WO2019082099A1

WO2019082099A1 - Methods and systems of producing microneedle arrays

Info

Publication number: WO2019082099A1
Application number: PCT/IB2018/058299
Authority: WO
Inventors: Johannes DE BROUWER; Herwig JUSTER
Original assignee: Sabic Global Technologies B.V.
Priority date: 2017-10-24
Filing date: 2018-10-24
Publication date: 2019-05-02

Abstract

This disclosure includes methods and systems for manufacturing an array of microneedles using embossing, as well as articles of manufacture formed by such methods and systems. The present methods and systems utilize tools including multiple belts in which at least one belt includes inverse microneedle cavities configured to permit a polymer to substantially fill the cavities to form microneedles of the array.

Description

METHODS AND SYSTEMS OF PRODUCING MICRONEEDLE ARRAYS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U. S. Provisional Patent Application No. 62/576,294 filed October 24, 2017, which is hereby incorporated by reference in its entirety.

FIELD OF INVENTION

[0002] The present disclosure relates generally to microneedle arrays, and, but not by way of limitation, to methods and systems for producing and using microneedles, such as microneedles formed from a multilayer polymer using an embossing technique.

BACKGROUND

[0003] Health and wellness monitoring of a patient often requires sampling fluid (e.g., blood or interstitial fluid). For example, individuals with diabetes often use a lancing device to puncture tissue and draw blood provided to a test device, such as a blood glucose meter. As another example, a syringe is used to acquire fluid from a patient. Depending on an individual's health, multiple fluid samples may be acquired per day and, in severe situations, continuous sampling and monitoring may be warranted. Frequent or continuous sampling and monitoring is often painful, uncomfortable (e.g., causes skin sensitivity), and inconvenient.

[0004] A microneedle array has potential to provide a pain-free or reduced-pain alternative to a syringe for sampling fluid from a patient for testing (e.g., blood glucose level, insulin level, medication level, etc.). Microneedles can be virtually painless because they do not penetrate deep enough to contact nerves and are typically limited to penetration of the outermost layer of the skin, unlike traditional syringes and hypodermic needles. Additionally, a more-shallow penetration may also reduce the risk of infection or injury. Microneedles may also facilitate delivery of a more precise dosage of a therapeutic which enables the use of lower doses in treatments. 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.

[0005] While there are a number of benefits to the use of microneedles and considerations with respect to forming them, certain challenges remain in microneedle production, such as challenges related to production of microneedle arrays at sufficient scale and efficiency such that they are cost effective. For example, given the relatively small sizes of microneedles and features of the microneedles, expensive production processes are needed. To illustrate, to have proper transcription of mold texture and shape to the molded part of a microneedle array, high flow may be necessary, especially having low viscosity at extremely high shear rates. Furthermore, good release from the production mold is important to reduce cycle time to improve the cost efficiency. The needles formed therefrom should exhibit good strength to prevent breaking of the microneedle during usage. Additionally, microneedles need to have a combination of properties for different phases of use. For example, microneedles need to have an aspect ratio and overall dimensions to obtain a sharp tip and a sharp blade to cut the skin, and length to penetrate the skin sufficiently. As another example, microneedles need to have mechanical and chemical properties to be able to withstand manufacturing and handling processes, tolerate (without degradation) interactions with therapeutic drugs, and functionally need to penetrate tissue (tip and cutting surface), remain in tissue, removed from tissue, and be handled before and after insertion, all without breaking.

[0006] Continuous hot embossing is a conventional technique for molding a film of thermoplastic to generate for surface effects and features with a low aspect ratio (low feature height relative to feature width/base), such as light reflecting prisms. For example, U.S. Pat. No. 4,601,861 describes a continuous hot embossing device that uses a large circular mold that includes "inverse" microstructures to be embossed onto a first film of thermoplastic material. As described in U.S. Pat. No. 4,601,861, the large circular mold is used to heat the first film its glass transition temperature (Tm) and to emboss microstructures (based on the "inverse microstructures of the mold) onto the film. Additionally, a second "unprocessed" film is in direct contact with the first "processed" film to allow a set of small rolls to apply pressure on the heated first film to enable replication of the microstructures on the first film. However, such a device has limitations for producing features (e.g., micro structures) with high aspect ratios (high feature height relative to feature width/base). For example, feature aspect ratios are limited by the curvature of the mold and increasing the size of the circular mold to reduce/minimize the curvature results in an impractical mold design and dimensions. Additionally, the continuous hot embossing device uses relatively thick films and sheets that, when cooled, do not bend easily without damage.

[0007] Another example of a continuous embossing technique is described in U.S. Pat. No. 6,908,295 in which a thermoplastic material is feed between two parallel bands, one of which includes an inverse topology of a microstructure surface to be formed on the thermoplastic material. As described in U.S. Pat. No. 6,908,295, the parallel bands are used to form a retroreflective pattern films, a substrate including recesses, and microstructures (e.g., a microfluidic channel) for microfluidic devices. U.S. Patent No. 6,908,295 does not describe use of the parallel bands to form microneedles or to form features (e.g., micro structures) having high aspect ratios (high feature height relative to feature width/base). Thus, neither U.S. Pat. No. 4,601,861 or U.S. Patent No. 6,908,295 address forming high aspect ratio microstructures, such as microneedles, or overcoming the known and longstanding problems of forming high aspect ratio microstructures, such as demolding-related defects (e.g., broken and/or distorted features).

[0008] 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" molds each defining a microneedle. Stated another way, the mold defines a plurality of "inverse" microneedles. For example, U.S. Pat. No. 9,289,925 discloses a method of manufacturing hollow microneedles via injection molding. However, such injection molding is challenging. For example, it 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.

SUMMARY

[0009] The present disclosure describes systems and methods for manufacturing the present microneedle arrays having the desired varying aspect ratio, strength, and mechanical performance sufficient to provide a sharp tip among the microneedles and/or a sharp blade to properly penetrate or cut the skin. For example, the microneedle arrays can be manufactured using an embossing process (e.g., a dual band process) such that the microneedles have acceptable aspect ratios for use and are free of demolding-related defects (e.g., broken and/or distorted features).

[0010] Systems and methods of the present disclosure include a first belt and a second belt positioned relative to the first belt. The first belt has a molding surface associated with a negative image of a microneedle shape and the second belt has a pressing surface configured to face the molding surface of the first belt. To illustrate, in one example, the first belt can be positioned relative to second belt such that molding surface contacts a first side of a sheet (of polymer) and the pressing surface is configured to contact a second side of the sheet. The molding surface may define a plurality of cavities and each of the cavities can extend from a base at molding surface to a distal end within first belt to define a negative mold of a microneedle. Each cavity may include a characteristic selected from the group consisting of: a depth from 400 micrometers (μπι) to 1,000 μπι, a tip having a radius of curvature of less than or equal to 25 μπι, a cavity base having a cross-sectional area larger than that of the respective distal end, and an aspect ratio of the depth to a transverse dimension of the cavity base of greater than or equal to 1. Additionally, or alternatively, in some implementations, the cavity base of each cavity is entirely surrounded by a perimeter lying in a single plane, and/or each cavity has a depth that is greater than or equal to 1000 μπι. In a particular implementation, the aspect ratio (of the cavity) is greater than or equal to 2. The base of each of the cavities includes a primary maximum transverse dimension measured in a first direction, and a secondary maximum transverse dimension measured in a second direction that is perpendicular to the first direction. The transverse dimension of the aspect ratio (of the cavity) can include the primary or secondary maximum transverse dimension or another transverse dimension of the base of the cavity (e.g., a minimum transverse dimension of the base).

[0011] In a particular implementation of the first belt, each of the cavities includes: a cavity base having a cross-sectional area larger than that of the respective distal end, and a tip at the distal end having a radius of curvature of less than or equal to 25 μπι. In such implementations, each of the cavities has an aspect ratio of a depth of the cavity to a transverse dimension of the cavity base of greater than or equal to 1, the cavity base of each cavity is entirely surrounded by a perimeter lying in a single plane, and/or each cavity has a depth is greater than or equal to 1000 μπι. In another particular implementation of the first belt, each of the cavities includes a depth from 400 μπι to 1,000 μπι, a tip having a radius of curvature of less than or equal to 25 μπι, a cavity base having a cross-sectional area larger than that of the respective distal end, and an aspect ratio of the depth to a transverse dimension of the cavity base of greater than or equal to 2.

