Microneedle Array

Abstract

The present invention discloses a microneedle system comprising a cooperating array of microneedles (12, 16) having specific geometric shapes and orientations, and a method for manufacturing such a microneedle system that uses the microneedle arrays manufactured according to the present invention to improve the effectiveness of device introduction and operation.

Description

[Technical field]

[0001] The present invention relates to a microneedle system including a cooperating array of microneedles, and a method of manufacturing such a microneedle system, which method of manufacturing improves the efficiency of introduction and operation of medical devices that use microneedle arrays manufactured in accordance with the present invention. [Background technology]

[0002] Microneedles are increasingly being used in a variety of medical applications due to the many demonstrated benefits to both patients and medical professionals, such as reduced tissue damage, shorter surgery and patient recovery times, reduced risk of infection, and minimization of surgical or medical instruments required for procedures involving microneedle-based devices. Such microneedle-based devices are also used in applications where the end user can apply and remove the device without the need for medical professional intervention, such as in various drug delivery applications, e.g., large-scale vaccination programs.

[0003] International patent applications WO2018 / 069543 and WO2019 / 201903 provide detailed disclosures of the construction and operation of microneedles and opposing microneedle arrays that may be provided in the form of a device or patch to be applied to tissue matrices for a variety of surgical and therapeutic uses, one particular application being drug delivery directly from or through the provided microneedles, again which may be used for delivery of vaccinations and the like. The disclosures of WO2018 / 069543 and WO2019 / 201903 are incorporated herein by reference in their entirety.

[0004] As a result of the increased use of microneedles in medical applications, there is an increasing demand for large-scale, economical methods for manufacturing microneedle arrays for use in such medical devices.

[0005] It is therefore an object of the present invention to provide a microneedle system operable to quickly and easily introduce microneedles into a tissue matrix such as the skin, and a method for manufacturing such microneedle arrays that improves the economics of production while enhancing the performance of the final product. Summary of the Invention

[0006] According to a first aspect of the present invention, there is provided a microneedle system for application to tissue comprising a first array of microneedles formed from a first sheet and folded out of the plane of the first sheet, and a second array of microneedles formed from a second sheet and folded out of the plane of the second sheet, wherein the first and second sheets overlap one another, the second array of microneedles extending through an array of apertures in the first sheet to be interdigitated with the first array of microneedles, the first array of microneedles being displaceable relative to the second array of microneedles in a direction parallel to the plane of the first sheet and the plane of the second sheet, and at least some of the microneedles are folded out of the plane of the first sheet or the plane of the second sheet about a folding axis extending parallel to the direction of relative displacement between the first array of microneedles and the second array of microneedles.

[0007] Preferably, the folding axis lies in the plane of the first sheet or in the plane of the second sheet.

[0008] Preferably, the openings in the first sheet are shaped and dimensioned to facilitate relative displacement between the first array of microneedles and the second array of microneedles.

[0009] Preferably, the apertures in the first sheet are at least partially formed by bending each microneedle out of the first sheet to at least partially define the aperture.

[0010] Preferably, the longitudinal axis of each microneedle in the first array and second array extends at an oblique angle relative to the plane of the first sheet or the plane of the second sheet.

[0011] Preferably, the longitudinal axis of each microneedle of the first array extends in a first direction and the longitudinal axis of each microneedle of the second array extends in a second direction.

[0012] Preferably, the first direction extends away from the second direction.

[0013] Preferably, the longitudinal axis of each microneedle of the first array extends at a first oblique angle relative to the plane of the first sheet and the plane of the second sheet, and the longitudinal axis of each microneedle of the second array extends at a second oblique angle relative to the plane of the first sheet and the plane of the second sheet.

[0014] Preferably, each microneedle of the first array and the second array has a tapered tip.

[0015] Preferably, the tip is tapered in multiple directions.

[0016] Preferably the tip is multi-faceted.

[0017] Preferably, each microneedle of the first array and the second array is substantially planar and lies in a plane that is perpendicular to the plane of the first sheet and the plane of the second sheet and parallel to the direction of relative displacement between the first sheet and the second sheet.

[0018] Preferably, the first sheet and the second sheet comprise metal.

[0019] Preferably, at least a portion of the one or more microneedles comprises an outer coating.

[0020] Preferably, the coating comprises a pharmacologically active ingredient.

