WO2020023804A1

WO2020023804A1 - Microneedles, apparatus comprising microneedles and methods for using same

Info

Publication number: WO2020023804A1
Application number: PCT/US2019/043530
Authority: WO
Inventors: Iman MANSOOR; Boris Stoeber; Sahan RANAMUKHAARACHCHI; Mehrsa RAEISZADEH; William E. Saltzstein
Original assignee: Microdermics Inc.
Priority date: 2018-07-25
Filing date: 2019-07-25
Publication date: 2020-01-30

Abstract

A sensor apparatus and a microneedle apparatus are disclosed. In one aspect, a sensor apparatus has a microneedle projecting and monolithically formed with a substrate and a probe supported by the microneedle for insertion with the microneedle into the skin of a subject. The microneedle provides a first electrode and the probe provides a second electrode of a sensing circuit. In another aspect, a sensor apparatus has an array of microneedles including a first microneedle and a second microneedle. A probe is supported by the second microneedle. The first microneedle provides a first electrode and the probe provides a second electrode of a sensing circuit. In another aspect, a microneedle apparatus with a support structure is provided. In another aspect, a microneedle apparatus capable of providing a physical and electrical contact away from the microneedle is provided.

Description

MICRONEEDLES, APPAFIATUS COMPRISING MICRONEEDLES AND METHODS

FOR USING SAME

Related Applications

[0001] This application claims the benefit of the priority of US application No.

62/703,409 filed on 25 July 2018, and entitled MICRONEEDLES, APPARATUS

COMPRISING MICRONEEDLES AND METHODS FOR USING SAME, which is incorporated herein by reference. For purposes of the United States, this application claims the benefit under 35 U.S.C. §1 19 of application No. 62/703,409, filed 25 July 2018, and entitled MICRONEEDLES, APPARATUS COMPRISING MICRONEEDLES AND METHODS FOR USING SAME.

Technical Field

[0002] The technology described herein relates to microneedles and applications for microneedles. Particular non-limiting embodiments provide sensor apparatus comprising microneedles and methods for using same. Particular non-limiting embodiments may comprise microneedles used for injecting materials into or extracting materials from or electroporation of the body of a subject.

Background

[0003] Many biosensors exist to provide diagnostic information about a subject’s health status. Some biosensors are subcutaneously implanted to sense characteristics of analytes (e.g. naturally occurring or artificially introduced, reactants, reaction products, metabolites, and/or other chemical constituents) present in blood. To subcutaneously implant such biosensors, hypodermic needles are often used to penetrate through the outer layers of the skin (the epidermis and the dermis) to deliver the biosensors to the subcutaneous layer of the subject’s body. A drawback with this approach is that this technique is invasive (the needle causes pain and local damage to the subject’s tissue), causes bleeding (which increases the risk of disease transmission) and causes wounds that may become infected. Another drawback is that many subcutaneous biosensors are limited for single-analyte measurement because it is difficult and costly to construct a multi-analyte sensor on a single implanted filament. Multi-analyte sensors are relatively large in size and can cause excessive tissue damage. It is almost infeasible to achieve multi-analyte measurement with an array of simultaneously-implanted subcutaneous sensors due to the excessive tissue damage, infection risk, and/or pain.

[0004] Other biosensors monitor analytes in interstitial fluid. Interstitial fluid is the extracellular fluid surrounding tissue cells. Blood readily exchanges biological analytes by diffusion with interstitial fluid and thereby interstitial fluid offers an alternative physiological fluid than blood to provide valuable diagnostic information. A percentage volume of interstitial fluid in the subcutaneous layer (~20%+/-10%) is generally smaller than in the dermis (~40%+/-5%) or in the epidermis ~25%+/-10%). Interstitial fluid can be used for minimally invasive monitoring and sensing of analytes.

[0005] Microneedles can be used for interstitial fluid sensing. For example, US Patent No. 6334856 discloses that microneedles formed of metal or biodegradable polymer may function to support biosensors.

[0006] Figure 1 illustrates a prior art microneedle apparatus 10 having a microneedle 1 1 fixed onto a substrate 16. Microneedle 1 1 extends in a longitudinal direction 18 from a base 12 to a tip 20.

[0007] Microneedle apparatus 10 has a particularly mechanically weak region around the base 12 of the microneedle 1 1 (i.e. close to the substrate 16), where the microneedle apparatus 10 transitions discontinuously from a typically planar surface 14 of the substrate 16 to extend in a longitudinal direction 18 away from the substrate 16. The mechanical weakness of this base region 12 may be exacerbated when the microneedle 1 1 is inserted into the skin of a subject until the outermost surface of the skin reaches the base region 12 or the substrate surface 14. In such applications, the portion of the microneedle 1 1 inserted into the skin and away from the substrate surface 14 is stabilized by the subject’s tissue. However, transverse forces caused by the tissue of the subject can cause relatively high torques at the base region 12 of the microneedle 1 1 leading to needle breakage. The mechanical weakness of this region is partially attributed to discontinuities (non-smooth transitions) between the substrate 16 and extension of the microneedle 1 1 in longitudinal direction 18 away from the substrate surface 14, as shown in Figure 1.

[0008] There is a general desire to provide microneedles which are sufficiently strong for any of a variety of applications, particularly in the base region where the microneedle transitions from the generally planar surface of the substrate to a direction of longitudinal extension away from the substrate. At the same time, however, the thicker the microneedle (i.e. the larger the transverse microneedle cross-section), the more damage will be done to the tissue of the subject into which the microneedle is inserted.

Consequently, there is another general desire to minimize the transverse cross-sectional area of the microneedle, particularly in the regions of the microneedle that are inserted into the body of the subject.

[0009] For practical applications associated with housing sensor probes or for many other practical applications, microneedles and/or arrays comprising pluralities of microneedles are attached to support structures. This attachment may be referred to as the integration of the microneedle(s) with the support structure. Techniques currently in use for integration of the microneedle(s) and the support structure include adhesively bonding the substrate of the microneedle(s) to the support structure. A drawback with this approach is the limited robustness of the bond, as there is only a small surface area available for this bond. A strong bond is desirable, for example, when injecting fluid through a microneedle, where the associated high fluid pressure can exceed the strength of the bond, potentially causing detachment of the microneedle(s) from the support structure. Further, adhesive based solutions are not scalable in the sense that manufacturing devices comprising microneedles is challenging (e.g. costly and time consuming) and becomes increasingly challenging when integration is performed by individually gluing microneedles to support structures. Further still, in some cases where an electrical connection between an external electrical circuit and a microneedle is desired, adhesives bonding may not maintain sufficient physical contact between the microneedle and the external electrical circuit.

[0010] There is a general desire to provide techniques for integration of one or more microneedles to a support structure that overcome or ameliorate some of the drawbacks associated with adhesively bonding the microneedle substrate to the support structure.

[0011] Prior art microneedle arrays (i.e. pluralities of microneedles) comprise microneedles that project from a substrate. Because the penetration depth of microneedles is generally relatively small (e.g. when compared to hypodermic needles), it can be desirable to cause the microneedles to penetrate the skin until the subject’s skin contacts the substrate. For example, when such microneedles effectively penetrate the skin of a subject, they may locate sensor probes at desirable locations within the subject’s tissue. However, when the microneedles are pushed into the subject’s skin in such circumstances, the skin deforms, which, in turn, causes the skin to exert force against the substrate in a direction that tends to push the microneedles out of the skin. There is a general desire for effective methods and apparatus for supporting

microneedles in a manner which improves the efficacy of the microneedles for penetrating at least outer layers of the skin of a subject.

[0012] The foregoing examples of the related art and limitations related thereto are intended to be illustrative and not exclusive. Other limitations of the related art will become apparent to those of skill in the art upon a reading of the specification and a study of the drawings.

Summary

[0013] The following embodiments and aspects thereof are described and illustrated in conjunction with systems, tools and methods which are meant to be exemplary and illustrative, not limiting in scope. In various embodiments, one or more of the above- described problems have been reduced or eliminated, while other embodiments are directed to other improvements.

[0014] One aspect of the invention provides a sensor apparatus with a relatively large bio-sensing surface area. In some embodiments, the sensor apparatus comprises a conductive microneedle monolithically formed with a conductive substrate from a conductive material which provides the structural integrity of the microneedle, the microneedle projecting from the conductive substrate in a projection direction, the projection direction having at least a directional component in a longitudinal direction, the longitudinal direction normal to a first surface of the substrate in a region where the microneedle projects from the substrate. The microneedle comprises an exterior surface, an interior bore-defining surface opposed to the exterior surface and defining a bore through the microneedle, and a tip portion distal to the substrate, the tip portion defining an opening of the bore. A probe is disposed at least partially within the bore for insertion, with the microneedle, into the skin of a subject, the probe comprising a probe electrode. The conductive material of the microneedle and the substrate provide a first electrode of a sensing circuit and the probe electrode provides a second electrode of the sensing circuit.

[0015] The probe electrode may be coated with a membrane for electrochemical sensing. For example, the probe electrode may be coated with an enzyme-based coating, the enzyme-based coating sensitive to a particular biological analyte. The probe electrode may coated with an ion-selective coating, the ion-selective coating sensitive to a particular ion.

[0016] The probe electrode may be movable longitudinally relative to the

microneedle and extendable through the opening at the tip portion to a location more distal from the substrate than the tip portion. The probe may also be removably disposed at least partially within the bore.

[0017] In some embodiments, the first electrode is a reference electrode and the second electrode is a working electrode. The sensing circuit measures an

electrochemical signal between the reference electrode and the working electrode.

[0018] Another aspect of the invention provides a sensor apparatus comprising an array of microneedles. The array of microneedles comprising (a) a first conductive microneedle monolithically formed with a conductive substrate from a conductive material which provides the structural integrity of the microneedle, the microneedle projecting from the conductive substrate in a projection direction, the projection direction having at least a directional component in a longitudinal direction, the longitudinal direction normal to a first surface of the substrate in a region where the microneedle projects from the substrate and (b) a second microneedle different from the first microneedle, the second microneedle projecting from the substrate. The sensor apparatus also comprises (a) a probe that is at least partially disposed in the bore of the first microneedle for insertion, with the first microneedle, into the skin of a subject and (b) a second probe supported by the second microneedle for insertion, with the second microneedle, into the skin of a subject.

[0019] In some embodiments, the conductive material of the first microneedle and the substrate provide the first electrode of the sensing circuit. The probe electrode provides a second electrode of the sensing circuit. The second probe electrode provides a third electrode of the sensing circuit

[0020] The first electrode may be a counter electrode. The second electrode may be a working electrode. The third electrode may be a reference electrode. As such, the sensor apparatus may form a three-electrode system, wherein the working electrode acts as an anode; the counter electrode acts as a cathode; and the reference electrode acts to provide a stable working potential for the working electrode.

[0021] In some embodiments, the probe is sensitive to an analyte-specific electrochemical condition and generates a first signal in the sensing circuit in response to the analyte-specific electrochemical condition. The second probe is not sensitive to the analyte-specific electrochemical condition and generates a common-mode signal in the sensing circuit. The sensor apparatus may be configured to subtract the common mode signal from the first signal in the analog or digital domain to remove noise from the first signal and to thereby obtain a noise-reduced signal reflective of the analyte-specific electrochemical condition. For example, the sensor apparatus may comprise a differential amplifier that is part of the sensing circuit, the differential amplifier connected to subtract the common-mode signal from the first signal in the analog domain to remove noise from the first signal and to thereby obtain the noise-reduced signal reflective of the analyte-specific electrochemical condition. The sensor apparatus may comprise a digital processor that is part of the sensing circuit, the digital processor configured to subtract the common-mode signal from the first signal in the digital domain to remove noise from the first signal and to thereby obtain the noise-reduced signal reflective of the analyte- specific electrochemical condition.

[0022] In some embodiments, the probe and the second probe are sensitive to different analytes.

[0023] In some embodiments, the first probe electrode is coated with a first layer of a biodegradable material. The second probe electrode is coated with a second layer of the biodegradable material. The first layer has a thickness that is different than that of the second layer.

[0024] Another aspect of the invention provides a sensor apparatus comprising an array of microneedles. The array of microneedles comprising (a) a first microneedle fabricated from a conductive material, the first microneedle providing a first electrode of a sensing circuit; (b) a second microneedle different from the first microneedle, the second microneedle comprising an interior bore-defining surface shaped to define a bore through the second microneedle; and a third microneedle different from the first microneedle and the second microneedle. A probe is at least partially disposed in the bore of the second microneedle for insertion, with the second microneedle, into the skin of a subject, the probe comprising a second electrode of the sensing circuit.

[0025] In some embodiments, the first electrode is a reference electrode and the second electrode is a working electrode. The sensing circuit measures an

electrochemical signal between the reference electrode and the working electrode. [0026] In some embodiments, the sensor apparatus may comprise a third microneedle different from the first microneedle and the second microneedle and a second probe is supported by the third microneedle for insertion, with the third microneedle, into the skin of a subject. The second probe comprises a second probe electrode that forms part of the sensing circuit.

[0027] In some embodiments, the first microneedle provides the first electrode. The probe electrode provides the second electrode. The second probe electrode provides a third electrode of the sensing circuit. The first electrode may be a counter electrode. The second electrode may be a working electrode. The third electrode may be a reference electrode. In such circumstances, the sensor apparatus forms a three-electrode system, wherein the working electrode acts as an anode; the counter electrode acts as a cathode; and the reference electrode acts to provide a stable working potential for the working electrode.

[0028] In some embodiments, the first probe is sensitive to an analyte-specific electrochemical condition and generates a first signal in the sensing circuit in response to the analyte-specific electrochemical condition. The second probe is not sensitive to the analyte-specific electrochemical condition and generates a common-mode signal in the sensing circuit. The sensing circuit may be configured to subtract the common-mode signal from the first signal in the analog or digital domain to remove noise from the first signal and to thereby obtain a noise-reduced signal reflective of the analyte-specific electrochemical condition. For example, the sensing circuit may comprise a differential amplifier that is part of the sensing circuit, the differential amplifier connected to subtract the common-mode signal from the first signal in the analog domain to remove noise from the first signal and to thereby obtain the noise-reduced signal reflective of the analyte- specific electrochemical condition. The sensing circuit may comprise a digital processor that is part of the sensing circuit, the digital processor configured to subtract the common-mode signal from the first signal in the digital domain to remove noise from the first signal and to thereby obtain the noise-reduced signal reflective of the analyte- specific electrochemical condition.

[0029] Another aspect provides a microneedle apparatus comprising a conductive substrate and a conductive microneedle monolithically formed with the substrate and projecting from the substrate in a projection direction, the projection direction having at least a directional component in a longitudinal direction, the longitudinal direction normal to a first surface of the substrate in a region where the microneedle projects from the substrate. The microneedle apparatus also comprises a conductive circuit component in physical contact with at least one of the microneedle and the substrate and connectable to an external circuit to thereby electrically connect the microneedle to the external circuit.

[0030] In some embodiments, the conductive circuit component is in physical contact with the substrate at a location spaced apart from the microneedle in a transverse direction orthogonal to the longitudinal direction.

[0031] In some embodiments, the substrate comprises a second surface generally opposed to the first surface, and a perimeter edge between the first and second surfaces. The conductive circuit component physically contacts the second surface.

[0032] In some embodiments, the microneedle apparatus comprises a support structure abutting against a surface of the substrate to support the microneedle. The support structure may abut against the conductive circuit component at a location where the conductive circuit component contacts the second surface to force the conductive circuit component into physical contact with the substrate.

[0033] Another aspect of the invention provides a microneedle apparatus. The microneedle apparatus comprises a conductive substrate comprising a first surface, a second surface generally opposed to the first surface, and a perimeter edge between the first and second surfaces. A conductive microneedle monolithically is formed with the substrate, the microneedle projecting from the substrate in a projection direction the projection direction having at least a directional component in a longitudinal direction, and the first surface extending with at least a directional component in a transverse direction orthogonal to the longitudinal direction. A support structure abuts against the first surface and against the second surface to thereby encapsulate at least a portion of the perimeter edge.

[0034] In some embodiments, the support structure comprises a first component abutting against the first surface of the substrate and a second component connected to the first component, the second component abutting against the second surface of the substrate.

[0035] In some embodiments, at least one of the first component and the second component is elastically deformable such that, when deformed, the at least one of the first component and the second component exerts restorative force that tends to lock the first and second components to one another. The at least one of the first component and the second component may exert restorative force which tends to force at least one of: the first component abutting against the first surface and the second component abutting against the second surface

[0036] In other embodiments, the first component and the second component may be connected by a retaining mechanism. In other embodiments, at least one of the first component and the second component comprises a retaining mechanism, the retaining mechanism being elastically deformable such that, when deformed, the retaining mechanism exerts restorative deformation force that tends to lock the first and second components to one another.

[0037] The retaining mechanism may comprise a groove defined by the first component and a flexible projection projecting from the second component, the flexible projection being complementary to the groove so that the flexible projection, when deformed, exerts restorative deformation force which snap fits the flexible projection into the groove to thereby connect the first component with the second component.

[0038] The retaining mechanism may comprise a cut-out defined by the first component and a guiding member projecting from the second component, the guiding member being complementary to the cut-out for guiding the engagement between the first and second components. The guiding member may be configured to guide the engagement between the first and second components in the longitudinal direction.

[0039] The support structure may be monolithically formed.

[0040] The support structure may be adhered to at least one of the first surface and the second surface of the substrate.

