Self-insertion trocar-free analyte sensing cannula

Abstract

The present disclosure describes devices and methods for inserting and delivering insulin or insulin analogue formulations and measuring subcutaneous glucose concentrations. A device for delivering an insulin or insulin analogue preparation and measuring subcutaneous glucose concentration may comprise: (a) a tube comprising a proximal end and a distal end, where the proximal end is in fluid communication with a source of the insulin or insulin analogue preparation, and where the distal end is configured to deliver the insulin or insulin analogue preparation subcutaneously; (b) a glucose sensor disposed along the central axis of the tube; and (c) a penetrating body disposed along a central axis of the tube, wherein the penetrating body includes a cross-sectional area that does not exceed a cross-sectional area of the glucose sensor.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 439,480, filed January 17, 2023, which is incorporated herein by reference in its entirety.

[0003] Statement regarding federally sponsored research or development

[0004] This invention was completed with government funding under Contract No. 2R44DK123766-02 granted by the National Institutes of Health (part of the National Institute of Diabetes and Digestive and Kidney Diseases). The government holds certain rights to this invention. Background Technology

[0005] People with diabetes may be at risk of developing complications such as kidney disease, eye disease, cardiovascular disease, and foot / nerve disease. Those who require insulin therapy may have more difficult-to-control blood sugar levels compared to those who do not require it. People with type 1 diabetes (T1D) may require insulin, and many of these individuals use continuous pumps to deliver insulin, which allows for precise, controlled delivery of insulin 24 hours a day. Summary of the Invention

[0006] One valuable technique for managing type 1 diabetes (T1D) is continuous glucose monitoring (CGM), where a subcutaneously inserted sensor provides the user with interstitial glucose data every few minutes. For example, a JDRF-sponsored trial showed that subjects of all ages who used CGM regularly experienced better glycemic control (e.g., as measured by hemoglobin A1C (A1C)) than non-users. However, many subjects may find CGM use cumbersome, and many may only use it occasionally. Unsurprisingly, when CGM is used infrequently or infrequently, its use may not lead to better glycemic control.

[0007] For people who regularly use insulin pumps and CGMs, daily life can be challenging. Such individuals may require two devices inserted through the skin, which can increase the risk of pain and infection and negatively impact device operation characteristics, such as the formation of a seal between the subject's subcutaneous tissue and the inserted insulin delivery cannula and / or tissue damage and / or bleeding during CGM sensor insertion, which can interfere with the CGM device's sensors.

[0008] To overcome the drawbacks of separate CGM sensors and insulin pump devices, advances in sensor materials chemistry (as described, for example, in U.S. Patent Nos. 10,780,222 and 11,135,369, each of which is incorporated herein by reference in its entirety) have enabled combinations of CGM sensors and insulin pumps that are adjacent to each other and / or collinear or coaxially configured.

[0009] While such advancements have reduced, for example, the risk of pain and infection in patients by decreasing the number of insertion points, there remains an unmet need for mechanisms to assist in inserting CGM sensors, insulin pump cannulas, and / or combination devices into the patient's subcutaneous tissue to ensure proper device function.

[0010] To address this unmet need, the disclosures provided herein offer devices and / or methods for inserting CGM sensors, insulin delivery cannulas, and / or combinations thereof, thereby providing optimal device performance in the form of a proper seal and / or electrical connection between the CGM sensor and the subject's surrounding subcutaneous tissue.

[0011] In one aspect, this disclosure provides an apparatus for delivering insulin or insulin analog formulations and measuring subcutaneous glucose concentrations, the apparatus comprising: (a) a tube including a proximal end and a distal end, wherein the proximal end is in fluid communication with a source of insulin or insulin analog formulations, and wherein the distal end is configured for subcutaneous delivery of insulin or insulin analog formulations; (b) a glucose sensor disposed along the central axis of the tube; and (c) a perforator disposed along the central axis of the tube, wherein the perforator comprises a cross-sectional area not exceeding the cross-sectional area of ​​the glucose sensor.

[0012] In some embodiments, the penetrator has a cross-sectional area smaller than that of the glucose sensor. In some embodiments, the penetrator has a cross-sectional area substantially equal to that of the glucose sensor. In some embodiments, the cross-sectional area of ​​the penetrator is less than or equal to the cross-sectional area of ​​the tube. In some embodiments, the cross-sectional area of ​​the penetrator is smaller than that of the glucose sensor.

[0013] In some embodiments, the tube includes a tapered tip at its distal end. In some embodiments, the tapered tip of the tube includes a conical or planar cone shape. In some embodiments, the cross-sectional area of ​​the distal end of the tapered tube is equal to the cross-sectional area of ​​the penetrating body.

[0014] In some embodiments, the device further includes a housing comprising an upper accessible surface and a lower surface configured to adhere to the skin surface.

[0015] In some embodiments, the glucose sensor includes a current-type glucose sensor. In some embodiments, the glucose sensor is disposed on a second tube including a second distal end, wherein the second distal end is configured for subcutaneous insertion.

[0016] In some embodiments, the tube includes a tapered shape oriented toward the distal end of the tube. In some embodiments, a glucose sensor is disposed on the surface of the tube. In some embodiments, the glucose sensor includes at least one electrode or at least two electrodes. In some embodiments, when outside the object, at least two electrodes are electrically isolated.

[0017] In some embodiments, at least one or at least two electrodes comprise a thermoplastic material as a substrate. In some embodiments, at least one or at least two electrodes are disposed on the surface of the penetrator. In some embodiments, at least one or at least two electrodes are one or more layers of a glucose sensor. In some embodiments, at least one or at least two electrodes comprise a material of gold, carbon, graphite, platinum, or iridium. In some embodiments, at least one or at least two electrodes are laminated to the surface of a thermoplastic substrate. In some embodiments, the surface of the thermoplastic substrate comprises at least two surfaces of the thermoplastic substrate. In some embodiments, the thermoplastic substrate is formed around the penetrator.

[0018] In some embodiments, the glucose sensor includes a reference electrode. In some embodiments, the reference electrode includes a silver (Ag) or silver chloride (Ag / AgCl) reference electrode. In some embodiments, the glucose sensor further includes an insulating layer and a metal layer, wherein the insulating layer is coupled to the metal layer, and wherein the metal layer is coupled to an electrode layer including at least one electrode or at least two electrodes. In some embodiments, the insulating layer comprises polyimide or a liquid crystal polymer. In some embodiments, the metal layer has a thickness of at least about 1 micrometer (μm), 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, or 10 μm. In some embodiments, the metal layer comprises a material of titanium, gold, or platinum. In some embodiments, the electrode layer comprises a film with a thickness not exceeding about 1000 nanometers (nm), 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, or 100 nm. In some embodiments, the metal compound of the metal layer comprises a metal selected from osmium, ruthenium, palladium, platinum, rhodium, iridium, cobalt, iron, and copper.