[0021] Preferably, the first sheet is electrically isolated from the second sheet.

[0022] According to a second aspect of the present invention, there is provided a method for manufacturing a microneedle system comprising the steps of forming a first array of microneedles in a first sheet, folding the first microneedles out of the plane of the first sheet, forming a second array of microneedles in a second sheet, folding the second microneedles out of the plane of the second sheet, and overlapping the first and second sheets such that the second array of microneedles extends through the array of apertures in the first sheet and is interdigitated with the first array of microneedles and is displaceable relative to the first array of microneedles in a direction parallel to the plane of the first and second sheets, characterized in that at least a portion of the microneedles are folded out of the plane of the first sheet or the plane of the second sheet about a folding axis extending parallel to the direction of relative displacement between the first array of microneedles and the second array of microneedles.

[0023] Preferably the method includes positioning each fold axis to be in the plane of the first sheet or in the plane of the second sheet.

[0024] Preferably, the method comprises forming the first array of microneedles and / or the second array of microneedles by stamping, pressing, etching or laser cutting.

[0025] Preferably, the method includes the step of at least partially forming each aperture in the first sheet by bending a respective microneedle from the first sheet to at least partially define the aperture.

[0026] Preferably, the method includes forming microneedles in the first sheet and in the second sheet with a shape and orientation such that when folded out of the plane of the respective sheet, the longitudinal axis of each microneedle extends at an oblique angle to the plane of the first sheet or the plane of the second sheet.

[0027] Preferably, the method includes orienting the first sheet relative to the second sheet such that a longitudinal axis of each microneedle of the first array extends in a first direction and a longitudinal axis of each microneedle of the second array extends in a second direction.

[0028] Preferably, the method includes securing the first sheet and the second sheet in face-to-face engagement while allowing relative displacement between the first sheet and the second sheet.

[0029] Preferably, the method includes forming the microneedles to be substantially planar in the first sheet and the second sheet, and bending the microneedles to lie in a plane that is perpendicular to the plane of the first sheet and the plane of the second sheet and parallel to the direction of relative displacement between the first sheet and the second sheet.

[0030] Preferably, the method includes forming a taper at the tip of each microneedle.

[0031] Preferably, the method includes forming a plurality of tapers on the tip.

[0032] Preferably, the method includes the step of forming a faceted tip.

[0033] Preferably, the method includes applying a coating to one or more microneedles.

[0034] Preferably, the method includes forming at least one tab in the first sheet or the second sheet adapted to engage the respective first microneedle or second microneedle when folded out of the plane of the first sheet or out of the plane of the second sheet to hold the microneedle in a desired orientation relative to the sheets.

[0035] The present invention will now be described with reference to the accompanying drawings, in which: [Brief description of the drawings]

[0036] [Figure 1] FIG. 1 illustrates a perspective view of a prior art array of microneedles stamped and folded from a sheet of metal. [Diagram 2] FIG. 2 illustrates an enlarged plan view of one microneedle from the array illustrated in FIG. [Diagram 3] FIG. 3 illustrates an enlarged side view of one microneedle as illustrated in FIG. [Figure 4] FIG. 1 illustrates a plan view of a portion of a first sheet in which the contour or outline of a first microneedle has been cut or otherwise formed and excess material removed to form a contoured opening surrounding the microneedle outline. [Diagram 5] 5 illustrates the arrangement of FIG. 4 where the first microneedle is folded out of the plane of the first sheet about the fold axis. [Figure 6] 1 illustrates a plan view of a portion of a second sheet with the contour or outline of second microneedles cut or otherwise formed into the second sheet. [Figure 7] 7 illustrates the configuration of FIG. 6 where the second microneedle is folded out of the plane of the second sheet about the fold axis. [Figure 8] 8 illustrates a perspective view of portions of the first and second sheets shown in Figures 5 and 7, positioned on top but vertically separated from each other, for illustrative purposes and for use in a microneedle system according to the present invention. [Figure 9] Illustrates a state in which the first sheet portion and the second sheet portion shown in FIG. 8 are assembled into a cooperative engaged state such that the second microneedle protrudes through the opening in the first sheet and the first microneedle and the second microneedle are in a disengaged state. [Figure 10] 10 illustrates the arrangement of FIG. 9, where the first microneedle and the second microneedle are in an engaged state. [Figure 11] 10 illustrates a side view of the arrangement of FIG. [Figure 12] 11 illustrates a side view of the arrangement of FIG. 10. [Figure 13] FIG. 11 illustrates an end view of the arrangement of FIG. 9 or FIG. 10. [Figure 14] FIG. 1 illustrates an exploded perspective view of a microneedle-based skin patch including a first array and a second array of microneedles shown separated from one another. [Figure 15] 15 illustrates the skin patch of FIG. 14 with the first array of microneedles and the second array of microneedles cooperatively engaged with one another. [Figure 16] FIG. 16 illustrates a side view of the skin patch shown in FIGS. 14 and 15. [Figure 17] 17 illustrates a side view of the skin patch shown in FIG. 16. [Figure 18] 18 illustrates the skin patch of FIGS. 14-17 with the modified retention tab in an open position. [Figure 19] 19 illustrates the skin patch shown in FIG. 18 with the retention tabs in a closed position. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] 1-3 of the accompanying drawings, there is illustrated a known array of microneedles M formed integrally with a sheet S by a known manufacturing method. The manufacturing method includes cutting or punching, preferably in a single punching operation, an array of apertures O in the sheet S to form the outline of each microneedle M within the array. The manufacturing method utilizes a conventional press (not shown) or the like to punch the apertures O from a sheet of a metal, for example steel or titanium, although other materials may be used.

