Patent Publication Number: US-2019184609-A1

Title: System and method for manufacturing microneedle devices

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation application of co-pending U.S. patent application Ser. No. 15/982,426, filed on May 17, 2018, which claims the benefit of, and priority to, U.S. Provisional Patent Application Ser. No. 62/507,656, filed May 17, 2017. Priority to the above-identified patent applications is expressly claimed, and the disclosures of these applications are hereby incorporated herein by reference in their entireties and for all purposes. 
    
    
     FIELD 
     The disclosed embodiments relate generally to manufacturing systems and processes and more particularly, but not exclusively, to tools and processes for manufacturing microneedle devices, including skin-applied patches for delivering cosmetic and therapeutic agents to the skin. 
     BACKGROUND 
     Microneedle arrays are used as transdermal and intradermal drug/therapeutic-delivery systems and to deliver polymers directly into and through the skin for cosmetic applications. Biodegradable microneedles are commonly used. Existing devices provide the biodegradable microneedles attached to a patch having a substrate layer that contacts the skin. In use, the substrate layer or patch is applied to the skin and pressure is applied which causes the microneedles to pierce the stratum corneum. One disadvantage of these devices is that the patch must remain affixed to the skin while the microneedles dissolve within the underlying skin layers. Microneedle dissolution may take several hours to a day or more, depending upon the specific microneedle composition. It is often inconvenient, unsightly, and/or uncomfortable for the user to wear the device for this extended period of time. 
     Microneedle arrays also are difficult to manufacture, particularly in mass production. The material forming the microneedle arrays typically is very viscous and presents challenges when shaped into the small form factor of microneedles. In addition, individual microneedles may not be fully formed during the manufacturing process and can be damaged during post-production handling. 
     In view of the foregoing, there is a need to efficiently manufacture and provide a biocompatible/biodegradable microneedle device that can effectively deliver the microneedles across the stratum corneum and be removed within a short period of time without affecting the performance of the device/microneedles. 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         FIG. 1A  is an exemplary detail diagram illustrating an embodiment of a microneedle. 
         FIG. 1B  is an exemplary detail diagram illustrating an alternative embodiment of the microneedle of  FIG. 1A , wherein the microneedle has a diamond shape. 
         FIG. 2A  is an exemplary top-level block diagram illustrating an embodiment of a microneedle device, wherein the microneedle device includes a plurality of the microneedles of  FIG. 1A . 
         FIG. 2B  is an exemplary plan view of the microneedle device of  FIG. 2A , wherein the microneedles are arranged in a predetermined pattern. 
         FIG. 3A  is an exemplary top-level block diagram illustrating an alternative embodiment of the microneedle device of  FIGS. 2A-B , wherein the microneedles are physically connected via a residual layer of microneedle material. 
         FIG. 3B  is an exemplary top-level block diagram illustrating another alternative embodiment of the microneedle device of  FIGS. 2A-B , wherein the microneedles are disposed on an optional backing layer. 
         FIG. 4  is an exemplary top-level flow diagram illustrating an embodiment of a method for manufacturing the microneedle device of  FIGS. 2A-B  via a replica mold. 
         FIG. 5A  is an exemplary detail diagram illustrating an embodiment of the replica mold of  FIG. 4 , wherein the replica mold defines a plurality of microneedle wells. 
         FIG. 5B  is an exemplary plan view of the replica mold of  FIG. 5A , wherein the microneedle wells are arranged in a predetermined pattern. 
         FIG. 6  is an exemplary top-level flow diagram illustrating an embodiment of a method for manufacturing the replica mold of  FIGS. 5A-B  via a master mold. 
         FIG. 7A  is an exemplary top-level block diagram illustrating an embodiment of the master mold of  FIG. 6 , wherein the master mold includes a plurality of microneedle projections. 
         FIG. 7B  is an exemplary plan view of the master mold of  FIG. 7A , wherein the microneedle projections are arranged in a predetermined pattern. 
         FIG. 8A  is an exemplary top-level block diagram illustrating an embodiment of the master mold of  FIGS. 7A-B , wherein replica mold material is disposed on the master mold. 
         FIG. 8B  is an exemplary top-level block diagram illustrating an alternative embodiment of the master mold of  FIGS. 7A-B , wherein the replica mold material receives the microneedle projections and is cured on the master mold to form the replica mold. 
         FIG. 9A  is an exemplary top-level block diagram illustrating an embodiment of the master mold of  FIG. 8B , wherein the master mold is disposed on a cooling device for cooling the replica mold material of the replica mold. 
         FIG. 9B  is an exemplary top-level block diagram illustrating an alternative embodiment of the cooling device of  FIG. 9A , wherein the cooling device comprise a plurality of cooling devices. 
         FIG. 9C  is an exemplary top-level block diagram illustrating another alternative embodiment of the cooling device of  FIG. 9A , wherein the cooling device includes a plurality of cooling regions. 
         FIG. 10A  is an exemplary top-level flow diagram illustrating an alternative embodiment of the method of  FIG. 6 , wherein the method includes manufacturing the master mold. 
         FIG. 10B  is an exemplary top-level flow diagram illustrating another alternative embodiment of the method of  FIG. 6 , wherein the method includes separating the replica mold from the master mold. 
         FIG. 11  is an exemplary top-level flow diagram illustrating an embodiment of a method for forming the microneedle array of  FIGS. 2A-B  via the replica mold of  FIGS. 5A-B . 
         FIG. 12  is an exemplary top-level block diagram illustrating an embodiment of the replica mold of  FIGS. 5A-B , wherein microneedle material is disposed on the replica mold. 
         FIG. 13  is an exemplary top-level flow diagram illustrating an alternative embodiment of the method of  FIG. 11 , wherein the microneedle material is distributed into one or more microneedle wells formed within the replica mold. 
         FIG. 14A  is an exemplary top-level block diagram illustrating an alternative embodiment of the replica mold of  FIG. 12 , wherein the microneedle material is distributed within the microneedle wells and is dried on the replica mold to form the microneedle array. 
         FIG. 14B  is an exemplary top-level block diagram illustrating another alternative embodiment of the replica mold of  FIG. 12 , wherein the replica mold is disposed on a vacuum system for distributing the microneedle material into the microneedle wells. 
         FIG. 15  is an exemplary top-level flow diagram illustrating another alternative embodiment of the method of  FIG. 11 , wherein the method includes separating the microneedle array from the replica mold. 
         FIG. 16  is an exemplary top-level flow diagram illustrating an alternative embodiment of the method for forming the microneedle array of  FIG. 11 , wherein the microneedle material is disposed on the replica mold via a reservoir system. 
         FIG. 17  is an exemplary top-level detail diagram illustrating an embodiment of the reservoir system of  FIG. 16 . 
         FIG. 18A  is an exemplary top-level block diagram illustrating an alternative embodiment of the replica mold of  FIG. 14B , wherein the microneedle material is received by, and/or stored in, the reservoir system of  FIG. 17 . 
         FIG. 18B  is an exemplary top-level block diagram illustrating an alternative embodiment of the replica mold of  FIG. 18A , wherein the replica mold cooperates with the reservoir system. 
         FIG. 18C  is an exemplary top-level block diagram illustrating an alternative embodiment of the replica mold of  FIG. 18B , wherein the reservoir system begins to dispense the microneedle material onto the replica mold. 
         FIG. 18D  is an exemplary top-level block diagram illustrating an alternative embodiment of the replica mold of  FIG. 18C , wherein the reservoir system stops dispensing the microneedle material onto the replica mold. 
         FIG. 18E  is an exemplary top-level block diagram illustrating an alternative embodiment of the replica mold of  FIG. 18D , wherein the replica mold and the reservoir system are separated. 
         FIG. 19A  is an exemplary top-level block diagram illustrating another alternative embodiment of the replica mold of  FIG. 14B , wherein the reservoir system of  FIG. 17  is disposed within a vacuum chamber. 
         FIG. 19B  is an exemplary top-level block diagram illustrating an alternative embodiment of the replica mold of  FIG. 19A , wherein the vacuum chamber is in a sealed position. 
         FIG. 19C  is an exemplary top-level block diagram illustrating an alternative embodiment of the replica mold of  FIG. 19B , wherein a vacuum system for applying a vacuum to the vacuum chamber is enabled. 
         FIG. 19D  is an exemplary top-level block diagram illustrating an alternative embodiment of the replica mold of  FIG. 19C , wherein the reservoir system is disposed adjacent to the replica mold. 
         FIG. 19E  is an exemplary top-level block diagram illustrating an alternative embodiment of the replica mold of  FIG. 19D , wherein the vacuum applied by the vacuum system is adjusted. 
         FIG. 19F  is an exemplary top-level block diagram illustrating an alternative embodiment of the replica mold of  FIG. 19E , wherein a shutter system of the reservoir system enters an open position for enabling reservoir openings formed by the reservoir system to communicate with microneedle wells formed in the replica mold. 
         FIG. 19G  is an exemplary top-level block diagram illustrating an embodiment of the shutter system of  FIG. 19F , wherein the shutter system is disposed in a closed position. 
         FIG. 19H  is an exemplary top-level block diagram illustrating an alternative embodiment of the shutter system of  FIG. 19F , wherein the shutter system is disposed in the open position. 
         FIG. 19I  is an exemplary top-level block diagram illustrating an alternative embodiment of the replica mold of  FIG. 19F , wherein the reservoir system dispenses the microneedle material onto the replica mold. 
         FIG. 19J  is an exemplary top-level block diagram illustrating an alternative embodiment of the replica mold of  FIG. 19I , wherein the shutter system is disposed in the closed position. 
         FIG. 19K  is an exemplary top-level block diagram illustrating an alternative embodiment of the replica mold of  FIG. 19J , wherein the replica mold is disposed distally from the vacuum system. 
         FIG. 19L  is an exemplary top-level block diagram illustrating an alternative embodiment of the replica mold of  FIG. 19K , wherein the vacuum system is disabled. 
         FIG. 20  is an exemplary top-level flow diagram illustrating an alternative embodiment of the method for forming the microneedle array of  FIG. 16 , wherein the reservoir system is disposed within the vacuum chamber of  FIGS. 19A-L . 
     
    
    
     It should be noted that the figures are not drawn to scale and that elements of similar structures or functions are generally represented by like reference numerals for illustrative purposes throughout the figures. It also should be noted that the figures are only intended to facilitate the description of the preferred embodiments. The figures do not illustrate every aspect of the described embodiments and do not limit the scope of the present disclosure. 
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     Since currently-available microneedle devices must remain affixed to the skin while the microneedles dissolve and are inconvenient, unsightly, and/or uncomfortable for the user, a microneedle device that overcomes these disadvantages can prove desirable and provide a basis for a wide range of microneedle device applications, such as delivery of polymeric and/or biocompatible compositions beneath and/or within the skin surface to reduce (or eliminate) fine lines, wrinkles, stretch marks, scars, cellulite, and other skin imperfections or to smooth, texture, tighten, and/or hydrate the skin. This result can be achieved, according to one embodiment disclosed herein, through the manufacture of a microneedle  100  as illustrated in  FIGS. 1A-B . 