[0012] Hot embossing according to the systems and methods (utilizing a first belt and a second belt positioned relative to the first belt) of the present disclosure may be used as a cost effective (e.g., low cost) process for mass production and large area texturing of geometrically accurate, defect free microneedle structures (e.g., a microneedle array). Additionally or alternatively, systems and methods described herein allow arrays (e.g., large arrays) of microneedles to be manufactured more rapidly than prior art methods. As another result, microneedle arrays formed with the present systems and methods need not be singular, discrete arrays, but can instead include one or more arrays extending along an elongated multilayer sheet of polymer. For example, a multilayer sheet of polymer with a length that is five or more times its width can have multiple microneedle arrays extending along a majority of its length.

[0013] The present disclosure also includes a microneedle array manufactured by the systems and/or methods of the present disclosure. Microneedle arrays of the present disclosure formed from one or more sheets (each having one or more layers) have microneedles with sharp tips to penetrate dermal surfaces (while still maintaining the benefit of being relatively pain free) and that maintain their structural integrity and strength during use. Dimensions of the microneedles (and/or the array of microneedles) may correspond to or be based on dimension of the first belt, such as dimensions of the cavities of the first belt. To illustrate, each microneedle may include a characteristic selected from the group consisting of: a tip having a radius of curvature of less than or equal to 25 μπι, a needle base of each of the microneedles surrounded entirely by a perimeter lying in a single plane, a height extending from the needle base to a distal end of the microneedle and that is from 400 μπι to 1,000 μπι, and an aspect ratio of the height to a transverse dimension of the needle base of greater than or equal to 1. In some implementations, the aspect ratio (of the microneedle) is greater than or equal to 2 and/or the radius of curvature is less than or equal to 15 μπι. Additionally, or alternatively, the base of each of the microneedles includes a primary maximum transverse dimension measured in a first direction, and a secondary maximum transverse dimension measured in a second direction that is perpendicular to the first direction. The transverse dimension of the aspect ratio (of a microneedle) includes the primary maximum transverse dimension, the secondary transverse dimension, or another transverse dimension of the base of the microneedle (e.g., a minimum transverse dimension of the base).

[0014] In a particular implementation of a microneedle array, each of the microneedles include: a needle base having a cross-sectional area larger than that of the respective distal end, and a tip at the distal end having a radius of curvature of less than or equal to 25 μπι. In such implementations, each of the microneedles has an aspect ratio of a height of the cavity to a transverse dimension of the needle base of greater than or equal to 1, a needle base of each of the microneedles surrounded entirely by a perimeter lying in a single plane, and/or each microneedle has a height that is greater than or equal to 1000 μπι. In another implementation, each of the microneedles includes a tip having a radius of curvature of less than or equal to 25 μηι, a needle base of each of the microneedles surrounded entirely by a perimeter lying in a single plane, a height extending from the needle base to a distal end of the microneedle and that is from 400 μιη to 1,000 μπι, and an aspect ratio of the height to a transverse dimension of the needle base of 2 or greater.

[0015] In various aspects, the microneedle array described herein have advantageous aspect ratios— i.e., with both a large-enough base to ensure stability and durability and a length long enough to penetrate deep enough into tissue— to provide a pain-free or reduced-pain alternative to a syringe. The microneedle array also exhibits both hardness and toughness that may be lacking in conventional microneedle arrays and individual microneedles have a sharp-enough blade and/or tip to effectively cut into skin. Additionally, or alternatively, the microneedle array provides resistance (e.g., does not degrade) to handling and environmental conditions, and provides sufficient hardness for microneedle use (e.g., being inserted into the biological barrier, remaining in place for up to a number of days, and being removed) while also enabling an appropriate amount of bending without breakage of the microneedles and with restriction of permanent deformation of the needles restricted limited. Additionally, in some implementations, the microneedle arrays possess a chemical resistance that fulfill regulatory critical to quality (CTQ) requirements, such that there is minimal or no chemical reaction among an active ingredient of a therapeutic, a carrier/coating, and/or the polymer forming the microneedle structures during production, sterilization, storage, and/or during the use of the microneedle array.

[0016] Some embodiments of the present methods (e.g., of manufacturing a microneedle array) comprise: disposing a sheet of polymer between a first and second belt such that a first side of the sheet contacts the first belt and a second side of the sheet faces the second belt, the first belt having a molding surface configured to contact the first side, the molding surface defining a plurality of cavities, each of the cavities extending from a cavity base at the molding surface to a distal end of the cavity within the first belt to define a negative mold of a microneedle, the cavity base of each of the cavities having a cross-sectional area larger than that of the respective distal end; heating a portion of the first belt such that a temperature of the first side increases above the polymer's glass transition temperature; and compressing the sheet between the first and second belt 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, with a needle base of each of the microneedles surrounded entirely by a perimeter lying in a single plane; where each of the microneedles comprises: a tip having a radius of curvature of less than or equal to 25 μιη; a height extending from the needle base to a distal end of the microneedle and that is from 400 μιη to 1,000 μιη; and an aspect ratio of the height to a transverse dimension of the needle base of greater than or equal to 2. In some such embodiments, the radius of curvature is less than or equal to 15 μιη.

[0017] In some of the foregoing embodiments of the present methods, the base of each of the microneedles comprises: a primary maximum transverse dimension measured in a first direction; and a secondary maximum transverse dimension measured in a second direction that is perpendicular to the first direction. In some such embodiments, the transverse dimension of the aspect ratio comprises the primary or secondary maximum transverse dimension.

[0018] In some of the foregoing embodiments of the present methods, the base of each of the microneedles has a primary maximum transverse dimension measured in a first direction, and each of the microneedles has a height extending from the needle base to the distal end of the microneedle that is from 1 to 5 times the primary maximum transverse dimension of the respective microneedle. In some such embodiments, each of the microneedles has a secondary maximum transverse dimension measured perpendicular to the first direction, and the ratio of the primary maximum transverse dimension to the secondary maximum transverse dimension is from 1 to 5.

[0019] In some of the foregoing embodiments of the present methods, the heating is performed by heating at least one of a plurality of first pressure plates between first and second pulleys within a loop of the first belt. In some such embodiments, the present methods further comprise cooling the first sheet by cooling at least one of the first pressure plates. In a particular embodiment, 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, polyetherimide, polyimide (PI), polycarbonate (PC), polycarbonate copolymer (PC COPO), cyclic olefin copolymer (COC), cyclo olefin polymer (COP), polyamide (PA), acrylonitrile butadiene styrene (ABS), polyphenylene ether (PPE), polymethylmethacrylate (PMMA), a biodegradable polymer and/or a copolymer of the biodegradable polymer, and a hydrogel forming polymer.

[0020] In some of the foregoing embodiments of the present methods, the sheet of polymer is a first sheet of polymer and the present methods further comprises: prior to compressing the first sheet, disposing a second sheet of polymer between the first sheet of polymer and the second belt 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 second belt. In some such embodiments, the heating is performed 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 first belt and the second belt such that polymer of the first sheet commingles with polymer of the second sheet.

[0021] Some embodiments of the present systems (e.g., for manufacturing a microneedle array from one or more sheets of polymer) comprise: a frame; a first belt movably coupled to the frame, the first belt having a molding surface defining a plurality of cavities, each of the cavities extending from a base at the molding surface to a distal end within the first belt to define a negative mold of a microneedle, each of the cavities comprises: a depth from 400 μπι to 1,000 μπι; a tip having a radius of curvature of less than or equal to 25 μπι; a cavity base having a cross-sectional area larger than that of the respective distal end; and an aspect ratio of the depth to a transverse dimension of the cavity base of greater than or equal to 2; a second belt having a pressing surface configured to face the molding surface of the first belt; a heater coupled to the first belt and configured to increase the temperature of a sheet of polymer in contact with the first belt above the polymer's glass transition temperature; where at least one of the belts is movable relative to the other to reduce a distance between the belts and compress the sheet between the first belt and the second belt to cause the polymer of the sheet to flow into the cavities until the polymer substantially fills the cavities to form a plurality of solid microneedles on a first side of the sheet.

[0022] In some of the foregoing embodiments of the present systems, the base of each of the cavities has a primary maximum transverse dimension measured in a first direction, and a height or depth 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 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.