[0038] 2 and 3 show one of the microneedles M and surrounding apertures O, cut away and enlarged from the array for illustrative purposes. Once the contours of the microneedles M have been formed by punching the apertures O, a further step in the manufacturing process is to bend or fold the microneedles M out of the plane of the sheet S, again using a conventional punch assembly. It can be seen that the microneedles M are bent about an axis A that extends transverse to the direction of displacement of the microneedles M during insertion into tissue.

[0039] 4-17, there is illustrated a microneedle system, generally designated 10, and a method of manufacturing the microneedle system 10 in accordance with the present invention. The microneedle system 10 has an array of first microneedles 12 formed integrally with a first sheet 14, as described below, and a cooperating array of second microneedles 16 formed integrally with a second sheet 18, as also described below. As will be described in more detail, the first sheet 14 and second sheet 18 are arranged in face-to-face engagement, preferably in cooperating pairs of first microneedles 12 and second microneedles 16, such that, in use, the second microneedles 16 pass through the first sheet 14 and are incorporated into the first microneedles 12. The first microneedle 12 and the second microneedle 16 are displaceable relative to one another in a longitudinal or "X" direction to transition the system 10 between a disengaged and engaged state to penetrate and thus anchor in tissue (not shown). The methodology underlying this introduction technique is described in detail in the above-mentioned international applications WO2018 / 069543 and WO2019 / 201903. For ease of reference, the direction or dimension along the length of the device 10 and the sheets 14, 18 will hereinafter be referred to as the "X" coordinate or "X" direction, the direction along the width will be referred to as the "Y" coordinate, and the direction along the depth will be referred to as the "Z" coordinate, as graphically represented in FIG. 9 for the microneedle system 10.

[0040] In the drawings, the complete first sheet 14 and / or second sheet 18 are only shown in Figures 14-17, while Figures 4-13 show a portion of each sheet 14, 18 including a respective single microneedle 12, 16 to clearly show the local alignment and interaction of one cooperating pair of microneedles 12, 16. It will be understood that this alignment and interaction, described below, is repeated throughout the array for each pair of cooperating microneedles 12, 16. The microneedles 12, 16 are integrally formed with their respective sheets 14, 18 through a process of removing material from the sheets 14, 18 to define the contours or profile of the microneedles 12, 16, as illustrated in Figures 4 and 6, and then a subsequent step in which the microneedles 12, 16 are folded out of the plane of the sheets 14, 18, as illustrated in Figures 5 and 7. The material around each microneedle 12, 16 can be removed by any suitable process, such as, for example, punching, chemical etching, laser cutting, or any other functional alternative process. The final shape of the microneedles 12, 16 can vary and have different geometries to suit a particular application or manufacturing process. In the illustrated embodiment, both microneedles 12, 16 have a similar geometry, being elongated along the longitudinal axis L compared to a width W across the longitudinal axis L, and having a thickness T equal to the thickness of the sheets 14, 18. However, it will be appreciated that the thickness T can be altered by additional manufacturing steps, for example, decreasing the thickness along all or part of the length of the microneedles 12, 16, or increasing the thickness, for example, by applying one or more coatings or materials via some other additive manufacturing process. However, for manufacturing efficiency, it is preferable to be able to punch or otherwise cut the final shape of the microneedles 12, 16 from the sheets 14, 18 in a single step. Additionally or alternatively, at least a portion of one or more of the microneedles 12, 16 may be provided with a coating, such as an electrically isolating or electrically insulating coating (not shown), and / or a pharmacologically active substance or composition.In the case of an electrically isolating or insulating coating, for example, it is possible to coat a substantial length of the microneedle(s) 12, 16 but leave portions uncoated, such as the tips, thereby allowing the microneedles 12, 16 to be used to measure skin impedance at particular depths.