[0041] Another aspect of the invention provides a method for making a microneedle apparatus. A conductive substrate is provided, the conductive substrate comprising a first surface, a second surface generally opposed to the first surface, and a perimeter edge between the first and second surfaces. A metallic microneedle projects from, and is monolithically formed with, the conductive substrate, the microneedle projecting from the metallic substrate in a projection direction, the projection direction having at least a directional component in a longitudinal direction and the first surface extending with at least a directional component in a transverse direction orthogonal to the longitudinal direction. A support structure is abutted against the first surface and against the second surface to thereby encapsulate at least a portion of the perimeter edge. [0042] Another aspect of the invention provides a microneedle apparatus. The microneedle apparatus comprises a conductive substrate comprising a first surface, a second surface generally opposed to the first surface, and a perimeter edge between the first and second surfaces; a conductive microneedle monolithically formed with the substrate, the microneedle projecting from the substrate in a projection direction the projection direction having at least a directional component in a longitudinal direction, and the first surface extending with at least a directional component in a transverse direction orthogonal to the longitudinal direction; and a monolithically-formed support structure that abuts against the first surface and against the second surface and wherein the support structure is adhered to at least one of the first and second surfaces to thereby encapsulate at least a portion of the perimeter edge.

[0043] In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent by reference to the drawings and by study of the following detailed descriptions.

Brief Description of the Drawings

[0044] Exemplary embodiments are illustrated in referenced figures of the drawings. It is intended that the embodiments and figures disclosed herein are to be considered illustrative rather than restrictive.

[0045] Figure 1 is an example illustrative representation of a prior art microneedle apparatus and the weakness of the prior art microneedle in the base region.

[0046] Figure 2 is an image of a microneedle apparatus according to a particular embodiment of the invention.

[0047] Figure 3 is a schematic cross-sectional representation of the Figure 2 microneedle apparatus.

[0048] Figure 4 is an image of a microneedle apparatus comprising an array of the Figure 2 microneedles.

[0049] Figure 5 is a schematic cross-sectional illustration of integration of a microneedle to a support structure according to a particular embodiment.

[0050] Figure 5A is an illustration of integration of a plurality of microneedles, each to a corresponding support structure according to a particular embodiment [0051] Figure 5B is an illustration of integration of an array comprising a plurality of microneedles to a support structure according to a particular embodiment.

[0052] Figure 5C is an image of integration of a microneedle to a support structure according to another embodiment.

[0053] Figure 5D is another image of the integrated microneedle and support structure shown in Figure 5C.

[0054] Figure 5E is an image of an ultrasonic bonding based integration techniques according to a particular embodiment.

[0055] Figure 5F is a schematic top view of the support structure shown in Figure 5.

[0056] Figure 5G is a schematic cross-sectional illustration of the support structure shown in Figure 5F along the line A-A.

[0057] Figure 5H is a schematic top view of a support structure according to a particular embodiment.

[0058] Figures 6A, 6B and 6C show various methods in which a substrate upon which one or more microneedles are arranged can be deformed for integration (e.g. snap-together or otherwise) with a support structure according to various embodiments.

[0059] Figures 7A and 7B show images of integrating a microneedle using a snap- together support structure according to a particular embodiment.

[0060] Figure 7C shows a schematic perspective view of the microneedle and the substrate shown in Figure 7A.

[0061] Figures 8A-8E show schematic cross-sectional images of different techniques for integrating one or more microneedles with a support structure according to particular embodiments.

[0062] Figure 9A is a schematic cross-sectional image showing a sensing probe extending through the lumen of a microneedle according to a particular embodiment.

[0063] Figure 9B is a schematic cross-sectional image showing a sensing probe housed in the lumen of a microneedle according to a particular embodiment.

[0064] Figures 9C and 9D respectively depict an optical sensor and an

electrochemical sensor using the Figure 9A architecture according to particular embodiments. [0065] Figure 9E is a schematic cross-sectional image showing an array of sensing probes extending through the lumens of a corresponding array of microneedles according to a particular embodiment.

[0066] Figure 9F is a schematic cross-sectional image showing a sensing probe comprising a plurality of electrodes extending through the lumen of a microneedle according to a particular embodiment.

[0067] Figure 9G is a schematic cross-sectional image showing an optical sensor (e.g. for glucose or lactate or a combination thereof) comprising a pair of optical fibers (for emission and detection of electromagnetic energy) and an immobilized enzyme layer according to a particular embodiment.

[0068] Figure 9H is a schematic cross-sectional image showing an optical sensor comprising a plurality of microneedles, one microneedle for housing a probe for electromagnetic energy emission, a second microneedle for housing a probe for electromagnetic energy detection and a third microneedle incorporating an enzyme or fluorescent emission layer according to a particular embodiment.

[0069] Figure 9I is a schematic cross-sectional image showing a multi-electrode sensor extending through the lumen of a microneedle according to a particular embodiment.

[0070] Figures 9J and 9K show schematic cross-sectional images showing sensors having probes mounted to the outer surface of the microneedle according to particular embodiments.

[0071] Figure 9L is a schematic cross-sectional drawing showing a sensor where at least a portion of the inner surface of the microneedle is reflective such that light may travel through the lumen of the microneedle according to a particular embodiment.

[0072] Figure 9M is a schematic cross-sectional drawing showing a sensor where at least a portion of the inner surface of the microneedle is coated with one or more functionalized surfaces for interacting with one or more analytes according to a particular embodiment.

[0073] Figure 9N is a schematic cross-sectional drawing showing a sensor apparatus comprising a plurality of probes according to a particular embodiment.

[0074] Figures 10A-10F are schematic cross-sectional images showing microneedle apparatus each having an conductive circuit component making electrical contract with the microneedle but making physical contact with the substrate at one or more locations spaced apart from a microneedle.

[0075] Figure 1 1 shows data correlating current and potassium concentrations evidencing that an electrochemical probe supported by a microneedle is responsive to potassium.

[0076] Figure 12 shows data correlating current and glucose concentrations evidencing that an electrochemical probe supported by a microneedle is responsive to glucose.

[0077] Figure 13 is a schematic cross-sectional drawing showing a sensor apparatus according to a particular embodiment.

[0078] Figure 14 shows a schematic cross-sectional drawing showing a sensor apparatus according to a particular embodiment.

[0079] Figures 15A and 15B show schematic cross-sectional images showing a probe movably disposed within a microneedle according to a particular embodiment.

[0080] Figure 16 shows a schematic cross-sectional drawing of a microneedle apparatus comprising a conductive circuit component that makes electrical contact with the microneedle but which make physical contact with the substrate at a location spaced apart from the microneedle according to a particular embodiment.

[0081] Figure 17 shows a schematic cross-sectional drawing of a sensor apparatus having a probe with an insulated tip portion.

Description

[0082] Throughout the following description specific details are set forth in order to provide a more thorough understanding to persons skilled in the art. However, well known elements may not have been shown or described in detail to avoid unnecessarily obscuring the disclosure. Accordingly, the description and drawings are to be regarded in an illustrative, rather than a restrictive, sense.

[0083] As used herein, unless the context dictates otherwise, the term“longitudinal” is defined relative to a substrate surface. The substrate surface has a tangent plane at the region from which a microneedle projects. The term“longitudinal” means a direction away from the substrate surface in a direction with at least a directional component that is orthogonal to the tangent plane. As used herein, unless the context dictates otherwise, the term“transverse” means a direction as being in a plane orthogonal to the longitudinal direction. For example, when a microneedle projects from a substrate surface

longitudinally, the microneedle has a longitudinal extension having at least a directional component that is orthogonal to the tangent plane of the substrate surface at the region from which the microneedle projects. In some embodiments, a microneedle can have a longitudinal extension having at least a longitudinal directional component that is orthogonal to the tangent plane and a transverse direction component that is orthogonal to the longitudinal direction.

[0084] As used herein, unless the context dictates otherwise, the term“continuity” or “continuous” or“continuously” means a smooth transition that is free from sharp edges.

In contrast, the term“discontinuity” or“discontinuous” or“discontinuously” means a non smooth transition. For example, a microneedle may project from a substrate in a discontinuous manner and this means that there is a sharp (or non-smooth) transition between the microneedle and the substrate.

[0085] As used herein, unless the context dictates otherwise: the term“epidermis” means the outermost layer of the skin; the term“hypodermis” means the inner subcutaneous tissue; and the term“dermis” means the layer that is inward of the epidermis and outward of the hypodermis.

[0086] As used herein, unless the context dictates otherwise, the term“probe” may refer to a transducer element configured to transform a physical quantity or physical parameter associated with an analyte into an electrical signal. By way of non-limiting example, the physical quantity or parameter associated with the analyte may comprise a presence or characteristic of matter, energy, environmental conditions and/or the like.

[0087] As used herein, the expression“probe electrode” refers to a portion of a probe that may act either as an anode or a cathode of an electrochemical cell. By way of non limiting example, a probe may comprise a probe electrode at a tip end of the probe. The probe electrode may be coated with an enzyme-functionalized coating configured to detect a biological analyte and the probe electrode may act as an anode of an electrochemical cell.

[0088] As used herein, the expression“monolithically formed” means that two or more components are made of one piece.

[0089] As used herein, unless the context dictates otherwise, the term "conductive” refers to electrical conductivity and the expression“conductive material” refers to a material that readily conducts the flow of electric current. A conductive material may have an electrical resistivity of less than 10^-7 p (W- m). Conductivity may be achieved by coating a non-conductive material with a layer of conductive material.

[0090] The technology disclosed herein includes several aspects. A first aspect provides a microneedle apparatus comprising a microneedle projecting longitudinally from and monolithically formed with a substrate. The microneedle comprises a base region connected to the substrate in a continuous transition and the base region is shaped to provide structural strength and rigidity to the microneedle. The microneedle may be used to inject energy, signals and/or matter into the body of a subject. The microneedle may also be used to withdraw energy, signals and/or matter from the body of a subject. The microneedle may be used to support a sensor probe and/or to locate an active portion of the probe below the skin of a subject.

[0091] Another aspect of the invention provides a support structure configured to support and to provide structural integrity to a microneedle for penetrating at least outer layers of the skin of a subject. The support structure is configured to encapsulate at least a portion of a perimeter edge of a substrate from which the microneedle projects.

[0092] Another aspect of the invention provide a microneedle apparatus comprising a conductive circuit component that connect the microneedle to an external circuit. The microneedle apparatus comprises a conductive microneedle monolithically formed with and projecting from a conductive substrate. The conductive circuit component is in physical contact with at least one of the microneedle and the substrate to thereby electrically connect the microneedle to the external circuit. The conductive circuit component may be physically connected to the substrate at a location spaced apart from the microneedle.

[0093] The microneedle apparatus described herein may be used to house or support a probe (or a portion thereof) to thereby provide a sensor apparatus. One function of the microneedle may be to facilitate insertion of the probe (or a portion thereof) into tissue such as skin, by providing a rigid structure that is capable of piercing the surface of the tissue to reach a desired depth. Another function of the microneedle may be to permit the sensor probe to be exposed to physical phenomena (e.g. matter, signals and/or energy) of interest (by way of non-limiting example matter in the form of an analyte of interest, signals in the form of a pH and/or the like or energy in the form of optical (electromagnetic) energy, thermal energy and/or the like) in the tissue of the subject, while minimizing or mitigating damage to the tissue and/or to the sensing probe during such procedure. Another function of the microneedle may be to provide a first electrode of a sensing circuit. A second electrode of the sensing circuit may be provided by the probe. The probe may permit the transport of matter, signals or energy into or out of tissue. The sensor apparatus can be used for detection of physical phenomena (e.g. matter, signals and/or energy) in tissue of a subject (e.g. a human subject). Such physical phenomena may be associated with one or more analytes to thereby permit the sensor apparatus to monitor and/or detect such analytes and to provide corresponding health information about a subject.

[0094] The target tissue may be a specific layer of skin such as the epidermis (e.g. the stratum germinativum), the dermis, or the subcutaneous layer. The sensing probe may be used to detect physical phenomena (e.g. matter, signals and/or energy) or characteristics of physical phenomena present in the interstitial fluid in the skin layer. The sensing probe may be inserted into the target tissue together with the microneedle and may be repositioned relative to the microneedle after insertion, or may be inserted after insertion of the microneedle into the tissue (e.g. through a lumen (bore) of the microneedle). Following insertion, the sensing probe may be placed (at least partially) within the microneedle, such that the end of the sensing probe resides beyond, before, or at equal depth as the end of the microneedle. That is, the end of the sensing probe may project through the lumen of the microneedle or may be located in the lumen of the microneedle or may just reach the end of the lumen of the microneedle (i.e. at the microneedle tip). The wide opening at the end of the lumen of the microneedle away from the microneedle tip may facilitate insertion of the sensing probe into the

microneedle either prior to or after insertion of the microneedle into tissue.

Microneedle Shape and Configuration

[0095] Figure 2 is a captured image of a microneedle apparatus 100 according to a particular embodiment of the invention. Figure 3 is a schematic cross-sectional representation of the Figure 2 microneedle apparatus 100, showing a number of its features. Figure 4 is a microneedle apparatus comprising an array of microneedles.

[0096] Microneedle apparatus 100 comprises a microneedle 102 that is

monolithically formed with a substrate 104.

[0097] Substrate 104 of the illustrated embodiment is generally planar, although this is not necessary. Substrate 104 comprises a first surface 1 12 and a second surface 1 14. Second surface 1 14 is generally opposed to first surface 1 12. The surface located between first surface 1 12 and second surface 1 14 is a perimeter edge 1 16. Note that elsewhere in this disclosure, first and second surfaces 1 12, 1 14 are also referred to as a substrate surface and an opposite surface, respectively.

[0098] In the illustrated embodiment, first surface 1 12 and second surface 1 14 are almost perfectly opposed to each other because substrate 104 is planar and has a uniform thickness between first surface 1 12 and second surface 1 14. At any given region of first surface 1 12, first surface 1 12 has a normal vector that is anti-parallel to the normal vector of the corresponding region of second surface 1 14. However, in other embodiments, this relationship between the normal vectors of first surface 112 and second surface 1 14 is not necessary. In some embodiments, the first and second surfaces 1 12, 1 14 are generally opposed to each other, which may be interpreted to mean that at any given region of first surface 1 12, first surface 1 12 has a normal vector that is less than 15°from anti-parallel to normal vector of second surface 1 14. In some embodiments, this angular relationship is less than 10° from anti-parallel. In some embodiments, this angular relationship is less than 5° from anti-parallel.

[0099] Substrate 104 may not be planar in some embodiments. As shown in Figures 6A-6C, for example, substrate 104 may be curved or may comprise a sharp transitional edge. With reference to the substrate of the embodiment shown in Figure 6C, first surface 1 12 and second surface 1 14 are each a discontinuous, compound surface. In other embodiments, substrate 104 may be planar around the vicinity of microneedle 102 but may be curved or discontinuous at locations beyond the vicinity of microneedle 102.

[0100] A number of directional conventions are used in this disclosure to assist with the description of microneedle apparatus 100 and the other microneedle apparatus described herein. Figure 3 situates microneedle apparatus 100 in a three-dimensional Cartesian coordinal system with the z-axis oriented in a longitudinal direction 106 and where the x and y axes (and any combination thereof) are transverse directions 108 which include any direction orthogonal to longitudinal direction 106. Microneedle 102 projects from substrate 104 in a projection direction. The projection direction of microneedle 102 comprises at least a directional component that is oriented in longitudinal direction 106. Longitudinal direction 106 may be defined to be a direction that is normal to first surface 1 12 of substrate 104 in a region where microneedle 102 begins to project from the substrate 104. In the illustrated embodiment, substrate 104 is generally transversely planar, although this is not necessary. As illustrated in Figure 3, microneedle 102 projects from first surface 1 12 of substrate 104 in a projection direction having at least a directional component oriented in a longitudinal direction 106 that is generally normal to first surface 1 12 of substrate 104 in a region where microneedle 102 begins to project from the substrate 104.

[0101] Microneedle 102 is shaped to provide structural strength and rigidity so that microneedle 102 can be inserted into the skin of a subject. Microneedle 102 comprises an outer surface 120 and an inner surface 122. In the illustrated embodiment, inner surface 122 is a bore-defining surface 122 that defines a lumen or bore 124 that extends through microneedle 102.

[0102] Microneedle 102 of the illustrated embodiment has a generally conical shape and comprises three regions (or portions): a base region 130 extending between DO and D1 , an intermediate region 132 extending between D1 and D2 and a tip region 134 extending between D2 and D3. D3 may be located at the point of the tip region 134 furthest (most distal) from the substrate surface 1 12 and may be referred to herein as the tip.

[0103] The point DO may be a non-zero percentage of the longitudinal extension h 136 of microneedle 102 away from substrate surface 112. For example, in some embodiments DO may be 0.1 % of longitudinal extension 136; in some embodiments DO may be 0.5% of longitudinal extension 136; and in some embodiments DO may be 1 % of longitudinal extension 136. In some embodiments, D1 may be less than or equal to 10% of longitudinal extension 136; in some embodiments, D1 may be less than or equal to 15% of longitudinal extension 136; in some embodiments, D1 may be less than or equal to 20% of longitudinal extension 136; in some embodiments D1 may be less than or equal to 25% of longitudinal extension 136; in some embodiments D1 may be less than or equal to 30% of longitudinal extension 136; in some embodiments D1 may be less than or equal to 35% of longitudinal extension 136; and in some embodiments D1 may be less than or equal 40% of longitudinal extension 136.