     Turning to  FIGS. 1A-B , the microneedle  100  can be provided as a three-dimensional structure with a predetermined shape, size and/or dimension and can comprise a preselected microneedle material  130 . The microneedle  100  can include a base region  110  and an apex (or upper body) region  120  that is opposite the base (or lower body) region  110 . A cross-section of the microneedle  100  adjacent to the base region  110  preferably is less than a cross-section of the microneedle  100  adjacent to the apex region  120 . Stated somewhat differently, the cross-section of the microneedle  100  can generally decrease from the base region  110  to the apex region  120 . The microneedle  100 , for example, can have a generally conical shape as illustrated in  FIG. 1A , a generally diamond shape as shown in  FIG. 1B , or a generally pyramidal shape. 
     A selected microneedle  100  can be characterized by an apex region  120  and a base region  110  that may or may not be symmetrical. The base region  110  may have any convenient dimension including for example, less than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% of a total height of the microneedle  100 . Advantageously, if provided with a diamond shape and/or a pyramidal shape, the microneedle  100  may more rapidly detach from a microneedle device, such as the microneedle device  200  shown in  FIGS. 2A-B , because the base region  110  provides a small point of attachment between the microneedle  110  and the microneedle device. 
     The microneedles  100  may have any height suitable to application to the skin. The microneedle height may be selected to reach or target specific depths or skin layers including for example, the epidermis, dermis, and subcutaneous tissue, or specific boundary regions such as the dermal/epidermal junction. 
     In one embodiment, the preselected microneedle material  130  can comprise any polymeric and/or nonpolymeric solution suitable for making microneedles for an intended purpose. Exemplary polymeric solutions can include a natural or synthetic polymeric solution, including a sugar, a sugar alcohol, a polysaccharide, a carbohydrate, cellulose, and/or a starch. In some embodiments, the microneedles  100  can be intended to deliver cosmetic and therapeutic agents to and across the skin by pressing the relatively hard microneedles of the array into the skin surface such that the microneedles penetrate the stratum corneum, epidermis, and/or dermis. Suitable polymeric solutions or ingredients that may be used in the manufacture of microneedles include, but are not limited to, gelatin, hydroxypropyl methylcellulose (HPMC), ethanol, arginine, polyols, silk, superabsorbent hydrogels, superporous hydrogels, polymethyl vinyl ether-alt-maleic anhydride (PMVE/MA), maltose, HEPES (influenza vaccine stabilizer), glycerol, collagen, calcium hydroxylapatite, poly-L-lactic acid (PLLA), polymethyl methacrylate (PMMA), alginate, fructose, raffinose, chondroitin sulfate, galactose, dextrin, self-assembling peptides, etc. 
     In some embodiments, the microneedles  100  contain at least one polymer selected from the group consisting of pullulan, hyaluronic acid (HA), polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), cellulose, sodium carboxymethyl cellulose (SCMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), amylopectin (AMP), silicone, polyvinylpyrolidone (PVP), polyvinyl alcohol (PVA), poly(vinylpyrrolidone-co-methacrylic acid) (PVA-MAA), polyhydroxyethylmethacrylate (pHMEA), polyethlene glycol (PEG), polyethylene oxide (PEO), polyacrylic acid, chrondroitin sulfate, dextrin, dextran, maltodextrin, chitin, chitosan, mono- and polysaccharides, galactose, and maltose. In particular embodiments, the microneedles  100  comprise hyaluronic acid or a mixture of hyaluronic acid and pullulan. In some embodiments, the microneedles  100  also contain at least one sugar alcohol (e.g., mannitol, sorbitol, and xylitol). In some embodiments, the microneedles  100  also contain an active ingredient. 
     In some embodiments, the microneedles  100  contain 1.0%-7.5% hyaluronic acid (HA), 2.5%-15% pullulan, and 0.5%-5.0% mannitol. The HA may be crosslinked or uncrosslinked. Optionally, uncrosslinked HA may be present at about 3%-6%. Optionally, crosslinked HA may be present at about 1%-4%. Optionally, pullulan is present in a concentration of about 3%-12%, including 3%-6%, 5%-10%, and 4%-12%. 
     In other embodiments, the microneedles  100  contain a mixture of low molecular weight HA (“low MW HA”) and high molecular weight HA (“high MW HA”). In some embodiments, the low MW HA is present in a concentration of about 0.25-5%, including for example, 1.0-3.0% (e.g., about 0.25%, 0.5%, 0.75%, 1.0%, 1.25%, 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25%, 4.5%, 4.75%, and 5%) and the high MW HA is present in a concentration of about 0.25%-3.0%, including for example, about 0.25%, 0.5%, 0.75%, 1.0%, 1.25%, 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, and 3.0%. 
     By “microneedles” is meant a plurality of protrusions, as described herein, and have a height, measured from the inner surface of the intermediate layer, or the inner surface of the substrate layer, if present, to the tip of the microneedle, of about 100 μm-1,500 μm, including for example about 300 μm-1,000 μm, or about 400 μm-800 μm, including about 100 μm, 200 μm, 300 μm, 400 μm, 500 μm, 600 μm, 700 μm, 800 μm, 900 μm, 1,000 μm, 1,100 μm, 1,200 μm, 1,300 μm, 1,400 μm, and 1,500 μm. In other embodiments, the aspect ratio (i.e., ratio of height to base) of the microneedles  100  is about 1.0-4.0, including about 1.5-3.5, and 2.0-3.0, including, for example, about 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, and 4.0. In some embodiments, the microneedles  100  have absolute dimension for the base of about 50 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, 500 μm, 550 μm, or 600 μm. In other embodiments, the microneedles  100  have an absolute dimension (height to base) of about 400:200 μm, 600:300 μm, or 800:400 μm. Microneedles  100  may be formed into any suitable shape including, for example, conical, diamond, tetrahedral, and pyramidal shapes. 
     By “pullulan” is meant a polysaccharide polymer consisting of maltotriose units in which the three glucose units in maltotriose are joined by an α-1,4 glycosidic bond and consecutive maltotriose units are joined to each other by an α-1,6 glycosidic bond. In some embodiments, pullulan has an average molecular weight of about 5,000-20,000 Da, including about 7,500-15,000 Da (e.g., about 5,000, 6,000, 7,000, 8,000, 9,000, 10,000, 11,000, 12,000, 13,000, 14,000, 15,000, 16,000, 17,000, 18,000, 19,000, and 20,000 Da, or more). 
     When referring to relative polymer concentrations (i.e., percentages), for convenience, reference is made to the polymer concentration in solution prior to molding and drying. 
     Advantageously, one or more microneedles  100  can collectively comprise a microneedle device  200  as illustrated in  FIGS. 2A-B . The microneedle device  200 , in other words, can include a microneedle array  210  having at least one microneedle  100 . The microneedles  100  in the microneedle array  210  can be disposed in any predetermined arrangement and/or configuration. As shown in  FIG. 2A , for example, the microneedles  100  can be uniformly aligned such that the base region  110  of a selected microneedle  100  is positioned adjacent to the base region  110  of a neighboring microneedle  100 . The apex regions  120  of the microneedles  100  can extend in substantially the same direction. Although shown and described as having microneedles  100  with uniform shape, size and/or dimension for purposes of illustration only, the microneedle array  210  can include microneedles  100  with uniform and/or different shapes, sizes and/or dimensions as desired. 
       FIG. 2B  is an exemplary plan view of the microneedle device  200  with the apex regions  120  of the microneedles  100  shown as extending from the drawing sheet. The microneedles  100  can be arranged in any predetermined pattern. For example, the microneedle array  210  can include one or more microneedles  100  disposed in a regularly-distributed pattern and/or one or more microneedles  100  disposed in an irregularly-distributed (or random) pattern. An exemplary regularly-distributed pattern for the microneedle array  210  can comprise can include a plurality of parallel rows of the microneedles  100  and/or a plurality of parallel columns of the microneedles  100 . As shown in  FIG. 2B , for instance, the microneedles  100  can be arranged in offset (or out-of-phase) rows. Incorporated by reference U.S. patent application Ser. No. 15/821,314, filed on Nov. 22, 2017, also sets forth additional detail about the structure and application of the microneedle device  200 . 
     The microneedles  100  of the microneedle array  210  can comprise at least one individual (or separate) microneedle  100  and/or at least one group of cooperating (or coupled) microneedles  100 . Stated somewhat differently, the microneedle array  210  can comprise one or more microneedles  100  that are discontinuous as illustrated in  FIG. 2A  and/or one or more microneedles  100  that are physically connected as illustrated in  FIGS. 3A-B . The cooperating microneedles  100  can be coupled in any conventional manner. For example, the cooperating microneedles  100  are shown in  FIG. 3A  as being coupled via the preselected microneedle material  130 . The preselected microneedle material  130  can extend from, and couple, the base regions  110  of the cooperating microneedles  100  in one embodiment. In other words, the cooperating microneedles  100  can be physically connected via a residual layer (or sheet)  150  of the preselected microneedle material  130 . The cooperating microneedles  100  thereby can comprise a contiguous structure. 
     By comprising a contiguous structure, the cooperating microneedles  100  advantageously are easier to manufacture than individual microneedles. In addition, the residual layer  150  of the preselected microneedle material  130  can contain the active ingredients of the preselected microneedle material  130  that may be delivered into the skin through diffusion upon dissolution of the microneedles  100 . A dosage of the active ingredients delivered by the microneedle array  210  thereby can be increased. Furthermore, the cooperating microneedles  100  as a contiguous structure can make a backing layer  220  (shown in  FIG. 3B ) optional, for example, when the microneedle material  130  forms a residual layer  150  with some strength and/or flexibility. 
     Additionally and/or alternatively, the microneedle device  200  is illustrated in  FIG. 3B  as including the optional backing layer  220 . The cooperating microneedles  100  of the microneedle array  210  thereby can be coupled via the backing layer  220 . By coupling the microneedles  100  in the microneedle array  210 , the predetermined arrangement, configuration and/or pattern of the microneedles  100  advantageously can be maintained. Incorporated by reference U.S. patent application Ser. No. 15/821,314, filed on Nov. 22, 2017, also sets forth additional detail about the coupling of the microneedles  100 , including the backing layer  220 , as well as optional treatment of the backing layer  220  with a liquid, such as water, after applying the microneedle device  200  to the skin during use. 
     Manufacture of the Microneedle Device  200   
     The microneedle device  200  can be manufactured via a manufacturing method as set forth herein, such as wet etching or dry etching using a silicon base, precision machining using metal or resin (electro-discharge machining, laser processing, grinding, hot embossing, injection molding, etc.), and/or machinery cutting, without limitation. For embodiments in which hollow microneedles  100  are desired, the microneedles  100  can be hollowed during the molding process and/or by secondary processing, such as via laser cutting. 
