ARRAYS

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority of U. S. Provisional Patent Application No. 62/508,755 filed May 19, 2017, which is hereby incorporated by reference in its entirety.

BACKGROUND

1. Field of Invention

[0002] The present invention relates generally to microneedles (i.e., a needle structure having a height from 200 micrometers (μπι) to 1, 100 μπι), and more specifically, but not by way of limitation, to methods and systems for producing polymer microneedles via ultrasonic embossing, and microneedle arrays produced using such methods and systems.

2. Description of Related Art

[0003] Microneedles have attracted the attention of researchers because of their potential to provide a pain-free or reduced-pain alternative to syringes for injecting fluid into a patient or drawing blood from a patient for testing (e.g., blood glucose and/or insulin levels). Additionally, microneedles offer the potential for improved logistics (e.g., reducing the free volume of medication in any one place to reduce or eliminate the need for refrigerated transport) and increased patient self-administration (e.g., reducing the need and resulting costs for a healthcare provider to be present to inject fluid or draw blood).

[0004] One approach that has been used to manufacture microneedles is injection molding. In such injection molding efforts, polymer has been melted and forced to flow into a mold that includes a plurality cavities or "negative" (female) molds each defining a microneedle. Stated another way, the mold defines a plurality of "inverse" microneedles. For example, U.S. Patent No. 9,289,925 discloses a method of manufacturing hollow microneedles via injection molding. As used in this disclosure, a "hollow" microneedle is a microneedle with an internal channel extending through at least a portion of the length of the microneedle and opening through at least one outer surface of the microneedle to permit fluid communication through the microneedle. In contrast, a "solid" microneedle is a microneedle that does not include a channel extending through an exterior surface of the microneedle such that fluid communication is not permitted through the microneedle. However, such injection molding efforts have met with challenges. For example, injection molding requires a polymer to be fully melted— i.e., the entirety of the material must be raised above its glass transition temperature— and cooling takes a relatively large amount of time because all of the polymer material must therefore be cooled and solidified before the polymer material can be removed from a mold.

[0005] Another approach that has been used to manufacture microneedles is ultrasonic embossing, typically with expensive roll embossing machines. In such ultrasonic embossing methods, a sheet of polymer material is disposed between a sonotrode and a solid mold that defines one or more inverse microstructure cavities. Ultrasound energy is applied to the sonotrode— i. e. , the sonotrode is vibrated as one or more ultrasonic frequencies— and the sheet of polymer material is compressed between the sonotrode and the solid mold. However, such ultrasonic embossing methods efforts have also met with challenges. For example, it has proven difficult to manufacture microneedles with a viable aspect ratio— i.e., with both a large- enough base to ensure stability and durability of the microneedle and a sharp-enough blade and/or tip to effectively cut into skin. One example of such a challenge is that, on the physical scale at which microneedles are produced, it has proven difficult to cause molten polymer to flow into the entirety of each cavity or inverse microneedle in a mold, resulting in partially formed microneedles that have a blunt or irregular tip. Another example of such a challenge is that gas can become trapped in the tip of an inverse microneedle cavity and, at the temperatures employed for molding polymer, can combust in similar fashion as happens in diesel engines, leaving a charred and/or weakened tip on the corresponding microneedle (which may also be mis-formed).

SUMMARY

[0006] The present disclosure includes embodiments of methods and systems for manufacturing arrays of solid microneedles using ultrasound energy, as well as article of manufacture, such as layers {e.g., rolled layers) of polymers with microneedles, formed by such methods and systems. The present systems and methods can be configured to form solid microneedles that do not suffer from the prior art shortcomings identified above. For example, the present methods and systems (and, for example, particularly the tools in which inverse microneedle cavities are defined by multiple laminae) permit gas to flow out of the cavities as polymer flows into the cavities, thereby permitting the polymer to substantially fill the cavities to form full microneedles with sharp tips. Additionally, the present ultrasonic embossing methods permit faster processing times because not all of the polymer needs to be heated above its glass transition temperature and, because, the heating that does occur is a result of the ultrasonic energy rather than external thermal energy, the tool or mold and sonotrode need not be independently heated above the glass transition temperature. As a result, the time needed to heat the polymer (e.g., a portion of the polymer) above the polymer's glass transition temperature and then cool back below the glass transition temperature after molding (e.g., about 2 second) is significantly lower than for injection molding (e.g., about 30-60 seconds, or more).

[0007] Additionally, ultrasonic embossing permits control of polymer temperature (e.g., within 2°C of a target temperature) to a degree that is very difficult if not impossible with injection molding, reducing the risk of overheating the polymer (e.g., which can potentially reduce the integrity of the polymer and molded microneedles), which can be particularly suitable for semi-crystalline polymers with narrow temperature processing windows (i.e., between the melting temperature and the entropy elastic temperature). The shorter time at which the polymer is in a molten state with ultrasonic embossing also increases the likelihood that the polymer will retain its molecular properties (e.g., not degrade).