[0104] The region between the heights DO and D1 may be referred to as base region 130 of microneedle 102. It may be desirable for base region 130 of microneedle 102 to be relatively strong (as compared to other regions of microneedle 102 and/or as compared to prior art microneedles) as discussed above. Accordingly, the base region 130 of microneedle 102 may be shaped to provide this strength. In particular

embodiments, the outer surface 120 of microneedle 102 transitions smoothly (e.g.

without discontinuities) in base region 130 between DO and D1 . In particular embodiments, the inner surface 122 of microneedle 102 transitions smoothly (without discontinuities) in base region 132 between DO and D1. In some embodiments, a transverse cross-sectional area of the outer surface 120 of microneedle 102 may be significantly larger at DO than at D1. For example, in some embodiments, the percentage change in the transverse cross-sectional area Abase% of outer surface 120 of microneedle 102 may be greater than or equal to A_{base thresh}. The percentage change in the transverse cross-sectional area of outer surface 120 of microneedle 102 in base region 130 may be defined according to:

where A_D0 is the transverse cross-sectional area of outer surface 120 at height DO and A_D1 is the transverse cross-sectional area of outer surface 120 at height D1. In some embodiments, A_{base thresh} is 20%; in some embodiments A_{base thresh} is 33%; in some embodiments A_{base thresh} is 50%; in some embodiments A_{base thresh} is 65%; in some embodiments A_{base thresh} is 80%; in some embodiments A_{base thresh} is 90%; in some embodiments A_base_ _thresh is 95%; in some embodiments A_base_ _thresh is 98%; and in some embodiments A_{base thresh} is 99%.

[0105] The region between the heights D1 and D2 may be referred to as

intermediate region 132 of microneedle 102. It may be desirable for intermediate region 132 of microneedle 102 to have a relatively small transverse cross-sectional area and/or a relatively small change in transverse cross-sectional area, as this may minimize damage to the tissue of a subject when microneedle 102 is inserted. The distance between D1 and D2 may be a non-zero percentage of the total longitudinal extension 136 of microneedle 102. For example, in some embodiments, the distance between D1 and D2 may be 30% of longitudinal extension 136; in some embodiments, the distance between D1 and D2 may be 40% of longitudinal extension 136; in some embodiments, the distance between D1 and D2 may be 50% of longitudinal extension 136; in some embodiments, the distance between D1 and D2 may be 60% of longitudinal extension 136; in some embodiments, the distance between D1 and D2 may be 70% of longitudinal extension 136; in some embodiments, the distance between D1 and D2 may be 80% of longitudinal extension 136; in some embodiments, the distance between D1 and D2 may be 90% of longitudinal extension 136. [0106] In some embodiments, the percentage change in transverse cross-sectional area of outer surface 120 of microneedle 102 in the intermediate region 132 may be defined according to:

where A_D2 is the transverse cross-sectional area of outer surface 120 at D2. In some embodiments, the percentage change in transverse cross-sectional area of outer surface 120 of microneedle 102 in intermediate region 132 A_inter% may be less than

A inter _jhresh- In some embodiments, A_{inter thresh} is 60%; in some embodiments,

inter _thresh is 50%; in some embodiments, A_{inter thresh} is 45%; in some embodiments,

A inter _thresh is 40%; in some embodiments, A_{inter thresh} is 35%; in some embodiments,

A inter _thresh is 30%; in some embodiments, A_{inter thresh} is 25%; in some embodiments,

A inter jthresh is 20%; in some embodiments, A_{inter thresh} is 15%; and in some

embodiments, A_{inter thresh} is 10%. In some embodiments, a ratio of A_base%/ A_inter% is greater than 0.3; in some embodiments, A_base%/ A_inter% is greater than 0.5; in some embodiments, A_base%/ A_inter% is greater than 0.7; in some embodiments, A_base%/ A_inter% is greater than 1 ; in some embodiments, A_base%/ A_inter% is greater than 2; in some embodiments, A_base%/ A_inter% is greater than 5; in some embodiments, A_base%/A _{inter %} is greater than 7; in some embodiments, A_base%/ A_inter% is greater than 10; and in some embodiments, A_base%/ A_inter% is greater than 12.

[0107] The region between D2 and the tip (D3) of microneedle 102 may be referred to as tip region 134 of microneedle 102 and may have a further change in the transverse cross-sectional area. In some embodiments, like Figure 2, tip region 134 is shaped to provide a point - for example, by beveling the tip region 134 as shown in Figure 2. In some embodiments, like Figure 3, the tip region 134 continues with the same rate of change of the transverse cross-sectional area (per unit of longitudinal extension 136) as in intermediate region 132. In some embodiments, (not shown), tip region 134 may have a faster rate of change of the transverse cross-sectional area (per unit of height h) than in intermediate region 132. Tip region 134 can have any suitable shapes as long as tip region 134 is configured to pierce the skin of a subject. In some embodiments, the shape of tip region 134 is beveled, curved or conical.

[0108] In some embodiments, longitudinal extension 136 (height h) of microneedle 102 is in the range of 20-5000pm. In some embodiments, longitudinal extension 136 of microneedle 102 is in the range of 20-2000pm. In some embodiments, longitudinal extension 136 of microneedle 102 is in the range is 200-1500pm. In some embodiments, longitudinal extension 136 of microneedle 102 is in the range is 400-1200pm.

[0109] Microneedle 102 is hollow and provides lumen (or bore) 124 that extends through microneedle 102. Lumen 124 may be used to house and/or otherwise protect portions of a sensor probe. By way of non-limiting example, hollow microneedle 102 and substrate 104 may be fabricated using the methods described in US Patent No.

9,675,790, which is incorporated herein by reference.

[0110] The thicknesses of microneedle 102 and substrate 104 may be on the same order, meaning that microneedle 102 may have a thickness that is not more than 10 times the thickness of substrate 104. For example, microneedle 102 may have a thickness that differs from the thickness of substrate 104 by less than 20%. In some embodiments, the thicknesses of microneedle 102 and substrate 104 are in the range of 5pm to 200pm or any thickness therebetween, e.g. 50pm, 60pm, 70pm, 80pm, 90pm, 100pm, 1 10pm, 120pm, 130pm, 140pm, 150pm, 160pm, 170pm, 180pm, 190pm, or 200pm.

[0111] Microneedle 102 has a thickness between outer surface 120 and inner bore defining surface 122 at base region 130 that is thicker than that at intermediate region 132 and tip region 134. In other embodiments, microneedle 102 has a uniform thickness between outer surface 120 and inner bore-defining surface 122.

[0112] In other embodiments, microneedle 102 may not be hollow (i.e. may not have lumen (bore) 124). Instead, microneedle 102 can be solid. In some such embodiments, microneedle 102 may protect a sensor probe by locating the probe behind the substrate or in a channel formed on the outer surface 120 of the microneedle 102. In some embodiments, a sensor probe 155 may be located on (or mounted on) an outer surface 120 of a microneedle 102 as shown in Figures 9J and 9K and the microneedle 102 may support the sensor probe 155 or may protect the probe 155 by reinforcing the probe 155 against external pressure.

[0113] Microneedle 102 is preferably fabricated from a conductive material. In some embodiments, microneedle 102 may be fabricated from conductive polymer which may comprise conductive particles (e.g. a uniform distribution of conductive particles) within the polymer or which may be otherwise conductive. Conductive particles that may be used in conductive composite polymer matrices include, without limitation, carbon black (CB) particles, metal particles (e.g. silver nanoparticles), metal oxide particles, particles comprising conductive polymers, and/or the like.

[0114] In some embodiments, microneedle 102 is fabricated from a metallic material including, without limitation, cobalt, nickel, chromium, manganese, iron, gold, copper, lead, ruthenium, rhodium, palladium, silver, mercury, rhenium, titanium, niobium, tantalum, osmium, iridium, platinum, combinations thereof, and/or the like.

[0115] Microneedle 102 may comprise multiple metal layers (not shown). For example, microneedle 100 may comprise a first layer having a structural metal and a second layer having a biocompatible metal. In some embodiments, microneedle 102 comprises a biocompatible coating. In some embodiments, microneedle 102 is coated with a layer of silver/silver chloride and used as the reference electrode in an

electrochemical sensing circuit. In some other embodiment, microneedle 102 can be coated with platinum, gold, silver, or carbon and used as a sensing electrode, such as a working electrode or used as a counter electrode.

[0116] Advantageously, microneedle 102 may be shaped to provide structural integrity, so that microneedle 102 can be inserted into the skin of a subject without bending, breaking, or buckling. The continuous transition in base region 130 provides structural integrity to minimize bending of microneedle 102 when microneedle 102 is inserted into the skin of a subject. Longitudinal extension 136 of microneedle 102 can be customized to target a specific layer of the skin, e.g. the dermis layer. As compared to hypodermic needles, microneedle 102 has a relatively small transverse cross-sectional area to minimize tissue damage when microneedle 102 is inserted into the skin of a subject.

[0117] Advantageously, microneedle 102 may be shaped to have a funnel-shaped lumen 124, so that a probe 155 (described further below) may be inserted into and/or be housed (at least partially) within lumen 124. Further, a funnel-shaped lumen 124 may be useful to prevent some regions of lumen 124 from being exposed to biological fluid. The changing transverse cross-sectional dimension of lumen 124 may be useful for introducing a sensing fluid only to tip region 134 so that the sensing fluid is only exposed to surface functionalization reagents coated in tip region 134 and not to base region 130. The fluid dynamics of a sensing fluid within lumen 124 may depend on (i) the contact angle between the sensing fluid and inner (bore-defining) surface 122 of microneedle 102 and (ii) surface tension. There may be an equilibrium point along the axis of lumen 124, where the contact line of the sensing fluid on inner bore-defining surface 122 comes to a rest. For example, an equilibrium point may be achieved at a position where the angle of the expanding lumen 124 takes on a value that combined with the lumen transverse width leads to a balance between surface tension and capillary forces. A ratio of the maximum transverse dimension of lumen 124 at D3 to DO may be in the range of 1 : 1.1 to 1 : 10; in some embodiments, this range is 1 :2-1 :10; in some embodiments, this range is 1 :5-1 :10; in some embodiments, this range is 1 :7-1 :10. The dimensions of the thickness of between inner surface 122 and outer surface 120 of microneedle 102 may be in the range of 1-200pm. In some embodiments, this range is 5-100pm. In some embodiments this range is 10-80pm. In some embodiments, thickness of between inner surface 122 and outer surface 120 of microneedle 102 is thicker (e.g. 1.1 to 10.0 times as thick) in base region 130 than is in the intermediate region 132. The thickness of between inner surface 122 and outer surface 120 of microneedle 102 may vary from base region 130 (e.g. from DO) to tip region 134 (e.g. to D3). While this variation of microneedle thickness is possible, it is not necessary.

[0118] Microneedle apparatus 100 may be fabricated according to techniques described, for example, in PCT/CA2014/050552 which is incorporated herein by reference, although this is not necessary. Any suitable fabrication techniques (such as, by way of non-limiting example, injection molding, metal electroplating, CNC, laser ablating and/or the like) can be used for fabricating microneedles.

[0119] Microneedle apparatus 100 may be used for injecting matter, energy or signals into the body of a subject or extracting matter, energy or signals from the body of a subject. Microneedle apparatus 100 may be used for housing sensor probes or portions thereof, as described further below.

Microneedle Apparatus Comprising a Conductive Circuit Component

[0120] Figure 16 shows a schematic drawing of a microneedle apparatus 1 100 comprising a conductive circuit component 1 138. Figures 10A-10E show other embodiments of microneedle apparatus 400, 500, 600, 700, 800 comprising conductive circuit components. The microneedle apparatus 400, 500, 600, 700, 800 of Figures 10A- 10E are described in more detail below.

[0121] Microneedle apparatus 1 100 of Figure 16 is similar to microneedle apparatus 100 except that microneedle apparatus 1 100 comprises a conductive circuit component 1 138 that electrically connects its microneedle 1 102 external circuit 1 140. Elements of microneedle apparatus 1 100 that correspond to elements of microneedle apparatus 100 are illustrated with like reference numerals that have been incremented by 1000. One or more conductive circuit components (similar to conductive circuit component 1 138) can be included in any microneedle apparatus described herein.

[0122] Microneedle apparatus 1 100 comprises a conductive substrate 1 104 and a conductive microneedle 1 102. Microneedle 1 102 is monolithically formed with substrate 1 104. Microneedle 1 102 projects from substrate 1 104 with at least a directional component in a longitudinal direction 106.

[0123] Conductive circuit component 1 138 electrically connects microneedle 1 102 to external circuit 1 140. To effect this electrical connection, conductive circuit component 1 138 is in physical contact with at least one of microneedle 1 102 or substrate 1 104. While conductive circuit component 1 138 may physically contact microneedle 1 102 and/or substrate 1 104 at any suitable location, in some embodiments, conductive circuit component 1 138 is in physical contact with substrate 1 104 at a location transversely spaced apart from microneedle 1 102. Advantageously, physical contact at such a transversely spaced apart location allows full access to lumen 1 124 of microneedle 1 102 (e.g. for insertion of probes and/or the like). Furthermore, physical contact of conductive circuit component 1 138 with substrate 1 104 at such a transversely spaced apart location facilitates maximal contact surface area between microneedle 1 102 and the tissue of a subject, particularly when the physical contact of conductive circuit component 1138 is to inner surface 1 122 of microneedle 1 102, as is the case in the illustrated embodiment of Figure 16. Such large surface area contact may increase sensitivity and/or reduce noise in embodiments where microneedle 1 102 acts as an electrode in a sensing circuit.

[0124] In some embodiments, microneedle 1 102 is made of a non-conductive material and one or both of its surfaces 1 120, 1 122 is/are then coated with a conductive layer. The conductive layer may cover the entire microneedle 1 102 or form conductive tracks/pads.

Microneedle Apparatus Comprising a Support Structure

[0125] Figure 5 is a schematic cross-sectional illustration of a microneedle apparatus 200 comprising a microneedle 202, a substrate 204 and a support structure 238 showing integration of the microneedle 202 with support structure 238 according to a particular embodiment. Figures 5A-5E show other example embodiments of microneedle apparatus comprising a microneedle, a substrate and a support structure showing integration of the microneedle with the support structure, wherein the support structure is monolithically formed. Figures 7 A and 7B show images of integrating a microneedle with a snap-together support structure. Figures 8A-8E show images of different techniques for integrating one or more microneedles with a support structure. Figures 10A-10E show example embodiments of microneedle apparatus comprising a microneedle, a substrate and a support structure showing integration of the microneedle with the support structure.

[0126] Aspects of the invention provide novel techniques (apparatus and methods) for integrating a microneedle with a support structure configured to support the microneedle. The support structure may comprise, without limitation, reservoirs, microfluidic channels, sensor components, electrodes, wires, mechanical components, springs, Luers and/or the like. These components may be incorporated in the support structure using methods known in the art. Techniques for integrating a microneedle with a support structure according to various aspects of the invention may comprise encapsulation of at least a portion of a substrate from which a microneedle projects. In some embodiments, such integration techniques involve the encapsulation of at least a portion of a perimeter edge of the substrate. Integration of microneedle(s) with a support structure can help to provide structural integrity to the microneedle(s), so that the microneedle(s) can be used to penetrate at least outer layers of the skin of a subject.

[0127] Advantageously, the integration techniques described herein involving encapsulation may provide a gas-tight and/or liquid-tight seal between the substrate surface and opposite surface of the substrate and/or between inner and outer surfaces of the microneedle with minimal coverage of the substrate surface and without materially sacrificing microneedle height. Another advantage of encapsulation is that an amount (e.g. a thickness) of encapsulation material on the substrate surface side of the microneedle may be used to shorten the effective height h of the microneedle and/or the depth of penetration of the microneedle into the skin of a subject, so that the insertion depth can be controlled.

[0128] The integration and/or encapsulation techniques described herein may be used with any of the microneedles or microneedle apparatus described herein and/or any of the features of such microneedles or any other microneedles. The integration and/or encapsulation techniques described herein may be applied to microneedles that are solid or hollow. In some embodiments, a thickness of the support structure may be between 1-10000pm. In some embodiments, a thickness of the support structure may be between 1-2000pm. In some embodiments, a thickness of the support structure may be between 1-1000pm. In some embodiments, this thickness is in the range of 2-500pm. In some embodiments, this thickness is in the range of 5-200pm. The support structure components that encapsulate the perimeter edge may be fabricated from any suitable materials, such as, by way of non-limiting example, plastics, glass, polymers, ceramics, metals and/or the like. The support structures may comprise pedestals, as described elsewhere herein. The integrated microneedles can be used for any of the purposes described herein or for any other suitable purpose or function.

(a) Monolithically Formed Support Structures

[0129] Figures 5, Figures 5A-5E and Figures 8D-8E show microneedle apparatus comprising microneedles, substrates and monolithically formed support structures wherein the microneedles are integrated with the monolithically formed support structures using integration techniques involving encapsulating a portion of the substrates from which the microneedles project. Encapsulation may be achieved by:

(i) abutting a monolithically-formed support structure against the first and second opposed surfaces of the substrate to thereby encapsulate at least a portion of a perimeter edge between the first and second surfaces; and/or (ii) adhering the monolithically-formed support structure to at least one of the first and second surfaces.

[0130] Figure 5 shows a microneedle apparatus 200. Microneedle apparatus 200 is similar to microneedle apparatus 100, except that microneedle apparatus 200 comprises a support structure 238. Elements of microneedle apparatus 200 that correspond to elements of microneedle apparatus 100 are illustrated with like reference numerals that have been incremented by 100.

[0131] Microneedle apparatus 200 comprises a microneedle 202 monolithically formed with substrate 204. Microneedle 202 projects from substrate 204 with at least a directional component in a longitudinal direction 106. In the illustrated embodiment, substrate 204 is generally planar (transversely planar), although this is not necessary. Microneedle 202 of the Figure 5 embodiment is hollow, defining an internal lumen 224 therethrough. Like microneedle 102 and substrate 104, the thicknesses of microneedle 202 and substrate 204 are on the same order. [0132] Microneedle apparatus 200 further comprises a support structure 238.