[0023] In some of the foregoing embodiments of the present systems, the present systems further comprise: a first pulley and a second pulley spaced from the first pulley, where the first belt defines a continuous loop extending around the first and second pulleys; a third pulley spaced from the first pulley; and a fourth pulley spaced from each of the second and third pulleys, where the second belt defines a continuous loop that extends around the third and fourth pulleys. In some such embodiments, the present systems further comprise: a plurality of first pressure plates between the first and second pulleys within the loop of the first belt, each of the plurality of first pressure plates in contact with the first belt. In some embodiments, the present systems further comprise: a cooler configured to reduce the temperature of at least one of the first pressure plates and/or the second and/or third pulley(s); where the heater is disposed within, and configured to heat the sheet via, at least one of the first pressure plates and/or the first and/or third pulley(s).

[0024] Some embodiments of the present systems (e.g., for manufacturing a microneedle array from one or more sheets of polymer) comprise: a frame; a first belt movably coupled to the frame, the first belt having a molding surface defining a plurality of cavities, each of the cavities extending from a base at the molding surface to a distal end within the first belt to define a negative mold of a microneedle, each of the cavities a characteristic selected from the group consisting of: a cavity base that has a cross-sectional area larger than that of the respective distal end and that is entirely surrounded by a perimeter lying in a single plane; a tip at the distal end having a radius of curvature of less than or equal to 25 μπι; and an aspect ratio of the depth to a transverse dimension of the cavity base of greater than or equal to 1; a second belt having a pressing surface configured to face the molding surface of the first belt; a heater coupled to the first belt and configured to increase the temperature of a sheet of polymer in contact with the first belt above the polymer's glass transition temperature; where at least one of the belts is movable relative to the other to reduce a distance between the belts and compress the sheet between the belts to cause the polymer of the sheet to flow into the cavities until the polymer substantially fills the cavities to form a plurality of solid microneedles on the first side of the sheet, with a needle base of each of the microneedles surrounded entirely by a perimeter lying in a single plane.

[0025] In some of the foregoing embodiments of the present systems, the base of each of the cavities comprises: a primary maximum transverse dimension measured in a first direction; and a secondary maximum transverse dimension measured in a second direction that is perpendicular to the first direction; and the transverse dimension of the aspect ratio comprises the primary or secondary maximum transverse dimension. In some such embodiments, each cavity has a depth is greater than or equal to 1000 μπι, and the aspect ratio is greater than or equal to 2. [0026] As used herein, various terminology is for the purpose of describing particular implementations only and is not intended to be limiting of implementations. For example, as used herein, an ordinal term (e.g., "first," "second," "third," etc.) used to modify an element, such as a structure, a component, an operation, etc., does not by itself indicate any priority or order of the element with respect to another element, but rather merely distinguishes the element from another element having a same name (but for use of the ordinal term). 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" may 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. 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.

[0027] 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.

[0028] 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. Additionally, it will be understood that the term "wherein" may be used interchangeably with "where." 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. 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.

[0029] Some details associated with the embodiments are described above, and others are described below. Other implementations, advantages, and features of the present disclosure will become apparent after review of the entire application, including the following sections: Brief Description of the Drawings, Detailed Description, and the Claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0030] 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.

[0031] FIG. 1 is a schematic view of an example of a system for manufacturing a microneedle array.

[0032] 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.

[0033] FIG. 2C is a diagram that that illustrates a cross-section view of the tool of FIGS. 2 A and 2B taken along the line A- A of FIG. 2B

[0034] FIG. 2D is an enlarged cutaway view of the tool of FIGS. 2A and 2B, showing a portion of a single cavity.

[0035] FIGS. 3A and 3B are perspective and top views, respectively, of an example a microneedle that can be formed with the system of FIG. 1 and, in particular, the tool of FIGS. 2A-2D.

[0036] FIG. 4 is a diagram that illustrates examples of microneedle arrays.

[0037] FIG. 5 is a schematic view of another example of a system for manufacturing a microneedle array. [0038] FIG. 6 is a flowchart illustrating an example of a method of manufacturing a microneedle array.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0039] Referring to FIG. 1, a schematic view of an example of a system 100 for manufacturing a microneedle array from one or more polymer sheets is shown. For example, system 100 may be configured for use in an embossing process to form a microneedle array.

[0040] System 100 includes an apparatus 110 having a frame 114 configured to support one or more components of system 100. System 100 includes spindles 118 and pulleys 122 rotatably coupled to frame 114. Frame 114 may include any structure (e.g., individual beams and/or other elongated frame members) that supports a physical relationship of one or more components to enable operations described herein.

[0041] A dispenser roll 124 is coupled to frame 114 by a corresponding spindle 118 (e.g., a dispenser spindle) and includes a sheet 126, such as a sheet of one or more softened or molten polymer films. Sheet 126 includes a first side 128 (e.g., a first surface) and a second side 130 (e.g., a second surface). Dispenser roll 124 is configured to rotate about the first spindle to provide sheet 126 in a direction associated with arrow 132.

[0042] A tool 134 configured to emboss sheet 126 includes a first belt 136 and/or a second belt 138, each of which is movably coupled to frame 114. First belt 136 is coupled to a first pulley 140 (e.g., a cylinder or a drum) and a second pulley 142, defines a loop, such as a continuous loop, that extends around the first and second pulleys. Second belt 138 is coupled to a third pulley 144 and a fourth pulley 146, defines a loop, such as a continuous loop, that extends around the third and fourth pulleys. First belt 136 and/or second belt 138 may include a material that is suitably rigid and durable to function as described herein (e.g., for use at pressures and temperatures of embossing of sheet 126 for which tool 134 is designed to function). Examples of such materials include metals and/or metal alloys, such as steel, nickel, aluminum, a combination thereof, and/or the like, as illustrative, non-limiting examples. First belt 136 and/or second belt 138 may include a sheet, one or more laminae (e.g., a steel lamina) bound together, one or more links, or a combination thereof. Features, such as cavities, of belt 136 and/or belt 138 may be formed using one or more techniques, such as electrical discharge machining (EDM), laser percussion drilling, micro milling, 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.

[0043] Each of pulleys 140, 142, 144, 146 is configured to rotate about a corresponding rotational axis 148 (e.g., a spindle) coupled to frame 114. For example, first pulley 140 is configured to rotate bout its axis 148 in a direction indicated by arrow 150a, second pulley 142 is configured to rotate bout its axis 148 in a direction indicated by arrow 150b, third pulley 144 is configured to rotate bout its axis 148 in a direction indicated by arrow 150c, and fourth pulley 146 is configured to rotate bout its axis 148 in a direction indicated by arrow 150d.

[0044] Second pulley 142 is spaced from first pulley 140 by a first distance Dl in a first direction. Third pulley 144 is spaced from first pulley 140 by a second distance D2 in a second direction that is perpendicular to the first direction. As shown, Dl is greater than D2. Alternatively, in other implementations, Dl is less than or equal to D2. Fourth pulley 146 spaced from third pulley 144 by a third distance D3 in the first direction, and spaced from second pulley 142 by a fourth distance D4 in the second direction. As shown, D3 is greater than D4. Alternatively, in other implementations, D3 is less than or equal to D4. In a particular implementation of system 100, Dl is equal to D3, and D2 is equal to D4.

[0045] First belt 136 has a molding surface 154 (e.g., a proximal surface) associated with a negative image of a microneedle shape. For example, molding surface 154 may define a plurality of cavities and each of the cavities can extend from a base at molding surface 154 to a distal end within first belt 136 to define a negative mold of a microneedle. The base of each of the cavities can have a cross-sectional area larger than that of the respective distal end that corresponds to a tip of the microneedle. Aspects of first belt 136, including one or more dimensions related to the cavities, are described with reference to FIGS. 2A-2D.

[0046] Second belt 138 has a pressing surface 156 configured to face molding surface 154 of belt 136. To illustrate, belt 136 is positioned relative to belt 138 such that molding surface 154 is configured to contact side 128 (of 126) and pressing surface 156 is configured to contact side 130 (of 126). In some implementations, at least one of the belts (e.g., 136, 138) is movable relative to the other to reduce a distance between the belts and compress sheet 126 between belt 136 and belt 138 to cause a polymer of sheet 126 to flow into the cavities until the polymer substantially fills the cavities to form a plurality of solid microneedles (e.g., in which a needle base of each of the microneedles surrounded entirely by a perimeter lying in a single plane, and/or the perimeters of all of the microneedles lie in a single, common plane) on first side 128 of sheet 126. For example, as shown, belt 136 is movable with respect to belt 138 as indicated by double arrow 158.