[0019] In some embodiments, the penetrator includes a proximal end and a distal end, wherein the distal end is tapered. In some embodiments, the penetrator includes a core needle or a sharp object. In some embodiments, the penetrator includes an inner lumen. In some embodiments, the penetrator includes a beveled tip.

[0020] In another aspect, this disclosure provides a method for delivering insulin or insulin analog formulations and measuring subcutaneous glucose concentration, the method comprising: (a) providing an apparatus for delivering insulin or insulin analog formulations and measuring subcutaneous glucose concentration, wherein the apparatus comprises: (i) a tube including a proximal end and a distal end, wherein the proximal end is in fluid communication with a source of insulin or insulin analog formulations, wherein the distal end is configured for subcutaneous delivery of insulin or insulin analog formulations; (ii) a glucose sensor disposed along the central axis of the tube; and (iii) a perforator disposed along the central axis of the tube, wherein the perforator includes a cross-sectional area not exceeding the cross-sectional area of ​​the glucose sensor; (b) subcutaneously inserting the distal end of the tube, the glucose sensor, and the perforator into a subject; and (c) subcutaneously delivering insulin or insulin analog formulations to the subject, or measuring the subcutaneous glucose concentration of the subject with the glucose sensor, or a combination thereof.

[0021] In some embodiments, the penetrator has a cross-sectional area smaller than that of the glucose sensor. In some embodiments, the penetrator has a cross-sectional area substantially equal to that of the glucose sensor. In some embodiments, the cross-sectional area of ​​the penetrator is less than or equal to the cross-sectional area of ​​the tube. In some embodiments, the cross-sectional area of ​​the penetrator is smaller than that of the glucose sensor.

[0022] In some embodiments, the tube includes a tapered tip at its distal end. In some embodiments, the tapered tip of the tube includes a conical or planar cone shape. In some embodiments, the cross-sectional area of ​​the distal end of the tapered tube is equal to the cross-sectional area of ​​the penetrating body.

[0023] In some embodiments, the device further includes a housing comprising an upper accessible surface and a lower surface configured to adhere to the skin surface.

[0024] In some embodiments, the glucose sensor includes a current-type glucose sensor. In some embodiments, the glucose sensor is disposed on a second tube including a second distal end, wherein the second distal end is configured for subcutaneous insertion.

[0025] In some embodiments, the tube includes a tapered shape oriented toward the distal end of the tube. In some embodiments, a glucose sensor is disposed on the surface of the tube. In some embodiments, the glucose sensor includes at least one electrode or at least two electrodes. In some embodiments, when outside the object, at least two electrodes are electrically isolated.

[0026] In some embodiments, at least one or at least two electrodes comprise a thermoplastic material as a substrate. In some embodiments, at least one or at least two electrodes are disposed on the surface of the penetrator. In some embodiments, at least one or at least two electrodes are one or more layers of a glucose sensor. In some embodiments, at least one or at least two electrodes comprise a material of gold, carbon, graphite, platinum, or iridium. In some embodiments, at least one or at least two electrodes are laminated to the surface of a thermoplastic substrate. In some embodiments, the surface of the thermoplastic substrate comprises at least two surfaces of the thermoplastic substrate. In some embodiments, the thermoplastic substrate is formed around the penetrator.

[0027] In some embodiments, the glucose sensor includes a reference electrode. In some embodiments, the reference electrode includes a silver (Ag) or silver chloride (Ag / AgCl) reference electrode. In some embodiments, the glucose sensor further includes an insulating layer and a metal layer, wherein the insulating layer is coupled to the metal layer, and wherein the metal layer is coupled to an electrode layer including at least one electrode or at least two electrodes. In some embodiments, the insulating layer comprises polyimide or a liquid crystal polymer. In some embodiments, the metal layer has a thickness of at least about 1 micrometer (μm), 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, or 10 μm. In some embodiments, the metal layer comprises a material of titanium, gold, or platinum. In some embodiments, the electrode layer comprises a film with a thickness not exceeding about 1000 nanometers (nm), 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, or 100 nm. In some embodiments, the metal compound of the metal layer comprises a metal selected from osmium, ruthenium, palladium, platinum, rhodium, iridium, cobalt, iron, and copper.

[0028] In some embodiments, the penetrator includes a proximal end and a distal end, wherein the distal end is tapered. In some embodiments, the penetrator includes a core needle or a sharp object. In some embodiments, the penetrator includes an inner lumen. In some embodiments, the penetrator includes a beveled tip.

[0029] In another aspect, this disclosure provides a device for delivering insulin or insulin analog formulations and measuring subcutaneous glucose concentrations, the device comprising: (a) a tube including a proximal end and a distal end, wherein the proximal end is in fluid communication with a source of insulin or insulin analog formulations, and wherein the distal end is configured for subcutaneous delivery of insulin or insulin analog formulations; (b) a glucose sensor disposed along the central axis of the tube; and (c) a penetrator disposed along the central axis of the tube, wherein the penetrator is configured for at least partial subcutaneous insertion without the use of a trocar.

[0030] In another aspect, this disclosure provides a method for delivering insulin or insulin analog formulations and measuring subcutaneous glucose concentration, the method comprising: (a) providing an apparatus for delivering insulin or insulin analog formulations and measuring subcutaneous glucose concentration, wherein the apparatus comprises: (i) a tube including a proximal end and a distal end, wherein the proximal end is in fluid communication with a source of insulin or insulin analog formulations, wherein the distal end is configured for subcutaneous delivery of insulin or insulin analog formulations; (ii) a glucose sensor disposed along the central axis of the tube; and (iii) a penetrator disposed along the central axis of the tube; (b) subcutaneously inserting the distal end of the tube, the glucose sensor, and the penetrator into a subject without the use of a cannula; and (c) subcutaneously delivering insulin or insulin analog formulations to the subject, or measuring the subcutaneous glucose concentration of the subject using the glucose sensor, or a combination thereof.

[0031] Other aspects and advantages of this disclosure will be readily apparent to those skilled in the art from the following detailed description, in which only illustrative embodiments of the disclosure are shown and described. As will be appreciated, this disclosure is capable of other and different embodiments, and several details thereof can be modified in various obvious ways, all without departing from the disclosure. Therefore, the drawings and descriptions should be considered illustrative in nature, not restrictive.

[0032] Incorporation

[0033] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent, or patent application is expressly and individually indicated to be incorporated by reference. If any publication or patent or patent application incorporated by reference contradicts the disclosure contained in this specification, this specification is intended to supersede and / or give precedence to any such contradictory material. Attached Figure Description

[0034] The novel features of the invention are particularly set forth in the appended claims. A better understanding of the features and advantages of the invention will be obtained by referring to the following detailed description and accompanying drawings (also referred to herein as “Figures”) of illustrative embodiments utilizing the principles of the invention, in which:

[0035] Figure 1 A glucose sensor surrounded by a cannula is shown, which is used to penetrate the subject's skin to place the glucose sensor in the subject's subcutaneous tissue.

