terms of similar meaning should not be construed as limiting the item described to items available at a given time or point in time, but should be construed as encompassing known, ordinary, or standard techniques that are or may be available or known at any current or future time. Terms such as "preferably", "preferred", "desired", or "desirable" and words of similar meaning should not be understood to imply that a particular feature is extremely important, essential, or even more important for the structure or function of the present invention, but are merely intended to emphasize alternative or additional features that may or may not be utilized in a particular embodiment of the present invention. Similarly, a group of items associated by the conjunction "and" should not be construed as requiring that every one of those items be present in the group, but should be construed as "and / or" unless expressly stated otherwise. Similarly, a group of items associated by the conjunction "or" should not be construed as requiring mutual exclusion among the groups, but should be construed as "and / or" unless expressly stated otherwise.

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

[0458] Regarding the use of substantially all plural and / or singular terms herein, one of ordinary skill in the art can convert from plural to singular and / or from singular to plural as appropriate for the situation and / or application. Various singular / plural substitutions may be explicitly recited herein for clarity. The indefinite articles "a" or "an" do not exclude the plural. A single processor or other unit may fulfill the functions of several items recited in the claims. The mere fact that certain measured values are recited in different dependent claims from one another does not indicate that a combination of these measured values cannot be used to advantage. Any reference signs within the claims are not to be construed as limiting the scope.

[0459] Where a specific number of claim limitations are intended, it will be further understood by those skilled in the art that such intent is expressly recited within the claims and that such intent does not exist absent such recitation. For example, by way of illustration, the appended claims below may include the use of the preambles "at least one" and "one or more" to introduce claim limitations. However, the use of such phrases does not imply that the same claim limitations are limited to embodiments containing only one such limitation where the claim includes both the preamble "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 this applies to the use of indefinite articles used to introduce claim limitations. Additionally, it will be understood that even where a specific number of claim limitations are expressly recited, such recitation should typically be interpreted to mean at least the recited number (e.g., the bare recitation of "two limitations" will typically mean at least two or more than two references without modifiers). Further, in instances where conventional like forms are used for "at least one of A, B, and C, etc.", generally such limitations are intended in the sense that those skilled in the art will understand the convention (e.g., "a system having at least one of A, B, and C" will include, but not be 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).In cases where conventional analogs for "at least one of A, B, or C, etc." are used, generally, such limitations are intended in the sense that one of ordinary skill in the art understands the convention (e.g., "a system having at least one of A, B, or C" would include, but not be 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). It will be further understood by one of ordinary skill in the art that virtually all disjunctive and / or phrases representing two or more alternative terms, whether within the description, claims, or drawings, are contemplated to include one of those terms, any of those terms, or both of those terms. For example, the phrase "A or B" would be understood to include the possibility of "A" or "B" or "A and B".

[0460] All numbers representing amounts of components, reaction conditions, etc. are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated otherwise, the numerical parameters set forth in this specification are approximate values and can vary depending upon the desired properties sought to be obtained. Finally, rather than limiting the application of the doctrine of equivalents to 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 the customary rounding approach.

[0461] Furthermore, while the foregoing has been described in some detail for purposes of illustration and example, it will be apparent to one of ordinary skill in the art that certain changes and modifications can be made. Accordingly, the description and examples are not to be regarded as limiting the invention to the particular forms and embodiments set forth herein, but rather as covering all modifications and alternative means consistent with the true scope and spirit of the invention.