[0047] A plurality of first pressure plates 160a, 160b is positioned between the first and second pulleys 140, 142 within the loop of first belt 136, and a plurality of second pressure plates 162a, 162b is positioned between third and fourth pulleys 144, 146 within the loop of second belt 138. When sheet 126 is positioned between belts 136, 138, each of first pressure plates 160a, 160b is configured to apply a force on first belt 136 in a direction towards sheet 126 (e.g., towards second belt 138), and each of second pressure plates 162a, 162b is configured to apply a force on second belt 138 in a direction towards sheet 126 (e.g., towards first belt 136). In some implementations, a position of each of pressure plates 160a, 160b, 162a, 162b is fixed, while in other implementations the position of the pressure plates is adjustable. Although each of the plurality of first pressure plates 160a, 160b and the second plurality of pressure plates 162a, 162b is described as having two pressure plates, in other implementations, the plurality of first pressure plates 160a, 160b and/or the plurality of second pressure plates 162a, 162b may include more than two pressure plates. Additionally, or alternatively, although the plurality of first and second pressure plates 160a, 160b, 162a, 162b is described as plates, in other implementations, the pressure plates may include other structures, such as rollers, cylinders, and/or drums, as illustrative, non-limiting examples.

[0048] One or more heaters 166a-166d may be coupled to tool 134 and may be configured to increase the temperature of sheet 126 (of polymer) in contact with first belt 136 and/or second belt 138 above the polymer's glass transition temperature. To illustrate, a first heater 166a is coupled to and/or disposed within pulley 140 and configured to heat at least a portion of belt 136 that is in contact with pulley 140. A second heater 166b is coupled to and/or disposed within at least one of the first pressure plates and is configured to heat sheet 126 by heating the at least one of the first pressure plates (e.g., a portion of first belt 136 that is in contact with the at least one of the first pressure plates). A third heater 166c is coupled to and/or disposed within pulley 144 and configured to heat at least a portion of second belt 138 that is in contact with pulley 144. A fourth heater 166d is coupled to and/or disposed within at least one of the second pressure plates and is configured to heat sheet 126 by heating the at least one of the second pressure plates (e.g., a portion of belt 138 that is in contact with the at least one of the second pressure plates). Although system 100 is described as including four heaters (e.g., 166a-166d), in other implementations, system 100 may include fewer (e.g., no heaters, a single heater, etc.) than or more than four heaters. In some implementations, the one or more heaters 166a-166d may include a heating element (e.g., a burden resistor) and/or a heating circulation system.

[0049] One or more coolers 168a-168d may be coupled to tool 134 and may be configured to decrease the temperature of sheet 126 (of polymer) in contact with first belt 136 and/or second belt 138 below the polymer's glass transition temperature. To illustrate, a first cooler 168a is coupled to and/or disposed within pulley 142 and configured to heat at least a portion of first belt 136 that is in contact with pulley 142. A second cooler 168b is coupled to and/or disposed within at least one of the first pressure plates and is configured to cool sheet 126 by cooling the at least one of the first pressure plates (e.g., a portion of first belt 136 that is in contact with the at least one of the first pressure plates). A third cooler 168c is coupled to and/or disposed within pulley 146 and configured to cool at least a portion of second belt 138 that is in contact with pulley 146. A fourth cooler 168d is coupled to and/or disposed within at least one of the second pressure plates and is configured to cool sheet 126 by cooling the at least one of the second pressure plates (e.g., a portion of second belt 138 that is in contact with the at least one of the second pressure plates). Although system 100 is described as including four coolers (e.g., 168a-168d), in other implementations, system 100 may include fewer (e.g., no coolers, a single cooler, etc.) than or more than four coolers. In some implementations, the one or more coolers 168a-168d may include a cooling element and/or a cooling circulation system.

[0050] A receiver roll 172 is coupled to frame 114 by a corresponding spindle 118 (e.g., a receiver spindle) and is configured to receive sheet 126 after definition of the microneedles on first side 128 of sheet 126. After embossing by tool 134, sheet 126 includes one or more portions 176 that each includes a microneedle array that includes microneedles (e.g., a microneedle 180). An example of microneedle 180 is described herein with reference to FIGS. 3A-3B, and examples of microneedle arrays are described herein with reference to FIG. 4.

[0051] During operation of system 100, sheet 126 is provided from dispenser roll 124 to tool 134. Sheet 126 is provided between first belt 136 and second belt 138, and pressed into the negative mold first belt 136 to form microneedles (e.g., 180). In some implementations, multiple sheets may be provided between belts 136, 138, as described with reference to FIG. 5.

[0052] As sheet 126 travels between belts 136, 138, a portion of sheet 126 between belts 136, 138 is heated (by the one or more heaters 166a-166d) to a temperature above the sheet's glass transition temperature. Additionally, pressure is applied by first and second pressure plates 160a, 160b, 162a, 162b to the belts 136, 138s as sheet 126 as sheet travels between belts 136, 138 (e.g., between substantially flat/planar portions of belts 136, 138. After being pressed between belts 136, 138 such that portions of sheet 126 are pressed into cavities of molding surface 154, a portion of sheet 126 between belts 136, 138 may be cooled (by the one or more coolers 168a-168d) to a temperature at or below the sheet's glass transition temperature such that the portion of sheet 126 including microneedles 180 solidifies or hardens. The substantially flat/planar portions allows higher pressures to be exerted on the molten film for a longer time as compared to conventional roll embossing using a circular mold, and thus produces better replication of mold features in sheet 126. The higher pressure exerted for the longer time period over the substantially flat/planar portion enables formation of high aspect ratio microneedles that can be released from the mold without demol ding-related defects, damage, and/or bending. Additionally, a high density microneedle patch, such as a patch with hundreds and/or thousands of microneedles per square centimeter, can be achieved.

[0053] Sheet 126 (including microneedles 180) is provided to receiver roll 172 as indicated by arrow 182. In some implementations, receiver roll 172 is omitted and sheet 126 (including microneedles 180) is provided for further processing, such as further processing to divide sheet 126 into individual microneedle arrays.

[0054] Sheet 126 may include one or more layers, such as a multilayer sheet. At least one of the layers of sheet 126 may include a material, such as a polymer. For example, the polymer may include liquid-crystal polymer (LCP), polyether ether ketone (PEEK), fluorinated ethylene propylene (FEP), polysulfone (PSU), polyethylenimine, polyetherimide, polyimide (PI), polymethylmethacrylate (PMMA), polycarbonate (PC), polycarbonate copolymer (PC COPO), cyclic olefin copolymer (COC), cyclo olefin polymer (COP), polyamide (PA), acrylonitrile butadiene styrene (ABS), polyphenylene ether (PPE), a biodegradable polymer (e.g., a polyhydroxyalkanoate (PHA), polylactic acid (PLA), polyglycolic acid and their copolymers), a hydrogel forming polymer (e.g., polyhydroxylmethacrylate), or a combination thereof. Additionally, or alternatively, the material may include a polyester, such as a semicrystalline polymer, polyethylene terephthalate (PET), polyethylene terephthalate glycol-modified (PETG), isophthalic acid-modified polycyclohexylenedimethylene terephthalate (PCTA), glycol-modified poly-cyclohexylenedimethylene terephthalate (PCTG), polycyclohexylenedimethylene terephthalate (PCT), and Tritan™ (a combination of dimethyl terephthalate, 1,4-cyclohexanedimethanol, and 2,2,4,4-tetramethyl-l,3-cyclobutanediol from Eastman Chemical). Additionally, or alternatively, the material may include a resin, such as Xylex™ (a combination of PC and an amorphous polyester), polybutylene terephthalate (PBT) (e.g., a resin from the Valox™ line of PBT), and/or a PET resin available from SABIC™.

[0055] In some implementations, sheet 126 may include various additives incorporated with a polymer (or a polymer composition), with the proviso that the additive(s) are selected so as to not significantly adversely affect the desired properties of the polymer (e.g., the additives have good compatibility with the polymer). Such additives can be mixed at a suitable time during formation of sheet 126. An exemplary polymer (of 126) may include additives, such as a mold release agent to facilitate ejection of a formed microneedle array from belt 136 (e.g., a mold assembly). Examples of mold release agents include both aliphatic and aromatic carboxylic acids and their alkyl esters, such as stearic acid, behenic acid, pentaerythritol tetrastearate, glycerin tristearate, and ethylene glycol distearate, as illustrative, non-limiting examples. Mold release agents can also include polyolefins, such as high-density polyethylene, linear low-density polyethylene, low-density polyethylene, and similar polyolefin homopolymers and copolymers. Some compositions of mold release agents may use pentaerythritol tetrastearate, glycerol monostearate, a wax, or a poly alpha olefin. Mold release agents are typically present in the composition at 0.05 to 10 wt %, based on total weight of the composition, such as 0.1 to 5 wt %, 0.1 to 1 wt%, or 0.1 to 0.5 wt%. Some mold release agents may have high molecular weight, typically greater than or equal to 300, to prohibit loss of the release agent from the molten polymer mixture during melt processing.