[0036] Figure 2 A glucose sensor and a circular and / or curved insulin delivery tubing and / or cannula are shown, having a penetrating member with a cross-sectional diameter less than or equal to that of the insulin delivery tubing and / or cannula.

[0037] Figures 3A-3B A side perspective view is shown of a glucose sensor and a circular and / or curved insulin delivery tubing and / or cannula, with an extended penetrating member. Figure 3A ) and its cross-sectional view ( Figure 3B ).

[0038] Figures 4A-4B A side perspective view of a glucose sensor and a planar insulin delivery tubing and / or cannula with an extended penetrating member is shown. Figure 4A ) and its cross-sectional view ( Figure 4B ).

[0039] Figure 5 A flowchart is shown for a method of delivering insulin or insulin analog formulations and measuring subcutaneous glucose concentration. Detailed Implementation

[0040] While various embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Many variations, modifications, and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed.

[0041] Whenever the terms "at least," "greater than," or "greater than or equal to" precede the first value in a series of two or more values, the terms "at least," "greater than," or "greater than or equal to" apply to each value in the series. For example, greater than or equal to 1, 2, or 3 is equivalent to greater than or equal to 1, greater than or equal to 2, or greater than or equal to 3.

[0042] Whenever the terms "not exceeding," "less than," or "less than or equal to" precede the first value in a series of two or more values, the terms "not exceeding," "less than," or "less than or equal to" apply to each value in the series. For example, less than or equal to 3, 2, or 1 is equivalent to less than or equal to 3, less than or equal to 2, or less than or equal to 1.

[0043] As used herein, the term “casing” generally refers to a hollow tube made of a material such as a polymer or metal, having an inner (e.g., inner) surface and an outer (e.g., outer) surface and openings at both ends.

[0044] As used herein, the term "sensing sleeve" generally refers to a sleeve having an analyte sensor (e.g., disposed on an internal or external surface) and one or more fluid delivery channels contained within the sleeve.

[0045] As used herein, the term "continuous glucose monitor (CGM)" generally refers to a system comprising electronic devices configured to continuously or nearly continuously measure glucose levels from a subject (e.g., a human, animal, or mammal) and / or report such measurements.

[0046] As used herein, the term “CGM infusion kit” generally refers to a device (e.g., a unified device) having a combination of sensors and cannulas configured for use on the skin of an object (e.g., a human, animal, or mammal), which includes an electrical interface with signal acquisition electronics and a port for attaching a fluid source (such as a pump or a source derived from gravity feed).

[0047] As used herein, the term "object" generally refers to a person, individual, or patient. An object can be a vertebrate, such as a mammal. Non-limiting examples of mammals include humans, apes, farm animals, racing animals, rodents, and pets. An object can be a person with diabetes or suspected of having diabetes. An object may exhibit symptoms indicative of the object's health or physiological state or condition, such as diabetes. Alternatively, an object may be asymptomatic in relation to such health or physiological state or condition.

[0048] One valuable technology for managing type 1 diabetes is continuous glucose monitoring (CGM), in which a subcutaneously inserted sensor provides the user with interstitial glucose data every few minutes. For example, trials sponsored by the JDRF have shown that subjects of all ages who regularly use CGM experience better glycemic control (e.g., as measured by hemoglobin A1C (A1C)) than non-users. Both the insulin infusion kit used with a continuous subcutaneous insulin infusion device (CSII, i.e., an insulin pump) and the minimally invasive CGM sensor need to be inserted through the skin into the subcutaneous sensor before use.

[0049] When inserting, for example, a subcutaneous insulin infusion device (e.g., an insulin infusion cannula), sharp objects and / or penetrators, as described elsewhere herein, can be used to facilitate insertion. In some cases, the insulin infusion cannula may contain soft and / or flexible materials (e.g., siloxanes) or rigid or hard materials. In some cases, the cannula may not be sharp or hard enough to pierce the skin on its own without bending. Bending of such a plastic cannula can occur due to forces generated during insertion (penetrating the skin and placing it in the subcutaneous tissue). Bending may not be the only way insertion may fail. It is possible to sense that the cannula can overcome the insertion force without bending, but cannot be fully inserted into the subcutaneous tissue. Skin is flexible and can relax to close relatively small wounds, such as those caused by a cannula or hypodermic needle, after the object is withdrawn. When the cannula remains in the skin and subcutaneous tissue, the skin's tendency to relax may exert pressure on the outer wall of the cannula, resulting in friction between the cannula and the surrounding tissue. This friction may cause the skin surface to fail to relax to its pre-insertion state and remain "wrinkled." As the device wears down and the minor stress from normal body movement helps relax the skin, slight skin wrinkling after insertion can subside on its own. If the wrinkling is too pronounced, the skin may not be able to relax, or there may be pain when it does relax, and the device may slowly damage more tissue as it embeds itself deeper.

[0050] Some characteristics that affect whether the skin remains wrinkled after insertion can include the force / speed of insertion and the friction at the outer surface of the device.

[0051] In some cases, insulin infusion cannulas may include a lumen configured to receive a sharp and / or penetrating body that can extend and / or penetrate the skin of the recipient to allow insertion of the insulin infusion cannula and subsequent withdrawal. Such a configuration and / or geometry of the sharp and / or penetrating body can benefit from not creating a wound in the recipient tissue larger than the insulin infusion cannula itself. A wound with a cross-sectional area larger than the cannula's cross-sectional area increases the probability that the inserted cannula will allow the infused fluid (e.g., insulin) to leak back out of the wound without being absorbed into the tissue. The possibility of fluid leakage from the wound site poses a serious risk to users who require insulin infusions to maintain their blood glucose levels, as the user may be unaware of the insulin leakage and the resulting dose reduction. Embodiments of sharp and / or penetrating bodies that penetrate the recipient tissue, with a cross-sectional area creating a cannula insertion point that prevents such leakage, are described elsewhere in this document. For successful insertion of a soft cannula, it is important that its own cross-sectional area does not exceed the cross-sectional area of ​​the core needle at the same point during insertion where the cannula begins to enter the skin. For this reason, flexible tubing typically narrows to a smaller outer diameter at its tip. In some cases, the penetrator may be made of stainless steel. In some cases, the stainless steel may include 316L stainless steel. In some cases, the penetrator may include a lumen and / or be hollow.