     Other suitable methods for manufacturing the microneedle array  210  can include centrifuge casting (see, for example, U.S. Patent Application Publication No. 2009/0182306 to Lee, et al.) and lithography (see, for example, Moga, et al., “Rapidly-Dissolvable Microneedle Patches Via a Highly Scalable and Reproducible Soft Lithography Approach,” Adv. Mater. 2013; DOI:10.102/adma.201300526). In centrifuge casting, a microneedle mold (not shown) that defines one or more microneedle mold cavities is produced by an appropriate technique such as photolithography or by etching in a silicon substrate, such as a substrate formed from polydimethyl siloxane (PDMS). An aqueous polymeric solution can be prepared and placed into the microneedle mold as, for example, a viscous and/or elastic gel or a non-viscous solution. The filled microneedle mold can be centrifuged under conditions that promote filling of the microneedle mold cavities. The filled microneedle mold can be dried. Optionally, the microneedle mold can be partially filled several times with the same and/or different polymeric solutions to allow for customization of the microneedles  100  over their length and/or for the incorporation of active ingredients in specific portions/layers of the microneedles  100 . In other casting techniques, the polymer solution can be forced into the microneedle mold using positive pressure (rollers, e.g. the Particle Replication in Non-wetting Templates (or PRINT) process) or negative pressure (or a vacuum). 
     An exemplary method  300  for manufacturing the microneedle device  200  is shown in  FIG. 4 . As shown in  FIG. 4 , the method  300  includes manufacturing a replica mold  400  (shown in  FIGS. 5A-B ), at  310 , and forming a microneedle array  210  (shown in  FIGS. 2A-B ) via the replica mold  400 , at  350 . Since a selected replica mold  400  can be reusable in some embodiments, manufacturing the replica mold  400 , at  310 , can be considered to be optional for manufacturing the microneedle device  200 , at  350 . In other words, the selected replica mold  400  can be repeatedly used to successively form multiple microneedle arrays  210 , at  350 , such that a new replica mold  400  need not be manufactured for the microneedle array  210  of each microneedle device  200 . 
     Manufacture of the Replica Mold  400   
     An exemplary replica mold  400  is illustrated in  FIGS. 5A-B . Turning to  FIGS. 5A-B , the replica mold  400  can be provided as a three-dimensional structure with a predetermined shape, size and/or dimension and can comprise a preselected replica mold material  450 . The replica mold  400  can include an upper region  410  and a lower region  440 . The upper region  410  preferably is opposite the lower region  440 . 
     The replica mold  400  can define a plurality of microneedle wells  420 . Each of the microneedle wells  420  comprises a respective recess  422  that is formed within the replica mold  400  and that communicates with an associated opening  424  formed in the upper region  410 . The microneedle wells  420  preferably are provided as a microneedle well array  430  that corresponds with the microneedles  100  in the microneedle array  210  (collectively shown in  FIGS. 2A-B ). Stated somewhat differently, each microneedle well  420  preferably has a shape, size and/or dimension that is a negative (or inverse) of the shape, size and/or dimension of a corresponding microneedle  100  in the microneedle array  210 . Thereby, when filled with the microneedle material  130 , a selected microneedle well  420  molds the microneedle material  130  into the shape, size and/or dimension of the corresponding microneedle  100 . 
       FIG. 5B  is an exemplary plan view of the replica mold  400  with the microneedle wells  420  of the microneedle well array  430  shown as extending into the drawing sheet. The microneedle wells  420  can be arranged in any predetermined pattern. For example, the microneedle well array  430  can include one or more microneedle wells  420  disposed in a regularly-distributed pattern and/or one or more microneedle wells  420  disposed in an irregularly-distributed (or random) pattern. An exemplary regularly-distributed pattern for the microneedle well array  430  can comprise can include a plurality of parallel rows of the microneedle wells  420  and/or a plurality of parallel columns of the microneedle wells  420 . As shown in  FIG. 5B , for instance, the microneedle wells  420  can be arranged in offset (or out-of-phase) rows, which correspond to the predetermined pattern of microneedles  100  illustrated in  FIG. 2B . Although shown and described as having microneedle wells  420  with uniform shape, size and/or dimension for purposes of illustration only, the microneedle well array  430  can include microneedle wells  420  with uniform and/or different shapes, sizes and/or dimensions as desired. 
     In one embodiment, the replica mold material  450  can comprise any suitable silicone elastomer, such as PDMS. Preferred characteristics of the silicone elastomer include biocompatibility (such as medical grade or implantable class), low viscosity, fast curing rate, high gas permeability, low elongation (without being brittle), a predetermined mixing ratio (such as a predetermined base-to-curing agent mixing ratio between about 1:1 and 10:1) and/or compatibility with dispenser systems. More specifically, the silicone elastomer preferably has a viscosity between 1-5 Pas and/or a curing time between one and fifteen minutes when exposed to heat or ultraviolet light. Exemplary silicone elastomers can include: SYLGARD® 184 manufactured by Dow Corning Corporation of Auburn, Mich.; the Wacker Silpuran series of silicone elastomers manufactured by Wacker Chemie AG of Munich, Germany; MED-6015 or MED-6215 silicone elastomer manufactured by NuSil™ Technology LLC of Carpinteria, Calif.; and/or Bluesil ESA 7246 manufactured by Bluestar Silicones USA Corp. of Brunswick, N.J. In some embodiments, the silicone elastomer can be hydrophobic; whereas, in other embodiments, such as replica molds  400  for forming individual microneedles  100 , the silicone elastomer can be hydrophilic. In one embodiment, the silicone elastomer can include one or more surface modifying agents. An exemplary surface modifying agent can be n-Wet  410 D silicone compound manufactured by Enroute Interfaces, Inc., of Ontario, Canada. 
     Additionally and/or alternatively, the replica mold material  450  can comprise any suitable type of porous material. Exemplary suitable porous materials can include polyethylene oxide (PEO) polybutylene terephthalate (PBT) block copolymers, and sulfonated polyetheretherketon (SPEEK); and/or METAPOR® ceramic composite material manufactured by Portec Ltd. of Aadorf, Switzerland. 
     In one embodiment, the replica mold material  450  can comprise a translucent (or transparent) material. Use of the translucent replica mold material  450  to form the replica mold  400  can enable light-based curing, such as ultraviolet (UV) curing, of the microneedle material  130  within the microneedle wells  420 . The translucent replica mold material  450  likewise can facilitate visualization and/or quality control as the microneedle wells  420  are filled with the microneedle material  130 , during the molding process and/or after the microneedles are cured. An operator thereby can visually monitor the microneedle material  130  within the microneedle wells  420  during manufacture of the microneedle device  200  via camera and/or fluorescence quality analysis. 
     In a different embodiment, the replica mold material  450  can comprise a black (or opaque) material. Use of the black replica mold material  450  to form the replica mold  400  can enable rapid infrared (IR) curing of the microneedle material  130  within the microneedle wells  420 . The black replica mold material  450  likewise can help to maintain heat within the replica mold  400 . 
     The properties of silicone microneedle molds provide significant advantages over conventional molds that are made from hard plastic, such as acrylic, or conventional silicone molds that are fixed to a hard substrate, such as a plastic, a ceramic, or an epoxy. The flexibility of silicone rubber advantageously minimizes damage to the cured microneedles  100  when the microneedle array  210  is removed from the mold, especially when the mold is manually peeled and/or automatedly peeled, such as via a robot arm, from the cured microneedle array  210  rather than the microneedle array  210  being peeled from the replica mold  400 . 
     The replica mold  400  (shown in  FIGS. 5A-B ) can be manufactured via any suitable process. An exemplary method  310  for manufacturing the replica mold  400  is illustrated in  FIG. 6 . As shown in  FIG. 6 , the method  310  includes disposing replica mold material  450  on a master mold  500  (shown in  FIGS. 7A-B ), at  314 , and curing the replica mold material  450  to form the replica mold  400 , at  316 . The master mold  500  can be manufactured from any suitable preselected master mold material, which preferably has a particularly high thermal conductivity, can be reliably micro-machined, is relatively lightweight and/or is relatively low cost. Preferably comprising a reusable mold, the master mold  500  can be created on a hard substrate such as a metal (e.g., aluminum, copper or brass), a plastic (e.g., an acrylic), silicon (e.g. SU-8 epoxy-type, near-UV photoresist, manufactured by MicroChem Inc. of Newton, Mass., on a silicon wafer), a ceramic and/or an epoxy, without limitation. In other words, a selected master mold  500  can be repeatedly used to successively manufacture multiple replica molds  400 . 
     An exemplary master mold  500  is illustrated in  FIGS. 7A-B . Turning to  FIGS. 7A-B , the master mold  500  can be provided as a three-dimensional structure with a predetermined shape, size and/or dimension. The master mold  500  can include an upper region  510  and a lower region  540 . The upper region  510  preferably is opposite the lower region  540 . 
     The master mold  500  can define a plurality of microneedle projections  520 . The microneedle projections  520  can extend from the upper region  510  and preferably are provided as a microneedle projection array  530  that corresponds with the microneedles  100  in the microneedle array  210  (collectively shown in  FIGS. 2A-B ). Stated somewhat differently, each microneedle projection  520  preferably is a replica of a corresponding microneedle  100  in the microneedle array  210  and has the same shape, size and/or dimension as the corresponding microneedle  100 . In one embodiment, the master mold  500  can include one or more dividers (or walls) (not shown) that at least partially enclose the microneedle projections  520 . The dividers advantageously can prevent the replica mold material  450  from spreading beyond the microneedle projections  520  and thereby reduce an amount of scrap when the replica mold material  450  is disposed on the master mold  500 . 
       FIG. 7B  is an exemplary plan view of the master mold  500  with the microneedle projections  520  of the microneedle projection array  530  shown as extending from the drawing sheet. The microneedle projections  520  can be arranged in any predetermined pattern. For example, the microneedle projection array  530  can include one or more microneedle projections  520  disposed in a regularly-distributed pattern and/or one or more microneedle projections  520  disposed in an irregularly-distributed (or random) pattern. An exemplary regularly-distributed pattern for the microneedle projection array  530  can comprise can include a plurality of parallel rows of the microneedle projections  520  and/or a plurality of parallel columns of the microneedle projections  520 . As shown in  FIG. 7B , for instance, the microneedle projections  520  can be arranged in offset (or out-of-phase) rows, which correspond to the predetermined pattern of microneedles  100  illustrated in  FIG. 2B . Although shown and described as having microneedle projections  520  with uniform shape, size and/or dimension for purposes of illustration only, the microneedle projection array  530  can include microneedle projections  520  with uniform and/or different shapes, sizes and/or dimensions as desired. 