[0041] The sheets 14, 18 may be formed from any suitable material, such as a metal or metal alloy, plastic or composite, or any suitable combination of materials, and may be of any suitable thickness and surface area; for example, a large sheet may be processed to form the microneedles 12, 16, and then the sheet may be divided into multiple smaller sections to form the final product.

[0042] It will be appreciated that when the microneedles 12, 16 are folded from the sheets 14, 18, holes are left in the sheets 14, 18 that are approximately the negative of the microneedles 12, 16. However, in forming the profile of each first microneedle 12, excess material is also removed to form a longitudinally extending aperture 20, which is preferably formed entirely in the same step that stamps or otherwise forms the profile of the first microneedle 12. The apertures 20 are arranged to allow a cooperating second microneedle 16 to pass through the first sheet 14 in the "Z" direction when the first and second sheets 14, 18 are disposed in face-to-face engagement, and thus to allow the second microneedle 16 to be disposed adjacent and aligned with the mating microneedle of the first microneedle 12, as shown in Figures 9 and 10. The opening 20 has a first longitudinally extending end 22 and an opposite, longitudinally extending second end 24, as well as an area resulting from the removal of the respective first microneedle 12. These ends 22, 24 allow the second microneedle 16 to be displaced in the longitudinal or "X" direction relative to the first microneedle 12 as the system 10 transitions between the disengaged and engaged states as described above. This is accomplished by the relative displacement of the first sheet 14 and the second sheet 18 in the longitudinal or "X" direction. The sheets 14, 18 slide substantially over one another along a limited path or distance, again as shown in Figures 9 and 10, respectively. This distance is substantially the distance over which the second microneedle 16 can be displaced in this embodiment from a position disposed at the first end 22 to a position disposed at the second end 24 of the opening 20. This distance can of course be varied as desired, most simply by increasing the longitudinal or "X" dimension of the aperture 20. Thus, the geometry of the aperture 20 can be used to determine the range of relative displacement between the microneedles 12, 16.

[0043] If necessary, the device 10 may be provided with suitable bearings (not shown) to facilitate relative displacement between the sheets 14, 18. This may take the form of, for example, a low friction coating or component (not shown) disposed between the sheets 14, 18 or on the surface of one of the sheets 14, 18. However, given that the relative displacement between the sheets 14, 18 is small, and given that most applications of the system 10 are single use, such bearings (not shown) are unlikely to be a mandatory requirement to ensure effective operation of the system 10. Alternatively, the coating may be of a suitable formulation that electrically isolates each sheet 14, 18 of the microneedle array from each other. This facilitates direct measurement of skin impedance using the microneedles 12, 16 as detailed above.