[0052] Some cannulas may contain soft plastic materials, but they are not required to be made of soft materials, even in devices intended for long-term use. Some users prefer rigid cannulas. In some cases, if the cannulas are made of a sufficiently rigid material and have a sharp geometry, insertion aids may not be necessary. For example, infusion kits can use stainless steel cannulas (similar to hypodermic needles) to deliver insulin. Many users prefer soft plastic cannulas for various reasons, but they are not required to be made of soft materials, even in devices intended for long-term use. Some users prefer rigid cannulas. If the cannulas are made of a sufficiently rigid material and have a sharp geometry, insertion aids may not be necessary. For example, infusion kits using stainless steel cannulas (similar to hypodermic needles) to deliver insulin are available on the market and are very popular.

[0053] In the case of CGM sensors, smaller and more flexible sensors are generally considered ideal for user comfort. Because the sensor is designed to be flexible, it also requires insertion aids similar to those used in soft plastic cannula infusion kits.

[0054] In contrast to separate devices consisting of a CGM sensor and an insulin infusion device, combined devices can also be created and used, in which the CGM sensor is integrated into the wall of the insulin infusion cannula. As taught in U.S. Patent Nos. 10,780,222 and 11,135,369 (each incorporated herein by reference in its entirety), such combined devices may require the use of specific CGM chemistry to avoid inaccurate glucose readings caused by compounds present in the insulin drug formulation. In the case of a combined CGM sensor / infusion cannula (sensing cannula), a cannula needle is not advisable because the risk of drug leakage / backflow due to the larger cross-sectional area created by the cannula needle is unacceptable. A cannula needle is a viable insertion aid if the cross-sectional area of ​​the sensing cannula does not exceed the cross-sectional area of ​​the needle placed inside it by a certain margin, and is used in the same manner as the sensing cannula, simply as the soft infusion cannula described above. To ensure that the cross-sectional area of ​​the cannula material relative to the cross-sectional area of ​​its internal fluid path does not exceed this margin, the thickness of the cannula wall must be minimized.

[0055] If the cannula wall is thick enough that the core needle cannot be used as an insertion aid, then a sufficiently sharp and rigid cannula can be inserted on its own without the need for additional insertion aids.

[0056] In some cases, the CGM sensor 100 may include a cross-sectional area smaller than that of the insulin infusion cannula and may be contained in a flexible material that is ideal for user comfort during insertion. In some cases where the CGM sensor 100 contains a flexible material, the CGM sensor may require an insertion aid such as a sharp object and / or a penetrator 102, similar to the aforementioned cannula infusion kit. In some embodiments, because the CGM sensor does not simultaneously function as an infusion cannula, the CGM sensor 100 may include a sensor that is not hollow (i.e., does not include a lumen). In some cases, the insertion aid may include, for example, Figure 1 The rigid, sharp structure 102 shown pierces the skin and surrounds the flexible sensor during insertion.

[0057] In some cases, rigid, sharp structures can include trocars. In some cases, such as... Figure 1As shown, a sharp object and / or penetrator 102 can surround the CGM sensor 100, thereby creating a wound in the object with a cross-sectional area larger than that of the sensor 100 itself. This larger wound leads to excessive trauma to the object's tissue, resulting in reduced CGM sensor accuracy, which can be observed within the first hour to one day after insertion with a sharp object and / or penetrator exceeding the cross-sectional area of ​​the CGM sensor. This large-diameter wound contrasts with the case of soft plastic infusion cannulas, where a relatively small wound can be created using a core needle with a diameter smaller than the cannulas. Insertion trauma caused by a sharp object and / or penetrator with a cross-sectional area exceeding that of the CGM sensor results in excessive bleeding and adds cellular debris to the environment surrounding the CGM sensor. In some cases, a sharp object and / or penetrator with a cross-sectional area exceeding that of the CGM sensor can cause a subsequent inflammatory response that alters the environment of the insertion area and / or location over the following hours, thus affecting the sensor's response characteristics and accuracy. In some cases, the insertion devices and methods for inserting glucose sensors described elsewhere in this document provide glucose sensor response characteristics with stability of at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% for up to approximately 2 hours from the initial insertion of the glucose sensor into the subject's body. Compared to inserting the same sensor using a cannula, using a sensing cannula with a core needle or a sharp object with a cross-sectional area smaller than the cannula itself minimizes insertion trauma, resulting in less change in sensor response characteristics during the initial time period after insertion, ultimately improving sensor accuracy during this period.

[0058] Electrochemical and / or current-type biosensors may include at least two electrodes that are electrically isolated from each other except when immersed in bodily fluids during use. Thermoplastic materials can be very suitable as substrates for electrodes because they typically have low conductivity. Therefore, a thermoplastic sheath with electrodes on its surface can be an attractive design for a sensing sheath. The problem with thermoplastic materials is that they are generally not rigid enough to perform as well as metals when used as needles (e.g., when piercing the skin during insertion). One way to combine the properties of both materials is to surround a metal needle / sharp with an electrically insulating thermoplastic on which the sensing electrode can be laminated / deposited. The metal needle / sharp can be removed after insertion of the sensing sheath, or it can remain in place, similar to a rigid metal needle infusion sheath.

[0059] The ability of a sensing cannula to be inserted without the use of insertion aids (e.g., a core needle or cannula needle) depends in part on the following characteristics: the rigidity of the cannula / sensor material, the sharpness / geometry of the penetrating tip, the overall size / geometry of the cannula / sensor, the lubricity / coefficient of friction of the cannula / sensor surface, and the speed / kinetic energy of the insertion motion. Other factors affecting successful insertion may include the insertion angle relative to the plane of the skin surface, the axial rotation of the object during insertion, and the orientation of the sharp geometry (hypotenuse) relative to the insertion direction.

[0060] Resistance to buckling due to insertion force can depend on both the geometry and material properties of the cannula / sensor. The Euler critical load equation is a well-known way to determine the maximum static load a column can withstand without buckling. In this case, the cannula can be considered as the column and the skin puncture force. The critical load can depend on the stiffness of the column material, its area moment of inertia (cross-sectional geometry), length, and / or the amount of movement allowed at the column's ends. A decrease in area moment of inertia, an increase in length, and greater freedom of movement at the column's ends all reduce the maximum static load the column can withstand.

[0061] The cannula cross-section can be kept to a minimum because insertion is generally more painful as the cross-sectional area / needle diameter increases. The cannula length can be reduced to a certain extent, but there is a minimum length required for successful drug infusion. The cannula can be secured at its exit point from the bottom surface of the medical device housing, which remains on the skin surface. Remaining factors include insertion speed, cannula tip geometry (bevel), surface friction / lubricity, and insertion angle.

[0062] Recognizing the challenges encountered in insertion and the interface of the CGM sensor and / or insulin infusion cannula with the subject's skin and / or subcutaneous tissue, this disclosure describes, in some embodiments, devices and / or methods for minimizing trauma to the subject tissue and ensuring proper device interface and functionality when inserted into the subject's subcutaneous tissue.