     In the manner discussed above with reference to  FIG. 6 , the replica mold material  450  can be disposed on the master mold  500 , at  314 .  FIG. 8A  shows the master mold  500  with the replica mold material  450  being disposed thereon. The replica mold material  450  can be disposed on the master mold  500  in a manual manner, such as via a syringe, and/or in an automated manner, such as via a dispenser nozzle. If the replica mold material  450  comprises a silicone elastomer, such as PDMS material, for example, the PDMS material can be mixed and/or poured under preselected environmental conditions. Exemplary environmental conditions can include a clean room with a predetermined clean room temperature, such as 21° C.±1° C., and/or a predetermined clean room relative humidity, such as 40% RH±10% RH. The PDMS material can be mixed in a manual manner and/or in an automated manner and/or can be degassed via a vacuum system  700  (shown in  FIGS. 18A-E ). In one embodiment, the PDMS material can be degassed for a predetermined time period, such as fifteen minutes, at the clean room temperature. Preferably, the PDMS material can be degassed in a periodic (or cyclic) manner with the PDMS material being subjected to a vacuum during a first time period, such as one minute, and then being permitted to return to normal pressure and settle during a second time period, such as three minutes. The first and second time periods can be repeated, as desired. 
     The replica mold material  450  is dispensed onto the master mold  500  to a suitable height and can receive the microneedle projections  520  as shown in  FIG. 8B . The dispensed replica mold material  450  can be cured, at  316 , to form the desired replica mold  400  with the microneedle well array  430  of the microneedle wells  420  as shown in  FIGS. 5A-B . 
     The replica mold material  450  may be cured using any suitable curing process, such as heat or UV, including according to the instructions of a manufacturer of the replica mold material  450 . In the case of PDMS material, the typical curing process involves the application of moderate heat (about 60-100° C.) for an extended period of time (about 35-90 minutes). The moderate heat can be applied to the PDMS material in any conventional manner, such as by placing the lower region  540  of the filled master mold  500  on a heat source (not shown), such as a hot plate or an oven. 
     The extended curing times associated with the manufacture of the replica mold  400  can be limiting in high-throughput operations, including those operations in which the resulting microneedle device  200  will be stored and/or shipped in the replica mold  400 . Thus, in some embodiments, the replica mold  400  may have only a single use. In an effort to increase the production rate of the replica mold  400 , various PDMS curing conditions were evaluated in order to reduce the curing time of the replica mold  400  without significantly impairing the performance of the cured PDMS material in the microneedle molding process. 
     It was surprisingly discovered that microneedle molding performance was not impaired when the PDMS material was cured at a high temperature (e.g., at least 150° C., 160° C., 170° C., 180° C., 190° C., 200° C. or more) for a relatively short time (e.g., less than five minutes, less than ten minutes, or less than fifteen minutes) and cooled quickly before removal of the master mold  500 . In other words, the PDMS material can be cured at a preselected temperature (and/or within a preselected range of temperatures) for a preselected time period (and/or within a preselected range of time periods). Exemplary preselected temperature ranges can include a predetermined temperature range between 150° C. and 300° C., including any temperature sub-ranges, such as a five degree sub-range (i.e., between 180° C. and 185° C.) and/or a ten degree sub-range (i.e., between 180° C. and 190° C.), within the predetermined temperature range, without limitation. Exemplary preselected time period ranges can include a predetermined time period range between one minute and twenty minutes, including any time period sub-ranges, such as a one minute sub-range (i.e., between nine minutes and ten minutes) and/or a five minute sub-range (i.e., between five minutes and ten minutes), within the preselected time period range, without limitation. When micro-molding, PDMS material generally is not cured at these elevated temperatures (and shorter curing times) because the resulting product may be more brittle and/or may contain crystallized regions. As the thermosetting PDMS material hardens with a higher modulus, the PDMS material may be less suitable for certain applications than that created by lower temperature cures. 
     The production rate of replica molds  400  can be limited by an extended time to heat the replica mold material. In an effort to reduce manufacturing time for replica molds  400 , a selected master mold  500  can include a predetermined number of the microneedle projection arrays  530  such that each of the microneedle projection arrays  530  can manufacture a separate replica mold  400 . The predetermined number of the replica molds  400  can be manufactured concurrently via the selected master mold  500 . Additionally and/or alternatively, more than one master mold  500  can be disposed on, and heated by, a selected heat source at a given time and/or a plurality of heat sources can be provided to heat a plurality of the master molds  500 . 
     The production rate of replica molds  400  likewise can be limited by an extended time to cool the replica mold material. For example, contrary to conventional cooling methods, rapid and controlled cooling of the PDMS material can be achieved by moving the master mold  500  from the heat source onto a cool surface to quickly dissipate the heat from the master mold  500  and thus from the PDMS material disposed on the master mold  500 . In one embodiment, the cooling time for the PDMS material can be reduced via water cooling. The master mold  500 , for example, can define one or more internal and/or external cooling channels (not shown) and an automatic water circulation cooling system (not shown) can circulate water through the cooling channels of the master mold  500 , cooling the master mold  500  and thus the PDMS material on the master mold  500 . 
     Turning to  FIG. 9A , the master mold  500  with the replica mold material  450  is shown as being disposed on a cooling device for cooling the replica mold material  450  to form the replica mold  400 . The cooling device can comprise any type of suitable cooling device. For example, the cooling device can comprise a metal block  600  at an ambient room temperature, such as 21° C. The material used to form the metal block  600  preferably has a particularly high thermal conductivity, is relatively lightweight and/or is relatively low cost such as aluminum, copper or brass. The heated master mold  500  with the replica mold material  450  can be disposed on the metal block  600  for a predetermined time period (and/or within a preselected range of time periods). Exemplary preselected time period ranges can include a predetermined time period range between thirty seconds and ten minutes, including any time period sub-ranges, such as a one minute sub-range (i.e., between four minutes and five minutes) and/or a three minute sub-range (i.e., between two minutes and five minutes), within the preselected time period range, without limitation. The heated master mold  500  with the replica mold material  450  thereby can be cooled to a preselected reduced temperature (and/or a preselected reduced temperature range), such as between 30° C. and 35° C. within the predetermined time period (and/or within the preselected range of time periods). 
     In one embodiment, the cooling device can comprise a plurality of cooling devices. For example,  FIG. 9B  shows that the cooling device can comprise a predetermined number of the metal blocks  600 . The heated master mold  500  with the replica mold material  450  can be disposed on a first metal block  600 A for the predetermined time period to be cooled to a first reduced temperature. Upon expiry of the predetermined time period, the heated master mold  500  with the replica mold material  450  can be disposed on a second metal block  600 B for the predetermined time period to be cooled to a second reduced temperature. The heated master mold  500  with the replica mold material  450  then can be disposed on a third metal block  600 C for the predetermined time period to be cooled to a third reduced temperature and so on until the heated master mold  500  with the replica mold material  450  achieves the preselected reduced temperature (and/or a preselected reduced temperature range). The metal blocks  600  can comprise a linear series of metal blocks  600 A- 600 N, as shown in  FIG. 9B , and/or can comprise a looped series of metal blocks  600 A- 600 N, wherein the heated master mold  500  with the replica mold material  450  returns to metal block  600 A after being cooled on metal block  600 N. Movement and/or positioning of the heated master mold  500  with the replica mold material  450  on the metal blocks  600  can be performed in a manual manner and/or in an automated manner, such as via a pick-and-place machine. 
     Additionally and/or alternatively, the cooling device can include a plurality of cooling regions. The cooling device of  FIG. 9C  is shown as being a metal block  600  with a plurality of cooling regions  610 . The heated master mold  500  with the replica mold material  450  can be disposed on a selected cooling region  610  for the predetermined time period to be cooled to a first reduced temperature. Upon expiry of the predetermined time period, the heated master mold  500  with the replica mold material  450  can be disposed on a different cooling region  610  for the predetermined time period to be cooled to a second reduced temperature. The heated master mold  500  with the replica mold material  450  then can be disposed on another cooling region  610  for the predetermined time period to be cooled to a third reduced temperature and so on until the heated master mold  500  with the replica mold material  450  achieves the preselected reduced temperature (and/or a preselected reduced temperature range). Movement and/or positioning of the heated master mold  500  with the replica mold material  450  on the cooling regions  610  can be performed in a manual manner and/or in an automated manner, such as via a pick-and-place machine. 
     After curing of the replica mold material  450  is complete, the replica mold  400  optionally can be separated from the master mold  500 , at  318 , as shown in  FIG. 10B . The replica mold material  450  preferably is easy to release from the master mold  500 . In other words, the replica mold  400  should be removable from the master mold  500  without incurring damage to either the replica mold  400 , the master mold  500  or both. The resultant negative replica mold  400  can be suitable for use in forming the microneedle array  210  of the microneedle device  200 , at  350  (shown in  FIG. 4 ). 
     Manufacture of the Microneedle Array  210   
     In one embodiment, the microneedle array  210  can be formed, at  350 , in the manner illustrated in  FIG. 11 . As shown in  FIG. 11 , the microneedle array  210  can be formed, at  350 , by disposing the microneedle material  130  on the replica mold  400  (shown in  FIG. 12 ), at  352 , and drying (and/or curing) the microneedle material  130  as disposed on the replica mold  400 , at  356 , to form the microneedle array  210  (shown in  FIGS. 2A-B ,  3 A). The replica mold  400  may be retained in a carrier jig (i.e., a rigid reservoir) (not shown) to facilitate filling, handling, and/or other processes associated with the manufacture of the microneedle array  210 . In the manner discussed in more detail above, the microneedles  100  can comprise cooperating microneedles  100  that can be physically connected via a residual layer  150  of the preselected microneedle material  130  in the manner illustrated in  FIG. 3A  and/or separate microneedles  100  in the manner illustrated in  FIG. 2A . 
     Manufacture of the Microneedle Array  210  with a Residual Layer  150   
     As set forth in additional detail above with reference to  FIG. 3A , the microneedles  100  can be physically connected via a residual layer  150  of the preselected microneedle material  130 . To form the microneedles  100 , the microneedle material  130  can be disposed on the replica mold  400 . Stated somewhat differently, the replica mold  400  can be coated with an excess of uncured microneedle material  130 . In one embodiment, the microneedle material  130  can be dispensed in droplets to one or more predetermined positions on the replica mold  400  to help assure that optimal coverage of the replica mold  400  can be achieved. 
     Turning to  FIGS. 13 and 14A -B, forming the microneedle array  210 , at  350 , can include distributing, at  354 , the microneedle material  130  into one or more microneedle wells  420  formed in the replica mold  400 . The microneedle material  130  preferably fills each of the microneedle wells  420  from the opening  424  formed in the upper region  410  of the replica mold  400  to the recess  422  that is formed within the replica mold  400 . The microneedle material  130 , when cured, thereby can form microneedles  100  each having the base region  110  and the apex region  120  in the manner described above with reference to  FIGS. 1A-B . 