Support structure 238 functions to encapsulate at least a portion of perimeter edge 216 of substrate 204 and thereby supports microneedle 202. Support structure 210 may help to provide structural integrity and rigidity to microneedle apparatus 200, so that microneedle 202 can penetrate at least outer layers of the skin of a subject without bending or breaking.

[0133] As shown better in Figure 5G, support structure 238 is monolithically formed, meaning that support structure 238 is made of one piece. Support structure 238 comprises a tubular ring body 240 having an interior bore-defining surface 242 defining an aperture 244 through tubular ring body 240. Aperture 244 has a diameter ( d) that is larger than that (d) of microneedle 202. Additionally, aperture 242 and lumen 224 are positioned concentrically, so that support structure 238 does not obstruct lumen 224.

[0134] Support structure 238 defines a transversely and circumferentially extending (annular) groove 246 which opens onto interior bore-defining surface 242 for receiving a portion of substrate 204, so that support structure 238 can encapsulate a portion of substrate 204. Groove 246 of the illustrated embodiment comprises two longitudinally opposed sides 260, 262.

[0135] Encapsulation is achieved when a portion of substrate 204 is received within groove 246 so that: (i) side 262 of groove 246 abuts against substrate surface 212; and (ii) side 260 of groove 246 abuts against opposite surface 214. The abutting nature of support structure 238 against substrate surface 212 and opposite surface 214 may provide a gas and/or liquid tight seal between substrate surface 212 and opposite surface 214 of substrate 204, although this is not necessary. In some embodiments, this abutting nature substantially immobilizes substrate 204 and the microneedle(s) 202 that project from substrate 204 from movement relative to the support structure 238, although this is not necessary.

[0136] In some embodiments, side 262 of groove 246 adheres to (or is adhered to) substrate surface 212 and/or side 260 of groove 246 adheres to (or is adhered to) opposite surface 214. However, this is not necessary. For example, in some

embodiments, only side 262 of groove 246 abuts against and adheres to substrate surface 212, whereas side 260 of groove 246 abuts against, but does not adhere to, opposite surface 214. [0137] In the illustrated embodiment, support structure 238 additionally abuts against perimeter edge 216 of substrate 202, although in other embodiments, support structure 238 may not abut against perimeter edge 216.

[0138] In some embodiments, support structure 238 may not encapsulate perimeter edge 216 in its entirely. Instead, support structure 238 may encapsulate only a portion of perimeter edge 216. For example, Figure 5H shows a support structure 238’ according to another embodiment. Support structure 238’ is similar to support structure 238 except that support structure 238’ is configured to encapsulate only a portion of perimeter edge 216. Support structure 238’ comprises a tubular ring body 240’ defining an interior bore defining surface 242’. Along interior bore-defining surface 242’ are transversely (e.g. radially) extending indents 264, so that support structure 238’ does not engage with substrate 204’ at the locations of indents 264.

[0139] Support structure 238 can have any suitable configurations and shapes, as long as support structure 238: (i) is monolithically formed; and (ii) is configured to encapsulate a portion of substrate 204. Figures 5A-5E and 8D-8E show example configurations of monolithically-formed support structure 238.

[0140] Monolithically-formed support structure 238 can be fabricated using any suitable fabrication methods known in the art.

[0141] Techniques for integrating support structure 238 and substrate 204 can comprise any methods known in the art, including molding or overmolding, insert molding, adhesive bonding, and ultrasonic bonding, laser welding, soldering or a combination of these methods. For example, overmolding can be used to monolithically form support structure 238 and to simultaneously mold the formed support structure 238 onto substrate 204. In some embodiments, a thickness of the overmolding (on the substrate surface 212 side and/or on the opposite surface 214 side of substrate 204) may be between 1-10000pm. In some embodiments, this thickness of the overmolding may be between 1-2000pm. In some embodiments, this thickness of the overmolding may be between 1-1000pm. In some embodiments, this thickness is in the range of 2- 500pm. In some embodiments, this thickness is in the range of 5-200pm.

[0142] Another non-limiting example of a technique for integrating a support structure involving encapsulation of the perimeter edge 216 comprises adhesively bonding the substrate surface 212, the opposite surface 214 and/or the perimeter edge 216 to one or more support structure components. When the adhesive dries or cures, the adhesive forms part of the support structure which abuts against the substrate surface 212, the opposite surface 214 and/or the perimeter edge 216 to thereby encapsulate the perimeter edge 216.

[0143] Another non-limiting example of a technique for integrating a support structure involves melting a material to encapsulate the perimeter edge 216. Examples of this technique include ultrasonic bonding, soldering, laser welding and/or the like to encapsulate the perimeter edge 216. As shown in Figure 5E, ultrasonic bonding or laser welding can be used to melt a portion of support structure 238 and the melted portion is then adhered to substrate 204.

[0144] Another non-limiting example of a technique for integrating a support structure involves contacting at least one of the substrate surface 212, the opposite surface 214 and/or the perimeter edge 216 of substrate 204 with a thermosetting resin such as polyurethane. The thermosetting resin is then cured to bond to at least one of the substrate surface 212, the opposite surface 214 and/or the perimeter edge 216 of substrate 204.

(b) Snap-Fit Support Structure

[0145] Still another non-limiting example of an integration technique involves the use of a multi-part snap-fit support structure. The snap-together fitting may involve deformation of one or more of the parts of the support structure, such that restorative forces associated with the deformation (i.e. restorative forces that tend to restore a support-structure part to its non-deformed state) act to lock the support-structure parts to one another and/or to exert abutting force by one or more of the support-structure parts onto one or more of the surfaces of the substrate.

[0146] Figures 7 A and 7B show a microneedle apparatus 300 comprising a microneedle 302 projecting from, and monolithically formed with, a substrate 304 and a snap-fit support structure 318. Snap-fitting support structure 318 may be used with any of the microneedles and/or substrates described herein, with, perhaps, suitable modification of the substrate to provide the features of substrate 304.

[0147] Substrate 304 is more clearly visible in Figure 7C. Substrate 304 comprises a discontinuous transition 306 between a central portion 308 (more proximate to microneedle 302) and distal portion 309 (more distal from microneedle 302). Distal portion 309 may comprise circumferentially spaced apart tabs 315, which may facilitate bending substrate 304 at discontinuity 306. Substrate 304 comprises a compound substrate surface 312 which itself comprises first sub-surface 312A in central portion 308 and a second sub-surface 312B in distal portion. Similarly, opposite surface 314 of substrate 304 comprises a first sub-surface (not visible) in central portion 308 and a second sub-surface (not visible) in distal portion 309. Substrate 304 may be fabricated from any of the planar substrates described herein, by suitable deformation of such planar substrates and, optionally, by removing material from such planar substrates to provide the spacing between tabs 315. It is not strictly necessary that the transition between central portion 308 and distal portion be discontinuous. In some embodiments, such a transition can be made without discontinuity 306.

[0148] Microneedle apparatus 300 also comprises a snap-fit support structure 318. Support structure 318 has two components (parts): a cap 320 and a base 322, which are attachable to each other in a snap-together fitting.

[0149] Figures 7A and 7B show images of integrating microneedle 300 with snap- together support structure 318. Figure 7A shows microneedle apparatus 300 in a disassembled configuration and Figure 7B shows microneedle apparatus 300 in a locked configuration. In the locked configuration, cap 320 and base 322 are attached to one another in a snap-together fitting. Cap 320 and/or base 322 is/are elastically deformed to create restoration forces (e.g. forces associated with restoring the deformation of cap 320 and/or base 322 to a non-deformed state) and the restoration forces act to at least partially restore the non-deformed shape of cap 320 and/or base 322 to thereby“snap” cap 320 into a locked configuration with base 322. When such restorative forces partially restore the non-deformed shape of cap 320 and/or base 322, there will continue to be restorative forces when cap 320 and base 3222 are locked to one another. When such restorative forces fully restore the non-deformed shape of cap 320 and/or base 322, cap and/or base is returned to its non-deformed state, such that there are no longer restorative forces when cap 320 and base 3222 are locked to one another.

[0150] The construction of support structure 318 (a particular, and non-limiting embodiment of a snap-together support structure) will now be described. Support structure 318 comprises cap 320 and base 322, which are constructed to cooperate and engage with one another.

[0151] Cap 320 has a hollow body 326 which may be generally tubular. The internal cavity within hollow body 326 is dimensioned to allow placement of base 322 within tubular body 326. Hollow body 326 comprises a first end 328 defining an aperture 330 therethrough. Aperture 330 has a dimension that is sufficient to accept microneedle 302, so that in the locked configuration, microneedle 302 extends through aperture 330 and extends beyond first end 328 of cap 320. Hollow body 326 has an open second end that allows sliding of cap 320 over base 322 during the assembly of supporting structure 318. Hollow body 326 also defines a plurality (e.g. two) opposing cut-out portions 332, 334 extending upwardly and transversely from an edge 336 opposite to first end 328. Cut-out portions 332, 334 are shaped to guide the slidable engagement between cap 320 and base 322. Cap 320 also comprises a plurality (e.g. two) of receptacles 338, 340 extending transversely away from hollow body 326.

[0152] Base 322 comprises a main body member 342 which is shaped to be complementary to and to be placed within hollow body 326 of cap 320. Base 322 also comprises structures that complement corresponding structures on cap 320, thereby facilitating the assembly of base 322 and cap 320 to form support structure 318 in the locked configuration. Extending transversely from main body member 342 are a plurality (e.g. two) of opposing guiding members 344, 346 and a plurality (e.g. two) of opposing tongues 348, 350. Guiding members 344, 346 are configured to engage and be received by cut-out portions 332, 334 of cap 320. Tongues 348, 350 are configured to engage and be received by receptacles 338, 340 of cap 320. Bottom edges 352, 354 provide respective shoulders for the snap fit of tongues 348, 350 into receptacles 338, 340.

[0153] As shown in Figure 7A, substrate 304 sits on a surface of base 322 so that base 322 abuts against opposite surface 314 of substrate 304 to support microneedle 302. When cap 320 and base 322 are assembled in the locked configuration, cap 320 abuts against substrate surface 312 of substrate 304, so that support structure 318 encapsulates at least a portion of substrate 304. In the locked configuration of the Figure 7A-C embodiment, tabs 314 may also be in abutting contact with the surfaces of cap 320 and base 322 when cap 320 and base 322 are in their locked configuration.

[0154] It will be appreciated that support structure 318 of the Figure 7A-C

embodiment represents a particular implementation of a snap-together support structure 318. Support structure 318 may have any other suitable multi-part snap-fit constructions (e.g. where one or more parts are deformed and restorative forces act to at least partially restore the shape of the one or more parts to thereby provide a locked configuration and, optionally, to assert abutting force on one or more of the surfaces of the substrate), as long as in the locked configuration, support structure 318 supports microneedle 302 and abuts against one or more of the surfaces of the substrate or otherwise encapsulates at least a portion of substrate 304.

(cl Restorative Forces Associated with Substrate Deformation

[0155] The support structure embodiments discussed herein may comprise snap- together fittings (e.g. where one or more parts of the support structure are deformed and restorative forces act to at least partially restore the shape of the one or more parts to thereby provide a locked configuration and, optionally, to assert abutting force on one or more of the surfaces of the substrate). In some embodiments, the substrate itself may be deformed when it is mounted on support structure (or otherwise) and restorative forces associated with this substrate deformation may assert abutting force between one or more surfaces of the substrate and the support structure. Figures 6A, 6B and 6C illustrate the deformability of the substrate from which one or more microneedles extend. Such deformability can be used for asserting abutting force between one or more surfaces of the substrate and the support structure.

(dt Support Structure Comprising More Than One Component

[0156] In some embodiments, the support structure a plurality of components configured to cooperate with each other to encapsulate at least a portion of the perimeter edge of the substrate. Some such embodiments are shown in Figures 8A-8C.

[0157] Figure 8A depicts a microneedle apparatus 300a comprising a support structure 318a that may not be a snap-fit support structure. Instead, cap 320a and base 332a of support structure 318a may adhere to (or be adhered to) substrate 304a. Base 322a abuts against substrate 304a to support microneedle 302a. Cap 320a is slidable over base 322a. In an assembled configuration, cap 320a may surround base 322a and substrate 304a is sandwiched between cap 320a and base 322a. Microneedle apparatus 300a is substantially identical to the embodiment shown in Figure 10E, which is further described below.

(e) Support Structure with a Conductive Circuit Component

[0158] Still another non-limiting example of an integration technique provides a support structure comprising a conductive circuit component in physical contact with the substrate. In currently preferred embodiments, such physical contact between the conductive circuit component and the substrate is at a location transversely spaced apart from the microneedle. Advantageously, such support structures with conductive circuit components may be useful, for example, in sensing applications where the microneedle functions as an electrode and where it might be desirable to access the lumen of the microneedle and/or to maximize the surface area of the microneedle electrode in contact with the tissue of the subject.

[0159] Figures 10A-10E show a number of embodiments of microneedle apparatus comprising support structures which provide conductive circuit components.

[0160] Figure 10A shows a microneedle apparatus 400comprising a plurality of (e.g. three) hollow conductive microneedles 402. Microneedles 402 project longitudinally from and are monolithically formed with a conductive substrate 404. Conductive substrate 404 comprises a first surface 406 and a second surface 408 that is opposed to first surface 406. A perimeter edge 410 is defined between first and second surfaces 406, 408.

Microneedle 402 and substrate 404 can be any of the microneedles and substrates described herein.

[0161] Microneedle apparatus 400 also comprises a support structure 412 configured to support microneedles 402 and to abut against first and second surfaces 406, 408 of substrate 404 to thereby encapsulate at least at least a portion of perimeter edge 410. Support structure 412 of the Figure 10A embodiment comprises two components: a first component 414, which abuts against first surface 406 of substrate 404, and a second component 416, which abuts against second surface 408 of substrate 404. First component 414 and second component 416 can be connected to each other in a snap-fitting configuration, as discussed above, although this is not necessary. In some embodiments, first component 414 and second component 416 of support structure 412 are connected to each other by being bonded to substrate 404, although this too is not necessary. In some embodiments, first component 414 and second component 416 are connected in any known methods in the art, including being bonded or welded to each other.

[0162] First component 414 of support structure 412 is fabricated from a conductive material and the physical contact 418 between first component 414 and substrate 404 may thereby provide an electrical connection between microneedles 402 and an external electrical circuit 440. Where first component 414 of support structure 412 provides an electrical connection to substrate 404 and/or microneedle 402, first component may also be referred to as a conductive circuit component 414. As discussed above, the physical connection between conductive circuit component 414 and substrate 404 is

advantageously spaced apart from microneedles 402.

[0163] In some embodiments, second component 416 of support structure 412 may additionally or alternatively be conductive to provide a conductive circuit that electrically connects microneedles 402 to external circuit 440.

[0164] Figure 10B shows a microneedle apparatus 500 which is similar to microneedle apparatus 400 except that: (i) microneedle apparatus 500 comprises solid microneedles 502 instead of hollow microneedles 402 and (ii) support structure 512 has a different configuration than support structure 412.

[0165] Instead of having two components, support structure 512 comprises three components: a first component 514, a second component 516, and a third component 520. First component 514 has a similar construction as first component 414 of support structure 412 in that first component 515 also has a hollow body 522 with a top flange 524, hollow body 522 and top flange 524 forming an L-shaped cross section. Second component 516 has a similar construction as second component 416 of support structure 412 in that second component 516 has a hollow body. However, unlike support structure 412, first component 514 and second component 516 are in direct contact with each other.

[0166] Support structure 512 also comprises third component 520. Flange 524 is in direct contact with third component 520 and flange 524 and second component 516 sandwich third component 520 and substrate 504 therebetween. Third component 520 is fabricated from a conductive material and is physically connected to substrate 504 at contact 518 to provide an electrical connection between microneedles 502 and n external circuit (not shown). In this regard, third component 520 of support structure 512 may be referred to as a conductive circuit component 520.

[0167] In some embodiments, first and second components 514, 516 of support structure 512 may be electrically non-conductive. Flange 524 may provide an insulating barrier to separate the skin surface and substrate surface 508 of substrate 504 so that the surface of the skin surface is not electrically connected to substrate 504 to minimize unwanted noise or signal. For example, once microneedles 502 are inserted into the skin of a subject, flange 524 provides an insulating barrier so that substrate 504 does not physically contact the skin surface. However, it is not necessary that first and second components 514, 516 of support structure 512 may be electrically non-conductive and, in some embodiments, one or both of first and second components 514, 516 512 may be conductive. In other embodiments, third component 520 of support structure 512 may be in direct contact with substrate 504 and second component 516 and thereby be sandwiched between substrate 504 and second component 516.

[0168] Support structure 512 may act as an electromagnetic shield (e.g. as a Faraday cage) to isolate microneedle apparatus 500 from incident radiation 530.

[0169] Figure 10C shows a microneedle apparatus 600 which is similar to microneedle apparatus 500 except that (i) substrate 604 has a discontinuous transition 626 and (ii) support structure 612 has a different configuration than support structure 512.

[0170] Microneedles 602 project from and are monolithically formed with a conductive substrate 604. Conductive substrate 604 has a discontinuous transition 626. Discontinuous transition 626 connects a transversely planar portion 628 and a hollow, longitudinally extending portion 630. Planar portion 628 comprises a substrate surface 606 and an opposite substrate surface 608. Hollow portion 630 comprises an outer surface 610 and an inner surface 61 1. As discussed elsewhere, substrate 604 may be understood as comprising a first discontinuous, compound surface (comprising substrate surface 606 and outer surface 610) and a second discontinuous, compound surface (comprising opposite surface 608 and inner surface 61 1).