[0063] In some aspects, the disclosure provides a device for delivering insulin analog formulations and measuring subcutaneous glucose concentrations, such as... Figure 2 , Figures 3A-3B and Figures 4A-4B As shown, the device includes: (a) a tube (200, 212) comprising a proximal end (214, 216) and a distal end (218, 220), wherein the proximal end is in fluid communication with a source of insulin and / or an insulin analog formulation, and wherein the distal end is configured to deliver insulin and / or an insulin analog formulation subcutaneously to a subject; and (b) a glucose sensor disposed along the central axis of the tube (200, 212), for example, as shown in the figure. Figure 2As shown; and (c) a penetrating body 210 disposed along the central axis of the tubes (200, 212), wherein the penetrating body 210 includes a cross-sectional area equal to the cross-sectional area of ​​the glucose sensor. In some cases, the cross-sectional area of ​​the penetrating body 210 may include a cross-sectional area less than or equal to the cross-sectional area of ​​the tubes (200, 212), such as... Figure 2 , Figures 3A-3B and Figures 4A-4B As shown. In some cases, the cross-sectional area of ​​the penetrator 210 may include a cross-sectional area smaller than that of the glucose sensor. In some cases, a penetrator with a cross-sectional area smaller than or equal to that of the tube and / or glucose sensor may provide a penetration site in the subject's skin and / or subcutaneous tissue such that the penetration site prevents leakage of fluid flowing through the tube and reduces interference from bleeding and / or cell debris on the glucose sensor reading glucose in the subject's subcutaneous tissue, as described elsewhere herein.

[0064] In some cases, the tubes (200, 212) may include a taper oriented toward the distal end (218, 220) of the tube. In some cases, the tubes (200, 212) and / or the distal taper tip (218, 220) may include, for example... Figure 3A The circular and / or curved surface geometry and / or shape (224) shown or such as Figure 4A The planar geometry and / or shape (222) shown. In some cases, the cross-sectional area of ​​the distal portion of the distal tapered tip (218, 220) may include a cross-sectional area less than or equal to the cross-sectional area of ​​the penetrating body 210. In some cases, the tube (200, 212) may comprise a polymer material. In some cases, the tube may be molded around the penetrating body 210. In some cases, the tube (200, 212) may include a polymer molding assembly or an extrusion assembly. In some cases, the device may further include a housing comprising an upper accessible surface and a lower surface configured to adhere to the skin surface.

[0065] In some cases, the glucose sensor may include a current-type glucose sensor. In some cases, the glucose sensor may be disposed on a second tube including a second distal end, wherein the second distal end is configured for subcutaneous insertion into the body of the recipient. In some cases, the glucose sensor 202 may be disposed on the surface of the tubes (200, 212), such as... Figure 2 As shown. The glucose sensor 202 can be disposed on the inner surface of the tubes (200, 212) or on the outer surface of the tubes (200, 212). In some cases, the glucose sensor 202 may include at least one electrode or at least two electrodes.

[0066] In some cases, when outside the object, at least two electrodes of the glucose sensor may be electrically isolated from each other. In some cases, at least one electrode and / or at least two electrodes may comprise a thermoplastic material as a substrate. In some cases, the thermoplastic material may comprise a planar thermoplastic material that can be molded around a metal needle. In some cases, the planar thermoplastic material molded around the metal needle may be heated and conformed to a circular cross-section. In some cases, at least one electrode and / or at least two electrodes may be disposed on the surface of the penetrator. In some cases, at least one electrode and / or at least two electrodes may at least partially surround the penetrator.

[0067] In some cases, at least one electrode and / or at least two electrodes may be laminated and / or deposited on the surface of the thermoplastic material deposited on the surface of the penetrator. In some cases, the tube may include a thermoplastic sheath. In some cases, the thermoplastic sheath may be formed with a lumen configured to receive a metal conduit (e.g., a sharp metal conduit) as described elsewhere herein. In some cases, at least one electrode and / or at least two electrodes may be deposited and / or laminated on two or more surfaces of the thermoplastic sheath, after which a sharp metal conduit may be provided as a penetrator at the distal end of the thermoplastic sheath to the thermoplastic sheath lumen, which facilitates a fluid path connection between the proximal and distal ends of the thermoplastic sheath. In some cases, the thermoplastic sheath may be formed with a lumen, wherein the lumen of the thermoplastic sheath may be configured as a fluid path. In some cases, the distal tip of the thermoplastic sheath may be formed into a sharp distal end. In some cases, at least one electrode and / or at least two electrodes may be deposited and / or laminated on two or more surfaces of a thermoplastic material formed around a metal tube and / or a solid metal mandrel.

[0068] In some cases, after molding and laminating and / or depositing at least one and / or at least two electrodes onto the thermoplastic material, a solid metal mandrel can be removed and replaced with one or more sharp metal conduits of varying lengths. In some cases, at least one and / or at least two electrodes laminated and / or deposited on the surface of the thermoplastic material can be molded around metal conduits of various lengths that are kept straight. In some cases, at least one and / or at least two electrodes laminated and / or deposited on the surface of the thermoplastic material molded on metal conduits of various lengths can be cut into multiple segments shorter than the lengths of the metal conduits. In some cases, multiple segments of electrodes laminated and / or deposited on the thermoplastic material molded around the metal conduit can be tapered (tapered) towards the distal end of the thermoplastic material. In some cases, at least one and / or at least two electrodes laminated and / or deposited on the thermoplastic material can be molded around a solid and / or circular mandrel and / or wire. After at least one and / or at least two electrodes are formed by laminating and / or depositing on a thermoplastic material, the solid and / or round mandrel and / or wire can be removed and replaced with a sharp object (e.g., a sharp metal pipe).

[0069] In some cases, at least one electrode and / or at least two electrodes may constitute one or more layers of the glucose sensor. In some cases, at least one electrode and / or at least two electrodes may comprise materials such as gold, carbon, graphite, platinum, or iridium. In some cases, at least one electrode and / or at least two electrodes may be laminated to the surface of a thermoplastic substrate. In some cases, the surface of the thermoplastic substrate may include at least two surfaces of the thermoplastic substrate. In some cases, the thermoplastic substrate may be molded around a transducer.