[0008] In some of the present embodiments, a roll-to-roll approach allows arrays (e.g., large arrays) of microneedles to be manufactured more rapidly than prior art methods. Specifically, the present roll-to-roll can involve unrolling one or more sheets of polymer material from a dispenser roll, passing sequential portions of the sheet(s) between a sonotrode and a tool or mold to form microneedles on a side of the sheet(s), and rolling the formed or molded sheet(s) onto a receiver roll. As a another result, microneedle arrays formed with the present systems and methods need not be singular, discrete arrays as known in the prior art, but can instead include one or more arrays extending along an elongated sheet or layer of polymer. For example, a sheet of polymer with a length that is five or more times its width can have one or more microneedle arrays extending along a majority of its length.

[0009] Some embodiments of the present methods (e.g., of manufacturing a microneedle array) comprise: disposing a sheet of polymer between a sonotrode and a proximal surface of a tool such that a first side of the sheet contacts a proximal surface of the tool, the tool comprising a plurality of laminae cooperating to defining a plurality of cavities, each of the cavities extending from a base at the proximal surface to a distal end within the tool to define a negative mold of a microneedle, the base of each of the cavities having a cross-sectional area larger than that of the respective distal end; delivering ultrasonic energy from the sonotrode to the sheet such that a temperature of the first side of the sheet increases above the polymer's glass transition temperature; and compressing the sheet between the sonotrode and the tool such that polymer of the sheet flows into the cavities until the polymer substantially fills the cavities to form a plurality of solid microneedles on the first side of the sheet. In some embodiments, each of the cavities has a pyramid shape. In some embodiments, a cross- sectional shape of the base of each of the cavities is a rhomboid.

[0010] In some of the foregoing embodiments of the present methods, the base of each of the cavities has a primary maximum transverse dimension measured in a first direction, and each of the cavities has a height extending from the base of the cavity to the distal end of the cavity that is from 1 to 5 times the primary maximum transverse dimension of the respective cavity. In some such embodiments, each of the cavities has a secondary maximum transverse dimension measured in a second direction that is perpendicular to the first direction, and the ratio of the primary maximum transverse dimension to the secondary maximum transverse dimension of the respective cavity is from 1 to 5.

[0011] In some of the foregoing embodiments of the present methods, a length of each of the plurality of microneedles is from 400 micrometers (μπι) to 1,000 μπι. In some such embodiments, the length is from 400 μπι to 800 μπι.

[0012] In some of the foregoing embodiments of the present methods, each of the laminae has a proximal side, a first lateral side intersecting the proximal side along a first edge, and a second lateral side intersecting the proximal side along a second edge opposite the first edge; a majority of the laminae each defines a plurality of first recesses, each of the first recesses extending into the respective lamina through the proximal side and the first lateral side (e.g., such that each first recess defines: at the proximal side of the lamina, a portion of the base of a cavity; and at the first lateral side of the lamina, at least a portion of the distal end of the cavity); and the laminae are coupled together such that their proximal sides cooperate to define the proximal surface of the tool, and the first lateral side of each of the majority of the laminae is adjacent to the second lateral side of another one of the laminae. In some such embodiments, at least a majority of the laminae each defines a plurality of second recesses, each of the second recesses extending into the respective lamina through the proximal side and the second lateral side such that the second recess at the proximal side of the lamina defines at least a portion of the base of a cavity and the second recess at the second proximal side of the lamina defines at least a portion of the distal end of the cavity, and each of the second recesses is aligned with one of the first recesses. In some such embodiments, each of the first recesses is substantially symmetrical to the second recess with which the respective first recess is aligned. [0013] In some of the foregoing embodiments of the present methods, the sheet of polymer comprises a polymer selected from the group consisting of: liquid-crystal polymer (LCP), polyether ether ketone (PEEK), fluorinated ethylene propylene (FEP), polysulfone (PSU), polyethylenimine (PEI), polyimide (PI), polycarbonate (PC), polycarbonate copolymer (PC COPO), cyclic olefin copolymer (COC), cyclo olefin polymer (COP), polyamide (PA), acrylonitrile butadiene styrene (ABS), and polyphenylene ether (PPE).

[0014] In some of the foregoing embodiments of the present methods, the sheet of polymer is a first sheet of polymer and the method further comprises: prior to delivering ultrasonic energy, disposing a second sheet of polymer between the first sheet of polymer and the sonotrode such that a first side of the second sheet contacts a second side of the first sheet, and a second side of the second sheet contacts the sonotrode; where the ultrasonic energy is delivered such that respective temperatures of the second side of the first sheet and the first side of the second sheet both increase above their respective polymer' s glass transition temperatures, and the first sheet and the second sheet are both compressed between the sonotrode and the tool such that polymer of the first sheet commingles with polymer of the second sheet.

[0015] In some of the foregoing embodiments of the present methods, a first end of the sheet of polymer is wrapped around a first roll on a first side of the tool, a second end of the sheet of polymer is coupled to a second roll on a second side of the tool, and the method further comprises: unrolling a first portion of the sheet of polymer from the first roll; performing the disposing, delivering, and compressing steps on the first portion of the sheet; after all of the first portion of the sheet has cooled to a temperature below the polymer' s glass transition temperature, separating the first portion of the sheet from the tool; rotating the second roll to move the first portion of the sheet away from the tool; and repeating the disposing, delivering, and compressing steps on a second portion of the sheet.