[0044] Turning now to the specific design of the microneedles 12, 16, it can be seen that the longitudinal axis L of each microneedle 12, 16 extends at an oblique angle φ relative to the plane of the sheets 14, 18, i.e., the "XY" plane. This angle φ may be varied as needed, for example to be application specific. The first microneedle 12 is oriented to extend in a first direction, and the second microneedle 16 extends in a substantially opposite second direction. In the illustrated embodiment, the microneedles 12, 16 are arranged to overlap in the longitudinal or "X" direction with the system 10 in a disengaged state, as most clearly seen in FIG. 11, which can also be seen in FIG. 9. By displacing the sheets 14, 18 longitudinally relative to one another, the system 10 is moved to an engaged state, and the microneedles 12, 16 are also displaced longitudinally relative to one another in the orientations shown in FIGS. 10 and 12. In this position, the microneedles 12, 16 are spaced apart longitudinally substantially beyond one another and do not overlap in the "X" direction. However, it should be understood that the microneedle system 10 may be modified, for example, to vary the longitudinal overlap between the microneedles 12, 16 to adopt alternative disengaged and engaged relative orientations. This intentional "X" overlap improves manufacturability by preventing entanglement or interference of the microneedles 12, 16 during the overlapping and initial sliding processes. As can be appreciated, this overlap reduces the need for the microneedles 12, 16 to be folded precisely against the plane of the first sheet 14 or second sheet 18, as folding metals at this scale can result in significant spring back that is difficult to control (especially with certain materials, e.g., stainless steel).

[0045] The length of the microneedles 12, 16 along the longitudinal axis L may also be varied as desired. It can also be seen from Figure 13 that in the "Y" direction, the microneedles 12, 16 are laterally separated from one another to avoid contact as they move relative to one another in the "X" direction.

[0046] It will also be appreciated that, as can be seen particularly in Figures 11-14, with the sheets 14, 18 combined, the microneedles 12, 16 extend to the same depth (in the "Z" direction), and thus the second microneedle 16 preferably has a larger "Z" dimension than the first microneedle 12, and in particular an increased "Z" dimension equal to the thickness of the first sheet 14 from which the second microneedle 16 projects. Thus, although both microneedles 12, 16 extend to the same depth in the "Z" direction, it is also envisioned that the microneedles may extend to different depths, or that particular pairs of microneedles 12, 16 within a Fuller array may be so configured. It is also contemplated that in machining and creating the openings in the first sheet 14 and the second sheet 18, geometric shapes (such as tabs, not shown) that effectively engage with one another to define the microneedles 12, 16 and, optionally, click-lock the individual needles 12, 16 vertically.

[0047] The microneedles 12, 16 preferably have tapered tips 26 to enhance tissue penetration. The tips 26 may be tapered or beveled in multiple directions / planes. This tapering or beveling is preferably formed prior to folding the microneedles 12, 16 from the sheets 14, 18, but may also be applied afterwards. The tips 26 or some or all of the microneedles 12, 16 may be provided with a coating (not shown) to modify the physical properties of the microneedles 12, 16, for example, a coating to harden the tips 26. The coating may be applied by any suitable method, for example, vapor deposition. Additionally or alternatively, the tips 26 and / or the microneedles 12, 16 may be coated with a pharmacologically active compound or drug that is delivered when the system 10 is introduced into tissue. Alternatively, the microneedles 12, 16 may be hollow and the system 10 may be adapted to effect drug delivery from or through the hollow microneedles.

[0048] With particular reference to Figures 4-10, it can be seen that the microneedles 12, 16 are folded out of the "XY" plane of the sheets 14, 18 along a fold axis 28 that extends in the longitudinal or "X" direction. This has many advantages, in particular it significantly increases the strength of the microneedles 12, 16 to withstand longitudinal loads during tissue insertion and can significantly increase the density of the microneedles 12, 16 in a given area of ​​the sheets 14, 18. Thus, as shown in Figures 4 and 6, when forming the profile of the microneedles 12, 16, the microneedles 12, 16 are aligned to extend at an oblique angle φ relative to the longitudinal or "X" direction such that once folded out of the "XY" plane of the sheets 14, 18, the microneedles 12, 16 are oriented at an oblique angle φ relative to the "XY" plane of the sheets 14, 18. Thus, an angle φ is defined between the folding axis 28 and the longitudinal axis L of the microneedles 12, 16. FIG. 13 further illustrates that the microneedles 12, 16 preferably extend in the "Z" direction, oriented perpendicular to the "XY" plane of the sheets 14, 18, although this orientation may be varied. By aligning the folding axis 28 to coincide with the direction of relative displacement between the microneedles 12, 16, when folded from the sheets 14, 18, the cooperating pairs of microneedles 12, 16 are oriented to have their smallest dimension, thickness T, side-by-side, as seen most clearly in FIG. 13. This orientation of the microneedles 12, 16 significantly increases the density of cooperating microneedles 12, 16 that can be arranged in a given area of ​​the sheets 14, 18, particularly as compared to prior art orientations such as those illustrated in FIG. 1. This increased density may result in increased adhesion to tissue and / or increased drug delivery capacity.