     Advantageously, manufacturing the individual needles  100  in this manner can generate less scrap than conventional manufacturing methods, such as a standard coating process. Scrap can be reduced, for example, because the individual needles  100  can be manufactured without the residual layer  150  of microneedle material  130 . Furthermore, the manufacture of the individual microneedles  100  in the manner set forth above can present cost savings such as when the active ingredient(s) of the preselected microneedle material  130  are expensive. Exemplary microneedle materials  130  with high-cost active ingredients can include, but are not limited to, crosslinked hyaluronic acid as well as certain drugs, vaccines, toxins, etc. 
     The microneedle material  130  can be distributed evenly across the replica mold  400  in any suitable manner. Exemplary suitable manners for distributing the microneedle material  130  can include passive distribution via, for instance, a flowing action of the microneedle material  130  and/or active distribution via positive pressure. The positive pressure can be applied to the microneedle material  130  in any appropriate manner, including via mechanical compression such as a flat sheet (formed from metal and/or plastic), a weight, a roller, a stencil, a squeegee or other similar tool. 
     As illustrated in  FIG. 13 , forming the microneedle array  210 , at  350 , optionally can include disposing backing material, such as the backing layer  220  (shown in  FIG. 3B ), onto the microneedle material  130 , at  355 . The backing layer  220  can comprise one or more additional layers of different materials that can be placed on the microneedle material  130  for facilitating efficient bonding between the various layers that comprise the final microneedle device  200  (shown in  FIGS. 2A-B ,  3 A-B). The backing layer  220  can be placed on the microneedle material  130  as a part of the disposing of the microneedle material  130  on the replica mold  400 , at  352 , the distributing the microneedle material  130  into one or more microneedle wells  420 , at  354 , and/or the drying the microneedle material  130 , at  356 , and/or can comprise a separate (or independent) placement process. A suitable backing layer  220  can include, for example, a dissolvable layer (e.g., comprising pullulan or another water soluble polymer or polysaccharide), an air- and/or liquid-permeable mesh, an occlusive layer, a non-occlusive layer and/or any other type of backing layer. 
     In one embodiment, the backing layer  220  is non-occlusive, water-permeable, and adapted to support the microneedle material  130  and/or the additional layers of different materials that can be placed on the microneedle material  130 . Backing layer  220  may be formed from any suitable web, mesh, or woven material including, for example, pressed, woven and non-woven cellulose fibers, PLA webs, and membrane filters (e.g., porous films of polyester, nylon, and the like). The backing layer  220  may be substantially the same dimension the microneedle material  130  and/or the additional layers and/or may overhang the microneedle material  130  and/or the additional layers in one or dimension. In one embodiment, the backing layer  220  can have an overhang region that extends beyond the dimension of the microneedle material  130  and/or the additional layers. The overhang region may or may not be water-permeable and may be made from the same or different material than the remainder of the backing layer  220  that overlays the microneedle material  130  and/or the additional layers. 
     Advantageously, the backing layer  220  can include an optional adhesive (not shown), such as a pressure-sensitive adhesive, a medical grade adhesive, and/or a skin-friendly adhesive. For selected applications of the microneedle device  200 , such as microneedle devices  200  intended for being affixed to the skin of a user, the adhesive can be disposed on a skin-facing region of the backing layer  220 . 
     In the manner set forth above, a flat sheet (not shown) can be placed on top of the microneedle material  130  and any backing layer(s)  220 . In one preferred embodiment, the flat sheet can have a preselected shape, size and/or dimension that is greater than the predetermined shape, size and/or dimension of the microneedle array  210  and preferably can be at least partially disposed and/or retained within a carrier jig (not shown). The flat sheet can form a substantially gas-tight seal with the carrier jig. In another embodiment, a gas-impermeable top layer (not shown) can be placed on top of the microneedle material  130  and any backing layer(s)  220 . The gas-impermeable top layer can cover the microneedle array  210  and/or an inner dimension of the carrier jig. The gas-impermeable top layer may be incorporated into the microneedle device  200  as a part of the backing layer  220  and/or may be disposable prior to use of the microneedle device  200 . For example, the gas-impermeable top layer can be retained after the microneedle material  130  has been dried, at  356  (shown in  FIG. 13 ) and/or throughout subsequent storage of the microneedle device  200  as a protective layer, a water-impermeable layer, and/or an occlusive backing layer of the microneedle device  200 . 
     Additionally and/or alternatively, the gas-impermeable top layer can be used during a vacuum molding process.  FIG. 14B  illustrates another alternative embodiment of the replica mold  400 . As shown in  FIG. 14B , the replica mold  400  is disposed on a vacuum system  700 , such as a vacuum chamber  900  (shown in  FIG. 19A ) and/or a vacuum table, for distributing the microneedle material  130  into the microneedle wells  420 . The vacuum system  700  can be disposed adjacent to the lower region  440  of the replica mold  400  and subject the replica mold  400  to vacuum from below in order to draw the microneedle material  130  into the microneedle wells  420 . Although available for activation and/or deactivation at any suitable time, the vacuum system  700  preferably is activated as the microneedle material  130  is being disposed on the replica mold  400  and can remain activated until the microneedle material  130  within the replica mold  400  is ready for drying, at  356 . In other words, to increase immediacy of the suction, the vacuum system  700  can pull the vacuum on the empty replica mold  400  to degas the replica mold  400  prior to dispensing of the microneedle material  130 . 
     The excess microneedle material  130  (i.e., the volume of microneedle material  130  in excess of that required to fill the microneedle wells  420 ) can remain on the upper region  410  of the replica mold  400  and eventually can form the residual layer  150 . The specific vacuum pressure for filling the microneedle wells  420  can vary based on a gas permeability and thickness of the replica mold  400  and/or a viscosity of the microneedle material  130 . The vacuum drawn by the vacuum system  700  preferably is sufficient for drawing the microneedle material  130  fully into the microneedle wells  420  and to evacuate a majority of the air beneath the gas-impermeable top layer, including any air in the microneedle wells  420  and/or between any backing layer(s)  220 . In one embodiment, the majority of the air beneath the gas-impermeable top layer can be removed before the backing layer  220  is disposed on the microneedle material  130 . 
     Since surface tension can become a dominant force at the microscale, breaking down or displacing trapped air through positive pressure can become increasingly difficult. Advantageously, the air-permeability of the replica mold material  450  enables the suction of the vacuum system  700  to vacate air in the microneedle wells  420  through the replica mold  400  to efficiently fill the microstructures with the microneedle material  130 . In most applications, a suitable vacuum pressure can comprise a predetermined vacuum pressure, such as approximately 20 kPa, 40 kPa, 60 kPa, 80 kPa 100 kPa or even higher, and/or a predetermined range of vacuum pressures. Exemplary preselected vacuum pressure ranges can include a predetermined vacuum pressure range between 20 kPa and 100 kPa, including any vacuum pressure sub-ranges, such as a five kilopascal sub-range (i.e., between 90 kPa and 95 kPa) and/or a ten kilopascal sub-range (i.e., between 90 kPa and 100 kPa), without limitation. The vacuum may be applied to the replica mold  400  by any suitable means including, for example, filling one or more individual replica molds  400  on a vacuum system  700  that is adapted to receive a single or multiple carrier jigs. Additionally and/or alternatively, the vacuum system  700  can simultaneously accept multiple carrier jigs each adapted for holding a single replica mold  400  and/or one or more carrier jigs each adapted for holding multiple replica molds  400 . 
     If the vacuum system  700  comprises a vacuum chamber  900  (shown in  FIG. 19A ), care should be taken to not apply too much vacuum pressure. Excessive vacuum pressure can cause any gases dissolved in the microneedle material  130  to expand, thereby potentially introducing imperfections into the finally-cured microneedle array  210 . In one embodiment, the microneedle material  130  can be placed in a vacuum chamber condition (removal of most of the air) for a selected length of time, such as between six seconds and ten seconds. 
     Filling the replica mold  400  under vacuum conditions can provide significant advantages over traditional top-filling methods. These top-filling methods typically apply a great excess of microneedle solution to a microneedle mold and then force the solution into the microneedle mold via positive pressure (e.g., centrifugation, applied by rollers, weights, etc.). These methods often result in incomplete microneedle formation because the surface tension of the air increases as the cross-sections of the well recesses  422  (shown in  FIGS. 5A-B ) formed in the microneedle mold decrease toward a bottom end region of the well recesses. Air and any other gasses may become trapped beneath the microneedle solution at the bottom tip of the well recesses, preventing complete filling of the well recesses and resulting in a dull microneedle. At these micro-dimensions, the applied pressure may be insufficient to overcome the surface tension of the air within the well recesses and/or to force trapped air to vacate up through or around the microneedle solution. Use of the replica mold  400  formed from the gas-permeable replica mold material  450  advantageously obviates these problems because any trapped air is drawn out from the bottom of the microneedle well  420 , thereby promoting more-complete filling of the microneedle well  420 . 
     After the microneedle material  130  is distributed on the replica mold  400 , the microneedle material  130  can be dried (or cured), at  356 . The microneedle material  130  can be dried in any suitable manner, including via solvent (for example, water) evaporation to solid form and/or application of infrared (IR) energy. Curing, such as ultraviolet (UV) light and/or crosslinking, preferably occurs in a temperature- and/or humidity-controlled oven to control patch shape, texture, and consistency, using either static curing temperature/humidity (e.g., 40 Celsius/40-30% RH) or multistage curing (e.g., ramping from 40% RH to 35% to 30%). 
     During the curing, the various layers (i.e., the microneedle array  210  and/or the residual layer  150 ) of the microneedle device  200  bond to any additional layers that may be present. As desired one or more additional layers can be added to the microneedle device  200  after the microneedle array  210  is cured. 
     The microneedle material  130  can be cured at a preselected temperature (and/or within a preselected range of temperatures) for a preselected time period (and/or within a preselected range of time periods) while being subjected to a preselected relative humidity (and/or within a preselected range of relative humidities). Exemplary preselected temperature ranges can include a predetermined temperature range between 25° C. and 100° C., including any temperature sub-ranges, such as a five degree sub-range (i.e., between 40° C. and 45° C.) and/or a ten degree sub-range (i.e., between 40° C. and 50° C.), within the predetermined temperature range, without limitation. Exemplary preselected time period ranges can include a predetermined time period range between thirty minutes and five hours, including any time period sub-ranges, such as a thirty minute sub-range (i.e., between one hundred and twenty minutes and one hundred and fifty minutes) and/or a one hour sub-range (i.e., between two hours and three hours), within the preselected time period range, without limitation. Exemplary preselected relative humidity ranges can include a predetermined relative humidity range between 5% RH and 50% RH, including any relative humidity sub-ranges, such as a five percent sub-range (i.e., between 40% RH and 45% RH) and/or a ten percent sub-range (i.e., between 40% RH and 50% RH), within the preselected relative humidity range, without limitation. In one embodiment, the microneedle material  130  can be cured at 60° C. for two hours while being subjected to a relative humidity between 14% RH and 30% RH. Very preferably, the microneedle material  130  can be cured at 45° C. for three hours while being subjected to a relative humidity between 7% RH and 10% RH. 