[0016] Some embodiments of the present systems (e.g., for manufacturing a microneedle array from one or more sheets of polymer) comprise: a frame; a tool coupled to the frame, the tool having a proximal surface and comprising a plurality of laminae cooperating to defining a plurality of cavities, each of the cavities extending from a base at the proximal surface to a distal end within the tool to define a negative mold of a microneedle, the base of each of the cavities having a cross-sectional area larger than that of the respective distal end; a sonotrode coupled to the frame and configured to be actuated to deliver ultrasonic energy to a sheet of polymer if the sheet is disposed between the sonotrode and the tool and in contact with the tool; and an actuator coupled to the frame; where at least one of the tool and the sonotrode is movably coupled to the frame, and the actuator is configured to reduce a distance between the tool and the sonotrode to compress the sheet such that polymer of the sheet flows into the cavities until the polymer substantially fills the cavities to form a plurality of solid microneedles on the first side of the sheet.

[0017] Some of the foregoing embodiments of the present systems further comprise: a dispenser spindle coupled to the frame on a first side of the sonotrode, the dispenser spindle configured to rotatably support a dispenser roll of a sheet of polymer; and a receiver spindle coupled to the frame on a second side of the sonotrode, the receiver spindle configured to rotatably support a receiver roll to receive portions of the sheet of polymer having microneedles after the portions are unrolled from the dispenser roll and compressed between the sonotrode and the tool to define microneedles on a first side of the polymer sheet. In some such embodiments, the dispenser spindle is a first dispenser spindle, the dispenser roll is a first dispenser roll of a first sheet of polymer, and the system further comprises: a second dispenser spindle coupled to the frame on a first side of the sonotrode, the dispenser spindle configured to receive a second dispenser roll of a second sheet of polymer; and the receiving spindle is configured to rotatably support the receiving roll to receive portions of a merged sheet of polymer having microneedles after corresponding portions of the first and second sheets of polymer are unrolled from the first and second dispenser rolls and compressed between the sonotrode and the tool to merge the first and second sheets of polymer and form microneedles on a first side of the merged sheet.

[0018] Some of the present article of manufacture comprise; a layer of polymer having a first side and an opposing second side, the polymer defining a plurality of solid microneedles on the first side of the layer, each microneedle having a distal end and a base between the distal end and the second side of the layer, the base of each of the microneedles having a cross- sectional area larger than that of the respective distal end; where the layer of polymer is rolled. In some embodiments, the first side and microneedles extend radially outward. In some embodiments, the layer of polymer comprises a first polymer and a second polymer that is harder than the first polymer, and a majority of an outer surface of the plurality of microneedles is defined by the second polymer. In some such embodiments, a length of each microneedle is from 400 micrometers (μπι) to 1,000 μπι.

[0019] The term "coupled" is defined as connected, although not necessarily directly, and not necessarily mechanically; two items that are "coupled" may be unitary with each other. The terms "a" and "an" are defined as one or more unless this disclosure explicitly requires otherwise. The term "substantially" is defined as largely but not necessarily wholly what is specified (and includes what is specified; e.g., substantially 90 degrees includes 90 degrees and substantially parallel includes parallel), as understood by a person of ordinary skill in the art. In any disclosed embodiment, the term "substantially" be substituted with "within [a percentage] of what is specified, where the percentage includes .1, 1, or 5 percent; and the term "approximately" may be substituted with "within 10 percent of what is specified.

[0020] The phrase "and/or" means and or or. To illustrate, A, B, and/or C includes: A alone, B alone, C alone, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B, and C. In other words, "and/or" operates as an inclusive or.

[0021] Further, a device or system that is configured in a certain way is configured in at least that way, but it can also be configured in other ways than those specifically described.

[0022] The terms "comprise" (and any form of comprise, such as "comprises" and "comprising"), "have" (and any form of have, such as "has" and "having"), and "include" (and any form of include, such as "includes" and "including"). As a result, an apparatus that "comprises," "has," or "includes" one or more elements possesses those one or more elements, but is not limited to possessing only those one or more elements. Likewise, a method that "comprises," "has," or "includes" one or more steps possesses those one or more steps, but is not limited to possessing only those one or more steps.

[0023] Any embodiment of any of the systems, methods, and article of manufacture can consist of or consist essentially of - rather than comprise/have/include - any of the described steps, elements, and/or features. Thus, in any of the claims, the term "consisting of or "consisting essentially of can be substituted for any of the open-ended linking verbs recited above, in order to change the scope of a given claim from what it would otherwise be using the open-ended linking verb.

[0024] The feature or features of one embodiment may be applied to other embodiments, even though not described or illustrated, unless expressly prohibited by this disclosure or the nature of the embodiments. [0025] Some details associated with the embodiments are described above, and others are described below. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The following drawings illustrate by way of example and not limitation. For the sake of brevity and clarity, every feature of a given structure is not always labeled in every figure in which that structure appears. Identical reference numbers do not necessarily indicate an identical structure. Rather, the same reference number may be used to indicate a similar feature or a feature with similar functionality, as may non-identical reference numbers. The figures are drawn to scale (unless otherwise noted), meaning the sizes of the depicted elements are accurate relative to each other for at least the embodiment depicted in the figures. Views identified as schematics are not drawn to scale.