[0049] 14-17, the microneedle system 10 is shown including an exemplary manual applicator 30 operable to cause relative displacement of the sheets 14, 18 to transition the system 10 between a disengaged and engaged state. The construction and operation of this form of applicator 30 is described and shown in detail in the applicant's co-pending European Patent Application No. 20198798.9. The applicator 30 has a pair of halves 32, 34 which are displaceable relative to one another and to which the pair of sheets 14, 18 may be removably or permanently secured on their undersides. The first sheet 14 is provided with a pair of tabs 36 which protrude through a corresponding pair of openings 38 in the second sheet 18. The openings 38 are dimensioned to allow relative longitudinal displacement of the tabs 36 to cause the relative displacement of the sheets 14, 18. The tab 36 is fixed to the underside of the applicator 30 and is arranged such that displacement of the pair of halves 32, 34 causes displacement of the tab 36 along the opening 38, which causes relative displacement of the sheets 14, 18 and, consequently, of the microneedles 12, 16. In this manner, the system 10 can be pressed into contact with tissue such as the skin (not shown) and the pair of halves 32, 34 can be manually pressed together to introduce the microneedles 12, 16 into the skin. The applicator 30 may then be removed, leaving the sheets 14, 18 against the skin, or the above procedure may be reversed, leaving the applicator 30 in place to allow subsequent removal of the sheets 14, 18 by retracting the microneedles 12, 16 from the skin or other tissue.

[0050] 18 and 19 illustrate a microneedle system 10 as shown in FIGS. 14-17, modified such that each of a pair of sheets of microneedles (not visible) is provided with a retaining tab 136 extending laterally from one edge of the microneedles and thereby extending beyond the edge of the respective half 32, 34 of the applicator 30. Each of the retaining tabs 136 is displaceable from an open position as illustrated in FIG. 18 to be folded around the edge of the respective half 32, 34 and overlay the respective half 32, 34, thereby securing the respective sheet of microneedles to the respective half 32, 34 of the applicator. The retaining tabs 138 may be used in place of or in combination with the pair of tabs 36 shown in FIG. 15. The tabs 138 may be elastically deformable or otherwise reversibly displaceable between open and closed positions. In this manner, once the sheet has been deployed on the skin, the retention tabs 138 may be returned to an open state, such as to allow the applicator 30 to be removed, leaving only the sheet of microneedles on the skin.

[0051] It will be understood that the applicator 30-based microneedle system 10 is merely an exemplary application of the microneedle system 10, the essential components of which are the pair of sheets 14, 18 carrying the arrays of cooperating microneedles 12, 16. These sheets 14, 18 may be incorporated into other suitable medical or surgical devices to allow introduction into tissue, whether externally, such as for application to the skin or eye, biosensing applications, drug delivery, or fixation of other medical implements, or internally for surgical or drug delivery applications.

[0052] It will therefore be appreciated that the system 10 and manufacturing method according to the present invention provides a microneedle array in a configuration which increases the strength of the microneedles during tissue penetration, increases the density of the microneedles for a given surface area of ​​the sheet on which the microneedles are formed, and facilitates mass production of such microneedle arrays.

[0053] The present invention is not limited to the embodiments described herein, which can be amended or modified without departing from the scope of the invention.

Claims

1. A microneedle system for application to tissue, the microneedle system comprising: an array of first microneedles formed from a first sheet and bent from the plane of the first sheet; and an array of second microneedles formed from a second sheet and bent from the plane of the second sheet; wherein the first sheet and the second sheet overlap each other, and the array of second microneedles extends through an array of openings in the first sheet and is incorporated into the array of first microneedles; the array of first microneedles is displaceable relative to the array of second microneedles in a direction parallel to the planes of the first sheet and the second sheet; at least some of the microneedles are bent from the plane of the first sheet or the second sheet about a folding axis extending parallel to the direction of relative displacement between the array of first microneedles and the array of second microneedles.

2. The microneedle system according to claim 1, wherein the folding axis is in the plane of the first sheet or the second sheet.

3. The microneedle system according to claim 1, wherein the openings in the first sheet are shaped and dimensioned to facilitate relative displacement between the array of first microneedles and the array of second microneedles.