[0056] In addition to including a corresponding polymer and/or a mold release agent, sheet 126 may further include one or more additives intended to impart certain characteristics to a microneedle array formed as described herein. As illustrative, non-limiting examples, a polymer of sheet 126 may include an impact modifier, flow modifier, antioxidant, heat stabilizer, light stabilizer, ultraviolet (UV) light stabilizer, UV absorbing additive, plasticizer, lubricant, antistatic agent, antimicrobial agent, colorant (e.g., a dye or pigment), surface effect additive, radiation stabilizer, or a combination thereof. To illustrate, in a particular implementation, sheet 126 includes a heat stabilizer and an ultraviolet light stabilizer. In some implementations, a microneedle array can include a coating (e.g., a hardcoat layer) coupled a side of the array that includes the microneedles 180. For example, the coating may include a therapeutic drug (e.g., isosorbide) or other material.

[0057] Additionally, or alternatively, sheet 126 may exhibit excellent release, as measured by ejection force (N) and coefficient of friction. In some implementations, sheet 126 includes (i) high flow at high shear conditions to allow good transcription of mold texture and excellent filling of the finest mold features, (ii) good strength and impact (as indicated by ductile Izod Notched Impact at room temperature and modulus), and/or (iii) high release to have efficient de-molding and reduced cooling and cycle time during molding. Microneedle arrays formed from sheet 126 may have sufficient mechanical strength to remain intact (i) while being inserted into the biological barrier, (ii) while remaining in place for up to a number of days, and (iii) while being removed from the biological barrier.

[0058] In some implementations, sheet 126 stored on dispenser roll 124 may include one or more protective skin layers (not shown), such as a first skin layer coupled to (e.g., in contact with) first side 128, a second skin layer coupled to (e.g., in contact with) second side 130, or both. The protective skin layer(s) may prevent physical damage to sheet 126 during/after formation of sheet 126, during storage, or other manipulation. At least one of the one or more skin layers may be removed prior to sheet 126 being provided to tool 134. For example, a protective skin in contact with side 128 may be removed to expose side 128 (e.g., surface) prior to side 128 contacting tool 134 (e.g., first belt 136). The one or more protective skin layers may include polypropylene or polycarbonate, as illustrative, non-limiting examples.

[0059] Thus, FIG. 1 depicts system 100 configured to manufacture one or more microneedle arrays. System 100 enable arrays (e.g., large arrays) of microneedles to be manufactured more rapidly than prior art methods and may be utilized as part of a cost effective (e.g., low cost) process for mass production and large area texturing of geometrically accurate, defect free microneedle structures (e.g., a microneedle array). For example, system 100 allows higher pressures to be exerted on the molten film for a longer time as compared to conventional roll embossing using a circular mold, and thus produces better replication of mold features. The higher pressure exerted for the longer time period enables formation of high aspect ratio microneedles that can be released from the mold without demolding-related defects, damage, and/or bending. Additionally, system 100 can vary processing conditions (e.g., temperature, pressure, duration, etc.) during array formation process and can produce one or more arrays extending along an elongated sheet rather than being limited to producing one singular discrete array at a time. For example, a sheet 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. The ability to produce multiple microneedle arrays reduces time and cost of manufacturing microneedle arrays.

[0060] Referring now to FIGS. 2A-2D, FIGS. 2A-2B show perspective and top views, respectively, of an example of a portion of first belt 136 FIG. 1, FIG. 2C shows a cross-sectional view of the portion of first belt 136 along line A- A, and FIG. 2D shows an enlarged cutaway view of the portion showing a single cavity of belt 136. As shown, belt 136 has a proximal surface 210 (e.g., molding surface 154) and a plurality of cavities 214 that are open at the proximal surface. As shown, each of cavities 214 extends from a base 218 at proximal surface 210 to a distal end 222 within belt 136 to define a negative or female mold for a microneedle (e.g., define an inverse microneedle). Each cavity is defined by a corresponding portion of proximal surface 210 (e.g., molding surface 154) that is substantially planar portion and that extends entirely around the base 218 of the cavity.

[0061] A tip 224 is positioned at distal end 222 of cavity 214. Sharpness of tip 224 may be expressed by a radius of curvature(s) of tip 224. In a particular implementation, sharpness of tip 224 is less than or equal to any one of 5, 10, 15, 20, or 25 μπι. In a particular implementation, sharpness of tip 224 is less than or equal to 15 μπι. Alternatively, sharpness of tip 318 may be greater than or equal to 25 μπι. Although microneedle 180 is illustrated as having a single tip, in other implementations, microneedle may include multiple tips, a blade, or a combination thereof, each having a radius of curvature less than or equal to any one of: 5, 7, 10, 15, 20, or 25 μπι.

[0062] As shown, cavities 214 are disposed in two or more rows, such as in rows 226a- 226e. Each row of the two or more rows includes at least two cavities 214. Although described as having five rows, in other implementations, first belt 136 may include cavities 214 arranged in fewer than or more than five rows. Additionally, or alternative, although each row (e.g., 226a-226e) is depicted as including four cavities, in other implementations, a row can include fewer than or more than four cavities. In a particular implementation, each row includes at least two cavities. In some implementations, two rows include a different number of cavities.

[0063] Adjacent (e.g., neighboring) cavities 214 in one of the rows are spaced apart by a distance 228. Although described as having the same spacing between neighboring cavities 214 of a particular row, in some implementations, at least one pair of neighboring protruding portions has a different distance 228 from another pair of neighboring protruding portions of the same row. Adjacent (e.g., neighboring) cavities 214 of two different (e.g., adjacent) rows are spaced apart by a distance 230. Although described as having the same spacing between neighboring cavities 214 of different (adjacent) rows, in some implementations, at least one pair of neighboring protruding portions has a different distance 230 from another pair of neighboring protruding portions of a different pair of neighboring rows. In such arrays, the rows can be spaced at intervals of 40 μιη to 1,000 μιη; for example, at equal or differing intervals. In some implementations, a spacing between two adjacent or closest cavities may be within a range from 75 μιη to 2 millimeters (mm). In other implementations, spacing between two adjacent or closest cavities is greater than 2 mm.

[0064] Each base 218 has a primary maximum transverse dimension 232 measured in a first direction, and a secondary maximum transverse dimension 236 measured in a second direction that is perpendicular to the first direction. Maximum transverse dimension 232 is greater than or equal to secondary maximum transverse dimension 236 and may range from 75 μπι to 350 μπι. In other implementations, maximum transverse dimension 232 may be less than or equal to 75 μπι, or is greater than or equal to 350 μπι. In some implementations, a ratio of the primary maximum transverse dimension 232 to the secondary maximum transverse dimension 236 of a respective cavity is from 1 to 5.

[0065] Each of the cavities 214 has a corresponding depth (e.g., a depth 238), extending from the base 218 of the cavity 214 to the distal end 222 of the cavity 214. A distance of the depth may be measured, when proximal surface is substantially flat (e.g., planar), from proximal surface 210 (e.g., molding surface 154) in a direction normal to proximal surface 210. In some implementations, the depth (e.g., 238) is from 200 μπι to 1, 100 μπι (e.g., from 400 μπι to 1,000 μπι, or from 400 μπι to 800 μπι). In other implementations, the depth may be less than or equal to 400 μπι) or may be greater than or equal to 1, 100 μπι.

[0066] In some implementations, an aspect ratio (of cavity 214) of depth 238 to a transverse dimension of the cavity base is greater than or equal to 1. In a particular implementation, the aspect ratio (of the cavity) is greater than or equal to 2. The transverse dimension of the aspect ratio (of the cavity) can include the primary maximum transverse dimension (e.g., 232), the secondary transverse dimension (e.g., 236), or another transverse dimension of base 218 (e.g., a minimum transverse dimension of base 218).

[0067] In some implementations, depth 238 is from one (1) to five (5) times primary maximum transverse dimension 232 (e.g., a depth 238 of 1,000 μπι and dimension 232 from 200 μπι to 1,000 μπι, inclusive of 200 μπι and 1,000 μπι). In some such implementations, depth 238 is from two (2) to four (4) times primary maximum transverse dimension 232 (e.g., a height of 1,000 μπι and a primary maximum transverse dimension 232 from 250 μπι to 500 μπι).