Description of Reference Numerals

[0462] 100 Sensor device 102 Inner part 104 Skin 106 Outer part 108 Tissue piercing element 110 Sensor body 112 Support member 114 Membrane 116 Skin contact type placement unit 122 Base 124 Adhesive layer 126 Tip 128 Proximal surface 140 Membrane 310 Tissue piercing element 312 Pocket 314 Sensor 330 Support member 332 Concave part 334 Window part 400 Sensor 408 Soluble tip 412 Sensor body 414 Membrane 418 Tissue fiber coated tip 426 Sensor body tip 500 Sensor 502 Needle 504 Lumen 506 Soluble tissue piercing tip 700 Sensor unit 702 Sensor body 704 Membrane 708 Tip 802 Sensor body 804 Membrane 808 Tip 900 Hardening agent 902 Membrane 904 Sensor body 906 Sensor unit 908 Skin 910 Tip 1000 Sensor 1002 Conductive core wire 1004 Non-conductive jacket 1006 Conductive component 1008, 1010 Electrodes 1012 Conductive trace 1016 Distal end 1020 Sensor 1022, 1024, 1026 Electrodes 1028 Non-conductive layer 1040 Sensor 1042 Core wire 1044, 1048 Electrodes 1046 Substrate 1060 Sensor 1062 Overlap region 1064, 1066 Edges 1070 Sensor 1072 Introduction sheath 1074 Membrane 1076 Tissue piercing element 1078 Sensor body 1080, 1082 Sensors 1084, 1086 Troughs 1085 Distal end 1088, 1090 Peripheries 1102 Sensor 1104 Protective sheath 1106 Sensor tip 1108 Sensor 1110 Through hole 1112 Membrane 1114 Tissue piercing distal tip 1116 Sensor 1118 Depression 1120 Sensor 1122 Dimple 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 film 1154 highly permeable outer layer 1156 sensor 1158 film 1160 outer surface 1161 film 1162 distal tip 1163 sensor processing member 1164 wire 1165 beads 1166 film 1167 tip 1168 channel 1170 tip 1172 protective outer layer 1174 wire stock 1176 film coating 1178 reel 1180 laser 1182 conductive wire 1184 film 1186 distal end 1188 film-coated wire 1190 tip 1192 coating 1194 sensor wire 1196 distal tip 1198 film 1200 distal end 1202 exposed portion 1204 sensor 1206 solution 1208 beads 1210 distal end 1212 fibrous body 1214 wire 1216 film coating 1218 so 1220 end cap 1224 wire 1226 film coating 1228 film 1230 rigid coating 1232 tip 1234 sensor 1236 Sensor body 1238 Piercing tip 1240 Distal end 1242 Proximal end 1244 Membrane 1246 Coating 1248 Retractable introduction sheath 1250 Sensor 1252 Sensor body 1254 Membrane 1256 Tip 1258 Distal end 1260 Proximal end 1262 Retractable introduction sheath 1264 Sensor 1266 Sensor body 1268 Membrane 1269 Sensor 1270 Tip 1271 Core wire 1273 Electrical insulation layer 1277 Distal tip 1275 Gap 1279 Conductive layer 1280 Membrane 1284 Sensor 1286 Sensor body 1288 Membrane 1290 Multiple layers 1292 Sensor 1294 Sensor body 1296 Distal tip 1298 Membrane 1300 Sensor 1302 Sensor body 1304 Distal tip 1306 Membrane 1310 Solvent 1312 Sensor 1314 Sensor body 1316 Tip 1320 Release agent 1322 Sensor 1324 Sensor body 1326 Tip 1328 Sacrificial material 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 core 1368 outer layer 1370, 1372 strip 1374 distal tip 1376, 1376’ cap 1380 wire stock 1382 the above 1384 distal end 1386 wire 1388 chemical substance 1390 tip 1394 sensor wire 1396 polished surface 1398 tip 1400 bevel angle 1402 sensor wire 1404 inner core 1406 outer layer 1408 exposed portion 1410 sensor wire 1412 polymer material 1414 tip 1416 sensor wire 1418 groove 1420 immersion coating 1422 tip 1424 sensor wire 1426 sensor body 1428 film 1430 tip 1431 sensor processing member 1432 mold 1433 shaping element 1434 PCB 1436 outer core 1438 tip 1440 window 1442 sensor 1444 film 1446 sensor 1448 sensor body 1450 distal end 1452 piercing tip 1454 proximal end 1456 sensor 1457 electrode 1458 MEMS substrate 1459 conductive trace 1460 piercing tip 1462 film 1470 sensor wire 1472 intermediate region 1474 resistive heating element 1476 heating region 1478, 1478’ sensor wire 1480, 1480’ cutting blade 1482, 1484 surface 1486, 1486’ cutting part 1488, 1488’ piercing tip 1490, 1490’ sensor wire

Claims

1. A sensor device for measuring the concentration of an analyte in a host, the sensor device being configured to be embedded in the host without using an inserter, comprising a sensor unit having a sensor body, at least one electrode, and a film 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 being configured to pierce the skin and / or tissue of the host, and a placement unit spaced from a tip of the sensor body and configured to support the sensor device on an outer surface of the skin of the host. The sensor body includes a stimulus-responsive material that changes at least one material property in response to hydration. The sensor device further includes a retractable introduction sheath that is applied around the sensor body and configured to cover at least a portion of the film during insertion of the sensor device and to retract from the skin of the host after insertion.

2. The sensor device according to claim 1, wherein the at least one material property is at least one of hardness, shape, permeability, relative hydrophilicity, elastic modulus, or higher-order structure of polymer orientation.

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

4. The sensor device according to claim 1, wherein the sensor body is a polymer, and optionally the sensor body is polyurethane, polyester, polyamide, polyacrylate, or polyether, or a copolymer thereof.

5. The stimulus-responsive material is a shape memory metal, and optionally, 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), the sensor device according to claim 1.

6. The sensor body defines a first shape before insertion of the sensor into the host's skin, the sensor device according to claim 1.

7. The sensor body defines a stored shape, and the sensor body returns to the stored shape after insertion of the sensor into the host's skin, the sensor device according to claim 6.

8. The first shape is curved or linear, the stored shape is curved or linear, and / or When the sensor body returns to the stored shape, accumulated spring energy is released from the sensor body, and optionally, the released spring energy creates a whipping action that facilitates penetration of the sensor into the host's skin, the sensor device according to claim 7.

9. The diameter of the retractable introduction sheath is substantially equal to or smaller than the diameter of the proximal end of the piercing element, the sensor device according to claim 1.

10. The inner surface of the retractable introduction sheath is a lubricious surface having a low coefficient of friction, the sensor device according to claim 1.

11. The lubricious surface is produced by locally coating silicone, fatty acids, fluorinated polymers (e.g., PTFE), or other surface modification additives and / or incorporating them into the substrate of the retractable introduction sheath, the sensor device according to claim 10.

12. The sensor device according to claim 1, wherein the length of the retractable introduction sheath is substantially equal to, shorter than, or longer than the length of the sensor body.

13. The sensor device according to claim 1, wherein the retractable introduction sheath is made of metal.

14. The sensor device according to claim 1, wherein the retractable introduction sheath is non-metallic.

15. The sensor device according to claim 14, wherein the non-metallic retractable introduction sheath is made of polyolefin, polyurethane, polyurethane urea, polyacrylate, polystyrene, polysulfone, polyether ketone, polycarbonate, polyimide, polyester, polyether, polyamide, or epoxide.

Images