4. The microneedle system according to claim 1, wherein the openings in the first sheet are at least partially formed by bending respective microneedles from the first sheet to at least partially define the openings.

5. The microneedle system according to claim 1, wherein the longitudinal axis of each microneedle in the array of first microneedles and the array of second microneedles extends at an angle to the plane of the first sheet or the second sheet.

6. The longitudinal axis of each of the micro-needles of the first micro-needle array extends in a first direction, and the longitudinal axis of each of the micro-needles of the second micro-needle array extends in a second direction. The micro-needle system according to claim 1.

7. The first direction extends away from the second direction. The micro-needle system according to claim 6.

8. The longitudinal axis of each of the micro-needles of the first micro-needle array extends at a first oblique angle with respect to the planes of the first sheet and the second sheet, and the longitudinal axis of each of the micro-needles of the second micro-needle array extends at a second oblique angle with respect to the planes of the first sheet and the second sheet. The micro-needle system according to claim 6.

9. Each of the micro-needles of the first micro-needle array and the second micro-needle array includes a tapered tip. The micro-needle system according to claim 1.

10. The tapered tip is tapered in a plurality of directions. The micro-needle system according to claim 9.

11. The tapered tip is multi-faceted. The micro-needle system according to claim 9.

12. Each of the micro-needles of the first micro-needle array and the second micro-needle array is substantially planar and is located in a plane perpendicular to the planes of the first sheet and the second sheet and parallel to the direction of relative displacement between the first sheet and the second sheet. The micro-needle system according to claim 1.

13. The first sheet and the second sheet include a metal. The micro-needle system according to claim 1.

14. At least a part of one or more of the micro-needles includes an external coating. The micro-needle system according to claim 1.

15. The external coating includes a pharmacologically active ingredient and / or an electrically insulating material. The micro-needle system according to claim 14.

16. The first sheet is electrically isolated from the second sheet. The micro-needle system according to claim 1.

17. A method of manufacturing a microneedle system, the method comprising: forming an array of first microneedles in a first sheet; bending the first microneedles from the plane of the first sheet; forming an array of second microneedles in a second sheet; bending the second microneedles from the plane of the second sheet; overlaying the first sheet and the second sheet such that the array of second microneedles extends through an array of openings in the first sheet and is incorporated into the array of first microneedles and is displaceable relative to the array of first microneedles in a direction parallel to the plane of the first sheet and the second sheet; characterized by: bending at least some of the microneedles from the plane of the first sheet or the second sheet about a fold axis extending parallel to the direction of relative displacement between the array of first microneedles and the array of second microneedles. **Claim 18** The method according to claim 17, further comprising positioning each fold axis within the plane of the first sheet or the second sheet. **Claim 19** The method according to claim 17, further comprising forming the array of first microneedles and / or the array of second microneedles by punching, blanking, etching or laser cutting. **Claim 20** The method according to claim 17, further comprising forming each opening in the first sheet at least partially by bending each microneedle from the sheet to at least partially define the opening. **Claim 21** The method according to claim 17, further comprising forming the microneedles in the first sheet and the second sheet in a shape and orientation such that when bent from the plane of each sheet, each longitudinal axis of the microneedles extends at an oblique angle to the plane of the first sheet or the second sheet. **Claim 22** Orienting the first sheet relative to the second sheet such that longitudinal axes of the micro-needles of the first micro-needle array extend in a first direction and longitudinal axes of the micro-needles of the second micro-needle array extend in a second direction, the method according to claim 17.

23. Fixing the first sheet and the second sheet in a facing and engaged state while allowing relative displacement therebetween, the method according to claim 17.

24. Forming the micro-needles to be substantially planar within the first sheet and the second sheet; Bending the micro-needles such that they are perpendicular to the planes of the first sheet and the second sheet and are located in a plane parallel to the direction of relative displacement between the first sheet and the second sheet; The method according to claim 17, comprising.

25. Forming a taper within each tip of the micro-needles, the method according to claim 17.

26. Applying a coating to one or more of the micro-needles, the method according to claim 17.

27. Forming at least one tab within the first sheet or the second sheet adapted to engage each of the first micro-needles or the second micro-needles when bent from the plane of the first sheet or the second sheet to hold the micro-needles in a desired orientation relative to the sheet, the method according to claim 17.

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