[0027] FIG. 1 is a schematic view of a first embodiment of the present systems for manufacturing a microneedle array.

[0028] FIGs. 2A and 2B are perspective and top views, respectively, of a first embodiment of the present tools for use in the system of FIG. 1.

[0029] FIG. 2C is an enlarged cutaway view of the tool of FIGs. 2A and 2B, showing a single cavity in a lateral side of one lamina of the tool.

[0030] FIGs. 3A and 3B are perspective and top views, respectively, of a second embodiment of the present tools for use in the system of FIG. 1.

[0031] FIGs. 4A and 4B are perspective and side views, respectively, of a first embodiment of a microneedle that can be formed with the system of FIG. 1 and, in particular, the tool of FIGs. 3A and 3B.

[0032] FIG. 5 is a flowchart illustrating one embodiment of the present methods of manufacturing a microneedle array.

[0033] FIG. 6 is a schematic view of a second embodiment of the present systems for manufacturing a microneedle array.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0034] Referring now to the drawings and, more particularly, to FIG. 1, shown there and designated by the reference numeral 10 is a schematic view of a first embodiment of the present systems for manufacturing a microneedle array from one or more sheets of polymer. In the embodiment shown, apparatus 10 comprises a frame 14, a tool 18 coupled to the frame, a sonotrode 22 coupled to the frame, and an actuator 26 coupled to the frame. Frame 14 is illustrated as a horizontal base 30 and vertical panel 34; however, in other embodiments, the frame may comprise any structure (e.g., individual beams and/or other elongated frame members) that supports a physical relationship of the components to permit a polymer sheet to be compressed between the sonotrode and the tool. In the embodiment shown, tool 18 is further supported by an anvil or base 38 that is, in turn, supported by horizontal base 30 of frame 14. [0035] Sonotrode 22 is configured to be actuated to deliver ultrasonic energy to a sheet 42 of polymer when the sheet is disposed between the sonotrode and tool 18 and in contact with the tool. For example, FIG. 1 depicts sheet 42 with a first side 46 facing tool 18, and a second side 50 facing sonotrode 22. As is known in the art of ultrasonic embossing, sonotrodes often includes a stack of piezoelectric transducers attached to a metal end effector. An alternating current oscillating at an ultrasonic frequency is applied by a power supply to the piezoelectric transducers and the current causes the piezoelectric transducers to expand and contract. The frequency of the applied current is typically selected to be the resonant frequency of the sonotrode and/or the tool, such that the entire sonotrode acts as a half-wavelength resonator, vibrating lengthwise with standing waves at the resonant frequency. Frequencies typically used with ultrasonic sonotrodes can range from 20 kilohertz (kHz) to 70 kHz. The amplitude of the vibration is often in the range of about 13 μπι to 130 μπι. While these characteristics are typical of sonotrodes in general, the term "sonotrode" is not limited to these characteristics and is used in this disclosure more-generally to denote a tool that generates ultrasonic vibrations and applies the generated vibrational energy to a material (e.g., sheet 42). [0036] At least one of tool 18 and sonotrode 22 is movably coupled to frame 14 (e.g., via actuator 26), and actuator 26 is configured to reduce a distance between the tool and the sonotrode to compress a sheet (e.g., sheet 42) such that polymer of the sheet flows into cavities of the tool until the polymer substantially fills the cavities to form a plurality of solid microneedles on first side 46 of the sheet, as shown on the right (in the orientation of FIG. 1) side of tool 18 in FIG. 1. For example, in the embodiment shown, tool 18 and anvil 38 are coupled in fixed relation to frame 14, and sonotrode 22 is coupled to actuator 26 which is, in turn, coupled in fixed relation to the frame. As such, in the depicted configuration, the actuator is configured to move sonotrode 22 up and down (in the orientation of FIG. 1) to compress the sheet between the tool and the sonotrode. As described in more detail below, tool 18 defines a plurality of cavities defining inverse microneedles such that as the sonotrode applies ultrasonic energy and the sheet is compressed, portions of the polymer at the first side of the sheet melt and flow into the cavities to define solid microneedles.

[0037] While the foregoing components are sufficient to form solid microneedle arrays and perform at least some of the present methods, the embodiment of system 10 depicted in FIG. 1 also includes a dispenser spindle 54 coupled to frame 14 on a first (e.g., left, in the orientation of FIG. 1) side of sonotrode 22, and a receiver spindle 58 coupled to the frame on a second (e.g., right, in the orientation of FIG. 1) side of the sonotrode. Dispenser spindle 54 is configured to rotatably support a dispenser roll 62 of a sheet of polymer (e.g., sheet 42). Receiver spindle 58 is configured to rotatably support a receiver roll 66 to receive portions of the sheet of polymer (e.g., sheet 42) having microneedles after the portions are unrolled from the dispenser roll and compressed between the sonotrode and the tool to define microneedles on a first side of the polymer sheet. For example, in the embodiment shown, sheet 42 includes a plurality of portions 70 that have been compressed between tool 18 and sonotrode 22 and therefore each such portion 70 includes an array 74 of microneedles on first side 46 of the sheet.