[0171] Similar to support structure 512, support structure 612 of the Figure 6C embodiment also has three components: a first component 614, a second component 616, and a third component 620. However, instead being sandwiched between flange 624 and second component 616, conductive third component 620 (and hollow portion 630 of conductive substrate 604) are sandwiched between hollow body 622 and second component 616. In this illustrated embodiment, third component 620 may surround second component 616; hollow portion 630 of substrate 604 may surround third component 620; and first component 614 may surround hollow portion 630 of substrate 604. The physical contact between electrically conductive third component 620 and substrate 604 provides an electrical connection between microneedles 602 and an external electrical circuit (not shown). In this regard, third component 620 of support structure 612 may be referred to as a conductive circuit component 620. In some embodiments, first component 614 and/or second component 616 of support structure 612 may be non-conductive and, in some embodiments, first component 614 and/or second component 616 of support structure 612 may additionally or alternatively be conductive.

[0172] Figure 10D shows a microneedle apparatus 700which is similar to microneedle apparatus 600 except that support structure 712 has a different configuration than support structure 612.

[0173] Similar to support structure 612, support structure 712 also comprises three components: a first component 714, a second component 716, and a third component 720. First component 714 and second component 716 are in direct contact with hollow portion 730 of substrate 704. Hollow portion 730 of substrate 704 extends beyond surface 732 of second component 716. Third component 720 abuts against inner surface 710 of hollow portion 730 and optionally to surface 732, so that hollow portion 730 surrounds third component 720. In alternative embodiments, third component 720 abuts against outer surface 712 of hollow portion 730 and a optionally to surface of first component 714, so that third component 720 surrounds hollow portion 730.

[0174] Substrate 704 and third component 720 of support structure 712 are in physical contact at a contact 718. In the illustrated embodiments, this physical contact 718 is at hollow portion 730 of substrate 704. Third component 720 of support structure 712 may be electrically conductive so that this physical contact 718 provides electrical connection between microneedles 702 and an external circuit (not shown). In this regard, third component 720 of support structure 712 may be referred to as a conductive circuit component 720. In alternative embodiments, third component 720 is only in physical contact with tubular portion 730 and may not be in physical contact with first component 714 or second component 716. In some embodiments, first component 714 and/or second component 716 of support structure 712 may be non-conductive and, in some embodiments, first component 714 and/or second component 716 of support structure 712 may additionally or alternatively be conductive.

[0175] Figure 10E shows a microneedle apparatus 800. Microneedle apparatus 800 is similar to microneedle apparatus 700 in that (i) microneedle apparatus 800 also has three hollow conductive microneedles 820 and (ii) the microneedles 802 project from and are monolithically formed with a conductive substrate 804 that comprises a discontinuous transition 826 connecting a planar portion 828 and a hollow portion 830. Planar portion 828 comprises first and second opposed surfaces 806, 808. Hollow portion 830 comprises third and fourth opposed surfaces 832, 834. Microneedle device 800 differs from microneedle device 700 in that microneedle device 800 has a different support structure 812.

[0176] Support structure 812 comprises two components: a first component 814 and a second component 816. First component 814 abuts against first and third surfaces 806, 832 of substrate 804. Second component 816 abuts against second and fourth surfaces 808, 834 of substrate 804. In this way, substrate 804 is sandwiched between first and second components 814, 816.

[0177] Second component 816 of support surface is fabricated from a conductive material. Because substrate 804 and second component 816 are in physical contact at a contact 818, second component 816 of support structure 812 provides an electrical connection between microneedles 802 and an external circuit (not shown). In this regard, second component 816 of support structure 812 may be referred to as a conductive circuit component 816. In some embodiments, first component 814 of support structure 812 is fabricated from a non-electrically conductive material. In some embodiments, first component 814 of support structure 812 may additionally or alternatively be fabricated from a conductive material.

[0178] Figure 10F shows a microneedle apparatus 1400 which is similar to microneedle apparatus 500 except that: (i) microneedle apparatus 1400 comprise three hollow conductive microneedles 1402 instead of solid microneedles 502; and (ii) support structure 1412 has a different configuration than support structure 512.

[0179] Support structure 1412 comprises two components: a first component 1414 and a second component 1416. First component 1414 of support structure 1412 is similar structure to support structure 210 illustrated in Figure 5G and described elsewhere herein. First component 1414 comprises a transversely and circumferentially extending (annular) groove 1415 similar to groove 246 of support structure 210 and abuts against first surface 1408 and second surface 1406 of substrate 1404 to thereby encapsulate perimeter edge 1414.

[0180] First component 1414 also comprises a longitudinally and circumferentially extending groove 1417, which receives a portion of second component 1416. The portion of second component 1416 may be received in groove 1417 may be held by a friction fit. This friction fit may comprise deformation of first component 1414, so that restorative forces associated with this deformation act to exert pressure on second component 1416 which tends to hold the portion of second component 1416 in groove 1417,

[0181] Second component 1416 may be fabricated from a conductive material. Substrate 1404 and second component 1416 of support structure 1412 are in physical contact at a contact 1418 and thereby second component 1416 may electrically connect microneedles 1402 to an external circuit (not shown). In this regard, second component 1416 of support structure 1412 may be referred to as a conductive circuit component 1416. In some embodiments, first component 1414 of support structure 1412 is fabricated from a non-electrically conductive material. In some embodiments, first component 1414 of support structure 1412 may additionally or alternatively be fabricated from a conductive material.

Pedestal-Supported Sensors

[0182] Patent Cooperation Treaty (PCT) application No. PCT/CA2018/050300 describes a number of potential and non-limiting features of how microneedles (and sensors incorporating microneedles) may be integrated with support structures comprising pedestals according to particular embodiments. Any of the microneedles disclosed in PCT application No. PCT/CA2018/050300 can be used to support or house sensor probes and/or portions thereof in accordance with particular embodiments of the invention. PCT application No. PCT/CA2018/050300 is hereby incorporated by reference herein for all purposes. In some embodiments, the use of such pedestals as support structures provides spatially separated paths. The support structures may comprise one or a plurality of transversely-spaced pedestals. The plurality of transversely-spaced pedestals may be separated from each other by inter-pedestal volumes (i.e., void spaces). Each pedestal may comprise a transversely extending contact surface (e.g. the contact surface may be (but need not necessarily be) the substrate surface of the microneedle embodiments described herein). For each of the pedestals, one or more microneedles extend from the contact surface of the pedestal. Forcing microneedles supported on transversely-spaced pedestals onto a tissue surface causes elastic deformation of the tissue into the inter-pedestal volumes. Sensor probes (or portions thereof) may be housed in the lumens of such microneedles, as described elsewhere herein. Some of the benefits of using pedestals include: • Improve penetration of the microneedle as the skin stretches into inter-pedestal volumes. The stratum corneum can more easily reach its tensile stress or strain limit if it is stretched around microneedles and slender pedestals.

• Less pain to a patient during insertion of microneedles due to less skin nerve compression.

• The pedestal shape may assist with effective penetration of the microneedles into the skin so that sensor probes reach the desired skin depth - e.g. into the dermal layer of the skin, for example. Effective microneedle penetration may also reduce the number of microneedles used for a particular sensing application, since a larger percentage of the microneedles are achieving the desired penetration and therefore have optimum or increased functionality (relative to microneedles having non-desired penetration depths).

[0183] Figures 5A-5D show example embodiments of microneedles on pedestals.

[0184] Sensors implemented by one or more microneedles integrated onto support structures comprising one or more pedestals may use any of the microneedle embodiments (or features of any of the microneedle embodiments) described herein or any other microneedles. The sensing probes of any such sensors may comprise any of the sensing probes (or features of any of the sensing probes) described herein. Sensors implemented by one or more microneedles integrated onto support structures comprising one or more pedestals may penetrate to different depths into the skin.

Sensors implemented by one or more microneedles integrated onto support structures comprising one or more pedestals may detect one or more analytes and/or may include one or more analyte-specific functionalized surfaces. Analyte-specific functionalized surfaces may include analyte-specific recognition moiety immobilized on the

functionalized surface, such that the analyte of interest can reversibly or irreversibly interact with or bind to the analyte-specific recognition moiety to facilitate a sensing mechanism to obtain a measurement of the analyte. For example, glucose (analyte) can interact with glucose oxidase (analyte-specific moiety bound to the functionalized surface) to catalyze a glucose oxidation reaction; or glucose can interact with a glucose- sensitive fluorophore immobilized on the functionalized surface to elicit a change in fluorescence emission properties of the analyte-specific functionalized surface. Sensors Comprising One or More Microneedles

[0185] Aspects of the invention provide a microneedle (e.g. a hollow metallic microneedle). In some embodiments, such a microneedle may act as a housing for a sensor probe (e.g. a transducer) or a portion thereof, where the sensor probe permits the transport of matter, signals or energy into or out of tissue. In some embodiments, such a microneedle may be used to inject energy, signals and/or matter into the body of a subject. In some embodiments, such a microneedle may be used to withdraw energy, signals and/or matter from the body of a subject (e.g. in the case of a sensor). Aspects of the invention also provide a sensor apparatus for detection of matter, signals or energy in tissue of a subject (e.g. a human subject), comprising a microneedle (e.g. a hollow metallic or polymeric microneedle) which may house a sensor probe (e.g. a transducer) or a portion thereof, where the sensor probe emits a signal in response to the presence of matter, signals or energy. A hollow microneedle may facilitate insertion of a sensor probe (or a portion thereof) into tissue such as skin, by providing a rigid structure that is capable of piercing the surface of the tissue to reach a desired depth. A function of the microneedles according to some embodiments is to permit the sensor probe to be exposed to matter, signals and/or energy of interest (by way of non-limiting example matter in the form of an analyte of interest, signals in the form of a pH and/or the like or energy in the form of optical (electromagnetic) energy, thermal energy and/or the like) in the tissue of the subject, while minimizing damage to the tissue and/or preventing any damage to sensing probe during such procedure. The hollow

microneedle may be integrated with supporting structures.

[0186] The target tissue may be a specific layer of skin such as the epidermis (e.g. the stratum germinativum), the dermis, or the subcutaneous layer The sensing probe may be used to detect matter, signals and/or energy present in the interstitial fluid in the skin layer. The sensing probe may be inserted together with the microneedle

simultaneously and may be repositioned relative to the microneedle after insertion, or may be inserted after insertion of the microneedle into the tissue (e.g. through a lumen (bore) of the microneedle). Following insertion, the sensing probe may be placed within the microneedle such that its end resides beyond, before, or at equal depth as the end of the microneedle. That is, the end of the sensing probe may project through the lumen of the microneedle or may be located in the lumen of the microneedle or may just reach the end of the lumen of the microneedle (i.e. at the microneedle tip). The wide opening at the end of the lumen of the microneedle away from the microneedle tip may facilitate easier insertion of the sensing probe into the microneedle either prior to or after insertion of the microneedle into tissue.

[0187] The sensing probe may comprise multiple sensing probes. The sensing probe may be in direct physical contact with the lumen of the microneedle or may be in fluidic communication with the lumen of the microneedle The sensing probe may be used to detect analytes such as, by way of non-limiting example, glucose, lactate, ketone, cholesterol, alcohol, choline, creatinine, proteins, or amino acids, or used to detect concentration of electrolytes such as, by way of non-limiting example, potassium, sodium, calcium, chloride, magnesium, and phosphate. The sensing probe may additionally or alternatively be used to measure biomarkers, vitamins, and drugs.

Examples of such compounds could include Vancomycin, Gentamicin, Cyclosporine, Mycophenolic acid, Tacrolimus, Valproic acid, Phenytoin, Phenobarbital, Methotrexate, Digoxin, Theophylline. The sensing probe may be used to detect thermal, electrical, or sonar signals. The sensing probe may be used to detect pH levels or gases such as O2 and CO2.

[0188] In one example of such device, an array of microneedles and corresponding sensing probes may be used to detect one or multiple analytes. The array may include microneedles from different materials including plastic, metal, glass, and silicon. The sensing probes may be a combination of different sensing transducers, such as, by way of non-limiting example, optical or electrochemical.

[0189] In one example of such device, the sensing probe may comprise one or a combination of electrochemical sensing probes for detection of one or multiple analytes, such as, by way of non-limiting example, glucose, lactate and/or the like. The electrochemical sensor probes may comprise one or a combination of multiple electrochemical sensing electrodes including a working electrode, a counter/auxilliary electrode, a reference electrode, and a ground electrode. In another example of such device, the microneedle may be conductive, more specifically metal, or coated with conductive layer and used as one of the electrodes, such as the reference electrode, the counter electrode, or the working electrode. In another example of such device, an array of microneedle and electrochemical sensing probes may be used to detect multiple analytes. In another example, the array may be used as a common reference electrode for multiple analytes.

[0190] In one example of such device, the sensing probe may comprise one or more optical components, such as, by way of non-limiting example, lenses, LEDs, optical fibers and/or the like. The optical component(s) may be used as part of a photochemical sensing probe and/or used to detect thermal signals or optical signals, and/or used as a part of a spectroscopy system. In one particular example embodiment, a photochemical sensor may be realized by using multiple optical fibers in which at least one fiber emits light to a functionalized surface comprising an immobilized enzyme that catalyzes a reaction or an optically-sensitive substance, and at least one fiber detects an optical signal emitted from the aforementioned functionalized surface in presence of one or more analytes, such as, by way of non-limiting example, glucose, lactate and/or the like. Such optical fibers and functionalized surfaces may reside completely within a single microneedle lumen, or on the outer surface of the microneedle, or extend through and to the outside of the tip of a microneedle lumen, or may be distributed within (or extend through) multiple microneedle lumens. In another example, the optical fibers are used as part of a Raman spectroscopy system for the detection of analytes, such as, by way of non-limiting example, glucose, lactate and/or the like. In some embodiments, such functionalized surface and/or optical fibers could be provided on the tip of a microneedle and/or on the outer surface of a microneedle.

[0191] Any of the microneedles described herein or features of any such

microneedles may be used to house, protect and/or support portions of one or more sensor probes for detecting various characteristics of a subject (e.g. a presence and/or concentration of analytes, pH, temperature and/or the like). Other aspects of the invention provide sensor apparatus based on a combination of such microneedles and sensor probes. Figures 9A-9M show various schematic cross-sectional drawings of sensors comprising one or more microneedles used to house, protect and/or support portions of one or more sensor probes.

[0192] The microneedles may facilitate the penetration of the probes (or portions thereof) to desired depths in the skin of a subject so that the probes can access the interstitial fluid within the skin. In the illustrated embodiments, the microneedles function as a sampling means configured to penetrate into the skin to a depth less than the subcutaneous layer to minimize pain felt by a subject. This enables minimally invasive biological fluid sensing and analyte measurement/detection, thereby enabling continuous monitoring of an interested analyte, e.g. glucose. In some embodiments, the

microneedles also function as an electrode assisting in analyte measurement/detection.

[0193] Probes (or portions thereof) may be housed and/or supported in the lumen of hollow microneedles. Examples of such embodiments are shown in Figures 9A-9I. Probes (or portions thereof) may additionally or alternatively be supported on the outer surface of microneedles which may be solid or hollow. Examples of such embodiments are shown in Figures 9J and 9K.

[0194] Probes (or portions thereof) may be fixed at a given location relative to the microneedle. This can be achieved by methods such as friction fit, attachment to components that are embedded in microneedle supporting structure (example: laser welded or soldered to metallic electrodes assembled in microneedle supporting structure), suitable adhesive, co-fabrication with the microneedle and/or the like. Any of the sensors of Figures 9A-9K could be provided with this feature. Alternatively, probes may be moved relative to the microneedle, before or after insertion of the microneedle into the skin of the subject. Any of the sensors of Figures 9A-9K could be provided with this feature some example embodiments, the probe moves axially relative to the microneedle inside the lumen of the microneedle. In some example embodiments, a probe is housed in the lumen of a microneedle until after the microneedle penetrates to a desired level in the skin of a subject and then the probe is moved further into the body of the subject, relative to the microneedle, so that an innermost portion of the probe is positioned relatively more proximate to the tip of the microneedle or even projects from the tip of the microneedle. In some such embodiments, the movement of the probe relative to the microneedle may form a friction fit of the probe in the narrowing lumen of the microneedle.

[0195] Probes can be any suitable biosensors providing diagnostic information about one’s health status. For example, probes can be enzymatic or ion-selective

electrochemical sensors. Alternatively, probes can be optical probes. Probes may be configured to measure glucose, cholesterol, and the like.

[0196] In some example embodiments, probes may be changed within one or more microneedles without removing the microneedles from the body of the subject. For example, a first set of one or more probes may be inserted into a set of one or more microneedles, be used to probe for some form of matter, signals or energy and then withdrawn from the one or more microneedles. After that, the microneedles may be used with a second set of one or more probes which may be inserted into the one or more microneedles and be used to probe for some (possibly the same or possibly different) form of matter, signals or energy.

[0197] In sensors having these features, microneedles may provide strength and/or protection to sensing probes during insertion into targeted layer of skin, and help to prevent or mitigate probe damage during insertion. Further, microneedles may provide structural support to probes, while remaining inserted in the skin.

[0198] In some embodiments, sensors comprising microneedles for housing, protecting and/or supporting probes may also comprise extraction units (e.g. for removal of interstitial fluid, blood, tissue samples and/or the like) from the body of a subject. In some embodiments, sensors comprising microneedles for housing, protecting and/or supporting probes may also comprise injection units for injecting matter (e.g. drugs, markers and/or the like) into the body of a subject. In some embodiments, sensors comprising microneedles for housing, protecting and/or supporting probes may also comprise extraction units and injection units.