[0068] In some implementations, depth 238 is from one (1) to five (5) times secondary maximum transverse dimension 236 (e.g., a depth 238 of 1,000 μιη and a secondary maximum transverse dimension 236 from 200 μιη to 1,000 μπι, inclusive of 200 μιη and 1,000 μιη). In some such implementations, depth 238 is from two (2) to four (4) times secondary maximum transverse dimension 236 (e.g., a height of 1,000 μιη and a secondary maximum transverse dimension 236 from 250 μιη to 500 μιη. In one particular example, primary maximum transverse dimension 232 is 170 μπι, secondary maximum transverse dimension 236 is 120 μπι, and depth 238 is 250 μιη.

[0069] As shown, base 218 of each of cavities 214 has a cross-sectional area (in a first plane corresponding to proximal surface 210, that is larger than a cross-sectional area (in second plane that is parallel to the first plane plane) of its distal end 222. Additionally, as shown, cavity 214 has a rhomboid cross-sectional shaped base (e.g., 218) and has a pyramid shape defined by four planar surfaces (e.g., representative planar surface 240). In other implementations, base 218 may have a different cross-sectional shape, such as ellipsoid, triangular, circular, square, rectangular, hexagonal, octagonal, star, or other shape, and cavity may have a different profile or shape, such as conical. For example, one or more surfaces of cavity 214 may be curved or curvilinear (e.g., concave), or one or more edges of two adjoining surfaces may be curved or curvilinear (e.g., concave). The shape of the present cavities (e.g., 214) 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 (e.g., belt 136).

[0070] Thus, FIGS. 2A-2D depict aspects of belt 136 that can be used to manufacture one or more microneedle arrays more rapidly than prior art methods and may be utilized as part of a cost effective (e.g., low cost) process for mass production and large area texturing of geometrically accurate, defect free microneedle structures (e.g., a microneedle array).

[0071] Referring to FIGS. 3A-3B, perspective and top views are shown of an example microneedle 180 formed with system of FIG. 1 and, in particular, with belt 136 as described with reference to FIGS. 2A-2D. As described herein, dimensions of microneedle 180 (and/or an array of microneedles) may correspond to or be based on dimension of belt 136, such as dimensions of cavities 214. Stiffness of microneedle 180 may be expressed by Young's modulus. In some implementations, stiffness of microneedle 180 is greater than or equal to 1.5 gigapascals (GPa). In other implementations, stiffness of microneedle is greater than or equal to 2.0 GPa. [0072] As shown, microneedle 180 is shaped as a pyramid and includes a base 310 and a distal end 314. Base 310 of a particular microneedle has a cross-sectional area larger than that of the respective distal end 314 of the particular microneedle. A tip 318 (e.g., an apex) is positioned at distal end 314 of microneedle 180. Sharpness of tip 318 may be expressed by a radius of curvature(s) of tip 318. In a particular implementation, sharpness of tip 318 is less than or equal to any one of 5, 10, 15, 20, or 25 μιη. In a particular implementation, sharpness of tip 318 is less than 15 μιη. Alternatively, sharpness of tip 318 may be greater than or equal to 25 μιη. Although microneedle 180 is illustrated as having a single tip, in other implementations, microneedle 180 may include multiple tips, a blade, or a combination thereof.

[0073] As shown, base 310 has a rhomboid cross-sectional shape with a primary maximum transverse dimension 322 and a secondary maximum transverse dimension 326 measured perpendicular to primary maximum transverse dimension 322. Maximum transverse dimension 322 is greater than or equal to a secondary maximum transverse dimension 326 and may range from 75 μιη to 350 μιη. In other implementations, maximum transverse dimension 322 may be less than or equal to 75 μπι, or is greater than or equal to 350 μιη. . In some implementations, a ratio of the primary maximum transverse dimension 322 to the secondary maximum transverse dimension 326 of a respective cavity is from 1 to 5.

[0074] Microneedle 180 also has a height 330 that is measured perpendicular to both of the primary and secondary maximum transverse dimensions (322 and 326) of base 310. Height 330 of microneedle 180 is from 200 μιη to 1,100 μιη (e.g., from 400 μιη to 1,000 μπι, or from 400 μπι to 800 μιη). In a particular implementation, height 330 is 250 μιη. In other implementations, height 330 is less than 250 μιη or is greater than 1,000 μιη.

[0075] In some implementations, an aspect ratio (of microneedle 180) of height 330 to a transverse dimension of the microneedle base (e.g., 310) is greater than or equal to 1. In a particular implementation, the aspect ratio (of the microneedle) is greater than or equal to 2. The transverse dimension of the aspect ratio (of the microneedle) can include the primary maximum transverse dimension (e.g., 232), the secondary transverse dimension (e.g., 326), or another transverse dimension of base 310 (e.g., a minimum transverse dimension of base 310).

[0076] In some implementations, height 330 of microneedle 180 is from one (1) to five (5) times primary maximum transverse dimension 322 (e.g., a height 330 of 1,000 μπι and a primary maximum transverse dimension 322 from 200 μπι to 1,000 μπι, inclusive of 200 μπι and 1,000 μπι). In some such implementations, height 330 is from two (2) to four (4) times primary maximum transverse dimension 322 (e.g., a height of 1,000 μιη and a primary maximum transverse dimension 322 from 250 μιη to 500 μιη).

[0077] In some implementations, height 330 is from one (1) to five (5) times secondary maximum transverse dimension 326 (e.g., a height 330 of 1,000 μπι and a secondary maximum transverse dimension 326 from 200 μπι to 1,000 μπι, inclusive of 200 μπι and 1,000 μπι). In some such implementations, height 330 is from two (2) to four (4) times secondary maximum transverse dimension 326 (e.g., a height of 1,000 μπι and a secondary maximum transverse dimension 326 from 250 μπι to 500 μπι. In one particular example, primary maximum transverse dimension 322 is 170 μπι, secondary maximum transverse dimension 326 is 120 μπι, and height 330 is 250 μπι.

[0078] As shown in FIGS. 3 A and 3B, microneedle 180 has a rhomboid cross-sectional shaped base (e.g., 310) and has a pyramid shape defined by four planar surface. In other implementations, base 310 may have a different cross-sectional shape, such as ellipsoid, triangular, square, rectangular, hexagonal, octagonal, star, or other shape. For example, referring to FIG. 4 examples (410a-410c) of a microneedle array that includes a surface (414a- 414c) are shown. A first microneedle array 410a includes microneedles having a base 310a with a rectangular (e.g., square) cross-sectional shape. Base 310a (of each microneedle) is surrounded entirely by a perimeter lying in a single plane. To illustrate, a portion 418a of surface 414a that is substantially planar and extends around each base 310a. A second microneedle array 410b includes microneedles having a base 310b with a hexagonal cross- sectional shape. Base 310b (of each microneedle) is surrounded entirely by a perimeter lying in a single plane. To illustrate a portion 418b of surface 414b that is substantially planar and extends around each base 310b. A third microneedle array 410c includes microneedles having includes a base 310c with an octagonal cross-sectional . Base 310c (of each microneedle) is surrounded entirely by a perimeter lying in a single plane. To illustrate a portion 418c of surface 414c that is substantially planar and extends around each base 310c. Additionally, or alternatively, in other implementations, microneedle 180 can have any suitable outer surface profile or shape. For example, outer surfaces may be curved or curvilinear (e.g., concave) to result in a relatively sharper tip 318, or one or more blades along the vertices along which the outer surfaces of the microneedle meet one another may be curved or curvilinear (e.g., concave). In yet further configurations, the present microneedles can have any suitable shape that permits the microneedle to puncture a patient's skin as contemplated by this disclosure. It is noted that, in some implementations, at least a portion of microneedles 180 may vary in size (e.g., primary maximum transverse dimension 322, secondary maximum transverse dimension 326, height 330, cross-sectional base shape, and/or profile) relative to each other. This variation in size creates a varying aspect ratio in a microneedle array.

[0079] As shown in FIGS. 3 A and 3B, microneedle 180 is "solid" and does not include a channel extending through the microneedle. In other implementations, microneedle 180 may be a "hollow" microneedle with a channel extending through at least a portion of the microneedle.