[0038] Referring now to FIGS. 2A-2C; FIGs. 2A and 2B show perspective and top views, respectively, of a tool 18a for use in system 10 of FIG. 1 (e.g., in place of tool 18 in FIG. 1); and FIG. 2C shows an enlarged cutaway view of tool 18a showing a single cavity in a lateral side of one lamina of the tool. As shown, tool 18a has a proximal surface 100 and comprises a plurality of laminae 104a, 104b, 104c, 104d, 104e, 104f that cooperate to define both the proximal surface and a plurality of cavities 108 that are open at the proximal surface. In the embodiment shown, each of cavities 108 extends from a base 112 at proximal surface 100 to a distal end 116 within the tool to define a negative or female mold for a microneedle (e.g. , define an inverse microneedle). As also shown, base 112 of each of cavities 108 has a cross-sectional area that is larger than a cross-sectional area of its distal end 116. In this embodiment, each cavity 108 has a pyramid shape. While shown here with triangular bases, and as also discussed below, the cavities can have other shapes, such as, for example, rhomboid, circular, oval, rectangular, and/or the like. [0039] In the embodiment of FIGS. 2A-2C, each of laminae 104a-104f has a proximal side 120 that cooperates with the proximal sides of the other laminae to define proximal surface 100 (e.g., a substantially planar and/or substantially continuous surface 100) of tool 18a when the laminae are combined as shown, a first lateral side 124 intersecting the proximal side along a first edge 128, and a second lateral side 132 intersecting the proximal side along a second edge 136 opposite the first edge.

[0040] As shown, each of a majority of the laminae defines a plurality of first recesses 140. In particular, all but one of the laminae (i.e., each of laminae 104b-104f) define a plurality of first recesses 140. For example, in the depicted embodiment, each of first recesses 140 extends into its respective lamina through the proximal side and first lateral side 124 such that the recess defines: (1) at proximal side 120 of the lamina, a portion of base 112 of the cavity; and (2) at first lateral side 124 of the lamina, at least a portion of distal end 116 of the cavity. The other lamina 104a does not include recesses 140— i.e., both of lateral sides 124 and 132 of lamina 104a are substantially planar. As shown, laminae 104a-104f are coupled together such that their proximal sides cooperate to define proximal surface 100 of the tool, and the first lateral side of each of the majority of the laminae is adjacent to the second lateral side of another one of the laminae. In this "stacked" configuration, second lateral side 132 of each of laminae 104a-104e cooperates with recesses 140 in first lateral side 124 of the adjacent one of laminae 104b-104f to define cavities 108.

[0041] As labeled in FIG. 2A, each recess 140 (and corresponding cavity 108) has a base width 144 measured at proximal side 120 along edge 128 of the corresponding lamina {e.g., 104b), and a base depth 148 measured perpendicular to first lateral side 124. In this embodiment, in which each recess 140 (and corresponding cavity 108) has a triangular base 112, base 112 is defined by width 144 and depth 148. As also labeled in FIG. 2A, each recess 140 (and corresponding cavity 108) also has a height 152.

[0042] Laminae 104a-104f can be secured relative to one another in any suitable fashion or by any suitable structure that permits tool 18a to function as described in this disclosure. For example, laminae 104a-104f may be secured together by one or more mechanical clamps and/or anvil 26 may include a recess with tight enough physical tolerances relative to tool 18a {e.g., with an interference fit between laminae 104a-104f and the surfaces of anvil 26 defining the recess) that the dimensions of the recess itself cause the laminae to be retained in the recess and secured relative to one another.

[0043] In the embodiment of FIGS. 2A-2C, lateral sides 120 and 128 of adjacent ones of laminae 104a-104f are parallel to each other. In other embodiments, lateral sides 120 and 128 of adjacent ones of the laminae may have complementary tapers in horizontal and/or vertical directions.

[0044] As will be appreciated by those of ordinary skill in the art, laminae 104a-104f may comprise any material that is suitably rigid and durable to function as described in this disclosure {e.g., to survive the pressures and temperatures of ultrasonic embossing of at least one polymer for which the tool is designed to function). Examples of such materials include metals and metal alloys, such as, for example, steel, aluminum, and alloys thereof. Recesses 140 may, for example, be defined in a lamina (e.g., a steel lamina) by mechanical structuring or by a process known as "LIGA." Mechanical structuring can include techniques such as electrical discharge machining (EDM), laser percussion drilling, micro miling, and/or micro grinding. "LIGA" refers to a German-derived acronym for a process termed "Lithographie, Galvanoformung, Abformung," which involves: (1) lithography of a polymer material to define the basic structure of the laminae; (2) electroplating to cover the polymer with a metal layer; and (3) replication, in which the electroplated piece is placed into an injection mold or hot-embossing mold to replicate the negative structure.