[0199] In some sensor embodiments comprising microneedles for housing, protecting and/or supporting probes, a portion of the probe (e.g. an innermost tip) may project from the lumen of the microneedle. This projection may permit the probe to be more exposed to, or to otherwise have greater access to, the body tissue and/or fluid in which the probe is designed to operate. Such embodiments are shown, for example, in Figures 9A, 9C-9I. As discussed above, in some such embodiments, the probes may be fixed in such positions relative to the microneedles. In some such embodiments, the probes may be moveable relative to the microneedles into such positions.

(a) Photochemical Sensors Comprising One or More Microneedles

[0200] Figures 9C, 9G, 9H and 9L schematically show embodiments of

photochemical sensors having one or more microneedles. The illustrated embodiments each have multiple optical fibers and a functionalized surface. At least one of the optical fibers is configured to emit light to the functionalized surface and at least one of the optical fibers is configured to detect an optical signal emitted from the functionalized surface in the presence of one or more analytes.

[0201] Optical probe of the Figure 9C embodiment may comprise one or more optically-relevant, analyte-specific materials (e.g. material comprising an enzyme and/or a fluorophore) and/or analyte-selective membranes allowing passive diffusion of specific analytes to a sensing region (e.g. ion selective membranes and/or glucose selective membranes).

[0202] In the illustrated embodiment, a combination of the optically-relevant, analyte- specific material and the analyte-selective membrane projects outwardly from the tip of the microneedle, although this is not strictly necessary. The optical probe of the Figure 9C embodiment comprises a pair of waveguides (e.g. optical fibers) which, in the illustrated embodiment, extend into the lumen of the microneedle. One fiber outputs electromagnetic energy which is received by the optically-relevant, analyte-specific material. When a particular analyte is present in a vicinity of the optically-relevant, analyte-specific material, the analyte may bind to the optically-relevant, analyte-specific material or may otherwise react in the presence of the electromagnetic energy output from the fiber to change the optical properties of the electromagnetic energy. For example, when the analyte interacts with the optically-relevant, analyte-specific material, the analyte and/or the optically-relevant, analyte-specific material may fluoresce in the presence of the electromagnetic energy output from the fiber. This fluorescence may be at a different wavelength than the electromagnetic energy output from the fiber. This fluorescent or otherwise altered electromagnetic energy may be received in the second one of the two optical fibers for sensing purposes. An amount of received

electromagnetic energy in the second one of the optical fibers may be indicative of a presence of and/or a concentration of a particular analyte. A surface of the optically- relevant, analyte-specific material of an optical sensor may be referred to herein as a functionalized surface. In some embodiments, it is not necessary to have two separate optical fibers. In some embodiments, a single optical fiber combined with other optical elements (e.g. a beam splitter or the like) may be used to perform the functionality of two fibers described elsewhere herein.

[0203] In the illustrated embodiment, the optical probe of the Figure 9C embodiment comprises a tip portion coated with an enzyme-functionalized coating configured to detect a specific analyte. The tip portion of the optical probe extends beyond the opening of microneedle. However, in other embodiments, the tip portion of the optical probe resides entirely within the microneedle bore. In some other embodiments, as illustrated in Figure 9B, optical probe may be movable longitudinally relative to the microneedle and extendable through the opening at the tip portion to a location more distal from the substrate than the tip portion.

[0204] Other embodiments of optical sensors are shown in Figure 9G (where the optically-relevant, analyte-specific material is located inside the lumen), Figure 9H (where each of the optical fibers and the optically-relevant, analyte-specific material are each provided in or on a corresponding microneedle in an array of microneedles) and Figure 9L (where a reflective coating is applied to the lumen-defining interior surface of the microneedle or the lumen-defining interior surface of the microneedle is otherwise sufficiently reflective to cause optical signals to propagate through the lumen. In the Figure 9L embodiment, optical elements (e.g. fibers) may be positioned behind the microneedle substrate (e.g. outside of the lumen) to facilitate the propagation of light through to and beyond the microneedle tip, where one or more functionalized sensing surfaces (e.g. enzymes) exist.

[0205] For such optical sensors, a highly reflective inner lumen-defining surface of the microneedle may provide high degree of light reflection and minimize optical losses during optical sensing. Further, the funnel-like shape of the microneedle lumen profile may assist in focusing optical signals into a confined region where a functionalized surface may exist for sensing of one or more analytes. Portions of the lumen-defining inner surface of the microneedle may be modified to provide one or more functionalized surface(s) comprising one or more analyte-specific materials for interacting with one or more analytes. Such an embodiment is shown in Figure 9M. This modification can be achieved by exposing liquid reagents containing constituents for creating specific self- assembled layers to the microneedle lumens by capillary action. In some embodiments, the microneedle lumen may be filled or at least partially filled with a liquid or a gas or a transparent solid, such as a polymer or glass. Having the lumen filled with a solid while working in a liquid environment has the advantage of a well characterized transparency & refractive index leading to predictable optical properties, while avoiding contamination. A similar effect may be achieved by confining a gas or a liquid to the lumen by sealing the lumen off, while a solid filling may be more durable.

(b) Electrochemical Sensors Comprising One or More Microneedles

[0206] Figure 9D schematically depicts a so-called electrochemical probe which may be a type of probe used in sensors of particular non-limiting embodiments. The electrochemical sensor of the Figure 9D embodiment comprises two or more electrodes, which may be referred to as a working electrode, a reference or a counter electrode. A potential difference is applied between the electrodes and, in the presence of an analyte, there may be a current flow. An amount of current flow may be dependent on a concentration of analyte. In the illustrated embodiment of Figure 9D, the microneedle is fabricated from metal and/or from conductive polymer, and the microneedle itself may provide one of the electrodes (e.g. the reference electrode) of the probe. In some embodiments, the electrodes may be used to detect changes in voltage due to presence of analytes in the sensing medium. In some embodiments, there may be two or more electrochemical probes which are housed, protected and/or supported by the microneedle. In some such embodiments, a metal-coated or conductive polymer microneedle may provide the reference electrode to each of the two or more probes. For example, two probes may be provided by each having one working electrode and sharing a reference electrode provided by the microneedle. In another example, two probes may be provided by one probe having a working electrode, and another probe having a reference electrode, both working with the conductive microneedle functioning as counter electrode. Advantageously, the microneedle surface is typically larger and has greater surface area than the surface of an electrode of a probe that is housed in the lumen of a microneedle. Consequently, probes which use the microneedle body as an electrode may have greater signal strength and increased detection accuracy, as compared to probes comprising conventional electrodes that are housed, protected or otherwise supported by microneedles. It should be note that the use of the microneedle itself as an electrode is not mandatory for the implementation of sensor apparatus comprising electrode-based probes. However, the use of the microneedle as an electrode may result in a more compact sensor apparatus.

[0207] In some embodiments, as alluded to elsewhere herein, multiple sensor probes may be housed, protected and/or supported by a single microneedle. In some such embodiments, the individual sensor probes may be sensitive to different phenomena. For example, one sensor probe may be sensitive to pH or to temperature while another sensor probe may be sensitive to a particular analyte. In such

embodiments, the output of one sensor probe may be used to calibrate or otherwise adjust or interpret the reading of the other sensor probe. In some embodiments, multiple sensor probes may be sensitive to different analytes. Figure 9F shows an example of a multi-electrode (multi-probe) sensor which is housed partially in a lumen of a single microneedle and which may be sensitive to one or more different phenomena or one or more different analytes. Figure 91 shows another example of a multi-electrode (multi probe) sensor which is housed partially in a lumen of a single microneedle and which may be sensitive to one or more different phenomena or one or more different analytes. In each of the embodiments, the microneedle body itself may be used to provide an electrode of one or more of the sensor probes.

[0208] The embodiments of Figures 9F and 91 depict electrode-based probes. In some embodiments, multiple probes that are housed, protected and/or supported by a microneedle could additionally or alternatively comprise optical probes. For example, one or more optical probes (including suitable optical fibers and functionalized material) may be combined in a single microneedle with one or more electrode-based probes to detect one or more different phenomena or analytes. As another example, a plurality of optical probes may be combined in a single microneedle to detect one or more phenomena or analytes. In some embodiments, a sensor that comprises multiple optical probes may share components as between the optical probes. By way of non-limiting example, a plurality of probes may share an input fiber (e.g. the fiber that provides electromagnetic energy to the functionalized material) and/or an output fiber (e.g. the fiber which receives electromagnetic energy). In embodiments where a plurality of optical probes is combined in a single microneedle to detect a plurality of analytes, analyte-specific functionalized material may be provided for each analyte that is desired to be detected. That is, multiple surfaces of functionalized material and/or multiple analyte-selective membrane materials may be provided for detecting multiple corresponding analytes.

[0209] In some embodiments, probes of multiple different sensing technologies may be housed, protected and/or supported by a single microneedle. For example, a single microneedle may support one or more probes that are electrode-based and one or more probes that are optical-based. Such embodiments are not limited to electrode-based or optical-based probes and other types of probes may be housed, protected and/or supported by a single microneedle. In some embodiments, different probes of different sensing technologies housed, protected and/or supported by the same microneedle may target (sense) the same phenomena or analyte. Such embodiments could provide comparative results. In some embodiments where multiple probes are housed, protected and/or supported by a single microneedle, the manner in which the individual probes are housed, protected and/or supported could be different. For example, on a single microneedle, one or more probes may be housed in the lumen of a microneedle (e.g. as in any of the embodiments of Figures 9A-9I) and one or more probes may be supported on the outer surface of the same microneedle (e.g. as in any of the embodiments of Figures 9J and 9K).

[0210] Advantageously, providing multiple probes housed, protected or otherwise supported by a single microneedle (e.g. a many to one probe to microneedle ratio) may reduce the number of microneedles that may be desired for a particular sensing application, thereby reducing the size of the corresponding sensor apparatus, increasing the ease of fabrication (or reducing the cost of fabrication) and/or making it easier to insert the microneedle(s) of the sensor into the skin of the subject.

(cl Sensors Comprising an Array of Microneedles

[0211] In some embodiments, an array of microneedles could house, protect and/or support a plurality of probes (e.g. one or more probes per microneedle) to provide sensitivity to one or a plurality of different phenomena and/or analytes. Figures 9E and 9N each show a schematic illustration of such an embodiment. In the Figure 9E embodiment, all of the microneedles are shown as being the same. This is not necessary. In some embodiments, particular microneedles in an array of microneedles could be provided with different characteristics. For example, the height or longitudinal extension h of one or more microneedles of the array could be different from the height or longitudinal extension h of one or more other microneedles of the array. This could provide capacity to detect different phenomena and/or analytes at different skin depths.

In some embodiments comprising an array of microneedles, some or all of the probes that are housed, protected and/or supported by the microneedles in the array could also be different. This may provide the ability for a device comprising a plurality of microneedles to detect different phenomena and/or different analytes (although different probes could also target the same phenomena and/or analyte). In some embodiments, the way in which one or more probes were housed, protected and/or supported by individual microneedles within the array could be different as between microneedles in the array or even in any one microneedle in the array.

[0212] Embodiments comprising arrays of microneedles with probes that target different phenomena (as shown in Figure 9N) and/or analytes may be less expensive that having one device for each target. Embodiments comprising arrays of microneedles with probes that target the same phenomena and/or analytes may provide: redundancy (if using independent probes or different probing technologies); increased signal strength (or sensing signal reliability) if combining signal from several probes; and/or large functionalized surface areas for analyte measurements.

(dt Example - Potassium Sensor

[0213] With reference to Figure 14, a potassium sensor apparatus 900 is shown. Potassium sensor apparatus 900 can perform minimally invasive and continuously potassium sensing in the dermal interstitial fluid. Potassium sensor apparatus 900 comprises a conductive microneedle 902, a conductive substrate 904 and a probe 908.

[0214] Microneedle 902 is similar to microneedle 102 in configuration. Microneedle 902 is monolithically formed and projects longitudinally from substrate 904. Microneedle 902 defines a bore 906 therethrough and potassium sensor probe 908 is disposed at least partially within bore 906. This means that at the minimum, a portion of potassium sensor probe 908 is disposed within bore 906. In some embodiments, probe 908 may be entirely disposed within bore 906. This means that at the minimum, a portion of potassium sensor probe 908 is disposed within bore 906. In some embodiments, probe 908 may be entirely disposed within bore 96. Microneedle 902 functions as a housing for potassium sensor probe 908 so that microneedle 902 facilitates the insertion of potassium sensor probe 908 into tissue such as skin.

[0215] Microneedle 902 is fabricated from a structural metallic material so that microneedle 902 can be inserted into the skin of a subject without bending, breaking, or buckling. Upon insertion into the skin, potassium sensor probe 908 comes into contact with dermal interstitial fluid, potassium sensor probe 908 functions as a transducer element to transform a signal resulting from the detection of potassium into an electrical signal. Potassium sensor probe 908 provides a working electrode and microneedle 902 provides a reference electrode of a potassium sensing circuit.

[0216] In an alternative embodiment, potassium sensor probe 908 may be entirely housed within bore 906. In such embodiment, upon insertion into the skin, bore 906 is filled with dermal interstitial fluid by passive capillary filling without the reliance on complex fluid extraction mechanisms. When potassium sensor probe 908 comes into contact with dermal interstitial fluid, potassium sensor probe 908 functions as a transducer element to transform a signal resulting from the detection of potassium into an electrical signal. Potassium sensor probe 908 provides a working electrode and microneedle 902 provides a reference electrode of a potassium sensing circuit.

[0217] Potassium sensor probe 908 can be any suitable potassium-selective electrodes that are dimensioned to be disposed within bore 906.

[0218] In some embodiments, an insulating layer is included to separate the skin surface and the substrate surface of substrate 904 so that the surface of the skin surface is not electrically connected to substrate 904 to minimize unwanted noise or signal. For example, such an insulating layer may be provided by a portion of the support structure as illustrated in Figures 10B-10E so that substrate 904 does not physically contact the skin surface. In other embodiments, such an insulating layer may be provided by coating the substrate surface of substrate 904 with a non-conductive material so that substrate 904 does not physically contact the skin surface.

[0219] With reference to Figure 17, a sensor apparatus 1500 is shown. Sensor apparatus 1500 is similar to sensor apparatus 900 except that sensor apparatus 1500 has a probe 1502 with an insulated tip portion 1510 that may function to protect probe electrode 1512. In the illustrated embodiment, insulated tip portion 1510 is shaped to provide a point. In other embodiments, insulated tip portion 1510 can have any suitable configurations.

[0220] In some embodiments, insulated tip portion 1510 is provided by coating the tip portion of probe electrode 1512 with an insulating material.

[0221] Figure 1 1 shows a plot of current versus potassium concentration evidencing that sensor apparatus 900 is responsive to potassium in a test potassium fluid.

(el Example - Glucose Sensor

[0222] Also with reference to Figure 14, potassium sensor probe 908 can be replaced with a glucose sensor probe to detect glucose concentrations in the dermal interstitial fluid. The glucose sensor probe is an amperometric sensor using glucose oxidase enzyme (GOx) to detect/monitor glucose concentration.

[0223] Figure 12 shows a plot of current versus glucose concentration evidencing that sensor apparatus 900 is responsive to potassium in a test glucose solution.

(f) Example - A Sensor Having an Array of Microneedles

[0224] With reference to Figure 13, a sensor apparatus 1000 is shown. Sensor apparatus 1000 may be used with a patch platform to allow sensor apparatus 1000 to be in continuous contact with the skin to thereby provide permanent access to the interstitial fluid.

[0225] Sensor apparatus 1000 has an array of microneedles 1002a, 1002b, 1002c, a support structure 1012, and a plurality of probes 1030a, 1030b, 1030c.

[0226] Microneedles 1002a, 1002b, 1002c are similar to microneedle 102 in that each one of microneedles 1002a, 1002b, 1002c is monolithically formed with substrate 1004 and each one defines a bore therethrough to house their respective probes. In other embodiments, microneedles 1002a, 1002b, 1002c can have any other suitable configurations. For example, first microneedle 1002a may not be a hollow microneedle but a solid one.

[0227] In the illustrated embodiment, microneedles 1002a, 1002b, 1002c are fabricated from the same conductive materials. In other embodiments, first microneedle 1002a, second microneedle 1000b, and third microneedle 1000c are fabricated from different materials. For example, first microneedle 1002a may be fabricated from a metallic material and second microneedle 1002b may be fabricated from glass.

[0228] In the illustrated embodiment, microneedles 1002a, 1002b, 1002c project longitudinally from substrate 1004 to the same extent. In other embodiments, microneedles 1002a, 1002b, 1002c may project longitudinally from substrate 1004 to different heights so that sensor apparatus 1000 has the capacity to detect different analytes at different skin depths. For example, second microneedle 1002b may have a longitudinal extension that is larger than that of first microneedle 1002a so that second microneedle 1002b may reach the dermis layer.

[0229] Substrate 1004 has a discontinuous transition 1006 similar to substrate 1 10c,

1 10d as shown in Figure 6C. Discontinuous transition 1006 connects a central planar portion 1008 and a tubular portion 1010. Central planar portion 1008 has a substrate surface 1020 and an opposite surface 1022. Tubular portion 1010 has an inner surface 1024 and an outer surface 1026. Note that substrate 1004 may be viewed as having two opposed, discontinuous, compound surfaces.

[0230] Similar to support structure 1 12, support structure 1012 is configured to support microneedles 1002a, 1002b, 1002c and to encapsulate at least a portion of perimeter edge 1040. Support structure 1012 has three components: a first component 1014, a second component 1016, and a third component 1018. Second component 1016 abuts against opposite surface 1022 and inner surface 1024 of substrate 1004. Third component 1018 abuts against outer surface 1026 of substrate 1004. First component 1014 surrounds third component 1018.