[0080] The shape of the present microneedles (e.g., 180) are not particularly limited, but certain considerations may guide selection and design of different shapes. For example, the shape of a mold cavity to form the present microneedles (e.g., 180) may impact the ability to manufacture molds. Additionally, the shape of the mold 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 (e.g., belt 136). Additionally, or alternatively, the shape of the microneedle can impact the ability of the microneedle to puncture a patient' s skin. For example, a microneedle may be designed to 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 may be 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).

[0081] FIG. 5 is a schematic view of another example of a system 500 for manufacturing a microneedle array. System 500 is substantially similar to system 100 (FIG. 1) in many respects, and similar reference numerals are used to denote elements in system 500 that are similar to corresponding elements in system 100. As such, the differences in system 500 relative to system 100 will primarily be described here. The primary difference is that system 500 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 500 includes two dispenser rolls: a first dispenser roll 124 and a second dispenser roll 510 rotatably supported by corresponding spindle 118. First dispenser roll 124 carries a first sheet 514 (of a first polymer material) having a first side 518 and a second side 522, and second dispenser roll 510 carries a second sheet 526 (of a second polymer material) having a third side 530 and a fourth side 534. Although system 500 is described as having two dispenser rolls (e.g., two sheets), in other implementations, system 500 may include more than two dispenser rolls such that two or more sheets are provided to tool 134 between belts 136, 138.

[0082] In the depicted embodiment, system 500 includes an alignment pulleys 540 that are aligned with the path the sheets (514 and 526) take between belts 136, 138. Sheets (514 and 526) are delivered to the alignment pulleys (540) under sufficient tension to maintain the orderly delivery of the sheets to the position between belts 136, 138. As shown, sheet 514 is provided from dispenser roll 124 in a direction indicated by arrow 132 and sheet 526 is provided from dispenser roll 510 in a direction indicated by arrow 544. In some implementations, one or more additional pulleys may be included in system 500 to guide the path of one or more of sheets 514, 526.

[0083] In system 500, heaters 166a-166d are configured to melt (raise the temperature above the polymer's glass transition temperature) both portions of sheets 514 and 526 at the interface between the sheets and at the interface between first sheet 514 and first belt 136, such that when the sheets are compressed between belts 136, 138, the polymer of first sheet 514 both flows into the cavities of first belt 136 to define microneedles and merges the sheets with one another, such that the polymer of first sheet 514 commingles with the polymer of second sheet 526.

[0084] During operation of system 500, sheet 514 is provided from dispenser roll 124 to tool 134 and sheet 526 is provided from dispenser roll 510 to tool 134. Sheets 514, 526 are provided between first belt 136 and second belt 138, and sheets 514, 526 commingle and sheet 514 is pressed into the negative mold first belt 136 to form microneedles (e.g., 180). In a particular implementation, portions of each of sheets 514, 526 between belts 136, 138 may be heated (by the one or more heaters 166a-166d) to a temperature above each sheet's glass transition temperature. After being pressed between belts 136, 138, portions of each of sheets 514, 526 between belts 136, 138 may be cooled (by the one or more coolers 168a-168d) to a temperature at or below a glass transition temperature of sheet 514 (and/or a glass transition temperature of sheet 526), such that the portion of sheet 126 including microneedles 180 solidifies or hardens. An output (e.g., a sheet including microneedles 180) of tool 134 is provided to receiver roll 172 as indicated by arrow 182.

[0085] In some implementations with multiple sheets of polymer material, the sheets can have different properties. For example, the first sheet (e.g., 522) closest to first belt 136 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. As an illustrative, non-limiting example, first sheet 514 may include PMMA and second sheet 526 may include PC.

[0086] In some implementations, sheet 526 includes a thermoplastic backing material that does not melt/soften. For example, second sheet 526 may have a higher glass transition temperature (Tg) than first sheet 514, a higher melt temperature (Tm) than sheet 514, or both. Second sheet 526 including the thermoplastic backing material may facilitate embossing facilitates of first sheet 514 by providing a structure/support via which pressure may be applied to side 522 of sheet 514.

[0087] Thus, FIG. 5 depicts system 500 configured to manufacture one or more microneedle arrays using the first and second sheets such that both sheets are heated and compressed between belts 136, 138. System 500 enable arrays (e.g., large arrays) of microneedles to be manufactured more rapidly than prior art methods and may be utilized as part of a cost effective (e.g., low cost) process for mass production and large area texturing of geometrically accurate, defect free microneedle structures (e.g., a microneedle array). For example, system 500 allows higher pressures to be exerted on the molten film for a longer time as compared to conventional roll embossing using a circular mold, and thus produces better replication of mold features. The higher pressure exerted for the longer time period enables formation of high aspect ratio microneedles that can be released from the mold without demolding-related defects, damage, and/or bending. Additionally, system 100 can vary processing conditions (e.g., temperature, pressure, duration, etc.) during array formation process and can produce one or more arrays extending along an elongated sheet rather than being limited to producing one singular discrete array at a time. System 500 enable arrays (e.g., large arrays) of microneedles to be manufactured more rapidly than prior art methods. Additionally, system 500 can produce one or more arrays extending along an elongated sheet rather than being limited to producing one singular discrete array at a time. For example, a sheet 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.

[0088] Referring to FIG. 6, method 600 may be performed by a manufacturing device or system, such as system 100 or system 500. The microneedle array includes a plurality of microneedles (e.g., microneedle 180), as described herein.

[0089] Method 600 includes disposing a sheet of polymer between a first belt and a second belt such that a first side of the sheet contacts the first belt and a second side of the sheet faces the second belt, the first belt having a molding surface configured to contact the first side of the sheet, the first belt defining a negative mold of a microneedle, at 610. For example, the sheet may include sheet 126, 514, and/or 530, and the first and second belts may include or correspond to the first and second belts 136, 138. The molding surface, such as molding surface 154, may define a plurality of cavities (e.g., 214), and each of the cavities extends from a cavity base (e.g., 218) at the molding surface to a distal end (e.g., 222) of the cavity within the first belt to define the negative mold of a microneedle. The cavity base of each of the cavities having a cross-sectional area larger than that of the respective distal end and/or the cavity base of each cavity is entirely surrounded by a perimeter lying in a single plane.

[0090] Method 600 also includes heating a portion of the first belt such that a temperature of the first side of the sheet increases above the polymer's glass transition temperature, at 612. For example, heat may be generated by one or more heaters, such as heaters 166a-166d. In a particular implementation, heating is performed by heating at least one of a plurality of first pressure plates between first and second pulleys within a loop of the first belt. In some implementations, method 600 may include cooling the first sheet by cooling at least one of the first pressure plates. For example, cooling may be performed by one or more coolers, such as coolers 168a-168d.

[0091] Method 600 further includes compressing the sheet between the first belt and the second belt 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, at 614. Each microneedle may include a characteristic selected from the group consisting of: a tip having a radius of curvature of less than or equal to 25 μπι; a needle base of each of the microneedles surrounded entirely by a perimeter lying in a single plane; a height extending from the needle base to a distal end of the microneedle and that is from 400 μπι to 1,000 μπι; and an aspect ratio of the height to a transverse dimension of the needle base of greater than or equal to 1. In some implementations, the aspect ratio is greater than or equal to 2 and/or the radius of curvature is less than or equal to 15 μπι. Additionally, or alternatively, the base (e.g., 310, 310a-310c) of each of the microneedles includes a primary maximum transverse dimension (e.g., 322) measured in a first direction, and a secondary maximum transverse dimension (e.g., 326) measured in a second direction that is perpendicular to the first direction. The transverse dimension of the aspect ratio (of a microneedle) includes the primary maximum transverse dimension or the secondary transverse dimension.

[0092] In some implementations, each of the microneedles has a height (e.g., 330) extending from the needle base to the distal end of the microneedle that is from 1 to 5 times the primary maximum transverse dimension of the respective microneedle. Additionally, or alternatively, the ratio of the primary maximum transverse dimension to the secondary maximum transverse dimension of the respective microneedle is from 1 to 5.

[0093] In some implementations, the sheet of polymer is a first sheet of polymer. In such implementations, method 600 may include, prior to compressing the first sheet, disposing a second sheet of polymer between the first sheet of polymer and the second belt 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 second belt. Heating may be performed 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 first belt and the second belt such that polymer of the first sheet commingles with polymer of the second sheet.