[0045] Referring now to FIGSs. 3A and 3B, perspective and top views, respectively, are shown of another tool 18b for use in place of tool 18 in system 10 of FIG. 1. Tool 18b is substantially similar to tool 18a in many respects. For example, tool 18b also has a proximal surface 200 and comprises a plurality of laminae 204a, 204b, 204c, 204d, 204e, 204f that cooperate to define both the proximal surface and a plurality of cavities 208 that are open at the proximal surface. By way of further example, each of cavities 208 extends from a base 212 at proximal surface 200 to a distal end 216 within the tool to define a negative or female mold for a microneedle (e.g., define an inverse microneedle), and base 212 of each of cavities 208 also has a cross-sectional area that is larger than a cross-sectional area of its distal end 216. Likewise, each cavity 208 has a pyramid shape. As yet a further example, each of laminae 204a-204f has a proximal side 220 that cooperates with the proximal sides of the other laminae to define proximal surface 200 (e.g., a substantially planar and/or substantially continuous surface 100) of tool 18a when the laminae are combined as shown. Given these similarities, the differences in tool 18b relative to tool 18a will primarily be described here.

[0046] Broadly, base 212 of each of cavities 208 has a rhomboid shape rather than a triangular shape. Additionally, each of cavities 208 is defined by two recesses 140, one of which is defined in each of two adjacent laminae. More particularly, as with tool 18a, each of laminae 204a-204f has a first lateral side 224 intersecting the proximal side along a first edge 228, and a second lateral side 232 intersecting the proximal side along a second edge 236 opposite the first edge. As shown, each of a majority of the laminae defines a plurality of first recesses 140 on both of their respective lateral sides. In particular, all but two of the laminae (i.e., each of laminae 104b-104e) define a plurality of first recesses 140 on their respective first lateral sides 224 and a plurality of second recesses 140 on their respective second lateral sides 232. Recesses 140 in the laminae of tool 18b are substantially similar to recesses 140 in the laminae of tool 18a, with the exception that the second recesses (140) in second lateral sides 232 are mirror images of (i.e., symmetrical to) the first recesses (140) in first lateral sides 224. As such, each of the second recesses (140) in second lateral sides 232 extends into the respective lamina through the proximal side (220) and second lateral side 232 such that each second recess 140 defines: at proximal side 220 of the lamina, a portion of base 212 of a cavity; and at second lateral side 232 of the lamina, at least a portion of distal end 216 of a corresponding cavity 208. The other two laminae— 204a and 204f— include recesses (140) on only one lateral side. Specifically, lamina 204f includes a plurality of first recesses (140) on its first lateral side 224, and lamina 204a includes a plurality of second recesses (140) on its second lateral side 232. [0047] As shown, laminae 204a-204f are coupled together such that their proximal sides cooperate to define proximal surface 100 of the tool, and the first lateral side of each of the majority of the laminae is adjacent to the second lateral side of another one of the laminae. In this "stacked" configuration, the first recesses (140) on first lateral sides 224 are each aligned with one of the second recesses (140) on second lateral sides 232 of adjacent laminae to define cavities 208.

[0048] In some embodiments, the tool can be configured to form a rectangular and/or square array of microneedles in which microneedles are arranged in 5 to 150 rows (e.g., greater than any one of, or between any two of: 5, 10, 15, 20, 25, 50, 75, 100, 125, and/or 150 rows), with each row including 5 to 150 microneedles (e.g., greater than any one of, or between any two of: 5, 10, 15, 20, 25, 50, 75, 100, 125, and/or 150 microneedles). In such arrays, the rows can be spaced at intervals of 40 μπι to 1,000 μπι; for example, at equal or differing intervals.

[0049] Referring now to FIGs. 4A and 4B, perspective and side views, respectively, are shown of a microneedle 300 that can be formed with system 10 of FIG. 1 and, in particular, tool 18b of FIGs. 3 A and 3B. As shown, microneedle 300 is shaped as a pyramid and has a base 304 and tip 308. In this embodiment, base 304 has a rhomboid cross-sectional shape with a primary maximum transverse dimension 312 and a secondary maximum transverse dimension 316 measured perpendicular to primary maximum transverse dimension 312. Microneedle 300 also has a height 320 that is measured perpendicular to both of the primary and secondary maximum transverse dimensions (312 and 316) of base 304. Height 320 of microneedle 300 is from 200 μπι to 1,100 μπι (e.g., from 400 μπι to 1,000 μπι, or from 400 μπι to 800 μιη).

[0050] In some embodiments of microneedle 300, height 320 is from one (1) to five (5) times primary maximum transverse dimension 312 (e.g., a height 320 of 1,000 μιη and a primary maximum transverse dimension 312 from 200 μιη to 1,000 μπι, inclusive of 200 μιη and 1,000 μιη). In some such embodiments, height 320 is from two (2) to four (4) times primary maximum dimension 312 (e.g., a height of 1,000 μιη and a primary maximum dimension 312 from 250 μιη to 500 μιη. Of course, cavities 208 would have similar ratios and/or dimensions in embodiments of tool 18b configured to form or manufacture microneedles 300 with such ratios and/or dimensions.

[0051] In some embodiments, height 320 is from one (1) to five (5) times secondary maximum transverse dimension 316 (e.g., a height 320 of 1,000 μπι and a secondary maximum transverse dimension 316 from 200 μπι to 1,000 μπι, inclusive of 200 μπι and 1,000 μπι). In some such embodiments, height 320 is from two (2) to four (4) times secondary maximum dimension 316 (e.g., a height of 1,000 μπι and a secondary maximum dimension 316 from 250 μπι to 500 μπι. Of course, cavities 208 would have similar ratios and/or dimensions in embodiments of tool 18b configured to form or manufacture microneedles 300 with such ratios and/or dimensions. In one particular example, primary maximum transverse dimension 312 is 170 μπι, secondary maximum transverse dimension 316 is 120 μπι, and height 320 is 250 μπι.