[0070] In some cases, the glucose sensor may include a reference electrode. In some cases, the reference electrode may comprise a material of silver (Ag) or silver chloride (AgCl). In some cases, the glucose sensor may further include an insulating layer and a metal layer, wherein the insulating layer is coupled to the metal layer, and wherein the metal layer is coupled to an electrode layer comprising at least one electrode and / or at least two electrodes. In some cases, the insulating layer may comprise a polyimide or a liquid crystal polymer. In some cases, the metal layer may comprise a thickness of at least about 1 micrometer (μm), 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, or 10 μm. In some cases, the metal layer may comprise a material of titanium, gold, or platinum. In some cases, the electrode layer may comprise a film with a thickness not exceeding about 1000 nanometers (nm), 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, or 100 nm. In some cases, the metal compound in the metal layer may contain a metal selected from osmium, ruthenium, palladium, platinum, rhodium, iridium, cobalt, iron, and copper.

[0071] In some cases, the penetrator 210 may include a proximal end 226 and a distal end (228). In some cases, the distal end 228 of the penetrator may be tapered. In some cases, the penetrator may include a core needle or a sharp object (e.g., a needle or a sharpened and / or pointed stainless steel tube). In some cases, the penetrator may include a beveled tip 208. In some cases, the penetrator includes an inner lumen and / or is hollow.

[0072] In some cases, the disclosure describes a method 300 for delivering insulin or insulin analog formulations and measuring subcutaneous glucose concentration, such as... Figure 5As seen in the document, the method includes: (a) providing a device for delivering insulin or an insulin analog formulation and measuring subcutaneous glucose concentration, wherein the device includes: (i) a tube comprising a proximal end and a distal end, wherein the proximal end is in fluid communication with a source of insulin or an insulin analog formulation, and wherein the distal end is configured for subcutaneous delivery of insulin or an insulin analog formulation; (ii) a glucose sensor disposed along the central axis of the tube; and (iii) a perforator disposed along the central axis of the tube, wherein the perforator includes a cross-sectional area 302 equal to the cross-sectional area of ​​the glucose sensor; (b) subcutaneously inserting the distal end of the tube, the glucose sensor, and the perforator into the body of a subject 304; and (c) subcutaneously delivering insulin or an insulin analog formulation to the subject, measuring the subcutaneous glucose concentration of the subject with the glucose sensor, or a combination thereof 304. In some cases, insertion further includes inserting the glucose sensor into the tissue of the subject, wherein the tissue of the subject includes the subject's skin, epidermis, dermis, subcutaneous tissue, or any combination thereof. In some cases, the cross-sectional area of ​​the perforator may include a cross-sectional area less than or equal to the cross-sectional area of ​​the tube. In some cases, the cross-sectional area of ​​the penetrator may include a cross-sectional area smaller than that of the glucose sensor. In some cases, a penetrator cross-sectional area smaller than or equal to that of the tube and / or glucose sensor may provide a puncture site in the subject's skin and / or subcutaneous tissue that prevents leakage of fluid flowing through the tube and reduces interference from bleeding and / or cellular debris with the glucose sensor reading glucose within the subject's subcutaneous tissue, as described elsewhere herein. In some cases, the penetrator may be made of stainless steel. In some cases, the stainless steel may include 316L stainless steel. In some cases, the penetrator may include a lumen and / or be hollow.

[0073] In some cases, the tube may include a tapered shape oriented toward the distal end of the tube. In some cases, the tube and / or the distal tapered tip may include a circular and / or curved geometry and / or shape, or a planar geometry and / or shape. In some cases, the cross-sectional area of ​​the distal portion of the distal tapered tip may include a cross-sectional area less than or equal to the cross-sectional area of ​​the penetrator. In some cases, the tube may contain a polymeric material. In some cases, the tube may be molded around the penetrator. In some cases, the tube may include a polymer molding assembly or an extrusion assembly. In some cases, the device may further include a housing comprising an upper accessible surface and a lower surface configured to adhere to the skin surface.

[0074] In some cases, the glucose sensor may include a current-type glucose sensor. In some cases, the glucose sensor may be disposed on a second tube including a second distal end, wherein the second distal end is configured for subcutaneous insertion into the body of the subject. In some cases, the glucose sensor may be disposed on the surface of the tube. In some cases, the glucose sensor may include at least one electrode or at least two electrodes. In some cases, when outside the body, at least two electrodes of the glucose sensor may be electrically isolated from each other.

[0075] In some cases, at least one electrode and / or at least two electrodes may comprise a thermoplastic material as a substrate. In some cases, the thermoplastic material may comprise a planar thermoplastic material that can be formed around a metal needle. In some cases, the planar thermoplastic material formed around the metal needle may be heated and conformed to a circular cross-section.

[0076] In some cases, at least one electrode and / or at least two electrodes may be disposed on the surface of the penetrator. In some cases, at least one electrode and / or at least two electrodes may at least partially surround the penetrator. In some cases, at least one electrode and / or at least two electrodes may be laminated and / or deposited on the surface of the thermoplastic material deposited on the surface of the penetrator.

[0077] In some cases, at least one and / or at least two electrodes laminated and / or deposited on the surface of a thermoplastic can be coupled to a penetrator and inserted into the object body, after which the penetrator is withdrawn, thereby leaving at least one and / or at least two laminated and / or deposited electrodes in the object.

[0078] In some cases, at least one electrode and / or at least two electrodes may constitute one or more layers of the glucose sensor. In some cases, at least one electrode and / or at least two electrodes may comprise materials such as gold, carbon, graphite, platinum, or iridium. In some cases, at least one electrode and / or at least two electrodes may be laminated to the surface of a thermoplastic substrate. In some cases, the surface of the thermoplastic substrate may include at least two surfaces of the thermoplastic substrate. In some cases, the thermoplastic substrate may be molded around a transducer.

[0079] In some cases, the tube may include a thermoplastic sheath. In some cases, the thermoplastic sheath may be formed with a lumen configured to receive a metal conduit (e.g., a sharp metal conduit) as described elsewhere herein. In some cases, at least one electrode and / or at least two electrodes may be deposited and / or laminated on two or more surfaces of the thermoplastic sheath, after which a sharp metal conduit may be provided as a penetrator as described elsewhere herein at the distal end of the thermoplastic sheath to the thermoplastic sheath lumen, the penetrator facilitating a fluid path connection between the proximal and distal ends of the thermoplastic sheath.

[0080] In some cases, the thermoplastic sleeve may be formed with a lumen, wherein the lumen of the thermoplastic sleeve can be configured as a fluid path. In some cases, the distal tip of the thermoplastic sleeve may be formed into a sharp distal end. In some cases, at least one electrode and / or at least two electrodes may be deposited and / or laminated on two or more surfaces of the thermoplastic material formed around a metal conduit and / or a solid metal mandrel. In some cases, after the thermoplastic material is formed and laminated and / or deposited with at least one electrode and / or at least two electrodes, the solid metal mandrel may be removed and replaced with a sharp metal conduit of one or more lengths.