     Crosslinks may be physical or chemical and intermolecular or intramolecular, and crosslinking polymers can be performed in any conventional manner. Crosslinking is the process whereby adjacent polymer chains, or adjacent sections of the same polymer chain, are linked together, preventing movement away from each other. Physical crosslinking occurs due to entanglements or other physical interaction. With chemical crosslinking, functional groups are reacted to yield chemical bonds. Such bonds can be directly between functional groups on the polymer chains or a crosslinking agent can be used to link the chains together. Such an agent could possess at least two functional groups capable of reacting with groups on the polymer chains. Crosslinking prevents polymer dissolution, but may allow a polymer system to imbibe fluid and swell to many times its original size. 
     In some embodiments, at least some of the microneedle material  130  can be lost during the drying, at  356 . If the microneedle material  130  is dried, at  356 , via solvent (for example, water) evaporation to solid form, for example, a selected amount of water volume of the microneedle material  130  can evaporate during drying. The water volume loss can result in one or more of the microneedles  100  being formed as a hollow shell of dried microneedle material  130  disposed on a periphery of the microneedle wells  420 . Additional microneedle material  130  can be disposed on the replica mold  400 , at  352 , distributed into one or more microneedle wells  420 , at  354 , and/or dried, at  356 , in the manner set for above, to fill the hollow shells of dried microneedle material  130  and thereby form the microneedle array  210  with solid microneedles  100 . In other words, the steps of disposing the microneedle material  130  on the replica mold  400 , at  352 , distributing the microneedle material  130  into one or more microneedle wells  420 , at  354 , and/or drying the microneedle material  130 , at  356 , can be repeated as needed to form solid microneedles  100 . 
     Optionally, one or more quality control measures can be performed while and/or after the microneedle array  210  is formed via the replica mold  400 , at  350 . The quality control measures can be performed at any suitable time, such as before, during and/or after all critical steps in the manufacturing of the microneedle device  200 , at  300 . The microneedle material  130 , for example, can be inspected for viscosity, pH and/or dry material content. The replica mold  400  can be inspected for thickness, mold cracking and/or discoloration, which may estimate residual buildup; whereas, any backing layer  220  can be inspected for thickness, holes and/or visual quality. Additionally and/or alternatively, the jig and other tools can be inspected for wear and tear, residuals, and/or sealings. These inspections can be performed in any conventional manner, including X-ray, motion check and light scanning, dissolution, disintegration, hardness/friability, uniformity of dosage units, water content, microbial limits, sterility, particulate matter, antimicrobial preservative content, extractables functionality testing, mold leachables, osmolarity, etc. 
     After drying of the microneedle material  130  is complete, the dried microneedle material  130  optionally can be separated from the replica mold  400 , at  358 , as shown in  FIG. 15 . The microneedle material  130  preferably is easy to release from the replica mold  400 . In other words, the microneedle material  130  should be removable from the replica mold  400  without incurring damage to either the replica mold  400 , the microneedle array  210  or both. If the microneedle array  210  is peeled from the replica mold  400 , for example, the microneedle array  210  and/or the replica mold  400  can become folded during the peeling. The vacuum system  700  advantageously can apply a vacuum on the replica mold  400  for maintaining the shape and position of the replica mold  400  while the microneedle array  210  is being peeled from the replica mold  400 . In one alternative embodiment, the replica mold  400  can serve as a storage container and/or a shipping carrier for the microneedle device  200 . The microneedle array  210  thereby can be separated from the replica mold  400  by an intermediate manufacturer or an end user, reducing handling and damage to the microneedle device  200  associated with the storage and shipping process. 
     Manufacture of the Microneedle Array  210  with Separate Microneedles  100   
     An alternative embodiment of the method  300  for manufacturing the microneedle device  200  is shown in  FIG. 16 . As illustrated in  FIG. 16 , the microneedle material  130  can be disposed onto the replica mold  400  via a reservoir system  800 , at  352 A, and dried (and/or cured), at  356 , to form the microneedle array  210  (shown in  FIGS. 2A-B ,  3 A). Use of the reservoir system  800  to dispose the microneedle material  130  onto the replica mold  400  advantageously can be used to manufacture the microneedle array  210  with separate microneedles  100  in the manner discussed in more detail above with reference to  FIGS. 2A-B . Conventional microneedle manufacturing methods do not support disposing microneedle material  130  into individual microneedle wells  420  (shown in  FIG. 14B ). For example, such conventional microneedle manufacturing methods include microdroplet dispensing and microneedle manufacture by plate separation. Dispensing of microdroplets becomes quite difficult when the microneedle materials are viscous and/or elastic. Advantageously, the method  300  supports disposing microneedle material  130 , including viscous and/or elastic microneedle materials  130 , into the individual microneedle wells  420 . 
       FIG. 17  illustrates an exemplary embodiment of the reservoir system  800 . As shown in  FIG. 17 , the reservoir system  800  can comprise an enclosure (or container)  810  that defines an internal chamber  860  for receiving and/or storing a predetermined amount (or volume) of the microneedle material  130 . The predetermined amount of the microneedle material  130  preferably is sufficient to fill the microneedle wells  420  (shown in  FIG. 14B ) formed in the replica mold  400  (shown in  FIG. 14B ) and can include more of the microneedle material  130  than is needed to fill the microneedle wells  420 . The enclosure  810  can be constructed from any suitable material, such as a thermoplastic polymer, such as acrylic, and/or a metal, such as stainless steel, aluminum, and razor steel. 
     The enclosure  810  includes a lower region (or surface)  820 . The lower surface  820  includes a reservoir opening array (or stencil)  840  that includes one or more reservoir openings  830  and that are in fluid communication with the internal chamber  860 . The lower surface  820  preferably is substantially flat and rigid so that a liquid- and/or gas-tight seal can be made with the replica mold  400 . The seal between the lower surface  820  and the replica mold  400  can help to ensure that the microneedle material  130  can flow from the reservoir system  800  directly into the microneedle wells  420  with substantially no leakage. The lower surface  820  can be formed from, or coated with, a hydrophobic material to help reduce loss of the microneedle material  130  when the reservoir system  800  is separated from the replica mold  400 . The lower surface  820  likewise can have a predetermined stencil thickness. The predetermined stencil thickness can comprise any suitable thickness, such as 0.1 mm, 0.2 mm or 0.3 mm, or any suitable range of thicknesses. 
     The reservoir openings  830  can be arranged in any predetermined pattern. For example, the reservoir opening array  840  can include one or more reservoir openings  830  disposed in a regularly-distributed pattern and/or one or more reservoir openings  830  disposed in an irregularly-distributed (or random) pattern. An exemplary regularly-distributed pattern for the reservoir opening array  840  can comprise can include a plurality of parallel rows of the reservoir openings  830  and/or a plurality of parallel columns of the reservoir openings  830 . The reservoir openings  830  preferably are arranged in a pattern that corresponds with the predetermined pattern of the microneedle wells  420  formed in the replica mold  400 . In other words, each reservoir opening  830  preferably aligns with a corresponding microneedle well  420  of the replica mold  400 . 
     The dimensions of the reservoir openings  830  formed in the reservoir system  800  can be greater than, less than and/or equal to the dimensions of the microneedle wells  420  formed in the replica mold  400 , and the shapes of the reservoir openings  830  can be the same as, or different from, the shapes of the microneedle wells  420 . Although shown and described as having reservoir openings  830  with uniform shape, size and/or dimension for purposes of illustration only, the reservoir opening array  840  can include reservoir openings  830  with uniform and/or different shapes, sizes and/or dimensions as desired. 
     One manner by which the microneedle material  130  can be disposed onto the replica mold  400  via the reservoir system  800 , at  352 A, and dried (and/or cured), at  356 , to form the microneedle array  210  as illustrated in  FIGS. 18A-E . As shown in  FIG. 18A , the reservoir system  800  can receive and/or store the microneedle material  130  within the enclosure  810 . The reservoir system  800  of  FIG. 18A  includes an optional shutter system  850  for selectively opening and/or closing the fluid communication between the internal chamber  860  and the reservoir openings  830 . Stated somewhat differently, a flow of the microneedle material  130  from the enclosure  810  through the reservoir openings  830  can be controlled via the shutter system  850 . 
     The reservoir system  800  can be positioned adjacent to, and lowered toward, the replica mold  400 . The replica mold  400  is shown as being disposed on the vacuum system  700  for generating a closed vacuum as the reservoir system  800  is lowered toward the replica mold  400 . The reservoir openings  830  of the reservoir opening array  840  preferably are axially aligned with the microneedle wells  420  of the microneedle well array  430 . Thereby, when the reservoir system  800  and the replica mold  400  make physical contact, the reservoir openings  830  can be in fluid communication with the microneedle wells  420  as illustrated in  FIG. 18B . The vacuum system  700  can maintain the closed vacuum as the reservoir system  800  is positioned on the replica mold  400 . As desired, the reservoir system  800  can receive the microneedle material  130  before and/or after being positioned on the replica mold  400 . 
     The shutter system  850  can be opened at a predetermined time as shown in  FIG. 18C . Although preferably no longer maintaining the closed vacuum, the vacuum system  700  can be activated to apply suction to the replica mold  400  before, after and/or at the predetermined time. Once the shutter system  850  is opened, the suction provided by the vacuum system  700  can draw the microneedle material  130  from the enclosure  810  through the reservoir openings  830  and onto the respective microneedle wells  420  of the replica mold  400 . 
     Once a suitable amount of the microneedle material  130  is disposed within the microneedle wells  420 , the shutter system  850  can close, stopping the reservoir system  800  from dispensing any additional microneedle material  130  onto the microneedle wells  420  as shown in  FIG. 18D . The reservoir system  800  then can be withdrawn (or separated) from the replica mold  400  as illustrated in  FIG. 18E . 
     In one embodiment, the microneedle material  130  can be disposed onto the replica mold  400 , at  352 A (shown in  FIG. 16 ), by placing the reservoir system  800  on top of the replica mold  400  and filling the microneedle wells  420  with the microneedle material  130 . The vacuum system  700  can apply the vacuum for drawing the microneedle material  130  into, and filling, the microneedle wells  420  in a single step. Once the microneedle wells  420  have been filled with the microneedle material  130 , the reservoir system  800  can be separated from the replica mold  400 . Any additional layers, such as the optional backing layer  220 , can be applied to the replica mold  400 , and the microneedle material  130  can be cured, at  356  (shown in  FIG. 16 ), to form the separate microneedles  100 . Additionally and/or alternatively, the additional layers can be added before curing the microneedle material  130 , at  356 , such that a top-facing surface of the microneedles  100  can become bonded to the most proximal (or bottom) additional layers during curing of the microneedle material  130 , at  356 . 