[0231] Third component 1018 is fabricated from a conductive material. In contrast, first component 1014 and second component 1016 are fabricated from a non-conductive material. Because substrate 1004 and third component 1018 of support structure 1012 are in physical contact at a contact 1032, substrate 1004 is electrically connected to external circuit 1042 via third component 1018 of substrate 1004. An electrical current can pass from at least one of microneedles 1002a, 1002b, 1002c to substrate 1004, then to third component 1018 of support structure 1012 and to external circuit 1042.

[0232] Third component 1018 may also be referred to as a conductive circuit component of external circuit 1042.

[0233] Probes 1030a, 1030b, 1030c are inserted into first microneedle 1002a, second microneedle 1002b, and third microneedle 1002c, respectively. In the illustrated embodiment, probes 1030a, 1030b, 1030c are identical. In other embodiments, probes 1030a, 1030b, 1030c are different to detect different analytes.

[0234] In some embodiments, a sensing circuit is provided by sensor apparatus 1000. First microneedle 1002a provides a reference electrode of the sensing circuit. Probe 1030b housed within second microneedle 1002b provides a working electrode. Probe 1030c provides a counter electrode.

[0235] In the illustrated embodiment, probes 1030a, 1030b, 1030c reside through the opening at the tip portion to a location more distal from the substrate than the tip portion, i.e. beyond the tip of their respective microneedles 1002a, 1002b, 1002c. Probes 1030a, 1030b, 1030c each have a non-conductive coating 1044 electrically insulating a conductive core 1046. Conductive core 1046 is spaced apart from microneedles1030a, 1030b, 1030c so that conductive core 1046 is not in physical contact with their respective microneedles1030a, 1030b, 1030c. In some embodiment, microneedles 1002a, 1002b, 1002c may be coated with a non-conductive layer on their respective interior bore-defining surfaces to further enhance insulation.

[0236] Conductive core 1046 has an enzyme-functionalized coating configured to detect a biological analyte, e.g. potassium and glucose.

[0237] With reference to Figure 9N, a sensor apparatus 1300 is shown. Sensor apparatus 1300 is similar to sensor apparatus 1000 except that sensor apparatus 1300 has three probes 1330a, 1330b, 1330c each for a different analyte. Elements of sensor apparatus 1300 that correspond to elements of sensor apparatus 1000 are illustrated with like reference numerals that have been incremented by 300.

[0238] Sensor apparatus 1300 has an array of conductive microneedles 1302a, 1302b, 1302c monolithically formed with a conductive substrate 1304. Each one of microneedles 1302a, 1302b, 1302c houses a probe 1330a, 1330b, 1330c therein. [0239] Each probe 1330a, 1330b, 1330c provides a working electrode for a different analyte. For example, probe 1330a has a probe electrode 1331 a that may be selective and specific to detect glucose in the dermal interstitial fluid. Probe 1330b has a probe electrode 1331 b that may be selective and specific to detect potassium in the dermal interstitial fluid. Probe 1330c has a probe electrode 1331c may be selective and specific to detect Creatinine. Microneedle array, i.e. microneedles 1302a, 1302b, 1302c and substrate 1304, acts as a common reference electrode for probes 1330a, 1330b, 1330c.

[0240] In some embodiments, perhaps similar to the embodiment illustrated in Figures 15A and 15B, probes electrodes 1331 a, 1331 b, 1331 c are movable within their respective bores of microneedles 1302a, 1302b, 1302c. In some embodiments, probes 1330a, 1330b, 1330c may each have a sleeve movable to expose probes electrodes 1331 a, 1331 b, 1331 c.

[0241] In the illustrated embodiment, probes electrodes 1331 a, 1331 b, 1331 c reside beyond their respective microneedles 1302a, 1302b, 1302c. In other embodiments, probes electrodes 1331 a, 1331 b, 1331 c are entirely housed within their respective microneedles 1302a, 1302b, 1302c.

[0242] In another example embodiment, probes 1330a, 1330b, 1330c may be used to detect the same analyte for redundancy and improved signal quality. In another embodiment, a forth electrode that may function as a ground electrode may have housed within a microneedle.

[0243] In another example embodiment, at least one of probes 1330a, 1330b, 1330c is used to pick up environmental noise or any other interacting phenomena in order to subtract from other analyte signals and improve signal quality.

[0244] In another example embodiment, microneedle array, i.e. microneedles 1302a, 1302b, 1302c and substrate 1304, is used as counter electrode, and at least one of microneedles 1302a, 1302b, 1302c houses a reference electrode and another microneedle houses a working electrode.

[0245] In another example embodiment, probes 1330a, 1330b, 1330c may have limited working life. To prolong the working life of sensor apparatus 1300, at least one of probe electrodes 1331 a, 1331 b, 1331 c may be coated with a biodegradable material.

For example, probe electrode 1331 a is not coated with a biodegradable material so that upon insertion into the skin of a subject, probe electrode 1331a is exposed to the dermal interstitial fluid and detects the presence of a specific analyte. Probe electrode 1331 b is coated with a first layer of a biodegradable material and probe electrode 1331 c is coated with a second layer of a biodegradable material. The first layer is thinner than the second layer. Upon insertion into the skin, the coated biodegradable material degrades over time to first expose probe electrode 1331 b and then probe electrode 1331c thereby prolonging the working life of sensor apparatus 1300.

[0246] In the illustrated embodiment, probes 1330a, 1330b, 1330c are each partially coated by a non-conductive layer 1333a, 1333b, 133c, exposing probe electrodes 1331 a, 1331 b, 1331 c. As such, probes 1330a, 1330b, 1330c physically contact their respective microneedles 1302a, 1302b, 1302c but are not electrically contacted via these physical contact surfaces.

[0247] In the above examples, the detection of analytes may be facilitate by using a multi-channel potentiostat for parallel measurement, or using a single-channel potentiostat that uses a switching action (i.e. multiplexer) to switch between different electrodes, or a combination of the two. .

(at Example - Movable Probe

[0248] To minimize damage to a sensing probe during the insertion process into the skin of a subject, the sensing probe may be initially housed within the bore of a microneedle and after insertion, the probe may be repositioned relative to the microneedle so that the probe resides beyond the tip of the microneedle.

[0249] Figures 15A and 15B show schematic cross-sectional images showing a probe movably disposed within a microneedle.

[0250] With reference to Figures 15A and 15B, a sensor apparatus 1200 is shown. Sensor apparatus 1200 is similar to sensor apparatus 900 except that probe 1208 is movably disposed within bore 1206. Probe 1208 is movable within bore 1206 relative to substrate 1204.

[0251] In a withdrawn configuration as shown in Figure 15A, probe 1208 is housed entirely within bore 1206 so that probe 1208 is protected against any damage to probe 1208 when microneedle 1202 is inserted into the skin of a subject. Once microneedle 1202 is inserted into the skin of a subject, probe 1208 moves longitudinally and extends through the opening at the tip portion of microneedle 1202 to a location more distal from the substrate 1204 than the tip portion, i.e. beyond the opening at the tip end, so that probe 1208 is in close proximity with the interstitial fluid in the skin and thereby reduce the delay introduced by skin-to-bore fluid diffusion time.

[0252] To enable the longitudinal movement of probe 1208 within bore 1206, sensor apparatus 1200 has biasing means 1210 normally urging probe 1208 toward the withdrawn configuration as shown in Figure 15A wherein probe 1208 is positioned within bore 1206. In the illustrated embodiment, biasing means 1210 has springs 1212, 1214 connecting a plate 1214 and substrate 1204. To convert sensor apparatus 1200 from the withdrawn configuration to a deployed configuration, longitudinal force is applied to plate 1214 to press plate 1214 towards substrate 1204 and thereby springs 1212, 1214 are compressed.

[0253] In other embodiments, biasing means may have other configurations and may not comprise springs. Also, in other embodiments, to expose probe 1208 beyond the tip of microneedle 1202, microneedle 1202 may be movable relative to probe 1208 and probe 1208 remains stationary within the skin.

[0254] In other embodiments, sensor apparatus 1200 may not comprise biasing means 1210. Instead, sensor apparatus 1200 has locking means for converting sensor apparatus 1200 from a withdrawn configuration where probe 1208 is entirely housed within bore 1206 to a deployed configuration where probe 1208 resides beyond bore 1206. For example, locking means may comprise a lock bar/groove mechanism wherein the lock bar is longitudinally moveable within the groove to cause the longitudinal movement of probe 1208.

[0255] PCT application No. PCT/CA2018/050300 describes a number of potential and non-limiting features of how microneedles (and sensors incorporating microneedles) may be integrated with support structures comprising pedestals according to particular embodiments. Any of the microneedles disclosed in PCT application No.

PCT/CA2018/050300 can be used to support or house sensor probes and/or portions thereof.

[0256] PCT application No. PCT/CA2018/051307 describes a number of potential and non-limiting features of how microneedles (and sensors incorporating microneedles) may be inserted into the tissue of a subject. Any of the microneedles or apparatus comprising microneedles described herein may be integrated with the adapter device for injecting the microneedle into the skin as described in PCT application No.

PCT/CA2018/051307. Such adapter devices could have any of the features described in PCT application No. PCT/CA2018/051307. By way of non-limiting example, the spring loaded mechanism and the retraction mechanism of the adapters described in PCT application No. PCT/CA2018/051307 may be used for insertion of the sensing device to the skin and targeting a specific depth by controlled insertion and/or retraction.

[0257] While a number of exemplary aspects and embodiments have been discussed above, those of skill in the art will recognize certain modifications, permutations, additions and sub-combinations thereof. It is therefore intended that the following appended claims and claims hereafter introduced are interpreted to include all such modifications, permutations, additions and sub-combinations as are consistent with the broadest interpretation of the specification as a whole.

Claims

WHAT IS CLAIMED IS:

1. A sensor apparatus comprising:

a conductive microneedle monolithically formed with a conductive substrate from a conductive material which provides the structural integrity of the microneedle, the microneedle projecting from the conductive substrate in a projection direction, the projection direction having at least a directional component in a longitudinal direction, the longitudinal direction normal to a first surface of the substrate in a region where the microneedle projects from the substrate,

the microneedle comprising an exterior surface, an interior bore-defining surface opposed to the exterior surface and defining a bore through the microneedle, and a tip portion distal to the substrate, the tip portion defining an opening of the bore; and

a probe disposed at least partially within the bore for insertion, with the microneedle, into the skin of a subject, the probe comprising a probe electrode; wherein the conductive material of the microneedle and the substrate provide a first electrode of a sensing circuit and the probe electrode provides a second electrode of the sensing circuit.

2. A sensor apparatus as defined in claim 1 or any other claim herein, wherein the probe electrode is coated with a membrane for electrochemical sensing.

3. A sensor apparatus as defined in claim 1 or any other claim herein, wherein the probe electrode is coated with an enzyme-based coating, the enzyme-based coating sensitive to a particular biological analyte.

4. A sensor apparatus as defined in claim 1 or any other claim herein, wherein the probe electrode is coated with an ion-selective coating, the ion-selective coating sensitive to a particular ion.

5. A sensor apparatus as defined in claim 1 or any other claim herein, wherein the probe electrode is movable longitudinally relative to the microneedle and extendable through the opening at the tip portion to a location more distal from the substrate than the tip portion.

6. A sensor apparatus as defined in claim 1 or any other claim herein, wherein the probe is removably disposed at least partially within the bore.

7. A sensor apparatus as defined in claim 1 or any other claim herein, wherein:

the first electrode is a reference electrode;

the second electrode is a working electrode; and

the sensing circuit measures an electrochemical signal between the reference electrode and the working electrode.

8. A sensor apparatus as defined in claim 1 or any other claim herein, comprising a second microneedle projecting from the substrate.

9. A sensor apparatus as defined in claim 9, wherein the second microneedle is monolithically formed with the substrate.

10. A sensor apparatus as defined in claim 8 or any other claim herein, comprising a second probe supported by the second microneedle for insertion, with the second microneedle, into the skin of a subject and the second probe comprising a second probe electrode.

1 1. A sensor apparatus as defined in claim 10 or any other claim herein, wherein the second probe electrode is electrically connected to the sensing circuit.

12. A sensor apparatus as defined in claim 10 or any other claim herein, wherein the second probe electrode provides a third electrode of the sensing circuit.

13. A sensor apparatus as defined in claim 12 or any other claim herein, wherein:

the first electrode is a counter electrode;

the second electrode is a working electrode;

the third electrode is a reference electrode; and

the sensor apparatus forms a three-electrode system, wherein the working electrode acts as an anode; the counter electrode acts as a cathode; and the reference electrode acts to provide a stable working potential for the working electrode.

14. A sensor apparatus as defined in claim 10 or any other claim herein, wherein: the probe is sensitive to an analyte-specific electrochemical condition and generates a first signal in the sensing circuit in response to the analyte-specific electrochemical condition; and

the second probe is not sensitive to the analyte-specific electrochemical condition and generates a common-mode signal in the sensing circuit.

15. A sensor apparatus as defined in claim 14 or any other claim herein, wherein the sensing circuit is configured to subtract the common-mode signal from the first signal in the analog or digital domain to remove noise from the first signal and to thereby obtain a noise-reduced signal reflective of the analyte-specific electrochemical condition.

16. A sensor apparatus as defined in claim 15 or any other claim herein, comprising a differential amplifier that is part of the sensing circuit, the differential amplifier connected to subtract the common-mode signal from the first signal in the analog domain to remove noise from the first signal and to thereby obtain the noise- reduced signal reflective of the analyte-specific electrochemical condition.

17. A sensor apparatus as defined in claim 15 comprising a digital processor that is part of the sensing circuit, the digital processor configured to subtract the common-mode signal from the first signal in the digital domain to remove noise from the first signal and to thereby obtain the noise-reduced signal reflective of the analyte-specific electrochemical condition.

18. A sensor apparatus as defined in claim 10 or any other claim herein, wherein:

the first probe electrode is sensitive to an electrochemical condition of a first analyte;

the second probe electrode is sensitive to an electrochemical condition of a second analyte; and

the first analyte differs from the second analyte.

19. A sensor apparatus as defined in claim 10 or any other claim herein, wherein: the first probe electrode is coated with a first layer of a biodegradable material;

the second probe electrode is coated with a second layer of the

biodegradable material;

the first layer has a thickness that is different than that of the second layer.

20. A sensor apparatus as defined in claim 10 or any other claim herein, wherein:

the second microneedle comprises an exterior surface, an interior bore defining surface defining a bore through the second microneedle, and a tip portion distal from the substrate defining an opening; and

the second probe is at least partially disposed within the bore of the second microneedle.

21. A sensor apparatus as defined in claim 20 or any other claim herein, wherein the second probe electrode is spaced apart from the interior bore-defining surface of the second microneedle.

22. A sensor apparatus as defined in claim 1 or any other claim herein, comprising a conductive circuit component in physical contact with at least one of the microneedle and the substrate and connectable to the sensing circuit to effect the electrical connection of the first electrode to the sensing circuit.

23. A sensor apparatus as defined in claim 22 or any other claim herein, wherein the conductive circuit component is in physical contact with the substrate at a location spaced apart from the microneedle.

24. A sensor apparatus as defined in claim 23 or any other claim herein wherein the physical contact location between the conductive circuit component and the substrate is spaced apart from the microneedle in a transverse direction, the transverse direction orthogonal to the longitudinal direction.

25. A sensor apparatus as defined in claim 22 or any other claim herein, wherein: the substrate comprises a second surface generally opposed to the first surface, and a perimeter edge between the first and second surfaces; and

the conductive circuit component physically contacts the second surface.

26. A sensor apparatus as defined in claim 25, wherein the second surface is a discontinuous, compound surface comprising a discontinuity between a first subsurface proximate the microneedle and a second subsurface distal from the microneedle and wherein the conductive circuit component physically contacts the second subsurface.

27. A sensor apparatus as defined in claim 25 or any other claim herein, comprising a support structure abutting against the second surface to support the microneedle.

28. A sensor apparatus as defined in claim 25 or any other claim herein, comprising a support structure abutting against the first and second surfaces of the substrate to thereby encapsulate the perimeter edge.

29. A sensor apparatus as defined in claim 28 or any other claim herein, wherein the support structure abuts against the conductive circuit component at a location where the conductive circuit component contacts the second surface to force the conductive circuit component into physical contact with the substrate.

30. A sensor apparatus as defined in claim 27 or any other claim herein, wherein the support structure is monolithically formed.

31. A sensor apparatus as defined in claim 27 or any other claim herein, wherein the support structure comprises:

a first component abutting against the first surface of the substrate; and a second component connected to the first component, the second component abutting against the second surface of the substrate.

32. A sensor apparatus as defined in claim 31 or any other claim herein, wherein at least one of the first component and the second component is elastically deformable such that, when deformed, the at least one of the first component and the second component exerts restorative force that tends to lock the first and second components to one another.

33. A sensor apparatus as defined in claim 32 or any other claim herein, wherein the at least one of the first component and the second component exerts restorative force which tends to force at least one of: the first component abutting against the first surface and the second component abutting against the second surface.

34. A sensor apparatus as defined in claim 1 or any other claim herein, wherein the first surface is a discontinuous, compound surface comprising a plurality of sub surface components and at least one discontinuity between the sub-surface components.

35. A sensor apparatus as defined in claim 1 or any other claim herein, the

microneedle comprising an outer biocompatible metal layer.

36. A sensor apparatus comprising:

an array of microneedles comprising:

a first microneedle fabricated from a conductive material, the first microneedle providing a first electrode of a sensing circuit; a second microneedle different from the first microneedle, the second microneedle comprising an interior bore-defining surface shaped to define a bore through the second microneedle;

a probe at least partially disposed in the bore of the second microneedle for insertion, with the second microneedle, into the skin of a subject, the probe comprising a second electrode of the sensing circuit.