[0081] In some cases, at least one and / or at least two electrodes laminated and / or deposited on a thermoplastic material surface can be formed around a metal tube of multiple lengths, held straight. In some cases, at least one and / or at least two electrodes laminated and / or deposited on a thermoplastic material surface formed on a metal tube of multiple lengths can be cut into multiple segments shorter than the lengths of the metal tube. In some cases, multiple segments of electrodes laminated and / or deposited on thermoplastic material formed around a metal tube can be tapered (tapered) towards the distal end of the thermoplastic material. In some cases, at least one and / or at least two electrodes laminated and / or deposited on a thermoplastic material can be formed around a solid and / or circular mandrel and / or wire. After at least one and / or at least two electrodes laminated and / or deposited on a thermoplastic material are formed, the solid and / or circular mandrel and / or wire can be removed and replaced with a sharp object (e.g., a sharp metal tube).

[0082] In some cases, the glucose sensor may include a reference electrode. In some cases, the reference electrode may comprise a material of silver (Ag) or silver chloride (AgCl). In some cases, the glucose sensor may further include an insulating layer and a metal layer, wherein the insulating layer is coupled to the metal layer, and wherein the metal layer is coupled to an electrode layer comprising at least one electrode and / or at least two electrodes. In some cases, the insulating layer may comprise a polyimide or a liquid crystal polymer. In some cases, the metal layer may comprise a thickness of at least about 1 micrometer (μm), 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, or 10 μm. In some cases, the metal layer may comprise a material of titanium, gold, or platinum. In some cases, the electrode layer may comprise a film with a thickness not exceeding about 1000 nanometers (nm), 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, or 100 nm. In some cases, the metal compound in the metal layer may contain a metal selected from osmium, ruthenium, palladium, platinum, rhodium, iridium, cobalt, iron, and copper.

[0083] In some cases, the penetrator may include a proximal end and a distal end. In some cases, the distal end of the penetrator may be tapered. In some cases, the penetrator may include a core needle or a sharp object (e.g., a needle or a sharpened and / or pointed stainless steel tube). In some cases, the penetrator may include a beveled tip. In some cases, the penetrator includes an inner lumen and / or is hollow.

[0084] While preferred embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. The invention is not intended to be limited to the specific examples provided in the specification. Although the invention has been described with reference to the foregoing specification, the description and illustration of embodiments herein are not intended to be construed as limiting. Many variations, modifications, and substitutions will now be conceived by those skilled in the art without departing from the invention. Furthermore, it should be understood that all aspects of the invention are not limited to the specific descriptions, configurations, or relative proportions set forth herein, and depend on various conditions and variables. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in the practice of the invention. Therefore, the invention is contemplated to also cover any such alternatives, modifications, variations, or equivalents. The appended claims are intended to define the scope of the invention and thereby cover the methods and structures within the scope of these claims and their equivalents.

Claims

1. A device for delivering insulin or insulin analog formulations and measuring subcutaneous glucose concentration, the device comprising: (a) A tube comprising a proximal end and a distal end, wherein the proximal end is in fluid communication with a source of the insulin or insulin analog formulation, and wherein the distal end is configured to deliver the insulin or insulin analog formulation subcutaneously. (b) A glucose sensor disposed along the central axis of the tube; and (c) A penetrating body disposed along the central axis of the tube, wherein the penetrating body comprises a cross-sectional area not exceeding the cross-sectional area of ​​the glucose sensor.

2. The apparatus of claim 1, wherein the penetrator comprises a cross-sectional area smaller than that of the glucose sensor.

3. The apparatus of claim 1, wherein the penetrator comprises a cross-sectional area substantially equal to that of the glucose sensor.

4. The apparatus of claim 1, wherein the cross-sectional area of ​​the penetrating body is less than or equal to the cross-sectional area of ​​the tube.

5. The apparatus of claim 1, wherein the cross-sectional area of ​​the penetrator is smaller than the cross-sectional area of ​​the glucose sensor.

6. The device of claim 1, wherein the tube includes a tapered tip at the distal end.

7. The apparatus of claim 1, wherein the tapered tip of the tube comprises a conical shape or a planar cone shape.

8. The apparatus of claim 6, wherein the cross-sectional area of ​​the distal end of the tapered tube is equal to the cross-sectional area of ​​the penetrating body.

9. The device of claim 1, further comprising a housing including an upper accessible surface and a lower surface configured to adhere to a skin surface.

10. The apparatus of claim 1, wherein the glucose sensor comprises a current-type glucose sensor.

11. The apparatus of claim 1, wherein the glucose sensor is disposed on a second tube including a second distal end, wherein the second distal end is configured for subcutaneous insertion.

12. The apparatus of claim 1, wherein the tube includes a tapered shape oriented toward the distal end of the tube.

13. The apparatus of claim 1, wherein the glucose sensor is disposed on the surface of the tube.

14. The apparatus of claim 1, wherein the glucose sensor comprises at least one electrode or at least two electrodes.

15. The apparatus of claim 14, wherein the at least two electrodes are electrically isolated when outside the object.

16. The apparatus of claim 14, wherein the at least one electrode or the at least two electrodes comprises a thermoplastic material as a substrate.

17. The apparatus of claim 14, wherein the at least one electrode or the at least two electrodes are disposed on the surface of the penetrator.

18. The apparatus of claim 14, wherein the at least one electrode or the at least two electrodes are one or more layers of the glucose sensor.

19. The apparatus of claim 14, wherein the at least one electrode or the at least two electrodes comprises a material of gold, carbon, graphite, platinum or iridium.

20. The apparatus of claim 14, wherein the at least one electrode or the at least two electrodes are laminated to the surface of the thermoplastic substrate.

21. The apparatus of claim 20, wherein the surface of the thermoplastic substrate comprises at least two surfaces of the thermoplastic substrate.

22. The apparatus of claim 20, wherein the thermoplastic substrate is formed around the penetrator.

23. The apparatus of claim 1, wherein the glucose sensor includes a reference electrode.

24. The apparatus of claim 23, wherein the reference electrode comprises a silver (Ag) or silver chloride (Ag / AgCl) reference electrode.

25. The apparatus of claim 14, wherein the glucose sensor further comprises an insulating layer and a metal layer, wherein the insulating layer is coupled to the metal layer, and wherein the metal layer is coupled to an electrode layer comprising the at least one electrode or the at least two electrodes.

26. The apparatus of claim 25, wherein the insulating layer comprises polyimide or liquid crystal polymer.

27. The apparatus of claim 25, wherein the metal layer has a thickness of at least about 1 micrometer (μm), 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm or 10 μm.

28. The apparatus of claim 25, wherein the metal layer comprises a material of titanium, gold, or platinum.

29. The apparatus of claim 25, wherein the electrode layer comprises a film with a thickness not exceeding about 1000 nanometers (nm), 900nm, 800nm, 700nm, 600nm, 500nm, 400nm, 300nm, 200nm, or 100nm.