     In an alternative embodiment, the microneedle material  130  can be disposed onto the replica mold  400 , at  352 A, by placing the reservoir system  800  on top of the replica mold  400  and filling the microneedle wells  420  with the microneedle material  130 . The vacuum system  700  can apply the vacuum for drawing the microneedle material  130  into the microneedle wells  420 . Here, the microneedle material  130  can be disposed onto the replica mold  400 , at  352 A, as a series of partial disposals of the microneedle material  130  under vacuum. 
     Each of the partial disposals of the microneedle material  130  can be disposed around an intermediate curing of the disposed microneedle material  130 , at  356 . In other words, the microneedle wells  420  are partially filled with a first dispensing of the microneedle material  130  from the reservoir system  800 , at  352 A. The first dispensing of the microneedle material  130  is cured, at  356 . A second dispensing of the microneedle material  130  from the reservoir system  800  is dispensed into the microneedle wells  420 , at  352 A, and the dispensed microneedle material  130  in the microneedle wells  420  is cured, at  356 , and so on. After each partial filling, the microneedle material  130  in the microneedle wells  420  can be partially and/or completely cured. The vacuum can maintain the vacuum or suspend the vacuum for a selected curing step, and/or the curing, at  356 , can include infrared curing for removing water from the dispensed microneedle material  130 . The cycle of filling, at  352 A, and curing, at  356 , can be repeated until the microneedle wells  420  are completely filled with the dispensed microneedle material  130 . 
     The intermediate curing process advantageously can improve the filling of the microneedle wells  420  with the dispensed microneedle material  130  and/or can promote formation of solid microneedles  100 . The microneedle material  130  can comprise approximately ninety percent water, which is lost during curing, at  356 . The intermediate curing process can drive off a substantial portion of the water in the microneedle material  130 , allowing for the incorporation of more microneedle polymer, such as hyaluronic acid (HA) and/or crosslinked materials, in the finally-formed microneedle  100 . The intermediate curing may be done by any suitable process. For high throughput applications, the partially-formed microneedles  100  can undergo infrared (IR) curing without removing the carrier jig from the vacuum system  700 . 
     In some embodiments, for example, the microneedles  100  are made of a material that contains hyaluronic acid, or derivative thereof, that is crosslinked with a cationic agent. In at least one embodiment, the microneedles  100  comprise hyaluronic acid, or derivative thereof, that is crosslinked with chitosan or a derivative thereof. In some embodiments, the microneedles  100  are made of a material that contains polyvinylpyrrolidone, polyvinylalcohol, a cellulose derivative, or other water soluble biocompatible polymer. In some embodiments, the microneedles  100  are made of a material that contains polyvinylpyrrolidone having an average molecular weight between about 20 kDa and about 100 kDa. In some embodiments, the substrate is made of a material that contains polyvinylpyrrolidone having an average molecular weight between about 20 kDa and about 100 kDa. In some embodiments, the substrate is made of a material comprising between about 20% and about 50% polyvinylalcohol. 
     In some embodiments, HA can be complexed with a suitable crosslinking agent. The crosslinking agent may be any agent known to be suitable for crosslinking polysaccharides and their derivatives via their hydroxyl groups. Suitable crosslinking agents include, but are not limited to, 1,4-butanediol diglycidyl ether (or 1,4-bis(2,3-epoxypropoxy)butane or 1,4-bisglycidyloxybutane, all of which are commonly known as BDDE), 1,2-bis(2,3-epoxypropoxy)ethylene and 1-(2,3-epoxypropyl)-2,3-epoxycyclohexane. The use of more than one crosslinking agent or a different crosslinking agent is not excluded from the scope of the present disclosure. The step of crosslinking may be carried out using any means known to those of ordinary skill in the art. Those skilled in the art appreciate how to optimize conditions of crosslinking according to the nature of the HA, and how to carry out crosslinking to an optimized degree. Degree of crosslinking for purposes of the present disclosure is defined as the percent weight ratio of the crosslinking agent to HA-monomeric units within the crosslinked portion of the HA based composition. It is measured by the weight ratio of HA monomers to crosslinker (HA monomers:crosslinker). In some embodiments, the degree of crosslinking in the HA component of the present compositions is at least about 2% and is up to about 20%. In other embodiments, the degree of crosslinking is greater than 5%, for example, is about 6% to about 8%. In some embodiments, the degree of crosslinking is between about 4% to about 12%. In some embodiments, the degree of crosslinking is less than about 6%, for example, is less than about 5%. In some embodiments, the HA component is capable of absorbing at least about one time its weight in water. When neutralized and swollen, the crosslinked HA component and water absorbed by the crosslinked HA component is in a weight ratio of about 1:1. The resulting hydrated HA-based gels have a characteristic of being highly cohesive. 
     In some embodiments, the polymers of the microneedles  100  are crosslinked, either physically, chemically or both and/or intermolecular or intramolecular. The microneedle array can comprise groups of microneedles  100  wherein a first group comprises at least one different cross-linker to at least a second group. Additionally and/or alternatively, the microneedles  100  may not be crosslinked and will dissolve following an initial swelling phase upon puncturing the stratum corneum and coming into contact with skin moisture. In this case, the therapeutic active agents can be released into the skin at a rate determined by the rate of dissolution of the microneedles  100 . 
     The rate of dissolution of particular microneedles  100  is dependent on their physicochemical properties which can be tailored to suit a given application or desired rate of drug release. Relatively slow dissolution times can, in some cases, advantageously enable prolonged retention of the active compound. In some embodiments, the microneedles  100  can have a dissolution time of about or at least about 60, 75, 90, 105, 120, 135, 150, 165, 180, 195, 210, 225, 240, 300, 360, 420, 480, 600, 720, or more minutes, or 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48 hours, or more. 
     In some embodiments, microneedles absorb interstitial fluids, e.g., fluids within the skin in order to increase volume and provide an improved aesthetic appearance, e.g., to eliminate or improve wrinkles for example. In some embodiments, the microneedles can, after insertion into the stratum corneum, have a maximal increase in weight (e.g., by the absorption of interstitial fluid) of about or at least about 20%, 40%, 60%, 80%, 100%, 120%, 140%, 160%, 180%, 200%, 220%, 240%, 260%, 280%, 300%, 350%, 400%, 500%, 600%, 700%, 800%, 900%, 1,000%, or more. In some embodiments, the maximal increase in weight (after which the weight of the microneedles can decrease as they dissolve), occurs after about or at least about 60, 75, 90, 105, 120, 135, 150, 165, 180, 195, 210, 225, 240, 300, 360, 420, 480, 600, 720, or more minutes. 
     Combinations of non-crosslinked, lightly crosslinked and extensively crosslinked microneedles  100  can be combined in a single device so as to deliver a bolus dose of an active agent e.g. or therapeutic substance(s), achieving a therapeutic plasma level, followed by controlled delivery to maintain this level. This strategy can be successfully employed whether the therapeutic substance is contained in the microneedles  100  and substrate or in an attached reservoir (not shown). 
     Dispensing of the microneedle material  130  from the reservoir system  800  can be aided by a pressure pulse formed within the enclosure  810 . For example, a positive pressure can be applied to a top surface of the microneedle material  130  within the reservoir system  800  to drive the microneedle material  130  from the reservoir system  800  and into the microneedle wells  420 . In one embodiment, the pressure pulse can be provided via a pressure valve and/or a pressurized sack that can through explosion and/or implosion create the pressure pulse in the reservoir system in a controlled manner. Additionally and/or alternatively, a second vacuum can be applied to the top surface of the microneedle material  130  within the reservoir system  800 . This second vacuum can supplement the suction of the vacuum system  700  below the replica mold  400 . The second vacuum, for example, can be provided via the same source that provides the above-referenced pressure pulse and/or via a separately-controlled vacuum source (not shown) for controlling top surface vacuum attributes to aid degassing and controlling of the dispensed materials. Advantageously, the second vacuum can vacate air and other dissolved gases from the uncured microneedle material  130  within the reservoir system  800  and promote more complete filling of the microneedle wells  420 . 
     After the final filling step, the microneedles  100  may be subjected to an optional intermediate cure step. In one embodiment, the microneedles  100  are not subject to an intermediate cure step after the final filling step. The reservoir system  800  can be separated from the replica mold  400  and/or additional layers, as described above, can be added to the top-facing surface of the microneedles  100 . The microneedles  100  can be subject to an optional final curing, at  356 , for bonding the base region  110  of the microneedles  100  to the bottom face of the additional layers to produce a unitary microneedle device  200  with any predetermined number of individual microneedles  100  in any predetermined arrangement and/or configuration and, in some embodiments, without a residual layer  130  for connecting the individual microneedles  100 . 
     In some embodiments, the microneedle device  200  can undergo a final curing process. Typically, the final curing process can provide a more complete curing of the microneedle material  130  than the microneedle material  130  underwent during the intermediate curing step(s). Suitable final curing conditions include, for example, room temperature curing at a room temperature between 21° C.-30° C. and a relative humidity of 40% RH±10% RH for a predetermined time between two hours and five hours, or environmental cabinet curing at a cabinet temperature of about 40° C. and a relative humidity of 20% RH±10% RH, or of 40% RH 10% RH, or a combination of relative humidity, for a predetermined time between fifteen minutes and sixty minutes. Faster curing and/or higher temperature current can be achieved, for example, via a combination of curing processes, such as infrared curing and heated air curing at low relative humidity. Additionally and/or alternatively, the curing can occur within an inert gas with low humidity and/or within a disinfectant/vacuum, which would destroy bacteria and other contaminants. 
     Additionally and/or alternatively, the reservoir system  800  can be disposed, at  352 B, in a vacuum chamber  900  as illustrated in  FIGS. 19A and 20 . The vacuum chamber  900  can be provided in any conventional manner. The exemplary vacuum chamber  900  of  FIG. 19A  is shown as comprising a vacuum chamber cover  910  and a vacuum chamber base  920 . The vacuum chamber cover  910  and/or the vacuum chamber base  920  can define a central chamber region  915  for receiving the reservoir system  800  and can be disposed in an open (or unsealed) position as shown in  FIG. 19A  or a closed (or sealed) position as shown in  FIG. 19B . In the closed position, the vacuum chamber cover  910  can cooperate with the vacuum chamber base  920  such that the vacuum chamber cover  910  and the vacuum chamber base  920  form an air-tight bond for the central chamber region  915 . As desired, the vacuum chamber cover  910  and the vacuum chamber base  920  can comprise separate vacuum chamber elements and/or can be coupled, for example, via a hinge or other coupling member (not shown). 