37. A sensor apparatus as defined in claim 36 or any other claim herein, wherein: the first microneedle is monolithically formed with and projecting from a conductive substrate in a projection direction, the projection direction having at least a directional component in a longitudinal direction, the longitudinal direction normal to a first surface of the substrate in a region where the microneedle projects from the substrate.

38. A sensor apparatus as defined in claim 36 or any other claim herein, wherein the probe electrode is coated with an enzyme-functionalized coating sensitive to a particular biological analyte.

39. A sensor apparatus as defined in claim 36 or any other claim herein, wherein the probe electrode is coated with an ion-selective coating sensitive to a particular ion.

40. A sensor apparatus as defined in claim 36 or any other claim herein, wherein:

the first electrode is a reference electrode;

the second electrode is a working electrode; and

41. A sensor apparatus as defined in claim 36, wherein:

the array of microneedles comprises a third microneedle different from the first microneedle and the second microneedle;

a second probe is supported by the third microneedle for insertion, with the third microneedle, into the skin of a subject; and

the second probe comprises a second probe electrode that forms part of the sensing circuit.

42. A sensor apparatus as defined in claim 41 or any other claim herein, wherein the probe electrode and the second probe electrode are sensitive to different analytes.

43. A sensor apparatus as defined in claim 41 or any other claim herein, wherein:

the second probe electrode provides a third electrode of the sensing circuit.

44. A sensor apparatus as defined in claim 43 or any other claim herein, wherein:

the first electrode is a counter electrode;

the second electrode is a working electrode;

the third electrode is a reference electrode; and

45. A sensor apparatus as defined in claim 36 or any other claim herein, wherein:

the second microneedle comprises a tip portion defining an opening; and probe electrode is movable longitudinally relative to the microneedle and extendable through the opening at the tip portion to a location more distal from the substrate than the tip portion.

46. A sensor apparatus as defined in claim 41 or any other claim herein, wherein:

the first probe is sensitive to an analyte-specific electrochemical condition and generates a first signal in the sensing circuit in response to the analyte- specific electrochemical condition; and

47. A sensor apparatus as defined in claim 46 or any other claim herein, wherein the sensing circuit is configured to subtract the common-mode signal from the first signal in the analog or digital domain to remove noise from the first signal and to thereby obtain a noise-reduced signal reflective of the analyte-specific electrochemical condition.

48. A sensor apparatus as defined in claim 47 or any other claim herein, comprising a differential amplifier that is part of the sensing circuit, the differential amplifier connected to subtract the common-mode signal from the first signal in the analog domain to remove noise from the first signal and to thereby obtain the noise- reduced signal reflective of the analyte-specific electrochemical condition.

49. A sensor apparatus as defined in claim 47 comprising a digital processor that is part of the sensing circuit, the digital processor configured to subtract the common-mode signal from the first signal in the digital domain to remove noise from the first signal and to thereby obtain the noise-reduced signal reflective of the analyte-specific electrochemical condition.

50. A sensor apparatus as defined in claim 36 or any other claim herein, comprising a conductive circuit component in physical contact with the array of microneedles and connectable to the sensing circuit to effect the electrical connection of the first electrode to the sensing circuit.

51. A sensor apparatus as defined in claim 36 or any other claim herein, wherein:

the array of microneedles comprises a substrate having a first surface from which the first and second microneedles project and a second surface that is generally opposed to the first surface;

a support structure abutting against the first and second surfaces of the substrate to thereby encapsulate the perimeter edge.

52. A sensor apparatus as defined in claim 36 or any other claim herein, wherein:

a monolithically-formed support structure abutting against the second surfaces to support the microneedles.

53. A sensor apparatus as defined in claim 36 or any other claim herein, wherein the first microneedle has a longitudinal extension from the substrate that is different from the longitudinal extension of the second microneedle from the substrate.

54. A sensor apparatus as defined in claim 36 or any other claim herein, wherein the first microneedle has a longitudinal extension that is longer than that of the second microneedle.

55. A microneedle apparatus comprising:

a conductive substrate;

a conductive microneedle monolithically formed with the substrate and projecting from the substrate in a projection direction, the projection direction having at least a directional component in a longitudinal direction, the longitudinal direction normal to a first surface of the substrate in a region where the microneedle projects from the substrate; and a conductive circuit component in physical contact with at least one of the microneedle and the substrate and connectable to an external circuit to thereby electrically connect the microneedle to the external circuit.

56. A microneedle apparatus as defined in claim 55 or any other claim herein,

wherein the conductive circuit component is in physical contact with the substrate at a location spaced apart from the microneedle.

57. A microneedle apparatus as defined in claim 56 or any other claim herein,

wherein the physical contact location between the conductive circuit component and the substrate is spaced apart from the microneedle in a transverse direction orthogonal to the longitudinal direction.

58. A microneedle apparatus as defined in claim 55 or any other claim herein,

wherein:

the substrate comprises a second surface generally opposed to the first surface, and a perimeter edge between the first and second surfaces;

the conductive circuit component physically contacts the second surface.

59. A microneedle apparatus as defined in claim 58 or any other claim herein,

comprising a support structure abutting against the second surface to support the microneedle.

60. A microneedle apparatus as defined in claim 58 or any other claim herein

comprising a support structure abutting against the first and second surfaces of the substrate to thereby encapsulate the perimeter edge.

61. A microneedle apparatus as defined in claim 58 or any other claim herein,

wherein the support structure abuts against the conductive circuit component at a location where the conductive circuit component contacts the second surface to force the conductive circuit component into physical contact with the substrate.

62. A microneedle apparatus as defined in claim 59 or any other claim herein,

wherein the support structure is monolithically formed.

63. A microneedle apparatus as defined in claim 59 or any other claim herein, wherein the support structure comprises:

64. A microneedle apparatus as defined in claim 63 or any other claim herein,

wherein at least one of the first component and the second component is elastically deformable such that, when deformed, the at least one of the first component and the second component exerts restorative force that tends to lock the first and second components to one another.

65. A microneedle apparatus as defined in claim 63 or any other claim herein,

wherein the at the at least one of the first component and the second component exerts restorative force which tends to force at least one of: the first component abutting against the first surface and the second component abutting against the second surface.

66. A microneedle apparatus as defined in claim 63 or any other claim herein, the retaining mechanism comprising:

a groove defined by the first component;

a flexible projection projecting from the second component, the flexible projection being complementary to the groove so that the flexible projection, when deformed, exerts restorative deformation force which snap fits the flexible projection into the groove to thereby connect the first component with the second component.

67. A microneedle apparatus as defined in claim 63 or any other claim herein, the retaining mechanism comprising:

a cut-out defined by the first component;

a guiding member projecting from the second component, the guiding member being complementary to the cut-out for guiding the engagement between the first and second components.

68. A microneedle apparatus as defined in claim 67 or any other claim herein, the guiding member configured to guide the engagement between the first and second components in the longitudinal direction.

69. A microneedle apparatus as defined in claim 55 or any other claim herein,

wherein the first surface is a discontinuous, compound surface comprising a plurality of sub-surface components and at least one discontinuity between the sub-surface components.

70. A microneedle apparatus as defined in claim 55 or any other claim herein,

wherein the second surface is a discontinuous, compound surface comprising a plurality of sub-surface components and at least one discontinuity between the sub-surface components.

71. A microneedle apparatus as defined in claim 55 or any other claim herein,

wherein the microneedle comprises an exterior surface, an interior bore-defining surface generally opposed to the exterior surface and defining a bore through the microneedle, and a tip portion distal from the substrate defining an opening.

72. A microneedle apparatus as defined in claim 71 or any other claim herein, the microneedle having a non-uniform thickness between the exterior surface and the interior bore-defining surface.

73. A microneedle apparatus as defined in claim 71 or any other claim herein, the microneedle having a uniform thickness between the exterior surface and the interior bore-defining surface.

74. A microneedle apparatus as defined in claim 73 or any other claim herein,

wherein the substrate has a thickness that is on the same order as the uniform thickness between the exterior surface and the interior bore-defining surface.

75. A microneedle apparatus as defined in claim 70 or any other claim herein, the microneedle apparatus comprising a probe disposed in the bore of the microneedle, the probe being insertable with the microneedle into the skin of a subject and the probe comprising a probe electrode providing a first electrode of the external electrical circuit.

76. A microneedle apparatus as defined in claim 75 or any other claim herein, the probe electrode being spaced apart from the interior bore-defining surface.

77. A microneedle apparatus as defined in claim 70 or any other claim herein, the probe electrode being movable within the bore longitudinally relative to the substrate.

78. A microneedle apparatus as defined in claim 70 or any other claim herein, at least a portion of the probe being movable longitudinally relative to the microneedle and extendable through the opening at the tip portion to a location more distal from the substrate than the tip portion.

79. A microneedle apparatus as defined in claim 78 or any other claim herein, further comprising biasing means biasing the at least a portion of the probe toward a withdrawn position wherein the at least a portion of the probe is positioned within the bore.

80. A microneedle apparatus as defined in claim 75 or any other claim herein,

wherein at least a portion of the probe electrode s coated with an enzyme- functionalized coating sensitive to a biological analyte.

81. A microneedle apparatus as defined in claim 75 or any other claim herein,

wherein:

the probe electrode provides the first electrode of the external electrical circuit; and

the microneedle and the substrate provide a second electrode of the external electrical circuit.

82. A microneedle apparatus as defined in claim 81 or any other claim herein,

wherein:

the first electrode is a working electrode; and

the second electrode is a reference electrode.

83. A microneedle apparatus as defined in claim 55 or any other claim herein, comprising:

a second microneedle monolithically formed with the substrate and projecting from the substrate in a projection direction, the projection direction having at least a directional component in the longitudinal direction, the longitudinal direction normal to a first surface of the substrate in a region where the microneedle projects from the substrate.

84. A microneedle apparatus as defined in claim 83 or any other claim herein,

wherein:

the second microneedle is electrically connected to the external circuit.

85. A microneedle apparatus as defined in claim 83 or any other claim herein,

comprising a second probe supported by the second microneedle.

86. A microneedle apparatus as defined in claim 85 or any other claim herein,

wherein the second probe is electrically connected to the external circuit.

87. A microneedle apparatus as defined in claim 86 or any other claim herein,

wherein:

the first probe provides the first electrode of the external electrical circuit; the microneedle, the second microneedle and the substrate provide the second electrode of the external electrical circuit; and

the second probe provides a third electrode of the external electrical circuit.

88. A microneedle apparatus as defined in claim 87 or any other claim herein,

wherein:

the first electrode is a working electrode;

the second electrode is a counter electrode; and

the third electrode is a reference electrode.

the microneedle apparatus provides a three-electrode system, wherein the working electrode acts as an anode; the counter electrode acts as a cathode; and the reference electrode acts to provide a stable working potential for the working electrode.

89. A microneedle apparatus as defined in claim 85 or any other claim herein, wherein:

the second microneedle comprising an exterior surface, an interior bore defining surface defining a bore through the second microneedle, and a tip portion distal from the substrate defining an opening; and

at least a portion of the second probe is disposed within the bore of the second microneedle.

90. A microneedle apparatus as defined in claim 89 or any other claim herein,

wherein the second probe is spaced apart from the interior bore-defining surface of the second microneedle.

91. A microneedle apparatus comprising:

a conductive substrate comprising a first surface, a second surface generally opposed to the first surface, and a perimeter edge between the first and second surfaces;

a conductive microneedle monolithically formed with the substrate, the microneedle projecting from the substrate in a projection direction the projection direction having at least a directional component in a longitudinal direction, and the first surface extending with at least a directional component in a transverse direction orthogonal to the longitudinal direction; and

a support structure that abuts against the first surface and against the second surface to thereby encapsulate at least a portion of the perimeter edge.

92. A microneedle apparatus as defined in claim 91 or any other claim herein,

wherein the support structure comprises:

93. A microneedle apparatus as defined in claim 91 or any other claim herein,

94. A microneedle apparatus as defined in claim 91 or any other claim herein,

wherein at the at least one of the first component and the second component exerts restorative force which tends to force at least one of: the first component abutting against the first surface and the second component abutting against the second surface.

95. A microneedle apparatus as defined in claim 93 or any other claim herein, the retaining mechanism comprising:

a groove defined by the first component;

96. A microneedle apparatus as defined in claim 93 or any other claim herein, the retaining mechanism comprising:

a cut-out defined by the first component;

97. A microneedle apparatus as defined in claim 96 or any other claim herein, the guiding member configured to guide the engagement between the first and second components in the longitudinal direction.

98. A microneedle apparatus as defined in claim 91 or any other claim herein,

wherein the support structure is monolithically formed.

99. A microneedle apparatus as defined in claim 91 or any other claim herein, the support structure adhered to at least one of the first surface and the second surface.

100. A microneedle apparatus as defined in claim 91 or any other claim herein, the support structure adhered to the first surface.

101. A microneedle apparatus as defined in claim 91 or any other claim herein, the support structure adhered to the second surface.

102. A microneedle apparatus as defined in claim 91 or any other claim herein, wherein the conductive microneedle is fabricated from a metal layer, the metal layer providing a principal layer of structural integrity to the conductive microneedle.

103. A microneedle apparatus as defined in claim 91 or any other claim herein, the microneedle comprising an outer biocompatible metal layer.

104. A microneedle apparatus as defined in claim 91 or any other claim herein, wherein the first surface is a discontinuous, compound surface.

105. A microneedle apparatus as defined in claim 91 or any other claim herein, wherein the second surface is a discontinuous, compound surface.

106. A microneedle apparatus as defined in claim 91 or any other claim herein, comprising a continuous transition between the first surface of the substrate and the outer surface of the microneedle.

107. A microneedle apparatus as defined in claim 91 or any other claim herein, the support structure abutting against the perimeter edge.

108. A microneedle apparatus as defined in claim 91 or any other claim herein, the support structure partially encapsulating the perimeter edge.

109. A microneedle apparatus as defined in claim 91 or any other claim herein, the microneedle having a base connected to the substrate and a tip distal from the substrate, the microneedle comprising:

a base region extending about 1 % to 40% of the microneedle; a tip region extending about 9% to 30% of the microneedle; and

an intermediate region connecting the base region and the tip region, the intermediate region extending about 30% to 90% of the microneedle;

wherein the microneedle transitions continuously and the intermediate region has a percentage change in its transverse cross-sectional area that is less than that of the base region.

1 10. A microneedle apparatus as defined in claim 109 or any other claim herein, wherein:

the percentage change in the transverse cross-sectional area in the base region is defined as

^AD ~^ADI

base °/°

^AD o

where A_D0 is the transverse cross-sectional area of the microneedle at the base and A_D1 is the transverse cross-sectional area of the microneedle at the interface between the base region and the intermediate region; and

the percentage change in the transverse cross-sectional area in the intermediate region is defined as

^AD1 ^~AD2

^ inter % ^AD l

where A_D2 is the transverse cross-sectional area of the microneedle at the interface between the intermediate region and the tip region.

1 1 1. A microneedle apparatus as defined in claim 91 or any other claim herein,

wherein the microneedle has a longitudinal extension in a range of 20-2000pm.

1 12. A method for making a microneedle apparatus comprising:

providing a conductive substrate comprising a first surface, a second surface generally opposed to the first surface, and a perimeter edge between the first and second surfaces;

providing a metallic microneedle projecting from, and monolithically formed with, the conductive substrate, the microneedle projecting from the metallic substrate in a projection direction, the projection direction having at least a directional component in a longitudinal direction and the first surface extending with at least a directional component in a transverse direction orthogonal to the longitudinal direction; and

abutting a support structure against the first surface and against the second surface to thereby encapsulate at least a portion of the perimeter edge.

1 13. A method as defined in claim 1 12 or any other claim herein, further comprising: adhering the support structure to at least one of the first surface and the second surface.

1 14. A method as defined in claim 1 12 or any other claim herein, wherein adhering the support structure to at least one of the first surface and the second surface comprises adhesively bonding the support structure to at least one of the first surface and the second surface.

1 15. A method as defined in claim 1 12 or any other claim herein, wherein adhering the support structure to at least one of the first surface and the second surface comprises melting a portion of the support structure and bonding the melted portion to at least one of the first surface and the second surface.

1 16. A method as defined in claim 1 12 or any other claim herein, wherein adhering the support structure to at least one of the first surface and the second surface comprises:

contacting at least one of the first surface and the second surface with a thermosetting resin;

curing the thermosetting resin to bond to at least one of the first surface and the second surface.

1 17. A method as defined in claim 1 12 or any other claim herein, wherein adhering the support structure to at least one of the first surface and the second surface comprises ultrasonic bonding or welding a portion of the support structure to at least one of the first surface and the second surface.

1 18. A method as defined as defined in claim 1 12 or any other claim herein wherein adhering the support structure to at least one of the first surface and the second surface comprises molding, including insert molding or overmolding.

1 19. A microneedle apparatus comprising:

a monolithically-formed support structure that abuts against the first surface and against the second surface and wherein the support structure is adhered to at least one of the first and second surfaces to thereby encapsulate at least a portion of the perimeter edge.

120. A microneedle apparatus as defined in claim 1 19 or any other claim herein, the support structure adhered to the first surface of the substrate.

121. A microneedle apparatus as defined in claim 1 19 or any other claim herein, the support structure adhered to the second surface of the substrate.

122. A microneedle apparatus as defined in claim 1 19 or any other claim herein, comprising a conductive circuit component in physical contact with at least one of the microneedle and the substrate and connectable to an external electrical circuit.

123. A microneedle apparatus as defined in claim 122 or any other claim herein, wherein the conductive circuit component is in physical contact with the substrate at a location spaced apart from the microneedle in a transverse direction orthogonal to the longitudinal direction.

124. Microneedle apparatus comprising any features, combination of features or sub combination of features disclosed herein.