30. The apparatus of claim 25, wherein the metal compound of the metal layer comprises a metal selected from osmium, ruthenium, palladium, platinum, rhodium, iridium, cobalt, iron, and copper.

31. The apparatus of claim 1, wherein the penetrator comprises a proximal end and a distal end, wherein the distal end is tapered.

32. The apparatus of claim 1, wherein the penetrator comprises a needle or a sharp object.

33. The apparatus of claim 1, wherein the penetrating body comprises an inner lumen.

34. The apparatus of claim 1, wherein the penetrator includes a beveled tip.

35. A method for delivering insulin or an insulin analogue and measuring subcutaneous glucose concentration, the method comprising: (a) A device for delivering insulin or insulin analog formulations and measuring subcutaneous glucose concentration, wherein the device comprises: (i) A tube comprising a proximal end and a distal end, wherein the proximal end is in fluid communication with a source of the insulin or insulin analog formulation, wherein the distal end is configured for subcutaneous delivery of the insulin or insulin analog formulation. (ii) a glucose sensor disposed along the central axis of the tube; and (iii) A penetrating body disposed along the central axis of the tube, wherein the penetrating body comprises a cross-sectional area not exceeding the cross-sectional area of ​​the glucose sensor; (b) Subcutaneously inserting the distal end of the tube, the glucose sensor, and the penetrator into the body of the subject; and (c) Subcutaneously delivering the insulin or an insulin analogue to the subject, or measuring the subcutaneous glucose concentration of the subject using the glucose sensor, or a combination thereof.

36. The method of claim 35, wherein the penetrator comprises a cross-sectional area smaller than that of the glucose sensor.

37. The method of claim 35, wherein the penetrator comprises a cross-sectional area substantially equal to that of the glucose sensor.

38. The method of claim 35, wherein the cross-sectional area of ​​the penetrating body is less than or equal to the cross-sectional area of ​​the tube.

39. The method of claim 35, wherein the cross-sectional area of ​​the penetrator is smaller than the cross-sectional area of ​​the glucose sensor.

40. The method of claim 35, wherein the tube includes a tapered tip at the distal end.

41. The method of claim 35, wherein the tapered tip of the tube comprises a conical shape or a planar tapered shape.

42. The method of claim 35, wherein the cross-sectional area of ​​the distal end of the tapered tube is equal to the cross-sectional area of ​​the penetrating body.

43. The method of claim 35, wherein the device further comprises a housing including an upper accessible surface and a lower surface configured to adhere to a skin surface.

44. The method of claim 35, wherein the glucose sensor comprises a current-type glucose sensor.

45. The method of claim 35, wherein the glucose sensor is disposed on a second tube including a second distal end, wherein the second distal end is configured for subcutaneous insertion.

46. ​​The method of claim 35, wherein the tube includes a tapered shape oriented toward the distal end of the tube.

47. The method of claim 35, wherein the glucose sensor is disposed on the surface of the tube.

48. The method of claim 35, wherein the glucose sensor comprises at least one electrode or at least two electrodes.

49. The method of claim 48, wherein when the object is outside the body, the at least two electrodes are electrically isolated.

50. The method of claim 48, wherein the at least one electrode or the at least two electrodes comprises a thermoplastic material as a substrate.

51. The method of claim 48, wherein the at least one electrode or the at least two electrodes are disposed on the surface of the penetrator.

52. The method of claim 48, wherein the at least one electrode or the at least two electrodes are one or more layers of the glucose sensor.

53. The method of claim 48, wherein the at least one electrode or the at least two electrodes comprises a material of gold, carbon, graphite, platinum or iridium.

54. The method of claim 48, wherein the at least one electrode or the at least two electrodes are laminated to the surface of the thermoplastic substrate.

55. The method of claim 54, wherein the surface of the thermoplastic substrate comprises at least two surfaces of the thermoplastic substrate.

56. The method of claim 54, wherein the thermoplastic substrate is formed around the penetrator.

57. The method of claim 35, wherein the glucose sensor includes a reference electrode.

58. The method of claim 57, wherein the reference electrode comprises a silver (Ag) or silver chloride (Ag / AgCl) reference electrode.

59. The method of claim 48, wherein the glucose sensor further comprises an insulating layer and a metal layer, wherein the insulating layer is coupled to the metal layer, and wherein the metal layer is coupled to an electrode layer comprising the at least one electrode or the at least two electrodes.

60. The method of claim 59, wherein the insulating layer comprises polyimide or liquid crystal polymer.

61. The method of claim 59, wherein the metal layer has a thickness of at least about 1 micrometer (μm), 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm or 10 μm.

62. The method of claim 59, wherein the metal layer comprises a material of titanium, gold, or platinum.

63. The method of claim 59, wherein the electrode layer comprises a film with a thickness not exceeding about 1000 nanometers (nm), 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm or 100 nm.

64. The method of claim 59, wherein the metal compound of the metal layer comprises a metal selected from osmium, ruthenium, palladium, platinum, rhodium, iridium, cobalt, iron, and copper.

65. The method of claim 35, wherein the penetrator comprises a proximal end and a distal end, wherein the distal end is tapered.

66. The method of claim 35, wherein the penetrator comprises a needle or a sharp object.

67. The method of claim 35, wherein the penetrating body comprises an inner lumen.

68. The method of claim 35, wherein the penetrator comprises a beveled tip.

69. A device for delivering insulin or an insulin analogue and measuring subcutaneous glucose concentration, the device comprising: (a) A tube comprising a proximal end and a distal end, wherein the proximal end is in fluid communication with a source of the insulin or insulin analog formulation, and wherein the distal end is configured to deliver the insulin or insulin analog formulation subcutaneously. (b) A glucose sensor disposed along the central axis of the tube; and (c) A penetrating body disposed along the central axis of the tube, wherein the penetrating body is configured to be inserted at least partially subsurface without the use of a cannula.

70. A method for delivering insulin or an insulin analogue and measuring subcutaneous glucose concentration, the method comprising: (a) A device for delivering insulin or insulin analog formulations and measuring subcutaneous glucose concentration, wherein the device comprises: (i) A tube comprising a proximal end and a distal end, wherein the proximal end is in fluid communication with a source of the insulin or insulin analog formulation, wherein the distal end is configured for subcutaneous delivery of the insulin or insulin analog formulation. (ii) a glucose sensor disposed along the central axis of the tube; and (iii) A penetrating body disposed along the central axis of the tube; (b) The distal end of the tube, the glucose sensor, and the penetrator are subcutaneously inserted into the body of the subject without the use of a cannula; and (c) Subcutaneously delivering the insulin or an insulin analogue to the subject, or measuring the subcutaneous glucose concentration of the subject using the glucose sensor, or a combination thereof.

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