[0094] In some implementations, each cavity may include a characteristic selected from the group consisting of: a depth from 400 μπι to 1,000 μπι; a tip having a radius of curvature of less than or equal to 25 μπι; a cavity base having a cross-sectional area larger than that of the respective distal end; and an aspect ratio of the depth to a transverse dimension of the cavity base of greater than or equal to 1. In some implementations, the cavity base of each cavity is entirely surrounded by a perimeter lying in a single plane, and/or each cavity has a depth is greater than or equal to 1000 μπι. In a particular implementation, the aspect ratio (of the cavity) is greater than or equal to 2. The base of each of the cavities includes a primary maximum transverse dimension measured in a first direction, and a secondary maximum transverse dimension measured in a second direction that is perpendicular to the first direction. The transverse dimension of the aspect ratio (of the cavity) includes the primary maximum transverse dimension (e.g., 232) or the secondary transverse dimension (e.g., 236).

[0095] In o implementation, each cavity may include a characteristic selected from the group consisting of: a cavity base that has a cross-sectional area larger than that of the respective distal end and that is entirely surrounded by a perimeter lying in a single plane; a tip at the distal end having a radius of curvature of less than or equal to 25 μπι; and an aspect ratio of the depth to a transverse dimension of the cavity base of greater than or equal to 1. In such implementations, each cavity can have a depth is greater than or equal to 1000 μπι, and the aspect ratio can be greater than or equal to 2. In other such implementations, each cavity depth can be less than 1000 μιη.

[0096] Thus, method 600 describes use of a tool (e.g., 134) and manufacturing of an array of microneedles, such as microneedle array 410a-410c. Method 600 advantageously enable arrays (e.g., large arrays) of microneedles, and multiple arrays of microneedles, to be manufactured more rapidly than prior art methods and at a lower cost. For example, method 600 allows higher pressures to be exerted on the molten film for a longer time as compared to conventional roll embossing using a circular mold, and thus produces better replication of mold features. The higher pressure exerted for the longer time period enables formation of high aspect ratio microneedles that can be released from the mold without demolding-related defects, damage, and/or bending. Additionally, arrays manufactured according to the method can beneficially have aspect ratios for microneedles with sharp tips to penetrate dermal surfaces (while still maintaining the benefit of being relatively pain free) and to maintain their structural integrity and strength during use.

[0097] 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 disclosure. 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 embodiments. For example, elements may be omitted or combined as a unitary structure, connections may be substituted, or both. 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. Accordingly, no single implementation described herein should be construed as limiting and implementations of the disclosure may be suitably combined without departing from the teachings of the disclosure. [0098] 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.

Claims

A method of manufacturing a microneedle array, the method comprising:

disposing a sheet of polymer between a first belt and a second belt such that a first side of the sheet contacts the first belt and a second side of the sheet faces the second belt, the first belt having a molding surface configured to contact the first side of the sheet, the molding surface defining a plurality of cavities, each of the cavities extending from a cavity base at the molding surface to a distal end of the cavity within the first belt to define a negative mold of a microneedle, the cavity base of each of the cavities having a cross-sectional area larger than that of the respective distal end;

heating a portion of the first belt 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 first belt and the second belt 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, with a needle base of each of the microneedles surrounded entirely by a perimeter lying in a single plane;

where each of the microneedles comprises:

a tip having a radius of curvature of less than or equal to 25 μπι;

a height extending from the needle base to a distal end of the microneedle and that is from 400 micrometers (μπι) to 1,000 μπι; and

an aspect ratio of the height to a transverse dimension of the needle base of greater than or equal to 2.

The method of claim 1, where the radius of curvature is less than or equal to 15 μπι.

The method of any of claims 1-2, where the base of each of the microneedles comprises: a primary maximum transverse dimension measured in a first direction; and a secondary maximum transverse dimension measured in a second direction that is perpendicular to the first direction.

The method of claim 3, where the transverse dimension of the aspect ratio comprises the primary maximum transverse dimension or the secondary transverse dimension.

The method of any of claims 1-2, where the base of each of the microneedles has a primary maximum transverse dimension measured in a first direction, and each of the microneedles has a height extending from the needle base to the distal end of the microneedle that is from 1 to 5 times the primary maximum transverse dimension of the respective microneedle.

6. The method of claim 5, where each of the microneedles 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 microneedle is from 1 to 5.

7. The method of claim 1, where the heating is performed by heating at least one of a plurality of first pressure plates between first and second pulleys within a loop of the first belt.

8. The method of claim 7, further comprising cooling the first sheet by cooling at least one of the first pressure plates.

9. The method of any of claims 1-8, where 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, polyethylenimine, polyetherimide, polyimide (PI), polycarbonate (PC), polycarbonate copolymer (PC COPO), cyclic olefin copolymer (COC), cyclo olefin polymer (COP), polyamide (PA), acrylonitrile butadiene styrene (ABS), polyphenylene ether (PPE), polymethylmethacrylate (PMMA), a biodegradable polymer and/or a copolymer of the biodegradable polymer, and a hydrogel forming polymer.

10. The method of any of claims 1-9, where the sheet of polymer is a first sheet of polymer and the method further comprises:

prior to compressing the first sheet, disposing a second sheet of polymer between the first sheet of polymer and the second belt 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 second belt.

11. The method of claim 10, where the heating is performed 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 first belt and the second belt such that polymer of the first sheet commingles with polymer of the second sheet.

12. A system for manufacturing a microneedle array from one or more sheets of polymer, the system comprising:

a frame;

a first belt movably coupled to the frame, the first belt having a molding surface defining a plurality of cavities, each of the cavities extending from a base at the molding surface to a distal end within the first belt to define a negative mold of a microneedle, each of the cavities comprises:

a depth from 400 micrometers (μπι) to 1,000 μπι;

a tip having a radius of curvature of less than or equal to 25 μπι; a cavity base having a cross-sectional area larger than that of the respective distal end; and

an aspect ratio of the depth to a transverse dimension of the cavity base of greater than or equal to 2;

a second belt having a pressing surface configured to face the molding surface of the first belt;

a heater coupled to the first belt and configured to increase the temperature of a sheet of polymer in contact with the first belt above the polymer's glass transition temperature;

where at least one of the belts is movable relative to the other to reduce a distance between the belts and compress the sheet between the first belt and the second belt to cause the polymer of the sheet to flow into the cavities until the polymer substantially fills the cavities to form a plurality of solid microneedles on a first side of the sheet.

13. The system of claim 12, where 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.

14. The system of claim 13, where 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.

15. The system of any of claims 13-14, further comprising:

a first pulley;

a second pulley spaced from the first pulley, where the first belt defines a continuous loop that extends around the first and second pulleys;

a third pulley spaced from the first pulley; and

a fourth pulley spaced from the third pulley and spaced from the second pulley, where the second belt defines a continuous loop that extends around the third and fourth pulleys.

16. The system of claim 15, further comprising:

a plurality of first pressure plates between the first and second pulleys within the loop of the first belt, each of the plurality of first pressure plates in contact with the first belt.

17. The system of any of claims 15-16, further comprising:

a cooler configured to reduce the temperature of at least one of the first pressure plates, the second pulley, and/or the third pulley;

where the heater is disposed within, and configured to heat the sheet via, at least one of the first pressure plates, the first pulley, and/or the third pulley.

18. A system for manufacturing a microneedle array from one or more sheets of polymer, the apparatus comprising:

a frame;

a first belt movably coupled to the frame, the first belt having a molding surface defining a plurality of cavities, each of the cavities extending from a base at the molding surface to a distal end within the first belt to define a negative mold of a microneedle, each of the cavities a characteristic selected from the group consisting of:

a cavity base that has a cross-sectional area larger than that of the respective distal end and that is entirely surrounded by a perimeter lying in a single plane;

a tip at the distal end having a radius of curvature of less than or equal to 25 micrometers (μπι); and

an aspect ratio of the depth to a transverse dimension of the cavity base of greater than or equal to 1 ; a second belt having a pressing surface configured to face the molding surface of the first belt;

where at least one of the belts is movable relative to the other to reduce a distance between the belts and compress the sheet between the first belt and the second belt to cause the polymer of the sheet to flow into the cavities until the polymer substantially fills the cavities to form a plurality of solid microneedles on the first side of the sheet, with a needle base of each of the microneedles surrounded entirely by a perimeter lying in a single plane.

19. The system of claim 18, where:

the base of each of the cavities comprises:

a primary maximum transverse dimension measured in a first direction; and a secondary maximum transverse dimension measured in a second direction that is perpendicular to the first direction; and

the transverse dimension of the aspect ratio comprises the primary maximum transverse dimension or the secondary transverse dimension.

20. The system of any of claims 18-19, where each cavity has a depth is greater than or equal to 1000 μπι, and the aspect ratio is greater than or equal to 2.