     The vacuum chamber base  920  can include a mold support region  930  for supporting the replica mold  400 . The mold support region  930  preferably is centrally disposed at the vacuum chamber base  920  and can comprise a planar support and/or, as illustrated in  FIG. 9A , include a support extension  935  that extends from the vacuum chamber base  920 . The support extension  935  can be at least partially integrated with, and/or separate from, the vacuum chamber base  920 . The mold support region  930  can receive and/or engage the replica mold  400  such that at least some of the microneedle wells  420  formed in the replica mold  400  can communicate with one or more vacuum openings  922  formed in the vacuum chamber base  920  and/or the mold support region  930 . Preferably, each of the microneedle wells  420  is axially aligned with a respective vacuum opening  922  when the replica mold  400  is properly engaged by the mold support region  930 . 
     The vacuum chamber base  920  and/or the mold support region  930  can further define one or more optional peripheral vacuum openings  924 . The vacuum openings  922  and/or the peripheral vacuum openings  924  can be formed in any predetermined pattern by the vacuum chamber base  920  and/or the mold support region  930 . For example, the vacuum openings  922  preferably are provided in a predetermined pattern that corresponds with the predetermined pattern of the microneedle wells  420  formed in the replica mold  400 . The peripheral vacuum openings  924  can be disposed in a predetermined pattern at one or more locations about a periphery of the mold support region  930 . In a preferred embodiment, the mold support region  930  and/or the vacuum openings  922  can be disposed centrally among the peripheral vacuum openings  924 . Stated somewhat differently, the peripheral vacuum openings  924  preferably are formed by the vacuum chamber base  920  on each side of (or bounding) the mold support region  930  and/or the vacuum openings  922 . 
     With the replica mold  400  engaged by the mold support region  930  and the reservoir system  800  being disposed within the central chamber region  915 , the vacuum chamber  900  can transition from the open position to the closed position as shown in  FIGS. 19A-B . A vacuum  710 ,  720  can be applied to the closed vacuum chamber  900 , at  352 C, as illustrated in  FIGS. 19C and 20 . The vacuum  710 ,  720  can be applied to the empty replica mold  400 , for example, to degas the replica mold  400  prior to dispensing of the microneedle material  130  and/or to the microneedle material  130 , for example, to degas the microneedle material  130  prior to being dispensed onto the replica mold  400 . In a preferred embodiment, the vacuum  710 ,  720  can be applied via a vacuum system  700  in the manner discussed herein with reference to  FIGS. 14B and 18A -E. The vacuum  710 ,  720  can include a central vacuum  710  applied via the vacuum openings  922  formed in the vacuum chamber base  920  and/or the mold support region  930  and/or a peripheral vacuum  720  applied via the optional peripheral vacuum openings  924  formed in the vacuum chamber base  920 . Preferably being independently controllable, the central vacuum  710  and the peripheral vacuum  720  can be applied to the closed vacuum chamber  900  via respective vacuum systems  700 , and/or a selected vacuum system  700  can at least partially provide the central vacuum  710  and the peripheral vacuum  720 . 
     Once the applied vacuum within the central chamber region  915  of the closed vacuum chamber  900  achieves one or more predetermined criteria, the microneedle material  130  within the reservoir system  800  can be dispensed onto the replica mold  400 , at  352 D, as shown in  FIGS. 19D-J  and  20 . Exemplary predetermined criteria can include the central chamber region  915  achieving a selected internal pressure level, a selected internal temperature level and/or a selected relative humidity level. Optionally, the selected internal pressure level can comprise a pressure level within a preselected range of internal pressure levels, and/or the selected internal temperature level can comprise a temperature level within a preselected range of internal temperature levels. The selected internal pressure level likewise can optionally comprise a relative humidity level within a preselected range of internal relative humidity levels. Illustrative pressure, temperature and relative humidity levels are set forth herein. 
     Turning to  FIG. 19D , the reservoir system  800  can be positioned adjacent to the replica mold  400  within the central chamber region  915 . The reservoir system  800  preferably is positioned such that the microneedle wells  420  formed in the replica mold  400  can be aligned with the reservoir openings  830  of the reservoir system  800 . Very preferably, each of the microneedle wells  420  is axially aligned with a respective reservoir opening  830  when the reservoir system  800  is properly positioned. The shutter system  850  is shown as being in a closed position and thereby inhibits a flow of microneedle material  130  stored within the reservoir system  800  into the microneedle wells  420  via the reservoir openings  830 . 
     The vacuum  710 ,  720  applied to the central chamber region  915  of the closed vacuum chamber  900  can comprise an adjustable vacuum. In one embodiment, the central vacuum  710  can be adjusted cooperatively with, and/or independently of, the peripheral vacuum  720 . The central vacuum  710 , for example, can be maintained while the peripheral vacuum  720  can be at least temporarily stopped in the manner illustrated in  FIG. 19E . Control of the vacuum  710 ,  720  can be provided in any manual and/or automated manner. 
     The shutter system  850  can be transitioned from a closed position to an open position. In the open position, the shutter system  850  enables the reservoir openings  830  of the reservoir system  800  to communicate with the microneedle wells  420  formed in the replica mold  400  as shown in  FIG. 19F . In other words, a reservoir opening array  840  of the reservoir system  800  can communicate with the microneedle wells  420  of the replica mold  400 . The reservoir system  800  thereby can be configured to dispense microneedle material  130  onto the replica mold  400 . 
       FIGS. 19F-H  illustrate an exemplary embodiment of the shutter system  850 . Turning to  FIG. 19G , the shutter system  850  can comprise a shutter member  852  that defines a reservoir opening array  840  with a plurality of shutter openings  855 . The shutter member  852  can slidably (or otherwise movably) engage the lower region  820  of the reservoir system  800 . In other words, the shutter member  852  can move relative to the lower region  820  of the reservoir system  800 . The relative motion between the shutter member  852  and the lower region  820  can include, for example, a translation and/or a rotation. The shutter member  852  can move relative to a stationary lower region  820 , the lower region  820  can move relative to a stationary shutter member  852 , or both the shutter member  852  and the lower region  820  can be movable. 
     The shutter openings  855  can be formed in the shutter member  852  with any predetermined pattern. Preferably, the shutter openings  855  are provided in a predetermined pattern that corresponds with the predetermined pattern of the reservoir openings  830  of the reservoir system  800 . The shutter openings  855  preferably are not aligned with the reservoir openings  830  in the closed position as shown in  FIG. 19G . The shutter member  852  thereby can obstruct any flow through the reservoir openings  830 . When the shutter system  850  is actuated to transition from the closed position to the open position, the shutter openings  855  preferably are aligned with the reservoir openings  830  as illustrated in  FIG. 19H . In the open position, the reservoir openings  830  are not obstructed by the shutter member  852 , and flow can be provided through the aligned shutter openings  855  and reservoir openings  830 . 
     Returning briefly to  FIG. 19F , the microneedle material  130  stored within the reservoir system  800  can be permitted to flow through the reservoir openings  830  and into the microneedle wells  420  via the shutter system  850  in the open position. The flow of the microneedle material  130  into the microneedle wells  420  can be facilitated via the central vacuum  710 . The central vacuum  710 , for example, can help draw the microneedle material  130  from the reservoir system  800  and into the microneedle wells  420  in the manner illustrated in  FIG. 19I . In a preferred embodiment, the central vacuum  710  can be adjusted to a suitable level for facilitating the flow of the microneedle material  130  into the microneedle wells  420 . Exemplary adjustments can include increasing the central vacuum  710 , decreasing the central vacuum  710 , and at least temporarily stopping the central vacuum  710 . A predetermined volume of the microneedle material  130  thereby can be disposed within the microneedle wells  420  of the replica mold  400 . Each microneedle well  420  of the replica mold  400  preferably is at least ninety percent filled, such as between ninety-five percent and one hundred percent filled, with the microneedle material  130 . 
     The shutter system  850  likewise can be actuated to transition from the open position to the closed position as illustrated in  FIG. 19J . In other words, the shutter system  850  can return to the closed position. Actuation of the shutter system  850  can be triggered by any conventional manner. The vacuum chamber  900 , for example, can include a control system (not shown) for actuating the shutter system  850  of the reservoir system  800 . The control system can enable manual and/or automated actuation of the shutter system  850 . As set forth in more detail herein, the shutter system  850  can selectively open and/or close the fluid communication between the internal chamber  860  and the reservoir openings  830  of the reservoir system  800 . In other words, the control system can control a flow of microneedle material  130  stored within the internal chamber  860  through the reservoir openings  830  via the shutter system  850 . The shutter system  850  thereby can be actuated while the vacuum chamber  900  is disposed in the closed position and without breaking the vacuum within the vacuum chamber  900 . 
     Actuation of the shutter system  850  from the open position to the closed position can be triggered by any predetermined criteria. The predetermined criteria, for example, can be based upon a determination that the predetermined volume of the microneedle material  130  has been disposed within the microneedle wells  420  of the replica mold  400 . In the closed position, the shutter system  850  again inhibits the flow of microneedle material  130  stored within the reservoir system  800  into the microneedle wells  420  via the reservoir openings  830  in the manner discuss in more detail above. The microneedle material  130  disposed within the microneedle wells  420  forms the microneedles  100 . 
     As desired, the shutter system  850  can be repeatedly actuated to transition between the closed and open positions and back to the closed position multiple times. Additional microneedle material  130  thereby can be successive disposed within the microneedle wells  420  until the microneedle wells  420  receive a final predetermined volume of the microneedle material  130 . 
       FIG. 19K  shows the reservoir system  800  being removed from the replica mold  400 . The reservoir system  800 , stated somewhat differently, is disposed distally from the replica mold  400  within the central chamber region  915 . To facilitate formation of the microneedles  100 , the vacuum  710  can continue to be applied to the replica mold  400  for a predetermined time period after the reservoir system  800  has been removed from the replica mold  400 . The predetermined time period can include a predetermined time period range between one minute and an hour, including any time period sub-ranges, such as a five minute sub-range (i.e., between five minutes and ten minutes) and/or a ten minute sub-range (i.e., between five minutes and fifteen minutes), within the preselected time period range, without limitation. 
     The vacuum chamber  900  of  FIG. 19K  also is shown as transitioning from the closed (or sealed) position to the open position. After the predetermined time period has expired, application of the vacuum  710 ,  720  to the vacuum chamber  900  can be discontinued, at  352 E, as illustrated in  FIGS. 19L and 20 . In other words, at  352 E, the vacuum system  700  can be disabled. The replica mold  400  can be removed from the vacuum chamber  900 , at  352 F, for subsequent processing in the manner discussed above. 
     The disclosed embodiments are susceptible to various modifications and alternative forms, and specific examples thereof have been shown by way of example in the drawings and are herein described in detail. It should be understood, however, that the disclosed embodiments are not to be limited to the particular forms or methods disclosed, but to the contrary, the disclosed embodiments are to cover all modifications, equivalents, and alternatives.