[0052] In the microneedle configuration shown in FIGs. 4A and 4B, the pyramid shape of microneedle 300, like the pyramid shape of cavity 208 in FIGs. 3A and 3B, is defined by four planar surfaces. In other configurations, however, the present microneedles can have any suitable outer surface profile or shape. For example, outer surfaces may be curved and/or curvilinear (e.g., concave to result in a relatively sharper tip 308 and/or blade(s) along the vertices along which the outer surfaces of the microneedle meet one another. In yet further configurations, the present microneedles (and cavities for forming such microneedles) can have any suitable shape that permits the microneedle to puncture a patient's skin as contemplated by this disclosure. For example, the present microneedles and cavities (e.g. , inverse microneedles) can be or comprise: a stepped pyramid, a prism, a cone, a half cone, a stepped cone, a frustum, a standard bevel, short bevel or true short bevel hypodermic shape, a trilobal shape, obelisk, beveled cylinder, and/or the like.

[0053] Ultimately, the shape of the present microneedles and corresponding cavities are not particularly limited, but certain considerations may guide selection and optimization of different shapes. For example, the shape of the cavity may impact the ability to manufacture molds. Additionally, the shape of the cavity may impact the ease with which a microneedle array can be separated from a tool or mold after the polymer solidifies (e.g., the ease or lack thereof with which the microneedles can be removed from the cavities). For example, draft angles in the mold greater than 0.5 degrees may facilitate removal of a molded microneedle array from a mold. Additionally, the shape of the microneedle can impact the ability of the microneedle to puncture a patient' s skin and/or deliver or extract fluids. For example, a microneedle must be strong enough to pierce the patient' s skin and, while a broader base may result in a stronger microneedle, the increased angles of the sides of such a microneedle (with a broader base) may cause relatively greater trauma to the patient' s skin. Thus, the aspect ratios discussed in this disclosure are selected to result in microneedles with tips that are sharp enough to puncture a patient's skin with relatively low force, while causing minimal disruption to the surface of the patient' s skin (e.g., the stratum corneum).

[0054] Various embodiments of the present microneedles and arrays of microneedles can comprise and/or be formed from or of one or more of: liquid-crystal polymer (LCP), polyether ether ketone (PEEK), fluorinated ethylene propylene (FEP), polysulfone (PSU), polyethylenimine (PEI), polyimide (PI), polycarbonate (PC), polycarbonate copolymer (PC COPO), cyclic olefin copolymer (COC), cyclo olefin polymer (COP), polyamide (PA), acrylonitrile butadiene styrene (ABS), and polyphenylene ether (PPE).

[0055] Referring now to FIG. 5, a flowchart illustrates an embodiment 400 of the present methods of manufacturing a microneedle array (e.g., using system 10 of FIG. 1). At its most basic, method 400 comprises: · a step 404 of disposing a sheet (e.g., 42) of polymer between a sonotrode (e.g., 22) and a proximal surface (e.g., 100) of a tool (e.g., 18b) such that a first side (e.g., 46) of the sheet contacts the proximal surface (e.g., 100) of the tool;

• a step 408 of delivering ultrasonic energy from the sonotrode (e.g., 22) to the sheet (e.g., 42) such that a temperature of the first side (e.g., 46) of the sheet increases above the polymer's glass transition temperature; and

• a step 412 of compressing the sheet (e.g., 42) between the sonotrode (e.g., 22) and the tool (e.g., 18b)— for example by using an actuator (e.g., 26) to reduce the distance between the sonotrode and the tool, such as by moving the sonotrode down toward the tool— such that polymer of the sheet (e.g., 42) flows into the cavities (e-g-, 208) until the polymer substantially fills the cavities to form a plurality of solid microneedles (e.g., 300) on the first side of the sheet.

[0056] In the embodiment of FIG. 5, method 400 also includes the following optional steps corresponding to a roll-to-roll approach as described above:

• a step 416 of unrolling the sheet of polymer from a dispenser roll (e.g., 62), prior to disposing the sheet between the sonotrode and the tool; and

• a step 420 of rotating a receiver roll (e.g., 66) to move a first portion of the sheet away from the tool (and sonotrode).

With these optional steps, and as shown in FIG. 1, a first end of the sheet (e.g., 42) of polymer may be wrapped around the dispenser roll (e.g., 62) on a first side of the tool, a second end of the sheet (e.g., 42) of polymer is coupled to a second roll (e.g., 66) on a second side of the tool. Additionally, in such a roll-to-roll approach, steps 404 (disposing), 408 (delivering), and 412 (compressing) can be performed on the first portion of the sheet, prior to step 420 (if any) of rotating the receiver roll to move the first portion away from the tool. Additionally, and also prior to step 420 (if any), the first portion of the sheet of polymer can be separated from the tool after all of the first portion of the sheet has cooled to a temperature below the polymer' s glass transition temperature. Once the first portion of the sheet of polymer has been moved away from the tool and sonotrode, steps 404 (disposing), 408 (delivering), and 412 (compressing) can be repeated on a second and subsequent portions of the sheet of polymer to form one or more microneedle arrays extending along the length of the sheet of polymer (e.g., a plurality of distinct microneedle arrays extending along a portion of the length of the sheet of polymer, or a single array of microneedles extending along a portion of the length of the sheet of polymer).

[0057] One product or article of manufacture that can be formed from the present methods is a layer of polymer (e.g., 42) having a first side (e.g., 46) and an opposing second side (e.g., 50), with the polymer defining a plurality of solid microneedles (e.g., 74) on the first side of the layer, each microneedle having a distal end and a base between the distal end and the second side of the layer, the base of each of the microneedles having a cross-sectional area larger than that of the respective distal end; where the layer of polymer is rolled (e.g., around receiver roll 66). In some embodiments of such products, and as also shown in FIG. 1, the first side of the polymer sheet and microneedles (e.g., 74) extend radially outward. Such a polymer layer can have a width of 25 centimeters (cm) to 200 cm (e.g., greater than any one of, or between any two of: 25, 50, 75, 100, 125, 150, 175, and/or 200).

[0058] FIG. 6 is a schematic view of a second embodiment 10a of the present systems for manufacturing a microneedle array. System 10a is substantially similar to system 10 (FIG. 1) in many respects, and similar reference numerals are used to denote elements in system 10a that are similar to corresponding elements in system 10. As such, the differences in system 10a relative to system 10 will primarily be described here. The primary difference is that system 10a is configured to form a layer of polymer with one or more microneedle arrays from a plurality of sheets of polymer source material. More specifically, system 10 includes two dispenser rolls: a first dispenser roll 62 rotatably supported by first dispenser spindle 54 and a second dispenser roll 500 rotatably supported by a second dispenser spindle 504. Second dispenser roll 500 carries a second sheet 508 of polymer material that is disposed between sonotrode 22 and tool 18 simultaneously with first sheet 42. [0059] In the depicted embodiment, system 10a also includes an alignment pulley 512 that is aligned with the path the sheets (54 and 508) take between sonotrode 22 and tool 18, as shown, and a plurality of intermediate pulleys 516 to deliver the sheets (54 and 508) to the alignment pulley (512) under sufficient tension to maintain the orderly delivery of the sheets to the position between the sonotrode 22 and tool 18. [0060] In system 10a, the sonotrode is configured to melt (raise the temperature above the polymer's glass transition temperature) both portions of sheets 54 and 508 at the interface between the sheets and at the interface between first sheet 42 and tool 18, such that when the sheets are compressed between the sonotrode and the tool, the polymer both flows into the cavities of the tool to define microneedles and merges the sheets with one another (i.e., such that the polymer of first sheet 42 commingles with the polymer of second sheet 508, as indicated on the right side of tool 18.

[0061] When method 400 is performed with system 10a, both sheets (42 and 508) of polymer are disposed between the sonotrode (e.g., 22) and tool (e.g., 18b), prior to delivering the ultrasonic energy, such that a first side (e.g., 520) of the second sheet (e.g., 508) contacts a second side (e.g., 50) of the first sheet, and a second side (e.g., 524) of the second sheet contacts the sonotrode. As noted above, in this configuration, the ultrasonic energy is then delivered such that respective temperatures of second side 50 of the first sheet and first side 520 of the second sheet both increase above their respective polymer's glass transition temperatures, and the first and second sheets (42 and 508) are both compressed between the sonotrode and the tool such that polymer of the first sheet commingles with polymer of the second sheet.

[0062] In some such embodiments with multiple sheets of polymer material, the sheets can have different properties. For example, the first sheet (e.g. , 42) closest to the tool can be harder than the other sheet(s), such that the first sheet forms the outermost surfaces of the microneedles and protects the other layers after the microneedles are formed. Such a difference can be beneficial in providing microneedles with relatively harder and more-durable outer surfaces, while potentially reducing costs by avoiding the need to provide harder (and potentially more- expensive) polymer materials in other sheets or sublayers.

[0063] The above specification and examples provide a complete description of the structure and use of illustrative embodiments. Although certain embodiments have been described above with a certain degree of particularity, or with reference to one or more individual embodiments, those skilled in the art could make numerous alterations to the disclosed embodiments without departing from the scope of this invention. As such, the various illustrative embodiments of the methods and systems are not intended to be limited to the particular forms disclosed. Rather, they include all modifications and alternatives falling within the scope of the claims, and embodiments other than the one shown may include some or all of the features of the depicted embodiment. For example, elements may be omitted or combined as a unitary structure, and/or connections may be substituted. Further, where appropriate, aspects of any of the examples described above may be combined with aspects of any of the other examples described to form further examples having comparable or different properties and/or functions, and addressing the same or different problems. Similarly, it will be understood that the benefits and advantages described above may relate to one embodiment or may relate to several embodiments.

[0064] The claims are not intended to include, and should not be interpreted to include, means-plus- or step-plus-function limitations, unless such a limitation is explicitly recited in a given claim using the phrase(s) "means for" or "step for," respectively.